Guduchi (Tinospora cordifolia)


Introduction 
From Indian mythology to Ayurveda and modern medicine Guduchi (Tinospora cordifolia) is extolled as a remedy par excellence for the treatment of many diseases especially those of the liver. 
It has a noble place in the epic Raamaayana: During the war between Raama and Raawana, to resurrect the army of Raama, Lord Indra gave “amrita” i. e. “divine nectar” to Raama’s army. The Guduchi plant grew from the few drops of ‘nectar’ that fell on the ground. [1], [2] 
From fever to cancer the herb protects the body from diseases; hence the epithet Guduchi (one that protects, one that acts as a savior from diseases). Another synonym of the plant is Madhuparnee (the one whose leaves are full of nectar). When we cut a fresh spring from Guduchi tree and hang it from a cord in the air; it will continue to grow without any visible or perceptible nutritional support. It gains its ‘life energy’ from environment. Hence in Sanskrit it is called ‘Amritaa’ meaning immortal! As the plant confers vitality, vigor and youthful longevity or imparts immortality on any one who consumes it, the plant is called ‘Amritaa’ (divine nectar of longevity). The other Sanskrit epithets used for Guduchi are: Chhinnaruhaa/Chhinnodbhawaa (the plant that grows from the cut side), Watsadini (eaten by grazing animals), Rasaayanaa (the plant possessing capacity to improve Rasa Dhaatu), Chakraangi/Chakralakshnaa (having wheel-like appearance), Jwaranaashee/Jwaraari (potent antipyretic), Wayastha (age-stabilizer, prevents ageing), Amritasambhawaa (ambrosia) and Bhishakpriyaa (favorite of physicians). [3], [4], [5] 
The name of its genus Tinospora is derived from the Greek teino which means “to stretch like a bow” and spora which means “seed”. Its leaves are heart shaped; hence the name of the species is cordifolia. 
In Ayurveda Guduchi has long been used as a tonic, vitalizer and as a drug to treat many ailments. Along with many beneficial properties of Guduchi, the noted Ayurvedic surgeon Sushruta described it as ‘shukra-shodhana’ meaning sperm purifier. Its property of imparting vigor and vitality and its ‘shukra-shodhana’ ability are probably misconstrued in the ‘Kaama-Sootra’ as ‘aphrodisiac’. In his translation of the classic text ‘Kaama-Sootra’ in 1883, Sir Richard Burton writes (free rendition by me): If the juice of fennel (English: Anise, Marathi: Badeeshepa) and milk are mixed with equal quantities of ghee, honey, sugar and liquorice (Glycyrrhiza glabra), the mixture acts like nectar and is said to be sacred, provocative of sexual vigor and stabilizer of age and life.
However Ayurvedic sources express mixed opinion. Some mention it, some don’t. 
George Playfair’s translation of the Indian Materia Medica, Taleef Shereef, 1833 does mention Guduchi but certainly not as being aphrodisiac!  
The first botanical reference to Guduchi in the English can be found in Transactions of the Linnean Society of London Volume 13, 1822. [6], [7]

Other Names

Botanical: Tinospora cordifolia (Wild), Miers ex Hook, f. and Thoms
Sanskrit: Guduchi, Madhuparnee, Amritaa, Chhinnaruhaa, Watsadaanee, Taantrikaa, Kundalanee, Chakralakshanika and many more
English: Tinospora
Assamese: Siddhilata, Amaralata
Bengali: Gulancha/Palo
Gujarati: Galo, Garo, Galac
Hindi: Giloy, Guduchi, Gurach
Kannada:  Amritaballi
Kashmiri: Amrita, Gilo
Malayalam: Ambrithu, Chittamritu
Marathi: Gulawela Gulvel
Oriya: Guluchi
Punjabi: Gilo
Sinhala: Rasakinda
Tamil: Shindilakodi, Amudom, Chindil, Seendilkodi
Telugu: Tippaatiga, Thippateega Urdu: Gilo 
AKA: Ambervel, Heart-leaved Moonseed, Heavenly Elixir, Jetwatika. [8], [9], [10], [11]

Taxonomic Classification 

Kingdom: Plantae-Plants.
Unranked: Angiosperm.
Division: Magnoliophyta- Flowering Plants
Class: Magnoliopsida, Liliopsida-Monocotyledons. 
Order: Ranunculales,  Zingiberales.
Family: Menispemaceae, Zingiberaceae- Ginger family. [12] 

Geographical Distribution 

This plant is found throughout tropical part of India; typically growing in deciduous and dry forests. It is also indigenous to Myanmar and Sri Lanka. The plants are long-lived and often locally abundant. It is a wild shrub, grows on its own, does not require harvesting and does not require any particular type of soil. It has adapted to grow in any soil and climate that offers good moisture and sunlight. It can grow in any temperature and in India can thrive 1200 meters above sea level. It mostly grows on mango or neem trees. In Ahmedabad, India, the plant grows wild on hedges. In India it is also seen climbing even on electric or telephone poles in many rural areas. [13], [14], [15] 

Plant Morphology

                                                                                                                                            Guduchi (Tinospora cordifolia) plant

                                          

                            Guduchi (Tinospora cordifolia) root


                                                  

                      

                      Guduchi (Tinospora cordifolia) stem



                                             Guduchi 






                          Guduchi (Tinospora cordifolia) leaves


                                            

                                    Guduchi (Tinospora cordifolia) flowers


                           

                               Guduchi (Tinospora cordifolia) fruit


                                                                                                     

      
                   Guduchi (Tinospora cordifolia) seeds 

Macroscopic Morphology

Guduchi (T. cordifolia) is a large, climbing, deciduous, extensively spreading, perennial herbaceous vine of weak and fleshy stem found throughout India. T. cordifolia is a big twining glabrous climber which generally climbs with several elongated twining branches on large trees preferring the support of mango and neem trees.
Roots are tuberous, long thread like, aerial; arise from branches, often growing on neem or mango trees. 
Bark is thin, succulent, creamy white to grey in color, with deep clefts spotted with lenticels. (A lenticel is an opening that allows gaseous exchange between air and the inner tissues of a plant) 
Stem succulent, fleshy, twining, 0.5 to 5 cm in diameter, green when young, with smooth surface and swelling at nodes; older ones are brown in color with warty protuberances. 
Branches are grey-green, up to 40 mm in diameter, becoming brown with age  
Leaves are heart-shaped, smooth, simple, alternate, exstipulate; petiole up to 15 long, roundish, pulvinate (having a swelling), both at the base and apex with the basal one longer and twisted partially and half way around. Laminabroadly ovate or ovate-cordate, 10-20 cm long, 8-15 cm broad, 7 nerved and deeply cordate at base, membranous, pubescent above, whitish tomentose with a prominent reticulum beneath. 
Flowers are small, leafless, yellowish-greenish in color, growing in lax axillary, terminal racemes (Marathee: Pushpamanjiree) emerge from nodes on old wood in spring. They are unisexual (male and female flowers are formed on different plants). Male flowers clustered, female usually solitary. Sepals six, free in two series of three each, the outer ones are smaller than the inner. Petals six, free, smaller than sepals obovate and membranous. 
Fruits are drupes, pea like, aggregate of 1-3, up to 10 mm in diameter, smooth, oval, glossy, succulent, fleshy, on thick stalk, single seeded, turning scarlet or orange-red when ripe, up to 10 mm in diameter. 
Seeds are curved, pea-sized. [16], [17], [18]

Microscopic Structure

Root: 
The aerial root is characterized by tetra- arch to penta- arch structure. The cortex has outer thick walled zone representing the velamen (a spongy epidermis that covers the roots of some plants) and inner parenchymatous zone containing secretory canals. Starch is present throughout the parenchyma of the aerial root. The starch grains are elliptical in shape, mostly simple but sometimes as compound grains of 2 to 5 components, with faintly marked concentric striations and central hilum appearing like a point. 
Stem:
Stem is characterized by the presence of bicollateral vascular bundles surrounded by pericycle fibers. The cork arises in the sub-epidermal layers giving rise to 2-3 layers of cork. Starch is present throughout the parenchyma of the stem.  
(Note: The bicollateral vascular bundle consists of two patches of phloem, two strips of cambium and one patch of xylem at the center. It is confined to certain dicot stems only) [19], [20], [21] 
Leaf: In transverse section the petiole is more or less circular in outline. No trichomes (fine outgrowths or appendages) found. The cross section shows a single layered epidermis and a wide zone of cortex composed of 3-4 layers of endodermis. The vascular bundles consist of radial rows of xylem on the inner side and a few rows of cambium cells on the outer side followed by phloem. The mid-rib is more or less circular in outline and palisade does not extend over the stellar tissue. The cross section of lamina shows a dorsiventral structure with its mesophyll differentiated into palisade and spongy tissue. The mesophyll is clearly differentiated into a palisade layer made up of one row of thin-walled columnar cells which occupy a little more than half of the width of mesophyll. Glandular hairs are present in lower surface only. They are unicellular and somewhat club shaped. The base is surrounded by 4 to 5 epidermal cells. Starch is present throughout the tissue. [22], [23], [24] [25], [26]  

Parts used 

Every part of the plant has medicinal use. In Auyrveda the whole plant is valued. 
In Ayurvedic pharmacopoeia the stem is approved because of higher content of alkaloid in it. The traditional preparation ‘Guduchi Sattwa’is obtained from the herb growing with the support of neem (Azadirachta indica). The preparation is said to incorporate the medicinal values of neem. Hence the preparation is bitterer and more efficacious.
Seeds are curved, pea-sized. [16], [17], [18]

Phytochemistry

According to the class of chemical to which they belong, a large number of chemical compounds isolated from Guduchi (Tinospora  cordifolia) can be described as: 
A- 1. Alkaloids (Stem), (Root) 
Berberine, Tembetarine, Magnoflorine, Choline, Tinosporin, Isocolumbine, Palmatine, Tetrahydropalmatine, Jatrorrhizine, bitter Gilonin, non-glycoside gilonin gilosterol,
1,2-Substituded pyrrolidine [27]
A- 2. Glycosides (Stem) 
18-neoclerodane glucoside, Furanoid-diterpene glucoside, Tinocordiside, Tinocordifolioside, Cordioside, Cordifolioside A to E, Syringin, Syringin-apiosyl glucoside, Palmatosides C and F, Amritoside 
A- 3. Diterpinoid lactones (Whole Plant) 
Furanolactone, Clerodane derivatives, Tinosporin, Tinosporides and Jateorine 
Recently four new clerodane furano diterpene glucosides (amritosides A, B, C and D) have been isolated as their acetates from stems. [28]  
Cordifolide A, a sulfur-containing Clerodane Diterpene Glycoside has been isolated from Tinospora cordifolia. Probably this is responsible for anti-microbial activity of the plant. Cordifolide B and C have also been isolated as a white powder in the form of a mixture that could not be further separated by any chromatographic methods. [29] 
A- 4. Sterols (Arial parts, Stem) 
Beta Sitosterol, Delta Sitosterol, 20- Beta Hydroxy ecdysterone, Makisterone A, Giloinsterol (Gilosterol)   
A- 5. Sesquiterpenoid (Stem) 
Tinocordifolin 
A- 6. Aliphatic Compound (Whole plant)
Octacosanol, Heptacosanol  
A- 7. Phenolic compounds (Whole plant) 
A- 8. Miscellaneous (Root, Whole plant) 
Nonacosan, Jatrorrhizine, Tinosporidine, Cordifol, Cordifelone, N-Trans-feruloyl Tyramine diacetate, Giloin, Gilonin, Tinosporic acid, 
The adaptogenic compounds for which the plant is valued most need a special mention. They are: 
Diterpine compounds, Tinosporin, Tinosporides, Berberine, Giloin, Giloinin, Arabinogalactan, Picrotene and bergenin.
A new hypoglycaemic agent was isolated from the plant. It was found to be 1, 2-substituted pyrrolidine. [30] 
The phytochemical analysis of T. cordifolia revealed that alkaloids, flavonoids, tannins, phenols, saponins, glycosides, aminoacids and steroids contained in the plant might be accountable for its antimicrobial potential. [31] 
B- 1. Terpenoids
Tinosporide, Furanolactone diterpene, Furanolactone clerodane diterpene, furanoid diterpene, Tinosporaside, ecdysterone makisterone and several glucosides isolated as poly acetate, phenylpropene disaccharides cordifolioside A, B and C, cordifoliside D and E, Tinocordioside, cordioside, palmatosides C and F, Sesquiterpene glucoside tinocordifolioside, Sesquiterpene tinocordifolin.
B- 2. Alkaloids 
Tinosporine, Magnoflorine, Tembetarine, Berberine, Choline, Palmatine, Jatrorrhizine, 1,2-Substituted pyrrolidine, Alkaloids, viz. jatrorrhizine, palmatine, beberine, tembeterine, choline. 
B- 3. Lignans
3(a, 4-dihydroxy-3-methoxybenzyl)-4-(4-hydroxy-3-methoxybenzyl), 
B- 4. Steroids
Giloinsterol, ß-Sitosterol, 20a- Hydroxy ecdysone, 
B-5 Others   
Giloin, Giloinin, Tinosporan acetate, Tinosporic acid, Tinosporal acetate, Tinosporidine, Heptacosanol, Cordifolone, Octacosanol, Tinosponone, Tinosporic acid, tinosporal, tinosporon, 20-hydroxyecdysone, two phytoecdysones, an immunologically active arabinogalactan [32] 
Inorganic chemicals in aqueous extract of stem: (in µg/g) 
Chloride (Cl) 5.509, Potassium (K) 46.622, Calcium (Ca) 5.425, Chromium (Cr) 68.2, Manganese (Mn) 35.3, Iron (Fe) 377.1, Nickel (Ni) 39.6, Copper (Cu) 158.5 Zinc (Zn) 91.0, Bromin (Br) 15.9  [33] 

Identity, Purity and Strength 

1. for dried drug-
Foreign matter: Not more than 2 %
Total ash:  Not more than 16 %
Acid-insoluble ash: Not more than 3%
Alcohol-soluble extractive: Not less than 3 %
Water-soluble extractive: Not less than 11 % 
2. for fresh drug- 
Foreign matter: Nil   
Moisture content:  75 %  [34] 
3. Quantitative Standards 
Recommendations according to ICMR:
Foreign matter: Not more than 2 %
Total ash: Not more than 7 %
Acid-soluble ash: Not less than 0.8 %
Ethanol- extractive: Not less than 6 %
Loss on drying: Not more than 7.5 % 
Bitters content on dry basis by Gravimetry/HPTLC: Not less than 3 % w/w [35], [36], [37]
4. Standards for Purity of Tinospora cordifolia stem according to WHO guidelines
Total Ash: 7.5 %
Acid Insoluble ass: 1.16 %
Water Soluble extractive value: 12.05 %
Alcohol Soluble extractive value: 7.12 %
Loss on drying: 2.31 %  [38] 

TLC pattern 

On TLC identity test the drug showed six major molecules having Rf value and color 0.24 (Yellow); 0.35 (dark green) (tinosporoside); 0.42 (green); 0.44 (light yellow); 0.76 (dark green) and 0.79 (dark green) using chloroform and methanol (9:1) as a solvent system and anisaldehyde - sulphuric acid as spraying reagent   [39], [40], [41] 

Cytological Identity 

Guduchi (Tinospora cordifolia) Willd is a diploid plant with 2n=22 chromosomes and is characterized by eleven pairs of chromosomes. [42]

Genetic study 

Researchers developed DNA (RAPD) markers for identification and relationships within 15 clones of Guduchi (Tinospora cordifolia) Willd. This study helps to identify the plant species accurately. [43], [44] 
Ritu Paliwal et al generated g-SSR markers for the identification of Guduchi (Tinospora cordifolia). This study is a valuable genomic resource for effective utilization in crop improvement of Guduchi (Tinospora cordifolia) germplasm.  [45] 
Using advanced molecular markers such as SCARS, CAPS and AFLP researchers are able to identify the species of Guduchi (Tinospora cordifolia) accurately. [46] 

Safety Tests:

Heavy Metals: 
1. Recommendations according ICMR: 
Lead: Not more than 10 ppm
Arsenic: Not more than 2 ppm
Heavy metals: Not more than 20 ppm [47], [48], [49]
2. Recommendations according to WHO: (Tinospora cordifolia stem) 
Arsenic: Nil
Lead: Less than 5 ppm
Cadmium: Nil
Mercury: Nil   [50] 
Microbial Limits:
1. Recommendations according to ICMR:
Total bacterial count:  Not more than 3000 CFU/gm                         
Total yeast and mould count: Not more than 100 CFU/gm    [51], [52], [53]
2. Recommendations according to WHO: (Tinospora cordifolia stem)
Total bacterial count: 5 cfu/gm
Yeast and moulds: Nil  [54] 
3. Specific Pathogens: 
Recommendations according to WHO: (Tinospora cordifolia stem) 
E. coli: Nil
Salmonella: Nil
S. aureus: Nil  [55]
4. Recommendations according to WHO for tablets of Tinospora cordifolia : 
Aflatoxin: Nil
Pesticides: Nil   [56]

Properties and Pharmacology   

Ayurvedic Properties 
Ganas (Classical Categories) 
Charaka Ganas: Vayahsthaapana (Anti aging, Age stabilizer), Daaha prashamana (Respites burning sensation, Anti-inflammatory, Anti-histaminic), Trishnaa nigrahana (Quenches thirst), Stanya shodhana (Milk purifier)
Sushruta Ganas: Guduchyaadi, Patolaadi, Aaragwadhaadi, Kaakolyaadi, Wallipanchaka

Energetics 

Rasa (Taste): Kashaaya (Astringent), Tikta (Bitter)
Weerya (Energy State): Ushna (Hot)
Wipaaka (End result, Post digestive effect): Madhura (sweet)
Prabhaawa (Special Effect, Prominent Effect): Wishaghna (Alexipharmic, acting as antidote to poisons)
Gunas (Qualities): Guru (heavy), Snigdha (Anointing)

Effects on Doshas: Waata, Pitta, Kapha, (Tridoshaghna i. e. passifies the three ‘doshas’) 

Actions on Dhaatus (Tissues): Rasa (Lymph), Rakta (Blood), Maansa (Muscles), Meda (Adipose tissue, Fat), Majjaa (bone marrow), Aartava (Menstrual blood?) and Shukra (Semen)

Medowaha Srotas: Adipose system:  

Eons ago Ayurveda recognized Meda (Fat) as one of the components of Adipose system. Ayurveda also described some functions of Meda. However, for centuries Modern medical science did not recognize adipose tissue as a component of any system. It is only recently we say ‘Fat is not a lump of lard!’ 
Now according to modern view, Adipose tissue is a complex, metabolic and endocrine organ. It is highly active. The adipose tissue contains adipocytes, connective tissue matrix, nerve tissue, stromal cells, and immune cells. These components function as an integrated unit. Adipose tissue responds to afferent signals from endocrine system and the CNS. It secretes leptin, cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue (system?) is a major site for metabolism of sex steroids and glucocorticoids. Collectively they perform important endocrine functions. 
Well! This is not the place to discuss in detail about the ‘Adipose System’. However the author decided to give only an overview necessary for the current context. [57] 

Ayurvedic Actions

Deepana - Appetizer
AamapaachanaFreeradical scavenger
Anulomana - Prokinetic
Balya - Strengthening tonic
Daaha-hara – Respites burning sensation, anti-inflammatory, antihistaminic.
Graahee - Constipating
Jwaraghna -Anti-pyretic
Kaasahara – Anti tussive
Kushthaghna - Antileprotic
Pramehaghna - Anti-diabetic
Rasaayana – Rejuvenator, Adaptogen
Stanya shodhana- Purifier of the breast milk
Shwaasahara –Allays breathlessness
Waatahara -Pacifies Waata
Wishagna – Alexipharmic, acting as antidote to poison

Actions against diseases: 

Waatarakta- Gout
Netraroga- Ophthamic disorders
Trishna- Excessive thurst
Daaha- Inflammations
Chhardee- Vomiting
Aruchi-Dislike to eat
Agnimaandy- Anorexia
Shoola-Acute abdominal pain
Yakritwikaar- Hepatic disorders
Kaamalaa-Jaundice
Amlapitta-Hyperacidity
Prawahikaa- Dysentery
Atisaara-Diarrhea
Raktaatisaara-Dysentery with blood in stools
Grahanee-Chronic colitis
Krimi-Helminthiasis
Arsha-Piles
Hrid-daurbalya- Weakness of the heart
Pleehawriddhee-Splenomegaly
Bastishotha-Cystitis
Raktawikaara-Blood disorders
Aamawaata-Rheumatoid arthritis
Pandu-Anaemia 
Shwaasa- Bronchial asthma, breathlessness
Kaasa-Cough
Shukra-daurbalya-Oligospermia, impotence
Prameha-Polyuria
Madhumeha-Diabetes mellitus
Mootrakrichcha- Dysuria
Kushtha- (?)Leprosy
Wisarpa-Erysipelas
Twagroga- Skin disorders
Jwara, Wishamajwara, Jeernjwara-Various fevers [58]

When taken internally routinely (daily) Guduchi choorna (powder) can delay aging thus Guduchi acts as wayahsthaapak rasaayana (anti aging, age-stabilizer-rejuvenator)
Guduchi improves microcirculation, hence it is recommended for correcting ischemic vascular diseases like PVDs.
Guduchi possesses antiseptic and analgesic properties.
Because of its Snigdha Guna and Madhur Wipaaka Guduchi is a very good aphrodisiac. [59] 
Guduchi (Tinospora cordifolia) is antipyretic, antiperiodic (a remedy possessing the property of preventing the periodic exacerbations), blood purifier, paandunaashaka (anti-anemic), waataraktahaaraka (anti-gout), daaha prashamana (the one which respites or allays or relieves burning sensation), kushthanaashaka, (anti-leprotic), walee-palita naashaka (arrests and prevents balding), trishaa shaamaka (alleviates and quenches excessive thirst), bitter, appetizer, digestive (digestant), antiemetic, anthelmintic, kaamalaahara (allays  jaundice), hepatoprotectant, antitussive, antiasthmatic, hridroganaashaka (relives cardiac disorders), mehanaashaka (antidiabetic), diuretic, balya (tonic, increases strength), wayah-sthaapaka (stabilizes age and prevents aging), adaptogen, rasaayana (rejuvenator), chakshushya (beneficial to eye and useful in ophthalmic disorders), nervine tonic and memory booster ( does it mean prevention of  Alzheimer’s disease?), tonic and vitalizer, wrishya (aphrodisiac). The well-ground whole plant paste is applied on fractures. 
Maharshi Charaka makes a special mention about it as ‘stanya shodhana’ (the one which purifies breast milk) 
Sushruta the noted surgeon mentioned it as ‘shukra shodhana’ (the one which purifies the semen and sperms)  [60] 

Modern View 

Guduchi (Tinospora cordifolia) has anti-inflammatory, antioxidant, immunomodulatory, antipyretic, anti-allergic, anti-leprotic, antispasmodic, antiemetic, cholagogue, hepatoprotective, detoxicating, antiarthritic, adaptogenic, antidiabetic, antimalarial and anti-neoplastic activities. The main target organs for Guduchi are liver, spleen and kidney 

Alkaloids 

The protection offered by Guduchi (Tinospora cordifolia) against afflatoxin-induced nephrotoxicity is attributed to the presence of alkaloids such as choline, tinosporin, isocolumbin, palmatine, tetrahydropalmatine and magnoflorine. [61] 

Berberine 

Molecular formula: C20H18NO4+
Structural formula:
   
[62]

Berberine is a quaternary ammonium salt. It belongs to protoberberine group of isoquinoline alkaloids. Berbirine is strongly yellow in color. Under ultraviolet light it shows a strong yellow fluorescence. It has pleiotropic properties and pharmacological actions. [63] 
When administered orally, absorption of berberine is poor because P-glycoprotein ejacts it back in the intestines. Its absorption is greatly increased when taken with P-glycoprotein inhibitors such as Silymarin. However whatever small quantity absorbed after administration of 1000-1500 mg, berberine still exerts beneficial effects. Administration of large doses is associated with constipation. This effect can be useful to reduce watery diarrhea. Absorption has also been enhanced with Sodium Caprate, a medium chain fatty acid. Enhancing absorption can reduce the dose of berberine required for desired effect. [64], [65]
Berberine binds to serum albumin. Berberine can cross blood-brain barrier and reach brain parenchyma in dose and time dependent manner.  [66]
Berberine is metabolized into four metabolites, all being active on the same mechanisms as berberine but to a lesser potency. They are excreted in urine. [67] 
Berberine is anti-inflammatory, antioxidant, immunomodualtor, neuroprotector, analgesic. It exerts protective effect on cardiovascular, respiratory, gastrointestinal system, urinary system, pancreas and liver. It cures mouth ulcers.  
Berberine may cause nausea, vomiting, hypertension, respiratory failure, paresthesias, headache, skin irritation, but not in clinically approved doses 
Berberine may decrease the efficacy of tetracycline and other bactericidal agents. Berberine bisulphate may stimulate platelet formation and may have antiheparin action. Thus berberine may interact with aspirin, clopidogrel, warfarin and heparin, non-steroidal anti-inflammatory agents (ibuprofen, naproxen). However being hepatoprotective agent may prevent hepatotoxicity induced by acetaminophen. As berberine lowers blood pressure, care should be taken when using hypotensive agents. Berberine may be synergism between berberine and fluconazole. Berberine may reverse secretary properties of neostigmine.
 Pharmacology of berberine has been described in detail separately in the article: Anti-aging “Rasaayana” [68] 

Pharmacology of Berberine 

Berberine is a quaternary ammonium salt. It belongs to protoberberine group of isoquinoline alkaloids. Berbirine is strongly yellow in color. Under ultraviolet light it shows a strong yellow fluorescence. It has pleiotropic properties and pharmacological actions 
Berberine is a quaternary ammonium salt. It belongs to protoberberine group of isoquinoline alkaloids. Berbirine is strongly yellow in color. Under ultraviolet light it shows a strong yellow fluorescence. It has pleiotropic properties and pharmacological actions

Anti-inflammatory activity

Cyclooxygenase-2 (COX-2) plays a key role in the synthesis of prostaglandins which are elevated in inflammation. A study showed that treatment with berberine reduced prostaglandin production in oral cancer cell line. The effect was dependent on dose. Pretreatment with berberine of Wistar rats inhibited the production of PGEand inflammatory exudates in carrageenan-induced inflammation. This suggests that berberine exerts its anti-inflammatory action by inhibiting prostaglandin synthesis.[69]  
Increased levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF–α) are markers of pulmonary inflammations. By suppressing the cytokine production berberine exhibits its anti-inflammatory activity in pulmonary inflammations. [70] 
Recently 13-alkyl-substituted berberines, [13-methylberberine (13-MB) and 13-ethylberberine (13-EB)] are shown to suppress the productions of IL-12, iNOS, TNF-α and COX-II better than what berberine does. Thus they are better anti-inflammatory agents than berberine. [71]

Antioxidant activity 

Oxidative stress is the key factor in development of many diseases. Oxidative stress arises when the balance of intrinsic antioxidants and reactive oxygen species tilts towards the latter. By establishing this balance via various mechanisms berberine shows a potent antioxidant activity.[72] 

Immunomodulatory activity 

Berberine showed a strong immunomodulatory effect. Immunomodulatory activity of Guduchi (Tinospora cordifolia) has been extensively investigated by using extract of the plant. Much of the work has also been conducted on berberine, jatrorhhizine, tinosporide and columbine. The possible mechanism of immunomodulatory activity was elucidated as activation of macrophages leading to increases in granulocytes. [73], [74]

Actions on the Skin 

Exposure to Ultra Violet (UV) rays induces inflammation of the skin and expedites the aging process which is indicated by the elevation of matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6). Berberine suppresses MMP-9 and IL-6 expression. This effect is dependent on the dose of berberine used. This suggests that berberine may be used as an anti-skin aging product (‘Rasaayana’ concept of Ayurveda) [75], [76]

Actions on the Endocrine System 

Thymic stromal lymphopoietin (TSLP) plays a key role in allergic diseases such as atopic dermatitis and bronchial asthma. Berberine inhibits the production of TSLP in human mast cell line (HMC-1). Berberine inhibits production and mRNA expression of TSLP in HMC-1 cells. These findings suggest that berberine is useful in the treatment of inflammatory and atopic diseases. [77]
Antiviral activity 
Berberine and the structurally related compounds show antiviral activity against human cytomegalovirus (anti-HCMV). This activity was found to be equal to that of ganciclovir. Berberine inhibits the replication of the virus after the latter has penetrated the host cell but before the viral DNA synthesis. [78]

Naturally occurring protoberberine alkaloids, berberine and berberrubine along with 9-substituded derivatives of berberine show anti-viral activity against human immune deficiency virus (HIV).  Berberine is more effective than the other two but is more toxic than the others. The anti-HIV activity of these compounds might be due to reverse transcriptase inhibitory activity and some other additional but ununderstood mechanism.  [79]

Recently berberine has been shown to exert antiviral activity against Influenza A virus [80] 
Recently berberine at 150 µg/kg body weight has been shown to be effective against herpes simplex viruses 1 and 2 (HSV-1, HSV-2). [81] 
“Dr. Ashok Vaidya informed me that when he was at the KEM Hospital, berberine eyedrops were prepared by the Unichem R&D, which were then tried by Dr. Laheri and him in viral conjunctivitis with good activity and withour side effects. Later in his group, Dr. Talwalkar and Dr. Chhaya Godse also showed that berberine fluoresces the malarial parasites in the red blood cells” 
[About Dr. Ashok DB Vaidya, at the end of the list of references, i. e. after Ref. No. 383]

Antifungal activity 

Berberine, berberrubine and 13-substituted benzyl derivative of berberine show antifungal activities against human pathogenic fungi (Candida species). Synthesized compounds are more potent than berberine and berberrubine. Among the synthetic compounds 13-(4-isopropyl benzyl) berberine is most potent against Candida species. [82]

Anti-protozoal activity 

In an in vitro study, semi-synthetic berberine analogue, 5,6-didehydro-8, 8-diethyl-13-oxodihydroberberine chloride showed activity against parasites of malaria, leishmaniasis and trypanosomiasis. While berberine hemisulfate is inexpensive, 8,8-dialkyl-substituted analogues of berberine may lead to a new class of affordable antiprotozoal compounds. [83] 
Leishmaniasis is a vector-borne protozoal infection. It is caused by the Leishmania parasite. It is potentially lethal. It is endemic in 88 countries. Its annual incidence estimated as 1-1.5 million cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis. [84]    

The Leishmania parasite resides within macrophages. From this abode they deviously manipulate innate and acquired immune mechanism of the host. This ensures their survival within the hostile environment of macrophages and hinges on their capability to modulate macrophage effector function including production of reactive nitrogen intermediates [85] 

Macrophages can induce host cells to produce cytokines that promote disease progression via regulation of T helper 1 (Th 1) and T helper 2 (Th 2) cells. The Th 1 cells enhance macrophage microbicidal activity, thus protecting the host from intracellular Leishmania pathogen. [86] 
Conversely, for their survival, the parasites augment the Th 2 response leading to an increased secretion of IL-4 and IL-10, resulting in attenuation of host defense mechanism and Leishmania infection ensues. [87]
Berberine chloride demonstrates potent anti-Leishmanial activity. It is suggested that besides being directly cytotoxic to Leishmania parasites, berberine chloride exerts immunomodulatory effect upon Leishmania infected macrophages. Moreover berberine has a high safety index which is necessary for anti-parasitic compounds. [88], [89]

Action on Hematopoietic System 

Berberine inhibits myeloma cells in the dose dependent manner. Its cytotoxic effect is explained by its direct blockade of potassium (K+) channels. [90]

Actions on Musculoskeletal System 

Berberine suppresses osteoclastic activity and bone resorption. The exact mechanism of this is unknown. However the recent evidence suggests that berberine inhibits osteoclast formation and their survival through suppression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), and Akt activation. Both pathways in the osteoclast lineage are highly sensitive to berberine treatment.
[Note: NF-κB is a protein complex that controls transcription of DNA, cytokine production and survival. Akt is a pathway that promotes survival and growth in response to extracellular signals] [91] 

Actions on Nervous System 

Administration of berberine protects and improves cell survival of the hippocampal cells in rat brain. This activity is also useful to prevent memory loss and improves memory deficit. [92]
Berberine has neuroprotective effect on damaged neurones and neurodegenerating brains of neonatal animal model [93]
To evaluate anticonvulsant and antioxidant effect of berberine, temporal lobe epilepsy was induced in rats by intrahippocampal injection of kainite (dose: 4µg). Intraperitoneal administration of berberine at 25, 50 and 100mg/kg bodyweight was effective in controlling seizure. Further, pretreatment with berberine significantly decreased the Racine score and rate of incidence of seizure in rats. Berberine ameliorated the lipid peroxidation and nitrite level but had no effect on superoxide dismutase (SOD) activity. It seems that anticonvulsant activity of berberine is due lessening of oxidative stress. [94]
Berberine inhibits the actions of morphine on the brain. This action is said to be via involvement of dopamine receptor. This suggests that berberine should be viewed as a potential antidote for attenuating morphine toxicity [95] 
In a study on mice, berberine attenuated the actions of nicotine, cocaine and morphine. Berberine is also demonstrated to modulate the activities of dopamine, nitric oxide and serotonin. Further berberine blocked the stimulant effects of ethanol [96] 
In a study on mice, at doses of 5, 10 and 20 mg/kg bodyweight, berberine inhibited the enzyme monoamine oxidase-A (MAO-A), thus acting as an antidepressant. The effect was not dependent on dose. The dose 5 mg was as effective as 20mg. Administration of berberine to mice resulted in increased levels of norepinephrine (31%), serotonin (41%) and dopamine (31%) in the whole brain. At lower dose berberine did not affect the locomotor activity and barbiturate-induced sleep time. It produced mild hypothermic action in rats and analgesic effect in mice [97], [98] 
SK Kulkarni and A Dhir are of the opinion that the antidepressant effect of berberine is due to the interaction of berberine with L-arginine-NO-cGMP pathway [99] 
A series of novel synthetisized berberine derivatives are inhibitors of acetylcholinesterase and butyrylcholinesterase. Some of them also inhibit β-amyloid aggregation.[100], [101], [102] 
As synthesized, hybride molecules of berberine inhibit acetylcholinesterase; they were used to treat Alzheimer’s disease. The hybrid molecules showed encouraging results and hence can be future candidates for the treatment of Alzheimer’s disease. The compounds showed capabilities (i) to inhibit multiple cholinesterases (ii) to prevent aggregation of β-amyloid and (iii) antioxidant activity. Berberine-pyrocatechol hybrid was much better inhibitor of acetylcholinesterase than unconjugated berberine and berberine-hydroquinone hybrid is the best antioxidant.  [103]
Recennly, a series of berberine-thiophenyl hybrids were designed and synthesized. They were found to be inhibitors of acetylcholinesterase, butyrylcholinesterase and beta amyloid as antioxidants [104]
Berberine exerts neuroprotective effects in the cerebral ischemia-reperfusion injury in mice [105], [106]
Berberine protects the brain from ischemic brain injury. The results of the study showed that berberine inhibited generation of reactive oxygen species and subsequently release of pro-apoptotic factor cytochrome c and apoptosis-inducing factors. This protection is modulated via inhibition of mitochondrial apoptotic pathway [107]
Recent studies show that by blocking potassium currents berberine protects the brain against ischemic damage [108]
Unlike the central nervous system, axons in the peripheral nervous system can regenerate following nerve injury. The effect of berberine was evaluated in rats with sciatic nerve injury.  The results showed that four weeks after administration of berberine at 20mg/kg body weight once a day for one week the thickness of remyelination of axon improved 1.4 fold. This showed that berberine promoted axonal regeneration in injured peripheral nerves.  [109] 

Actions on CVS 

Type 2 diabetes was induced in rats by injecting streptozotocin at a dose of 35mg/kg body weight, and a high carbohydrate, high fat diet for 16 weeks. The rats were the administered low (75mg/kg), middle (150mg/kg) and high (300mg/kg) doses of berberine, 100 mg/kg fenofibrate, and 4mg/kg of rosiglitazone for another 16 weeks. The myocardial hypertrophy and interstitial fibrosis improved with middle and high doses of berberine. This shows that berberine may ameliorate myocardial damage in diabetics [110]
By increasing 5’-activated protein kinase (AMPK) or 5’-adenosine monophosphate-activated protein kinase activity in insulin resistant H9c2 cells (a subclone of original cell line derived from rat heart tissue), berberine increases insulin sensitivity in the heart muscle. Berberine improves glucose uptake, glucose consumption and utilization in the myocardium. This action of berberine is beneficial for heart muscle in diabetics [111]
For long it was hypothesized that some of the cardiovascular effects of berberine are mediated through activation of cardiac Mmuscarinic cholinergic receptors. The research by Satin Salehi and Theresa M Filtz has now proved that berberine is a muscarinic agonist at Mreceptors [112]
Seahyong Lee et al decided to verify the hypothesis: “Berberine could inhibit vascular smooth muscle cell (VSMC) proliferation as it did endothelial cells or cancer cells” Their results show that berberine significantly inhibits growth factor, mainly angiotensin II and heparin binding growth factor. This effect is achieved by delaying or partially suppressing activation of Akt pathway rather than ERK pathway. Further study shows that berberine is a potent agent to control restenosis after balloon angioplasty and warrants further study for its mechanism at a cellular level [113], [114]
After percutanoeus coronary artery angioplasty, platelet-derived growth factor (PDGF) is released from vascular smooth muscle cells (VSMCs), endothelial cells or macrophages. Berberine significantly inhibits PDGF-induced VSMC growth via activation of AMPK/p53/p21 [115]

Actions on RS 

Bleomycin is notorious for causing lung injury and fibrosis. To investigate the effect of berbrerine treatment against these, 2.5 µg/kg body weight of bleomycin was instilled in the trachea of male Wistar rats. Administration of berberine significantly ameliorated the bleomycin mediated ill effects on the lung. Berberine reduced inflammatory cell infiltrate, blocked collagen accumulation, mast cell deposition and histamine release. Berberine enhanced the antioxidant status in the lungs [116] 

Actions on GI System 

The side effects of antibiotic therapy for the treatment of Helicobacter pylori infection are unpleasant. Berberine was known to reduce Helicobacter pylori proliferation. Chiung-Hung Chang et al developed a novel nanoparticle berberine carrier with a heparin shell. The prepared nanoparticles significantly increased the suppressive effect of berberine onHelicobacter pylori growth while efficiently reducing cytotoxic effects in Helicobacter pylori-infected cells [117] 
Berberine may improve colitis by inhibiting lipid peroxidation, enterobacterial growth and NF-κB activation [118]
When administered intrarectally, TNBS (2,4,6-trinitrobenzenesulphonic acid) induces severe colonic inflammation. The colitis resulting from this procedure presents clinical and histopathological picture resembling that of Crohn’s disease [119] 
In a study on mice researchers showed that berberine played an important regulatory role in modulating the balance of immune responses in TNBS-induced colitis. This study will also help us understand the regulatory mechanisms exerted by berberine in the treatment of inflammatory bowel disease (IBD) [120]
Tight junctions, also known as occluding junctions are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates. Maintenance of the mucosal barrier is a critical function of intestinal epithelial tight junction. Berberine can ameliorate pro-inflammatory cytokines induced intestinal epithelial tight junction damage. Berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states [121]
Berberine exerts an anti-secretory action directly upon intestinal epithelial cells. The action is mediated by blocking potassium channels [122]

Actions on the Liver

A.  Hepatoprotection 

Berberine protects the liver from carbon-tetra-chloride (CCl4)-induced liver injury. The hepatoprotection may be due to its free radical scavenging property, antioxidant property (attenuation of oxidative stress), as well as inhibition of inflammatory response in the liver [123]
Chronic carbon-tetra-chloride (CCl4) poisoning culminates into liver fibrosis. Berberine ameliorated liver fibrosis in mice with CCl4 –induced liver injury and inhibited the proliferation of hepatic stellate cell in dose- and time-dependent manner [124] 

B.  Viral Hepatitis 

Berberine is a pharmacologically active constituent of Berberis vulgaris. Ethanolic extract of Berberis vulgariscontaining berberine 100µg/ml inhibits replication of hepatitis C virus. This effect is attributed to lymphoproliferative effect and phagocytic and immunostimulant activity of berberine. [125] 

C. Alcoholic Liver Disease

Consumption of alcohol produces a state of oxidative stress in liver. By reducing hepatic lipid peroxidation, elevating depleted levels of glutathione and repairing mitochondrial oxidative damage berberine reduces alcohol-induced liver fibrosis. Researchers feel that berberine can be a potential agent for preventing and treating alcoholic liver disease [126]

D. Non-alcoholic Fatty Liver Disease (NAFLD)

Non alcoholic liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. The precise mechanism of development of NAFLD being nebulous the mechanism by which berberine improves NAFLD is unclear. Defects in lipid metabolism-pathways, insulin resistance and inflammation are crucial players in the process of NAFLD. Recent evidence shows that berberine corrects all these and helps contain NAFLD [127] 
Two week’s treatment with a berberine containing formula attenuated fatty degeneration of liver in obese Zucker diabetic rats [128], [129] 
Treatment of hyperlipidemic hamsters with berberine significantly reduces fat storage in the liver [130]
Treatment for sixteen weeks with berberine could alleviate hepatic steatosis and decrease lipid content in the liver by 14% in rats with high-fat diet-induced fatty liver. Further berberine prevents the development of obesity, insulin resistance. Berberine may also prevent the development of liver fibrosis in alcoholic and non-alcoholic liver disease and steatosis due to hepatitis C infection. These activities are said to be due to antioxidant property of berberine [131], [132], [133] 

E. Hepatocarcinogenesis

Berberine arrests the cell cycle at G1/S phase. Berberine induces apoptotic events in hepatocellular carcinoma cells, through procaspase-9 and its effector caspases, procaspase-3 and procaspase-7. [134], [135]

Anti-diabetic activity

In a study, 36 adults with type 2 diabetes were treated with berberine for 3 months. The hypoglycemic effect of berberine was similar to that of metformin. Berberine also decreased total and low density cholesterol [136] 
Both in vitro and in animal models, berberine increased insulin receptor (InsR) expression and improved glucose utilization. The study showed that berberine increased InsR messenger RNA and protein expression in a variety of human cell lines. Berberine reduced insulin resistance through protein kinase C-dependent insulin receptor expression. Thus berberine lowered blood sugar by a mechanism different from metformin and rosiglitazone. Further it can be said that berberine represents a different class of anti-hyperglycemic agents [137], [138], [139] 
Oxidative stress coexists with diabetes. By reducing oxidative stress berberine lowers raised blood sugar. After treatment with 150-300mg/kg bodyweight for 16 weeks, berberine showed protective effect for diabetes through increasing insulin expression, β cell regeneration, antioxidant enzyme activity and decreasing lipid peroxidation [140]
Berberine is known as an AMP-activated protein kinase activator. Its insulin-independent hypoglycemic effect is related to inhibition of mitochondrial function, stimulation of glycolysis and activation of AMP-kinase pathway. Berberine may also act as an α-glucosidase inhibitor. In patients with poor β-cell function, berberine may improve insulin secretion by resuscitating exhausted islet cells. Its hypolipidemic activity protects cardiovascular system in diabetics. The antioxidant and aldose reductase inhibitory activities of berberine may alleviate diabetic nephropathy. Large scale trials are still necessary to evaluate the efficacy of berberine on diabetes and its related complications [141], [142]
Glucagon-like peptide (GLP)-1 is a glucose-dependent insulinotrpoic hormone released from intestinal L cells. In an in vivo study on rats, 5-week treatment with berberine enhanced GLP-1 secretion induced by glucose load and promoted proglucagon mRNA expression as well as L cell proliferation in intestine [143]
By activating extracellular signal-regulated kinase, berberine increased glucose uptake in preadipocytes (Preadipocyte=undifferentiated fibroblast that can be stimulated to form an adipocyte) and adipocytes. Thus berberine increases glucose uptake through a mechanism distinct from insulin, and activated adenosine monophosphate-activated protein kinase seems to be involved in the metabolic effect of berberine [144]  
While natural alkaloid berberine is well accepted as an antidiabetic agent, some researchers found its use in clinical practice is limited because of its poor bioavailability. Their study shows that dihydroberberine has enhanced bioavailability and in vivo efficacy as an antidiabetic agent compared with berberine [145] 
Treatment of streptozotocin-induced diabetic rats with berberine 200mg/kg body weight for 12 weeks, fasting blood glucose, urea nitrogen, creatinine and urine protein decreased. This was accompanied by a reduced aldose reductase activity and gene expression at both mRNA and protein levels. This suggests that berberine protects kidneys against diabetic nephropathy because of its anti-oxidative, anti-stress property.  [146]
Berberine stimulates glucose uptake in rat-skeletal muscles in a dose and time dependent manner. The detailed study suggests that berberine stimulates glucose uptake through AMP-AMPK-p38MAPK pathway which may account for its hypoglycemic effects [147]

Actions on Dyslipidemia

Berberine is a novel, natural lipid-lowering agent. Berberine at 100mg/kg/day enhances tumor necrosis factor-α (TNF- α) and thrombin induced endothelial tissue factor (TF) in human endothelial cells by 3.5-folds. Berberine should be considered for the treatment of dyslipidemia especially in statin resistant dyslipidemic subjects [148] 
Berberine lowers elevated serum levels of total cholesterol, triglycerides and LDL-cholesterol in hypercholesterolemic patients; and increases hepatic LDLR mRNA and protein levels through a post-transcriptional mechanism. By acting on multiple molecular targets as an inhibitor of PPARγ (peroxism proliferator activated receptorγ) and α berberine is a potential hypolipidemic, hypoglycemic and weight reducing agent. [149], [150] 
Administration of 100mg/kg/day to rats improved insulin resistance, lowered elevated blood sugar, lowered elevated triglyceride and low density lipoprotein levels, increased high density lipoprotein levels, regulated lipid metabolism and nitric oxide levels. In conclusion, berberine restored endothelial dysfunction through enhanced nitric oxide bioavailability by up-regulating eNOS expression and down-regulating expression of NADPH oxidase. [151], [152]
In another study on diabetic rats, intragastric administration of berberine (100 and 200mg/kg) significantly decreased fasting blood sugar levels, serum total cholesterol, triglyceride, LDL-cholesterol, effectively increased HDL-cholesterol and nitrous oxide  levels. Furthermore, berberine blocked the increase of malondialdehyde (MDA), increased super-oxide-dismutase (SOD) and glutathione peroxidase (GSH-px) contents in heart tissue. Furthermore as was evident by histopathological study, berberine restored damaged pancreatic tissue. [153]
Berberine improves free fatty acid-induced insulin resistance in myotubes through inhibiting fatty acid uptake at least in part by reducing PPARγ (peroxism proliferator activated receptor γ) and FAT/CD 36 expressions. [154] 
Berberine lowers elevated serum lipid levels in hyperlipidemic patients with chronic hepatitis or cirrhosis of the liver [155]
In elderly, statin-intolerant, hypercholesterolemic patients berberine lowered total cholesterol and low density lipoprotein levels [156] 
In a study on hamsters berberine decreased LDL-cholesterol and reduced fat storage in the liver. By activation of AMP-kinase berberine inhibits lipid synthesis in human hepatocytes. [157], [158] 

Actions on Urinary System

Diabetic nephropathy is heralded with renal fibrosis, glomerulosclerosis and tubulo-interstitial fibrosis. In vivo and in vitro studies showed that berberine ameliorates renal complications in diabetic mice
These effects are due to antioxidant and anti-inflammatory activities of berberine. [159] 
By inhibiting extracellular matrix (ECM) component and fibronectin (FN) expression berberine could improve renal function in rats and mice with diabetic nephopathy. The ameliorative effect might be associated with inhibition of NF-κB signaling pathway which is independent of hypoglycemic effect of berberine [160]

The possible mechanism by which berberine exerts renoprotective effects may be related to inhibition of glycosylation and improvement of antioxidant status that in turn upregulates the expressions of renal nephrin and podocin, the protein component of filtration unit of kidney [161]
Recently Sphingosine kinase-Sphingosine 1-phosphate (Sph K-S1P) signaling pathway has been implicated by some researchers in the pathogenesis of diabetic nephropathy (DN). Mice with diabetic nephropathy were treated with oral berberine 300mg/kg body weight/day for 12 weeks. Berberine lowered elevated blood glucose, blood urea nitrogen, serum creatinine, albuminuria and kidney/body weight ratio. Berberine also prevented renal hypertrophy, transforming growth β1 (TGF-β 1) polypeptide synthesis, accumulation of fibronectin (FN) and collagen IV found in the basal lamina. Moreover berberine down-regulated the elevated levels of mRNA and protein SphK1 and S1P production as well. These findings suggest that the inhibitory effect of berberine on the activation of SphK1-S1P signaling pathway in kidney of diabetic mouse is a novel mechanism by which berberine exerts protective effects on kidneys in diabetic nephropathy [162] 
Berberine has antioxidant effect. In Wistar rats at 5-20mg/kg body weight berberine increased urine out put accompanied by increased pH and sodium-potassium excretion and decreased calcium excretion. This effect was similar to that of hydrochlorothiazide. Berberine at 10mg/kg body weight prevented deposition of calcium oxalate crystals in renal tubules (anti-urolithic property) [163]

Anticancer activity

Berberine inhibits neuroblastoma through inhibition of fundamental characteristics of cancer stemness. (Stemness= an essential characteristic of a stem cell that distinguishes it from ordinary cells) [164] 
Growth inhibitory effect of berberine was well documented. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation has also been documented. By inhibiting STAT3 berberine inhibits the growth of nasopharyngeal carcinoma (NPC) cells. In future berberine may be used for treating nasopharyngeal carcinoma. [165] 
By intercalating into DNA, berberine inhibits cancer of thymus gland [166]
Berberine exhibits the ability to induce apoptosis in promyelocytic leukemia HL-60 cells. At the concentration of 25µg/ml, berberine showed that only about 20% cells underwent early time (6hours) apoptosis. However at extended time (up to 48 hours) number of cells underwent apoptosis in S phase [167], [168], [169]
Berberine exerts a dose and time-dependent inhibitory effect on motility and invasion ability of highly metastatic A549 cells. Berberine exerts its effect via regulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and urokinase-plasminogen activator inhibitor (PAI). It is said that the inhibitory effect is likely to be at the transcriptional level. These findings suggest that berberine possesses an anti-metastatic effect in non-small cell lung cancer cell and may be helpful for its treatment. [170] 
Yung-Tsuan Ho et al reported that berberine inhibited the migration and invasion of human squmaous cell carcinoma-4 tongue cancer cells. The action was mediated via multiple pathways [171] 
Berberine inhibits esophageal cancer in a dose dependent manner. The study also reveals that berberine may be useful as one of alternative therapies for esophageal cancers. [172]
Berberine inhibits the proliferation and reproduction of tumerigenic microorganisms, viruses such as Helicobacter pylori and hepatitis B virus. It also shows transcriptional regulation of some oncogene and carcinogenesis-related gene expression and interaction with both DNA and RNA. Besides berberine is a broad spectrum enzyme inhibitor, which affects N-acetyltransferase, cyclooxygenase-2 and topoisomerase activities and gene/protein expression. Thus by multiple mechanisms berberine inhibits tumor growth and metastasis. Recent research shows that berberine exerts anticancer activity both in vitro and in vivo through different mechanisms [173]
By inducing apotosis, cell cycle arrest, berberine inhibits Hepatoma HepG2 cells. Furthermore berberine enhanced DNA methylation level in whole genome. These findings suggest that antiproliferation effect of berberine might be mediated by the unique epigenetic modifying mechanism [174]
Zhaojian Liu et al demonstrated that berberine inhibited human osteosarcoma cells. The inhibition was attributed to cell cycle arrest at G1 and G2/M and apoptosis of the osteosarcoma cells by inflicting DNA damage [175] 
Berberine induces cell growth arrest, apoptosis in human colorectal cancer cells. This anti-cancer action is mediated via multiple pathways [176] 
The treatment of human prostate cancer cells with berberine induced dose-dependent apoptosis. Berberine did not harm normal, non-neoplastic human prostate epithelial cells. Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules. This effect of berberine on prostate cancer was regulated by reactive oxygen species. Berberine may be a promising therapeutic candidate for prostate cancer [177]

Interactions and Toxicity

Berberine interacts with metformin and limits its tissue uptake
Berberine may interact with macrolide antibiotics leading to cardiotoxicity
Too much berberine taken at once can result in stomach upset, abdominal cramping and diarrhea  

Dose of berberine:

The standard dose of berberine is 900-2000 mg a day divided into three or four doses.
Berberine should be taken with meal or soon after to take advantage of its hypogylcemic and hypolipidemic activity.

Tembetarine 

Molecular formula: C20H26NO4
Structural formula:
  [178]
Tembetarine is anti-inflammatory and anti-pyretic [179] 

Magnoflorine 

Molecular formula:  C20H24NO4      
Structural formula:
     [180]  
Magnoflorine (Mf) is a quaternary ammonium salt. It is ganglion blocking agent. Some curare-like action has also been noticed. It has practically no effect on the adrenergic system. The hypotensive action of magnoflorine is therefore, mainly associated with ganglionic blockade. [181] 
Magnoflorine is anti-inflammatory and anti-pyretic [182] 

Choline

Molecular formula: C5H14NO
Structural formula:
        [183]

(Note: SAMe or SAM is required for cellular growth and repair.  It is also involved in the biosynthesis of Choline a quaternary ammonium salt is a water soluble essential nutrient in the B vitamin family. But by strict definition choline is not a vitamin. It is the precursor molecule for the neurotransmitter acetylcholine. It can be synthesized in the liver and protects the liver from accumulating fat in it. Its dietary source is liver, meat, fish, egg yolk, milk, butter, nuts, peanuts, sesame seeds, oats, lentils, flax seeds, beans, peas, wheat germ, potatoes, cauliflower, sunflower oil and spinach.
Choline and its metabolites are needed for:
1. The integrity and signaling roles for cell membranes
2. The synthesis of neurotransmitter hormone acetylcholine and cholinergic neurotransmission
3. Methyl groups which participate in the S-adenosylmethionine (SAMe) synthesis pathways, hormones and neurotransmitters.
Choline is used in the synthesis of the constructional components in the body’s cell membranes. It supports the developing nervous system of the fetus. It is particularly important for brain health and its potential use in brain disorders is great. It has been used experimentally to help improve neuromuscular function in Alzheimer’s disease. It is important for the transmission messages from cells to cells. It is also important for the function of genes. People whose diets are rich in choline have lower levels of inflammatory markers (at least 20%). 
Athletes, alcoholics, pregnant women, older children, men and women having faulty dietary habits are at a risk for choline deficiency. 
Most common effects of choline deficiency are: fatty liver and hemorrhagic kidney disease. Unexplained fatigue, insomnia and neuromuscular problems are also associated with choline deficiency. [184], [185]

Administration of 14 mg/kg of choline to mice, attenuated the cardiac hypertrophic responses, as indicated by the reduced heart weight, LV weight, LV thickness, and reduced expression of biomarker genes of cardiac hypertrophy. This anti-hypertrophic efficacy was reproduced in a cellular model of cardiomyocyte hypertrophy induced by isoproterenol (ISO) in cultured neonatal cardiomyocytes.

This research showed the cardio-protective effect of choline against cardiac hypertrophy, with correction of expression of miR-133a and calcineurin as possible mechanism. This study suggests that choline supplementation may be considered for prevention and treatment of cardiac hypertrophy. [186]

Tinosporin (Columbin) 

Molecular formula: C20H22O6
Structural formula: 


      [187]

Isocolumbine

Molecular formula: C20H22O6
Structural formula: 


                [188]

Columbin (Tinosporin), Isocolumbin are anti-inflammatory (anti-phlogistic). They are used to prevent and treat acute and chronic inflammations, gastralgia and intestinal colic [189]

Palmatine 

Molecular formula: C21H22O4
Structural formula: 



Palmatine like berberine is a protoberberine alkaloid found in several plants. It has been extensively studied for its potential use in the treatment of inflammations, dysentery, jaundice, liver diseases and hypertension. Palmatine has weak in vitro activity against flavivirus. [190]
Palmatine has been shown to enhance the efficacy of Nerve Growth Factor (NGF) in neurons. These effects were also seen with berberine. [191]  
Protoberberine compounds suppress catecholamine synthesis, berberine being more effective in this regard than palmatine. [192]
Palmatine suppresses the biosynthesis of dopamine.  [193] 
Palmatine inhibits the multiplication of bacteria, fungi and viruses. Palmatine also exhibits insecticidal activity.  [194].
In a study on rats contractions were stimulated in isolated aortic strips by administering phenylephrine (PE). Palmatine relaxed the isolated strips of aorta. The response was dependent on the dose of palmatine. The response was mediated via calcium channel. [195]
Protoberberine alkaloids like berberine, palmatine, jatrorrhizine, coptisine and berberrubine show affinity for binding double helix of DNA. This property can be exploited to develop new anticancer drugs. [196] 

Tetrahydropalmatine

Molecular formula: C21H25NO4
Structural formula:


                [197] 

Tetrahydropalmatine (THP) is an alkaloid found in several plant species other than Guduchi (Tinospora cordifolia). The pharmaceutical industry has now synthetically produced the more potent chiral molecule Levo-tetrahydropalmatine (Levo-THP). 
Animal experiments have shown that sedative effect of Tetrahydropalmatine (THP) results from blocking dopaminergic neurons in the brain. Tetrahydropalmatine does not cause euphoria. It is therefore preferred to addicting anxiolytics and analgesics for the treatment of anxiety and pain.  [198] 
L-Tetrahydropalmatine (THP) is useful for treating cocaine addiction. THP is now recognized as an anti-addiction drug. THP significantly ameliorates opiate craving and increases the abstinence rate in heroin users. [199], [200] 
Tetrahydropalmatine is a calcium channel blocker and a potent muscle relaxant. [201] 
Tetrahydropalmatine significantly reduced left ventricle body weight ratio, lung body weight ratio and inhibited neurohormonal activation. Thus it may be useful in the treatment of heart failure induced by myocardial infarction in rats. [202] 
Tetrahydropalmatine has been demonstrated to possess anti-inflammatory, antioxidant, sedative and analgesic properties. It decreases the accumulation of TNF-α and oxidants derived from myeloperoxidase (MPO) there by lessening the extent of apoptosis. These properties of tetrahydropalmatine protect the myocardium from ischaemia-reperfusion injury.  [203] 
dl-tetrahydropalmatine protects the liver from carbon tetrachloride injury. [204]
Several cases of poisoning related to tetrahydropalmitine have been reported. They involved adverse effects on Respiratory and Cardiovascular system. In addition chronic hepatitis has been reported. [205]

Gilonin   
Gilonin is a single chain ribosome inactivating protein with potential application in the treatment of cancer and AIDS [206]

Furanoid-diterpene glucoside
Molecular formula: C26H34O11
This novel diterpenoid was isolated from the stem of Guduchi (Tinospora cordifolia). Its structure was determined by spectroscopic and chemical studies. [207] 
It is anti-inflammatory, antihypertensive.

Tinocordiside

Molecular formula: C21H32O7
Structural formula:


     [208]

Tinocardioside is immunomodulator. [209]

Tinocordifolioside 

Molecular formula: C21H32O8
Structural formula:


    [210] 
Tinocordifolioside is one of the ingredients used as memory enhancer herbal formulation. [211]

Cordioside

Molecular formula: C26H34012
Structural formula:


      [212]

The structure of cordioside was characterized by Versha Wazir et al on the basis of NMR spectroscopy.
Cordioside is clerodane furano diterpene glucoside
Cordioside exhibits immunomodulatory activity. [213]

Cordifolioside A to E 

Molecular formula of Cordifolide A:
Structural formula of Cordifolide A: 


 

Cordifolide A is a pale yellow powder. When recrystallized in a solvent mixture CD3OD and CH3OH it is in the form of colorless prisms.
Cordifolides B and C are in white powder form. 
Cordifolides are immunomodulators, play an important role against various pathogens. [214] 

Syringin

Molecular formula: C17H24O9
Structural formula:

Other names: Eleutheroside B, Ilexanthin A, Ligustrin, Lilacin, Magnolenin, Methoxyconiferine, Sinapyl alcohol 4-O-glucoside, Syringoside. [215]
Syringin has anti-inflammatory, antioxidant, immunomodulatory, anti-allergic antipyretic, antinociceptive, anti-diarrheal, anti-ulcer, antidiabetic and anti-leucorrhea activities. It protects neuronal cells from apoptosis. [216] 

Syringin-apiosyl glucoside 
Palmatosides C and F 

Palmatoside F
Structural formula:


        [217]

Palmatoside G

Molecular formula: C25H32O10
Structural formula:       

         [218]
Amritoside
A, B, C, D

Molecular formula: C26H26O18
Structural formula:                
       [219]

Amritosides A, B, C and D are Clerone Furano Diterpene Glycosides [220]
Amritosides are found in several plants. They belong to the class of hydrolysable tannins. Their pharmacological properties are similar to tannins. [221] 

Diterpinoid lactones

Furanolactone

Molecular formula: C20H22O[222] 
Structural formula:


According to Swaminathan K et al, the molecular formula of furanolactone is: C20H22O[223] 
Furanolactone is a heterocyclic chemical compound that contains a lactone and a furan ring structure. [224] 

Clerodane derivatives 

Tinosporin (Columbin)

Molecular formula: C20H22O6
Structural formula: 
         [225]

Tinosporin is immunostimulant. 
Through inhibition of cyclooxigenase-2 and nitric oxide columbin (tinosporin) shows anti-inflammatory activity. Columbin reduced carrageenan-induced paw-edema in mice. Columbin did not show toxicity during in vitro and in vivo studies. This suggests that columbin can be developed as an anti-inflammatory drug in future.  [226]

Tinosporides 

Molecular formula: 
Structural formula:

            [227]

Sterols 

Beta Sitosterol

Sitosterol
Molecular formula: C29H50O
Structural formola:


      [228]

Beta-Sitosterol is one of several phytosterols (plant-sterols) with chemical structure similar to that of cholesterol. Beta-Sitosterol is a white, waxy powder with a characteristic odor. It is hydrophobic and soluble in alcohol.   
Beta-Sitosterol is found in fruits, vegetables, nuts, and seeds. It is found in pumpkin seeds, cashew, rice bran, wheat germ, corn oils, soybeans and dandelion coffee.
It inhibits absorption of cholesterol from the intestine and reduces total cholesterol and LDL cholesterol. After absorption from the intestine it is incorporated in the cellular membrane.
One small study shows a positive effect on male hair loss in combination with Saw palmetto. In Europe Beta-Sitasterol is used in herbal therapy for benign prostatic hyperplasia (BPH). It is also used for boosting the immunity; prevent colonic cancer, gallstones, rheumatoid arthritis, tuberculosis, psoriasis, allergies, bronchial asthma, bronchitis, chronic fatigue syndrome and erectile dysfunction.
Beta-Sitosterol should be avoided during pregnancy and breast-feeding. 
Beta-Sitosterol should be avoided by individuals with sitosterolemia, a rare inherited fat-storage disorder. This condition is correlated with increased risk of heart disease (even heart attacks) and worsening existing heart disease. 
Beta-Sitosterol is a precursor of anabolic steroid boldenone undecyclate that is used in veterinary medicine to induce growth in cattle but commonly absued anabolic steroid in sports. [229], [230] 
A study conducted in the Department of Urology, Ruhr-University, Bochum, Germany showed significant improvement in symptoms of the patients of benign prostatic hyperplasia treated with beta-sitosterol. [231]

Jatrorrhizine

Molecular formula:
Structural formula:


Synonyms: Neprotin, jatrochizine, jatrorhizine, yatrorizine
Jatrorrhizine is a protoberberine alkaloid. It is anti-inflammatory, antimicrobial, MAO-A inhibitor and hepatoprotectant. Large doses (50-100mg/kg) reduce blood sugar levels in mice by increasing aerobic glycolysis.
Synthetic derivatives of jatrorrhizine have much stronger antibacterial effect. [232] 

Alpha-D-Glucan 

Molecular formula: C6H12O6, HO (C6H10O5)n
Structural formula:
         [233]
It activates the immune system through the activation of macrophages. [234]
The signaling mechanism of (1, 4)-alpha-D-glucan (RR1) was investigated in macrophages to evaluate its immune-stimulating properties. [235]
Further study revealed that this activity is mediated via TLR6 signaling, NF kappa B translocation and cytokine production.

Arabinogalactan (AG)

Molecular formula: C20H36O14
Structural formula:
     [236]


Pharmacological actions of AG have been discussed in detail in the chapter on Bhoomyaamalakee (Phyllanthus amarus)

Beta-ecdysone 

Molecular formula: C27H44O6 
Structural formula:


       [237]


Ecdysteroids are steroids found in invertebrates and plants. In mammals they have protein anabolic effects. Beta ecdysone found in Guduchi (Tinospora cordifolia) shows antiosteoporotic effect. [238] lar formula: C27H44O[238]
 Ecdysteroids have cytotoxic properties. [239]
The ethanolic extract of stem of Tinospora cordifolia has anti-osteoporotic effect. This effect is attributed to ecdysteroids contained in it. [240] 

Magnoflorine 

Molecular formula:  C20H24NO4  
Structural formula:

  [241]


Magnoflorine (Mf) is a quaternary ammonium salt. It is ganglion blocking agent. Some curare-like action has also been noticed. It has practically no effect on the adrenergic system. The hypotensive action of magnoflorine is therefore, mainly associated with ganglionic blockade. [242] 
Magnoflorine and tinocordiside enhance phagocytic activity. It has cytotoxic activity [243] adrenergic system. The hypotensive action of magnoflorine is therefore, mainly associated with ganglionic blockade. [242] 


Pharmacology of Guduchi (Tinospora cordifolia) at a glance

Activity
Part
  Extract
                 Phytochemicals
Anti-inflammatory
Daaha-hara 
Stem
Aqueous
Tinosporin, Tnosporide, Jatrorrhizine, Syringin Columbin, Clerodane derivatives
Antioxidant, Free-radical scavenger
Aamapaachana
Whole plant
Ethanolic
Berberine, Syringin, Tinosporin, Isocolumbin, Palmatin
Immunomodulatory
Aamapaachana, Balya
Whole plant
Aqueous
Berberine, Cordifolides, Tinocordiside, Syringin, Cordioside
Skin, Anti-allergic
Kushthaghna, Wisarp
Whole plant
Aqueous/ Guduchi-sattwa, Ethanolic
Berberine, Syringin


Radioprorective
Stem
Ethanolic
Berberine, Cordiofoliside A
Wound healing
Whole plant
Aqueous
Berberine

Antibacterial
Whole plant/Stem
Aqueous/ Ethanolic
Guduchi-sattwa
Berberine, Protoberberine alkaloids,
Tinosporin, Jatrorrhizine, Columbin
Antiviral
Whole plant/Stem
Aqueous/ Ethanolic
Guduchi-sattwa
Protoberberine alkaloids, Berberine and Berberrubine along with 9-substituded derivatives of berberine

Antifungal
Whole plant/Stem
Aqueous/ Ethanolic
Guduchi-sattwa
Berberine, Berberrubine and 13-substituted benzyl derivative of berberine
Antiprotozoal/
Antiamoebic
Whole plant/Stem
Aqueous/ Ethanolic
Guduchi-sattwa
Berberine, semi-synthetic berberine analogue, 5,6-didehydro-8, 8-diethyl-13-oxodihydroberberine chloride, Palmatin
Anthelmintic
Krimi-hara
Whole plant
Aqueous
Guduchi-sattwa
Berberine


Blood/Hematopoietc
Paandu, Rakt-wikaar, Pleehawriddhee
Whole plant
Aqueous
Guduchi-sattwa
Berberine


Musculoskeletal/
Antiarthritis, Anti- Osteoporosis
Waataraktahara,
Aamawaata
Stem /

Alcoholic
Berberine, β-Sitosterol, Gilosterol, Makesterone A, Beta-ecdysone


Neuroprotective
Aerial parts
Alcoholic
Berberine, Syringin, Choline,Tembetarine, Tinosporine, Palmatine, Jatrorhizine
Analgesic
Whole plant
Aqueous/
Ethanolic
Berberine, Choline,Tembetarine, Tinosporine, Palmatine, Jatrorhizine
Antipyretic
Jwaraghna
Whole plant
Aqueous
Guduchi-sattwa/
Guduchi ghrita
Berberine, Tinosporin, Tembetarine Tnosporide, Jatrorrhizine, Columbin, Clerodane derivatives, Syringin
Nootropic, enhance memory
Medhya
Whole plant
Ethanolic
Berberine, Choline, Palmatine Protoberberinederivatives, Jatrorrhizine, Tinocordifolioside
Antipsychotic
Whole plant
Aqueous
Guduchi-sattwa/
Ethanolic
Berberine, Choline, Tinosporin, Tembetarine, Magnoflorine, Jatrorrhize, Tetrahydropalmatine
Antidepressant
Whole plant
Aqueous
Guduchi-sattwa/
Petroleum ether
Berberine, Tetrahydropalmatine, Tinosporine, Jatrorrhizine, Tembetarine
Actions on the eye
Netraroga
Stem
Eye drops
Berberine
Cardio-vascular System, Hypertension
Hrid-daurbalya
Whole plant
Alcoholic
Berberine, Choline, Tinosporine,   Magnoflorine, Columbin, Clerodanederivatives,   Jateorine,
Respiratory System
Kaasahara, Shwaasahara
Stem
Hydro-alcoholic
Berberine
Allergic rhinitis
Whole plant
Aqueous
Guduchi-sattwa
Berberine, Syringin

Gastro-Intestinal
System
Deepana- Appetizer
Aruchi-Dislike to eat (Aversion to eat)
Agnimaandya-Anorexia
Shoola-Acute abdominal pain
Arsha-Hemorrhoids
Whole plant
Aqueous
Guduchi-sattwa/
Ethanolic
Berberine, Clerodane diterpine
Syringin

Anti-ulcer
Amlapitta
Whole plant
Aqueous
Guduchi-sattwa/
Ethanolic
Berberine, Clerodane diterpine,
Syringin

Antidiarrheal
Prawahikaa, Atisaara
Raktaatisaara
Grahanee
Whole plant
Aqueous
Guduchi-sattwa/
Ethanolic

Berberine, Syringin, Palmatin

Hepatoprotective
Yakritwikaar,
Kaamalaa
Whole plant
Aqueous
Guduchi-sattwa
Berberine,Tinosporin, Palmatine,
Isocolumbin, Tetrahydropalmatine
Hepato-cellular-
carcinoma
Aerial
parts
Aqueous
Guduchi-sattwa/ Ether extract
Berberine, Berberine,Tinosporin, Palmatine, Magnoflorine, Tinocordiside, Cordifolioside A,
Isocolumbin, Tetrahydropalmatine
Dyslipidemia
Medohara
Whole plant, Stem
Aqueous
Guduchi-sattwa
Berberine


Anti-diabetic
Pramehaghna, Madhumehaghna
Whole plant, Stem
Aqueous
Guduchi-sattwa
Berberine, Syringin, Choline, Tembetarine, Palmatine, Jatrorrhizine, Berbrrine analogue Y53. 1, 2-substituted pyrrolidine.
Diabetic neuropathy
Whole plant, Stem
Aqueous
Guduchi-sattwa
Berberine, Choline, Tembetarine, Palmatine, Jatrorrhizine
Aphrodisiac
Shukra-daurbalya
Whole plant, Stem
Aqueous
Guduchi-sattwa/
Hydro-alcoholic
Berberine, Tinosporine,  Magnoflorine,  Isocolumbin,  Palmatine, Tembetarine
Antileucorrhea
Shweta-pradara
Stem

Aqueous/ Alcoholic
Syringin
Anticancer
Stem/
Aerial parts
Aqueous/ Alcoholic/
Dichloromethane
extract
Berberine, Syringin, Tinosporin, Palmatine, Magnoflorine, Tinocordiside, Cordifolioside A,
Isocolumbin, Tetrahydropalmatine
Adaptogen
Rasaayana
Whole plant
Aqueous
Guduchi-sattwa
Tinosporin, Tinosporides, Berberine, Giloin, Giloinin, Arabinogalactan, Picrotene, Bergenin, Beta-ecdysone
Urinary System
Urinary calculi
Mootrakrichcha, Ashmaree

Whole plant
Aqueous
Guduchi-sattwa
Berberine

Some testimonials from modern research: 
General Pharmacology 

In experiments on mice 80 and 120mg/kg bodyweight of n-butanol fraction of Guduchi (Tinospora cordifolia) administered intraperitoneally for 15 days demonstrated radioprotective activity. This activity was attributed to cordifolioside-A.  [244], [245]

Adaptogenic Activity 

Guduchi (Tinospora cordifolia) exhibits a strong antistress and activity aptogenic activity. These activities are attributed to Phenylpropanoid glycosides and Tetrahydrofuranlignan glycosides present in the plant. [246], [247], [248]

Antistress Activity 

The anti-stress activity and tonic property of Guduchi (Tinospora cordifolia) was clinically tested in children. The response was good in children with moderate degree of behavior and mental deficit. 
The ethanol extract of Guduchi (Tinospora cordifolia) at 100mg/kg bodyweight showed a significant antistress activity which was comparable with 2.5 mg/kg bodyweight of diazepam. 
This activity was mediated through various neurotransmitters. [249], [250], [251] 

Antidote to snake-bite 

Guduchi (Tinospora cordifolia) was found to be a useful antidote against snake-bite [252] 

Anti-Inflammatory Activity

In doses of 100 and 200 mg/kg bodyweight the alcoholic extract of Guduchi (Tinospora cordifolia) showed 32.63% and 36.63% inhibition of paw edema in rodents. Guduchi (Tinospora cordifolia) is effective against acute and subacute inflammations. It also exhibits analgesic activity.
In a similar study in rats the decoction of Guduchi (Tinospora cordifolia) showed anti-inflammatory activity on carrageenin-induced hind paw edema. [253], [254], [255]
Guduchi (Tinospora cordifolia) growing with the support of Neem (Azadirachta indica) is known as Neem Giloe. The water extract of Neem Giloe exhibits much superior anti-inflammatory activity. When given orally and intraperitoneally (50 mg/100gram of bodyweight) it significantly inhibited the acute inflammation induced by carrageenan. It also significantly inhibits antibody formation by ‘typhoid H’ antigen. [256]
This effect is probably because of synergism with chemicals derived from Neem. [257]
The polysaccharides contained in T. cordifolia show anti-inflammatory activity and enhance phagocytosis in vivo. [258]
The aqueos extract of the stem antagonizes the effects of 5-hydroxytryptamine, histamine, bradykinin and prostaglandins E1 and E2. [259]
The dried stem of Guduchi (Tinospora cordifolia) exhibits anti-inflammatory activity in both acute and subaacute inflammations. But in subaacute inflammations it is is inferior to phenylbutazone. [260]

The aqueous extract of the stem of Guduchi (Tinospora cordifolia) exerts a significant anti-inflammatory effect in cotton pellet-induced granuloma and formalin-induced arthritis. [261] 

In an experimental study Guduchi (Tinospora cordifolia) was found to regulate elevation of proinflammatory cytokines, thus exhibiting anti-inflammatory activity. [262] 

Antioxidant Activity

Arabinogalactan (AG) isolated from Guduchi (Tinospora cordifolia) showed good protection against gamma-ray induced damage. This is attributed to antioxidant and free radical scavenging activity of AG. [263], [264] 
Oral administration of alcoholic extract of the root of T. cordifolia at 100mg/kg for six weeks to diabetic rats reinstates the depleted levels of glutathione in the liver and kidney; thus protecting these organs from oxidative stress injury. [265]
Administration of alcoholic extract of the root of Guduchi (Tinospora cordifolia) at a dose of 100mg/kg body weight for six weeks to diabetic Wistar rats normalized the antioxidant status of heart and brain. This effect was better than glibenclamide 600 µg/kg body weight though Insulin 6 units/kg body weight restored all parameters to normal.  [266]
In vitro, extract of Guduchi (Tinospora cordifolia) inhibits the lipid peroxidation and super oxide and hydroxyl radicals. To achieve 50 % inhibition the concentration needed was 6mg and 12.5 mg/ ml respectively. At 25mg/kg body weight for 10 days the extract also ameliorated the toxicity of cyclophosphamide. These effects are attributed to antioxidant property of Guduchi (Tinospora cordifolia). [267] 
Guduchi (Tinospora cordifolia) elevates glutathione (GSH) levels, expression of the gamma-glutamylcysteine ligase and Copper-Zinc Superoxide dismutase genes. The herb also exhibits strong free radical-scavenging properties
During and after ischemia and hypoxia of the brain, free radical insult leads to necrosis and brain cell death. Antioxidant activity of Guduchi (Tinospora cordifolia) neutralizes these insults and exhibits neuroprotective activity. [268] 
In 1894, H. J. H. Fenton discovered that some metals have a strong catalytic power to generate highly reactive hydroxyl radicals. This is known as Fenton’s reaction. Aqueous extract of Guduchi (Tinospora cordifolia) inhibits Fenton reaction and radiation-mediated 2-deoxyribose degranulation in a dose-dependent fashion. Similarly it showed inhibition of chemically generated superoxide anion. [269]

Immunomodulatory activity 

Immunomodulatory activity of Guduchi (Tinospora cordifolia) has been extensively studied by various researchers. The alcoholic and aqueous extracts of Guduchi (Tinospora cordifolia) show beneficial effects on immune system.
In some experimental studies on mice, by modulating the proinflammatory cytokines; G1-4A, a polysaccharide from T. cordifolia protected them against septic shock. [270]
Guduchi (Tinospora cordifolia) prevents the degradation of proteins due to photosensitization (immunomodulatory activity) [271]
1,4 α-D-glucan derived from Guduchi (Tinospora cordifolia) activates immune system through the activation of macrophages. [272]
Guduchi (Tinospora cordifolia) regulates elevation of cytokines. The anti-angiogenic activity of Guduchi (Tinospora cordifolia) is related to the regulation of cytokine levels and growth factors in the blood. [273] 
The aqueous extract of Guduchi (Tinospora cordifolia) enhanced phagocytosis in vitro. The aqueous and ethanolic extracts induced an increase in the production of antibodies in vivo. [274]
Treatment with Guduchi (Tinospora cordifolia) 100mg/kg bodyweight for ten days significantly increased the number of colony forming units of granulocyte-macrophage series. [275]
Treatment of HIV patients with Guduchi (Tinospora cordifolia) extract caused significant reduction in eosinophilic count and improvement in hemoglobin levels.[276]
When treated with  Guduchi (Tinospora cordifolia) diabetic patients with ulcers on foot showed significantly better final outcome in wound healing [277]
Administration of 200 mg/kg body weight of Guduchi (Tinospora cordifolia) one hour before irradiation showed recovery in the weight of spleenand antioxidant potential of plasma. It also stimulated splenocyte proliferation in a dose dependent manner. [278] 
Syringin and Cordiol found in Guduchi (Tinospora cordifoliainhibited immunohemolysis of antibody coated sheep RBCs by guinea pig serum. These compounds also increased Ig G in the serum.  However the humoral and cell mediated immunity was dose dependent. Cordoside, Cordiofolioside A and Cordiol contained in the plant also activated macrophages. [279]
In some studies the water and ethanolic extract of the stem of Guduchi (Tinospora cordifoliawas found to inhibit the cyclophosphamide induced immunosuppression [280]
In summary one can say Guduchi (Tinospora cordifolia) can build up specific and nonspecific immunity against many diseases.

Actions on the Skin 

In three government institutions 66 patients infected with scabies were treated with 50% lotion of Guduchi (Tinospora cordifolia) for three consecutive days in a week for two weeks. The lotion exhibited anti-scabies activity. The lotion was as effective as permethrin. [281]    
Guduchi (Tinospora cordifolia) shows a wide range of acivity in skin disorders. It is useful in kandu (pruritus), wisarpa (Erysipela), kushta (leprosy) and many more.[282]
Guduchi (Tinospora cordifolia) has chemopreventive potential against skin carcinogenesis in mice.[283]

Wound healing 

To evaluate the effect of Guduchi (Tinospora cordifolia) on wound healing, researchers from various groups inflicted excision wound; (sutured) dead space wound and sutured incised wounds in experimental animals. The wounds were treated by (a) topical application of 5% Guduchi (Tinospora cordifolia) ointment (b) topical application of  Guduchi (Tinospora cordifolia) cream 1 % for 16 days (c) oral administration of oral
 suspension of 200mg of Guduchi (Tinospora cordifolia) in 2% gum acacia at a dose of 5 ml/kg body weight once a day for 10 days and (d) methanol extract of Guduchi (Tinospora cordifolia) orally at a dose of 250 mg/kg body weight once a day for 10 days. 

Suspension of 200mg of Guduchi (Tinospora cordifolia) in 2% gum acacia at a dose of 5 ml/kg body weight once a day for 10 days and (d) methanol extract of Guduchi (Tinospora cordifolia) orally at a dose of 250 mg/kg body weight once a day for 10 days.

Antimicrobial Activity/ Antibacterial activity 

The alcoholic extract of the stem shows activity against E. coli. Active principles identified from the plant extract were found to inhibit in vitro the growth of Mycobacterium tuberculosis. [287] 
An investigation on antibacterial activity of Guduchi (Tinospora cordifolia) showed that ethanol extract of leaves and stem had maximum inhibitory against Klebsiella pneumoniae followed by Pseudomonas aeruginosa, while chloroform extract showed moderate activity against them and poor activity against E. coli. Aqueous extracts of leaves and stem had poor activity against these pathogens. Proteus vulgaris was resistant to all the extracts tested. [288] 
In another study, in addition to the antibacterial activity mentioned above aqueous, ethanol and chloroform extract of stem of Guduchi (Tinospora cordifolia) showed antibacterial activity against Enterobacter faecalis, Salmonella typhi, Staphylococcus aureus and Serratia marcesenss. [289] 
The ethanol extract of Guduchi (Tinospora cordifolia) shows a significant antibacterial activity against Bacillus subtilis, Escherichia coli, Proteus vulgaris; moderate activity against Enterobacter faecalis, less activity againstSalmonella typhi, Staphylococus aureus and Enterococcus faecalis and Serratia marcescens. The chloroform extract of the stem showed moderate inhibition of Escherichia coli, Proteus vulgaris and Enterobacter faecalis while the aqueous extract of the stem shows less activity against Enterococcus faecalis, Proteus vulgaris, Salmonella typhi, Staphylococus aureus and Serratia marcescens. [290], [291] 
In a study by Nagaprashanthi et al the hydroalcoholic extract of Guduchi (Tinospora cordifolia) showed anti-bacterial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Pseudomonas sp.[292], [293]

Antiviral activity 

The plant extract showed in vitro to inactivate Hepatitis B surface antigen. Dr. Nirmala Rege HOD, Dept. Pharma and Therapeutics and Ayurveda, G. S. Medical College, Mumbai, India is of the opinion that Guduchi (Tinnospora cordifolia) is superior to Bhoomyamalakee (Phyllanthus niruri/amarus) in this regard. [294] 
In a clinical trial at Regional Research Institute (Ayurveda) Jaipur, India; 20 patients of infective hepatitis (viral hepatitis, type of viruses not mentioned) were treated with tablets (500mg per tablet) prepared from stem of T. cordifolia. Each patient received 500mg tablet with water three times a day for four weeks. Fifteen patients were cured and five patients improved. [295] 
The extracts of leaves of Guduchi (Tinnospora cordifolia) show anti-HIV-1 activity. Extraction of important bio-active phytochemicals will be helpful for developing new antiviral drugs.  [296]

Antifungal activity 

Tricophyton is a genus of fungi. In humans various species of Tricophyton produce superficial, acute or chronic fungal infections of skin. Various organic solvent extracts of Guduchi (Tinnospora cordifolia) have shown antifungal activity againstTricophyton rubrum and Tricophyton simi. [297], [298] 
In a study by Nagaprashanthi et al the hydroalcoholic extract of Guduchi (Tinnospora cordifolia) crept up on Neem (Azadirachta indica) tree showed antifungal activity against Aspergillus niger, Aspergillus fumigates, mucor sp and Penicillium. [299] 

Anthelmintic activity 

The alkaloids isolated from Guduchi (Tinnospora cordifolia) possess anti-oxidant effects. They thus reduce nitrate generation and protein synthesis; suppress sugar transport from intestine to CNS causing CNS paralysis in helminthes; thus exerting anthelmintic activity.  [300] 

Actions on RES/ Hematopoietic System

Aqueous extract of Guduchi (Tinnospora cordifolia) has a high phagocytic index.  
The ethanol extract of Guduchi (Tinnospora cordifolia) inhibits the immunosupression and anemia produced by cyclophosphamide. 
HIV patients treated with Guduchi (Tinnospora cordifolia) showed reduction in neutrophil and eosinophil count and improvement in hemoglobin. They also showed overall clinical improvement as evidenced by regression of some symptoms. [301] 
The anti-angiogenic activity of Guduchi (Tinnospora cordifolia) is related to the regulation of the levels of cytokines and growth factors in the blood. [302] 
Malaria is often associated with splenomegaly and hypersplenism. As a prophylactic measure, aqueous extract of Guduchi (Tinnospora cordifolia)   500 mg was added to chloroquine base 300 mg weekly for six months. This schedule showed regression of spleen, increase in Hb and decrease in Ig M. [303]

Antimalarial Activity 

Although Plasmodium berghei dose not cause malaria in humans, in experimental studies Guduchi (Tinnospora cordifolia) showed antiparasitic activity against this species. Anti-parasitic activity of Guduchi (Tinnospora cordifolia) against human malarial parasites should be investigated. [304] 

Actions on Musculoskeletal System 

Anti-inflammatory property of Guduchi (Tinnospora cordifolia) was shown to be useful for the treatment of rheumatoid arthriris. [305] 
In an experimental study the aqueous extract of stem of Guduchi (Tinnospora cordifolia) exerted a significant anti-inflammatory activity in formalin-induced arthritis in rat models. It was useful in rheumatoid arthritis. [306], [307]   
To evaluate osteoprotective effect of Guduchi (Tinnospora cordifolia), rats were treated with the extract of the plant at the dose of 10 mg/kg bodyweight. The treated rats showed slower bone loss in tibia than that in controls (untreated rats). Osteocalcin and Crosslap (urinary type I collagen peptides) are markers of bone metabolism. In osteoporosis and bone loss, their serum values increase. When treated with Guduchi (Tinnospora cordifolia) serum osteocalcin and crosslap levels were significantly reduced. This study indicates that Guduchi (Tinnospora cordifolia) is osteoprotective and can be used as antiosteoporotic agent. [308]

Actions on the Breast

The hydroalcoholic extract of Guduchi (Tinnospora cordifolia) was found to be useful for the treatment of bovine subclinical mastitis. [309] 

Actions on Nervous System

Neuroprotective Effect

Neuroprotective activity of Guduchi (Tinospora cordifolia) was evaluated in rats. Neurotoxicity was induced in hippocampus by exposing hippocampal slices to oxygen glucose deprivation. Levels of superoxide dismutase, reduced glutathione, glutathione peroxidase, nitric oxide were measured to assess hippocampal damage. The animals were then treated with Guduchi (Tinospora cordifolia). The herb exhibited a strong freeradical scavenging activity and significantly diminished the expression of iNOS gene after 48 hours which plays a major role in in neuronal injury during ischemia/ hypoxia.
[The ischemic/hypoxic insult generating free radicals leads to cell death. A wide vatiety of antioxidants found in Guduchi (Tinospora cordifolia) prevent cell-apoptosis. This is the mechanism of neuroprotective action of Guduchi (Tinospora cordifolia)]   [310] 

Effects on Stress

In various experiments, ethanol extract of Guduchi (Tinnospora cordifolia) at 100mg/kg body weight showed significant antistress activity which was comparable to diazepam 2.5 mg/kg   [311], [312]

Effects on Learning and Memory

In some studies on rats aqueous and alcoholic extracts of the plant enhanced learning and memory in normal rats and reversed cyclosporine induced memory deficit. [313], [314]
All these activities are mediated through various neurotransmitters of the brain. [315]
In some clinical studies on children researchers tested anti-stress and tonic property of Guduchi (Tinnospora cordifolia). They found good response in children with moderate degree of behavior-disorders and mental deficit. Guduchi (Tinnospora cordifolia) also significantly improved the I. Q. levels of the children. [316], [317]
The aqueous extract of root of Guduchi (Tinnospora cordifolia) was found to enhance verbal learning and logical memory. [318] 
To evaluate Medhya (memory, cognition) effect of Guduchi (Tinnospora cordifolia) described in Ayurveda, thirty healthy volunteers of age 18-30 were selected for study. They received 500mg of water extract or a placebo for 21 days. Psychological tests were performed to assess the effects. The results showed that visual memory, logical memory, verbal memory, attention span and concentration improved in those volunteers who received the extract of Guduchi (Tinnospora cordifolia) [319]

Anti-depressant Effect

Petroleum ether extract of Guduchi (Tinnospora cordifolia) at doses of 50, 100 and 200mg/kg body weight administered orally to mice for consecutive 14 days to mice produced a significant antidepressant effect. The efficacy was equivalent to 15mg/kg body weight of imipramine and 20 mg/kg body weight of sertraline. The extract was most effective at the dose of 50 mg/kg body weight. The antidepressant effect was reversed by pretreatment of animals with prazocin (a α1-adrenoceptor antagonist), sulpiride (a selective dopamine D2- receptor antagonist), ρ-CPA (a serotonin synthesis inhibitor) and baclofen (GABA B agonist). This suggests that antidepressant like effect of the plant might be by interaction with α1-adrenoceptor, dopamine D2- receptors,serotonergic and GABA B receptors, hence increasing the levels of noepinephrine, dopamine and serotonin and decreasing the levels of GABA in brains om mice [320]

Analgesic/Anti-pyretic Effects

In Ayurveda Guduchi (Tinnospora cordifolia) is described to possess Jwarahara (antipyretic) property. Sanyal MN and Namhata D found that 95 % ethanolic extract of of Guduchi (Tinnospora cordifolia) possesses a significant antipyretic activity. [321]
In another experimental study hexane and chloroform-soluble portions of stem of Guduchi (Tinnospora cordifolia) were shown to exert antipyretic effect. [322]   
Various studies have shown remarkable anti-infective and antipyretic properties of Guduchi (Tinnospora cordifolia). [323], [324]
In an experimental study Guduchi (Tinnospora cordifolia) ameliorated sciatica pain. [235]

Actions on the eye

Recently the researchers developed berberine eyedrops for ophthalmic disorders

Actions on CVS 

Oxidative stress was suggested to be a major factor in the occurance of ischemia-reperfusion injury following myocardial infarction. Some researchers suggested that antioxidant property of Guduchi (Tinnospora cordifolia) might be useful to reverse this damage. In a study pretreatment with alcoholic extract of Guduchi (Tinnospora cordifolia) in a rat model protected the myocardium from surgically-induced myocardial ischemia performed by occlusion of left anterior descending coronary artery for 30 minutes followed byreperfusion for 4 hours. [326] 
Administered by intravenous route the aqueous extract of Guduchi (Tinnospora cordifolia) in doses of 5.0, 10.0 and 15.0 mg/kg body weight produced a marked fall in blood pressure and bradycardia in anaesthetized dogs. [327]

Actions on RS

In a clinical study, treatment with Guduchi (Tinnospora cordifolia) offered 100% relief from respiratory allergic disorders such as allergic rhinitis, nasal obstruction etc. [328], [329] 
In various studies on animal models, aqueous extract of stem of Guduchi (Tinnospora cordifolia) releaved histamine-induced bronchospasm in guinea pigs, reduced capillary permeability in mice and mast cell disruption in rats. [330] 

Actions on GI System

Antiulcer Activity

Administered orally at 125, 250, 500 and 1000mg/kg bodyweight a herbomineral formulation of containing Yashtimadhu (Glycerrhiza glabra), Aamalakee (Emblica officinalis) and Guduchi (Tinospora cordifolia) reduced volume of total gastric secretion, and prevented gastric mucosal injury in rats. The gastroprotective and anti-ulcer effect of this polyherbal formulation was attributed to antioxidant mechanism. [331]
Guduchi (Tinnospora cordifolia) is useful for the treatment of stomach disorders such as dyspepsia, flatulence, loss of appetite, nausea, diarrhoea etc. The anti-diarrhoeal activity of Guduchi (Tinnospora cordifolia) is due to berberine present in the plant. [332] 
Ayurvedic formulations containing Guduchi (Tinnospora cordifolia) protect gastric mucosa from ulceration. The formulations also reduce gatric acidity, incrase the pH of gastric fluid following ligation of pylorus and ethanol-induced injury of gastric mucosa    in rats. The formulations also exert anti- spasmodic action on the stomach. [333], [334]   
Pretreatment with Guduchi (Tinnospora cordifolia) imparts protection against mortality induced by intra-abdominal sepsis following coecal ligation in rats. The plant also significantly reduces the mortality from E. coli-induced peritonitis in mice. [335]

Actions on the Liver

(A). Hepatoprotection

Guduchi (Tinnospora cordifolia) stimulates the regeneration of hepatic tissue, normalizes the hepatic enzymes and prevents the liver fibrosis. 
 In experimental studies on mature albino rats, extract of Guduchi (Tinnospora cordifolia) protected the animals from CCl4 insult. This effect was attributed to hepatoprotective and immunomodulatory properties of Guduchi (Tinnospora cordifolia).The study showed a significant reduction in elevated levels of SGOT, SGPT, ALP and bilirubin was observed in mature rats following treatment with T. cordifolia during CClintoxication. [336]     
Antitubercular drugs are hepatotoxic. Guduchi (Tinnospora cordifolia), Amalakee (Phyllanthus emlica/Emblica officinalis) or their combination protects the liver from hepatotoxicity of antitubercular drugs. [337]
In another study, formulation containing Haridraa/Turmeric (Curcuma longa) and Guduchi (Tinnospora cordifolia) prevented the hepatic damage by anti-tubercular drugs. [338]
In Jammu, Thailand and Philippines T. cordifolia, T. crispa and T. rumphii Boerl are used as hepatoprotectants against many toxins. Recent research has shown that a combination of Turmeric extract (Curcuma longa) and Guduchi extract (T. cordifolia) offers better hepatoprotection than T. cordifolia alone to counter the side effects of anti-tubercular drugs. [339] 

(B). Viral Hepatitis/ Jaundice

Extracts of Guduchi (Tinnospora cordifolia) were useful for the treatment of Hepatitis B and E. The extracts also showed in vitro activity against these viruses inactivating them in 48 to 72 hours. [340] 
Extrahepatic obstructive jaundice is associated with immunosupression, deranged hepatic function and sepsis. This may mar the surgical outcome. Addition of T. cordifolia 16 mg/kg/day orally to conventional management (i. e. biliary drainage, antibiotics, vitamin K etc.) improved surgical outcome by boosting host defenses. [341]

(C). Alcoholic Liver disease/ Non-Alcoholic Fatty Liver Disease (NAFLD) 

Chronic liver damage is characterized by deposition of fat in the hepatocytes which if not treated early culminates into deposition of fibrous tissue. Prognosis of chronic liver damage worsens as the fibrosis increases. Kupffer cells exert inhibitory control on Hepatic stellaate cells also known as perisinusoidal cells or Ito cells and arrest liver damage due to fibrosis. Thus Kupffer cells have antifibrotic potential. In an experimental study on animal model Guduchi (Tinospora cordifolia) decreased the fibrosis and increased phagocytic activity of macrophages. [342]
Berberine contained in Guduchi (Tinnospora cordifolia) reduces hepatic fat content in rats of NASH or NAFLD. Berberine also prevents proliferation of hepatic stellate cells (HSCs), which are central for the development of fibrosis during liver injury. [343] 

Actions on metabolism 

Administration of aqueous extract of root of Guduchi (Tinnospora cordifolia) at doses of 2.5 and 5g/kg bodyweight for six weeks was found to be effective in lowering cholesterol, phospholipids and free fatty acids in alloxan induced diabetic rats. The dose of 5 g/kg body weight was better than glibenclamide in this regard. [344], [345] 
Administration of the methanolic extract of the stem of Guduchi (Tinnospora cordifolia) at doses of 200 and 400 mg/kg bodyweight for 30 days resulted in lowering elevated lipids in Sprague dawley rats. The reduction was compared with that caused by atorvastatin and was significant. The effective dose was 400mg/kg bodyweight. [346] 
Administration of petroleum ether extract of the stem of Guduchi (Tinnospora cordifolia) at doses of 50 and 100 mg/kg body weight for 28 days to female Wistar rats resulted in reduction of body weight and fat (obesity). [347] 

Actions on the Pancreas 

Administration of hexane, ethyl acetate and methanol extracts of stem of 
Guduchi (Tinnospora cordifolia) were shown to possess antidiabetic effect on streptozotocin induced diabetic rats. Methanol extract was more effective than the other two in this regard. In animals treated with methanol extract, the insulin and C-peptide levels improved suggesting regeneration of β cells. Histological studies also showed regeneration of β cells. [348] 

Antidiabetic activity 

Several studies using various parts and whole plant have shown hypoglycemic property of Guduchi (Tinnospora cordifolia) streptozotocin and alloxan-induced diabetic animals.    
The exact mechanism of antidiabetic activity by Guduchi (Tinnospora cordifolia) is not understood. The possible mechanisms are listed here----
1. Anti-inflammatory property reducing inflammation of β cells of the pancreas.
2. Antioxidant, free radical scavenging activity of phytochemicals.
3. Action similar to sulphonyl ureas.
4. Actions similar to glitazones.
5. Reduction in intrahepatic, intra-abdominal and extra abdominal fat and body weight.
6. Reduction in insulin resistance.
7. Promoting insulin secretion, inhibiting gluconeogenesis and glycolysis. [349], [350], [351], [352], [353], [354] 
In vitro clinical study show that Guduchi (Tinnospora cordifolia) is a potent aldose reductase inhibitor. It is this action that relieves pain in diabetic neuropathy. However the antioxidant activity of Guduchi (Tinnospora cordifolia) may also contribute to relieve the pain of diabetic neuropathy. [355], [356]

Actions on Urinary System 

In Ayurveda Guduchi (Tinnospora cordifolia) has been described to be useful in alleviating urinary problems. In a scientific study Guduchi (Tinnospora cordifolia) exhibited diuretic effect. It was also found to modulate morphology and some gluconeogenic enzymes in kidneys of diabetic rats. [357], [358] 
Aflatoxins are hepatotoxic and hepatocarcinogenic and nephrotoxic agents. By scavenging freeradicals generated by aflatoxins Guduchi (Tinnospora cordifolia) protects the liver and kidneys from aflatoxin-induced injury. To investigate this Aflatoxin B1 was administered to male Swiss albino mice orally at a dose of 2µg/kg bodyweight, with or withoutGuduchi (Tinnospora cordifolia) at doses of 50, 100, 200mg/kg body weight for 25 days. Those receiving Guduchi (Tinnospora cordifolia) were protected from nephrotoxicity as was evident by biochemical and histological studies. [359], [360] 

Actions on Male Reproductive System 

While Guduchi (Tinnospora cordifolia) has been described as having aphrodisiac activity in Ayurveda, some researchers report antifertility effects of the plant. Oral administration of 70% methanolic extract of stem of Guduchi (Tinnospora cordifolia) at a dose of 100 mg/day for 60 days significantly decreased the weight of testes, epididymis, seminal vesicles and prostate. [361] 
Actions on Female Reproductive System 

Ethanolic extract of Guduchi (Tinnospora cordifolia) was found to be useful in the treatment of Postmenopausal syndrome. It had no side effects of Hormone Replacement Therapy (HRT). [362] 
Guduchi (Tinnospora cordifolia) showed reversible contraceptive effect in animal model. [363] 

Antitumor activity 

The chemical constituents present in Guduchi (Tinospora cordifolia) belong to different classes of alkaloids, glycosides, flavonoids, steroids (phytosterols), terpenoids, phenolics and saponins. They impart pleotropic pharmacological activity to Guduchi (Tinospora cordifolia). Although individual phytochemical exhibits anti-tumor activity,   the antitumor activity is a synergistic action of the phytochemicals present in the plant. Here anti-tumot activity of individual phytochemical and that of plant as a whole is discussed in detail.
Recently researchers have isolated a novel polysaccharide, α-D-glucan (RR1). This polysaccharide possesses unique immune stimulating properties. It is nontoxic and nonproliferating to normal lymphocytes as well as tumor cell lines at 0-1000 microgram/ml concentrations. However at a concentration of 100 microgram/ml it activated a different subset of the lymphocytes such as natural killer (NK) cells, T cells and B cells. The activation of NK cells is associated with the dose dependent killing of tumor cells by activated normal lymphocytes. RR1stimulation did not produce any produce oxidative stress. Absence of oxidative stress clearly shows immunoprotective potential of α-D-glucan. [364]
Application of 7, 12-dimethylbenza (a)nthracene and croton oil to skin for more than two weeks would induce skin cancer. To evaluate anticancer activity of Guduchi (Tinospora cordifolia) by application of these chemicals, skin cancer was induced in Swiss albino mice. They were treated with Guduchi (Tinospora cordifolia). The data of the study indicated that Guduchi (Tinospora cordifolia) was useful for the treatment of skin cancers. The anticancer activity of Guduchi (Tinospora cordifolia) was attributed to the palmatine alkaloid present in the plant. [365]
In an experimental study on mice intraperitoneal injection of the alcoholic extract of Guduchi (Tinnospora cordifolia) slowed the growth of Dalton’s lymphoma cells and stimulated macrophage functions such as antigen-presenting ability, phagocytosis, secretion of interleukin-1(IL-1),  tumor necrosis factor (TNF) and Reference Nutrient Intake (RNI). [366] 
The methanol-extract of Guduchi (Tinospora cordifolia) shows antimutagenic activity in dose dependant manner. Administration of Guduchi (Tinospora cordifolia) at doses of 200, 400 and 600mg/kg bodyweight prior to administration of cyclophosphamide (50 mg/kg body weight) significantly prevented micronucleus formation, while in melanoma tumor model prevented the increase in tumor volume. Aqueous, methanolic and ethanolic extracts Guduchi (Tinospora cordifolia) increased the mean survival time and increased life span of experimental animals. Guduchi (Tinospora cordifolia) thus exhibits anti-neoplastic effects.  
At low doses, the ethanolic extract of Guduchi (Tinospora cordifolia) increased bone marrow cell counts while at higher doses resulted in decreased counts in mice with induced lymphoma.   
BALB/c mice are albino mice. In another experimental study, administration of methanolic extract of Guduchi (Tinospora cordifolia) to BALB/c mice at a dose of 200mg/kg body weight for 5 days increased total white blood cell count, marrow cellularity in the femur and α-esterase positive cells significantly. This is suggestive of increased maturation of stem cells. Administration of the extract also increased humoral immunity and enhancement in macrophage activity. The extract reduced solid tumor growth and in synergy with cyclophosphamide reduced the animal tumors by 83%.  In some experimental studies Guduchi (Tinospora cordifolia) was found to inhibit metastasis. [367], [368], [369], [370]
To evaluate radiosensitizing activity of Guduchi (Tinospora cordifolia), Ehrlich ascites carcinoma (EAC) was transplanted in mice. Before radiotherapy they received 0, 25, 30, 40, 50 or 100mg/kg bodyweight of dichloromethane extract of Guduchi (Tinospora cordifolia). The results showed radiosensitizing activity of the extract. This was evident by more number of long-term survivors as well as survivors beyond 120 days. The highest activity was observed at the dose of 30 mg/kg bodyweight. The radiosensitization by Guduchi (Tinospora cordifolia) may be due to depletion of glutathione and glutathione-s-transferase. Guduchi (Tinospora cordifolia) may be used in combination with γ radiation.  [371]   
A study revealed that administration of 200mg/kg body weight of Guduchi (Tinnospora cordifolia) to strain A mice before radiotherapy prevents ill effects of total body- gamma ray irradiation. The radioprotective effect of Guduchi (Tinospora cordifolia is attributed to the antioxidant activity of the plant. [372] 
Berberine is a key constituent of Guduchi (Tinospora cordifolia). In experimental studies on animals (in-vitro studies) berberine induced apoptosis in human tongue cancer (SCC-4) cells. But there was no report to show berberine inhibited SCC-4 cancer cells in vivo on a murine xenograft animal model. However treatment with 10mg/kg bodyweight of berberine and 4mg/kg bodyweight of doxorubicin resulted in reduction in tumor incidence. Therefore berberine may represent a preventive agent for tongue cancer and can safely be used in clinical practice. [373]      
When expressed abundantly the enzyme cyclooxygenase-2 (COX-2) plays a key role in genesis of cancer in colon. Therefore the compounds suppressing cyclooxygenase-2 (COX-2) expression or cyclooxygenase-2 (COX-2) activity are potential chemopreventive agents for human colon carcinoma. Researchers found that berberine effectively inhibits cyclooxygenase-2 (COX-2) transcriptional activity. Hence by inhibiting cyclooxygenase-2 (COX-2) activity Guduchi (Tinnospora cordifolia) suppresses colonic cancer. [374]  
Guduchi (Tinnospora cordifolia) has been shown to be effective in Ehrlich ascites carcinoma in mice. [375]
In a study exposure of HeLa cells to aqueous, methanol and methylene extracts of Guduchi (Tinospora cordifolia) to 0, 5, 10, 25, 50 and 100 micrograms/kg body weight resulted in significant increase in killing of HeLa cells. The effects of aqueous and methanol extracts were almost identical. However the killing effect of methylene chloride extract was 2.8 and 6.8 fold when compared either to methanol or aqueous extract at 50 and 100 micrograms/ Kg body weight respectively. Therefore Guduchi (Tinospora cordifolia) deserves merit and honor in cancer therapy. [376]
Cyclophosphamide (CP) is a commonly used anti-cancer drug. It causes toxicy by its metabolites. In a study administration of alcoholic extract of Guduchi (Tinnospora cordifolia) at 200mg/kg bodyweight for days reduced urotoxicity caused by cyclophosphamide. The results of the study were supported by histopathological examination of the urinary bladder. Furthermore the study revealed that Guduchi (Tinnospora cordifolia) can also be used to prevent uro-toxicity of cyclophosphamide. This beneficial effect of Guduchi (Tinnospora cordifolia) was attributed to antioxidant activity of the plant. [377], [378]      
Recently Guduchi (Tinospora cordifolia) was shown to affect the growth of the prostate in rats. To investigate the actions of Guduchi (Tinospora cordifolia) on the prostate, human LNCaP (Lymph Node Cancer Prostate) cells (prostate cancer cell line) were exposed to ethanolic extract of Guduchi (Tinospora cordifolia). This showed dose dependant proliferation LNCaP cells. Co-incubation with the anti-androgen flutamide (FLU) reversed the Guduchi (Tinospora cordifolia)-induced stimulation of Prostate Specific Antigen (PSA) secretion. This suggests Guduchi (Tinospora cordifolia) may contain androgenic compounds which act via androgen receptor. [379]

Culinary uses 

The fruit of the plant has a great capacity to absorb oxygen free radicals. Hence it should be included in daily dishes. 

Medicinal Actions and Uses

Traditional Uses 

From proverbial grandmothers’ medicinal chest, from folk medicine to classic text books of Ayurveda, Guduchi (T.cordifolia) is a popular medicine. 
It is used to treat PUO, malaria and periodic fever, allergic rhinitis, sinusitis, URTI, bronchial asthma, in ophthalmic disorders, as tonic to boost immunity and body resistance, GI disorders, diarrhea, jaundice, as hepatoprotectant, in ascites, anemia, RA, OA, gout, diabetes, skin allergies, leprosy, as adaptogen and rejuvenator, in gynecological problems, as aphrodisiac, as nervine tonic and in psychosomatic disorders.

Uses in folk and tribal medicine     

The tribals of Naugarh and Chakia Block of Varanasi prepare pills of the stem of Guduchi (T. cordifolia) and the roots of Bhatkatiaya (Solanum surattense) and use in the treatment of fever. 
The fishermen along the sea coast of Mumbai use T. cordifolia in the treatment of fever, jaundice, dysentery and chronic diarrhea.  
The tribals of Khedbrahma, North Gujarat use powdered stem and root of T. cordifolia with milk for the treatment of (?liver) cancer; decoction of root to cure diarrhea and dysentery and decoction of old stem for the treatment of fever.     
The people of Jammu and Kashmir, Bigwada (Rajasthan), Bhuvaneshwar (Orissa), Patiyala (Punjab) use T. cordifoliafor the treatment of fever. 
The tribals of Maharashtra use cold water infusion (faanta or sheeta) or hot water decoction (kwaatha) of the stem (3-4 gm) in the morning on empty stomach as tonic for general debility.   
Paste or juice of Amritaaa (T. Cordifolia) leaves and Sarshapa beeja choorna (seed powder of Brassica campestris) is applied locally for daaha (burning sensation).     
A mixture of equal parts of Amritaa (Tinospora cordifolia), Hareetakee (Terminalia chebula), and Ajwain (Trachyspermum ammi) powders with salt is administered orally once daily early morning by the people of Dhurala (Haryana) for the treatment of cough.    
Lambative of Guduchi (T. Cordifolia) and 5 seeds of Krishna Marich (Piper nigrum) is administered orally by women of Arjunpura (Rajasthan) to women suffering from menorrhagia (excessive vaginal bleeding)    
The inhabitants of Badala (U.P.) take the juice of the stem of T. cordifolia with honey for the treatment of shwaasa (Bronchial asthma)
Decoction of stem is administered orally by the people of Dehrabara Kolaras, Shivpuri District of M. P. for the treatment of skin- diseases. 
The Muslim tribals of Rajouri, Jammu comprising Gujjar and Backwals use the plant for the treatment of fractured bones. [380]

Usages in Ayurveda 

As adaptogen it is recommended for routine, continuous use for the wellbeing of physical and mental health.
It is used to treat PUO
It is used to treat many skin disorders
It is used to treat OA, RA, and gout
It is used to quench thirst.
It is recommended for all GI disorders (loss of appetite, acid-peptic disease, intestinal colic, diarrhea, dysentery, worm infestation)
It is specially recommended for biliary colic, jaundice, alcoholic liver disease, portal hypertension and hepatosplenomegaly
It is used to treat anemia.
It is used for diabetes
It is useful to treat disorders of central and peripheral nervous system 
It is used to treat ED (erectile dysfunction)     [381] 

Usages in Modern Medicine 

Inspite of favourable results of modern research on T. cordifolia the herb is not utilized properly in modern practice. It is used as an adjuvant to treat: 
Chronic diarrhea and dysentery
Viral hepatitis
Obstructive jaundice
Portal sepsis
NASH
Septic shock
To boost non specific immunity
Some disorders of bone marrow
Anemia
Diabetes and allied conditions

Toxicity

That Ayurvedic medicines especially herbal preparations have no untoward side effects is a common misconception. T. codifolia can show interactions with other drugs. It can be dangerous in patients with Ca prostate.

Possible Interactions:

It can potentiate the action of OHAs.
One should stop using it 2-3 weeks before surgery. 

Contraindications 

It is advisable not to use it during pregnancy and lactation 

Preparations and dosages 

Powder (whole plant): 1-2 gms twice a day with lukewarm  water or honey or with one teaspoon ghee or with  equal amount of sugar
Poder of the Stem: 3-6 gm
Tablet of Extract: 250-500 mg
Decoction: 50-100 ml
Guduchyaadi kwaatha: 10 - 20 ml
Amritaarishta: 10 -20 ml
Amritaa Ghrita: ¼ - ½ tea spoon with water usually before food once or twice a day.
Samshamanee Watee: 1 gm twice a day
Sudarshana Choorna: 3-6 gm
Guduchi Kashaya: 10-20 ml.
Guduchi Ghana: 250 mg three times a day
Guduchi Loha (Iron): Dose not mentioned
Tablets: 250 mg three times a day
Capsules: 250 mg three times a day
Giloy sattwa, Gulawel sattwa: Dose not mentioned
Guduchyaadi tailam: For external use only 
For PUO: Fresh decoction: 15 ml or Guduchi Ghana: 250 mg three times a day for 7 days
For URTI: It has been used for prophylactic and therapeutic purposes. Guduchi Ghanawatee 250 mg three times a day
For Gout: It is used in combination with guggul. This combination is known as Kaishor guggul. Dose: 500 mg B.D. for one month.  [382]
To boost immunity or strengthen immune system 1-2 capsules twice a day after meal or as directed by Ayurvedic physician [383] 

Additional Information 

Formulations, preparations and Dosages reported by Dr. N. N. Rege et al: 
Swaras (Juice from the fresh Strm): 10-20 ml/day
Kalka (Paste of the fresh Stem): 10g/day
Choorna (Powdered dry stem): 1-3 g/day
Kwaatha (Decoction or hot water extract from the ground dried Stem): 20-30 mL two or three times a day
Fant (Hot water infusion): 10-20 mL/day
Arishta (Stable processed formulation from decoction containing self generated alcohol): 10-20mL/day
Sattwa (Sedimented starch extract of the Stem): 750mg to 2 g/day; 2.5 or 5 gms (as indicated)
Ghana (Solidified aqueous extract): 500mg to 1g three to four times a day
Guduchi Ghrita (Guduchi processed in ghee): 10 to 20 g/day
Guduchi Tailam:  Guduchi processed in oil for external use.

References:

[1] S V Ayurveda: From Sutra to Science, Vaidya Mishra, “Guduchi—Learn About The Most Divine Herb in Ayurveda”,https://vaidyamishra.com/shop/media/draya-guna-vigyan-ayurvedic-pharmacopoeia/guduchi-learn-about-themost-divine-herb-in-ayurveda.html  
[2]. http://www.ayurvedacollege.com/articles/students/Guduchi 
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[5]. https://ca.wikipedia.org/wiki/Tinospora_cordifolia 
[6] http://www.ayurvedacollege.com/articles/students/Guduchi 
[7] http://www.gits4u.com/agri/agri5giloy.htm#introduction 
[10]. https://en.wikipedia.org/wiki/Tinospora_cordifolia 
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Volume 1, Issue 3; May-June 2013 
[12]. http://en.wikipedia.org/wiki/Tinospora_cordifolia 
[13]. Giloyherb.com/index.php/articles/the origin
K. M. Nadkarni, Indian Materia Medica, Popular Prakashan, 1908, pp. 356-357 
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[21]. http://www.niscair.res.in/sciencecommunication/ResearchJournals 
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[24]. http://www.niscair.res.in/sciencecommunication/ResearchJournals 
[25]. Premila M. S. Ayurvedic Herbs: A clinical Guide to the Healing Plants of Traditional Indian Medicine, Haworth Press: New York. P 69-76 
[26]. http://www.iamj.in/images/upload/14.pdf
[27]. Devprakash, K. K. Shrinivasan,T. Subburaju, Suhas Gaurav, Sachin Singh; Tinospora Cordifolia:- A Review On Its Ethnobotany, Phytochemical & Pharmacological Profile: Asian Journal of Biochemical and Pharmaceutical Research: Issue 4 (Volume 1) 2011. 
[28]. Maurya R, Manhas LR, Gupta P, Mishra PK, Singh G, Yadav PP Amritosides A, B, C and D : Clerodane furano diterpene glucosides from Tinospora cordifolia , Phytochemistry 2004; 65: 205 1-5 
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About Dr. Vaidya
Ashok D. B. Vaidya MD, PhD, FAIM
Research Director
Kasturba Health Society-Medical Research Centre
Director
Clinical Pharmacology, BSES & Global (BK) Hospital /span
Kasturba Health Society-Medical Research Centre
Adjunct Professor
Saurashtra University, Rajkot,
Drexel University, Philadelphia,
Transdisciplinary University Bengaluru,
Gujarat Vidyapeeth, Ahmedabad
Former
Regional Medical Director (South Asia)
Ciba-Geigi (Now Novartis)
Senior Scientific Officer
CSIR, Clinical Drug Trials Unit,
Seth G. S. Medical College & KEM Hospital

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