Pippali (Piper longum) Part 2



Pippali (Piper longum) Part 2

Modern View


Piperine
Molecular formula: C17H19NO3
Structural formula:



Piperine was discovered and isolated in 1819 by Hans Christian Orsted from fruits of black and white pepper. Piperine is also found in Pippali (Piper longum). [65] 

Piperine was first synthesized in 1882. It is an alkaloid. The solubility of piperine in water is 40mg/L. Piperine enhances the bioavailability of vitamins, minerals and curcumin. The mechanism of this activity is still under study. Piperine is known to inhibit the enzymes P-glycoprotein and cytochrome P450 3A4 (abbreviated CYP3A4) in humans. Animal studies also show that piperine inhibits cytochrome P450 (CYP 450) enzymes that metabolize many drugs. 

Piperine raises levels of dopamine and serotonin. It induces natural sleep and serenity. It enhances memory and recall. It relieves stress. It improves metabolism and helps weight loss. By correcting malfunctioning of immune system, it improves immunity.

One may take piperine to increase effect of nutrients such as vitamins, curcumin, beta-carotene and selenium. Piperine can also be useful in respiratory distress, indigestion, joint discomfort and low mood.
Piperine can interact with many medications. It may have anti-platelet aggregation effect. It may cause GI bleeding when taken at higher than suggested doses.  [66], [67]

Piperine shows anti-inflammatory, antioxidant, immunomodulatory, antibacterial, antiviral, anthelmintic, antiparasitic, antihistaminic, antiasthmatic (brocncodilator), anti-platelet aggregation, antihypertensive, hepatoprotective and antitumor properties.  [68]

A study in mice for Parkinson’s disease showed that piperine exerted protective effect on dopaminergic neurons via anti-inflammatory, antioxidant and anti-apoptotic properties. By these mechanisms piperine could prevent and protect the animals from Parkinson’s disease. This suggests that piperine may be used to treat Parkinson,s disease. [69]

By inhibiting tyrosine kinase, piperine mitigates progression of hepatocellular carcinoma (HCC). Histological study supported this observation. This effect was attributed to antioxidant and free radical scavenging property of piperine. A study showed that piperine down regulated expression of catalase in Hep G2 cells. Piperine ameliorated diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) by inducing apoptosis in an in vitro model. Piperine targeted insulin-like-growth-factor-1 (IGFR 1), fibroblast-growth-factor-receptor-1 (FGFR 1) and hepatocyte-growth-factor-receptor (HGFR) or c-Met downstream pathways (also called tyrosine-protein kinase Met) in Hep G2 cells. 

Piperine is a potent inhibitor angiogenesis. This property can be useful for the treatment of cancers. [70]

Piperine inhibits the growth of human breast cancer cells without affecting the growth of normal mammary epithelial cells.

Piperine inhibits cell cycle progression and induces caspase-dependent apoptosis via the mitochondrial pathway.

Piperine inhibits matrix metalloproteinase-2 and 9 mRNA expression, as well as breast cancer cell migration.  [71]

Piperine inhibits the growth of breast cancer xenografts in immune-deficient mice. [72]

Piperine inhibits the proliferation of prostate cancer. However the apoptosis-inducing activity of piperine in these cells is low. Piperine induces cell-cycle arrest by down regulating cyclin D1 and cyclin A. Piperine treatment induces autophagy in prostate cancer cells. [73],

Toxicity of Piperne

Piperine is acutely toxic to mice, rats and hamsters. The LD50 values for a single intravenous (i. v.), intraperitoneal (i. p.), subcutaneous (s. c.), intragastric (i. g.) and intramuscular (i. m.) administration to adult mice were 15.13, 43, 200, 330 and 400mg/kg bodyweight respectively. Most animals given a lethal dose died of respiratory paralysis within 3-17 minutes. Histopathologic changes included severe haemorrhagic necrosis and oedema in gastrointestinal tract, urinary bladder and adrenal glands. [74]

Pipernonaline
Molecular formula: C21H27NO3
Structural formula: 


[75]


Pipernonaline belongs to the class of organic compounds known as benzodioxoles. Pipernonaline is a solid insoluble in water. Within the cell it is located in the membrane. Pipernonaline is found in many herbs and in spices. This makes pipernonaline a potential biomarker for the consumption of many food products. [76]

Phytochemicals derived from the fruit of Pippali (Piper longum) show fungicidal activity against six pathogenic fungi: Pyricularia oryzae, Rhizoctonia solani, Botritis cineria, Phytophthora infestans, Puccinia recondita and Erysiphe graminis. Of three phytochemicals (Piperidine, Pipernonaline and Piperettine) piprenonaline exerted the strongest fungicidal action.  [77]

The methanol extract of the fruit of Pippali (Piper longum) containing pipernonaline, was found to be larvicidal against larvae of Culex pipiens    at a concentration of 10 μg /ml after 24 hours of exposure. This activity was much higher than malathion, methyl chlorpyrifos and methyl pirimiphos the three commonly used organophosphorus insecticides. [78]

A crude methanol extract of the fruit of Pippali (Piper longum) containing pipernonaline showed a strong larvicidal activity of 100% mortality of Aedes aegypti mosquito larvae. No such activity was observed with phytochemicals piperine, piperlongumine and piperettine [79], [80] 

The ethanol-extract of the fruit of Pippali (Piper longum) shows appreciable antihyperlipidemic activity in vivo. This activity was attributed to piperine, pipernonalin and piperlonguminine (C16H19NO3). The antihyperlipidemic activity was comparable to simvastatin. [81]
Through production of reactive oxygen species (ROS) pipernonaline exhibits apoptotic properties. This causes disruption of mitochondrial function and induces apoptosis in prostate cancer cells. This was the first report of use of pipernonaline on human prostate cancer. [82]

Piperettine
Molecular formula: C19H21NO3
Structural formula:





Piperettine belongs to the class of organic compounds known as benzodioxoles. It is a yellow solid. It was first identified and isolated from the extract of Mareechee (Piper nigrum) and later synthesized in the laboratory. It is insoluble in water. Within the cell piperettine is located in the cell membrane. Outside of human the body piperettine can be found in many herbs and spices. This makes piperretine a potential biomarker for the consumption of these food products. Its pharmacological actions are not studied yet. [84], [85]

Asarinine
Molecular formula: C20H18O6
Structural formula:



Asarinine belongs to phenylpropene family. Asarinine is a physiologically active compound exerting actions on some systems of the body.
Asarinin/Asarinine is one of the slimming dietary supplements. [87]

Pellitorine
Molecular formula: C14H25NO
Structural formula:


Synonym: (2E, 4E)-N-(2-Methylpropyl)-2, 4-decadienamide [88]

Pellitorine is a natural product (alkaloid) obtained from the roots of Pellitor (Anacyclus pyrethrum), Mareechee (Piper nigrum) and some other plants.
Pellitorine was isolated from the roots of Mareechee (Piper nigrum). It is a very stable toxic, crystalline solid. [89], [90]
Pellitorine modulates the function of sensory neurons and induces tingling sensation (paresthesia). Pellitorine is inhibitor of Acyl-CoA cholesterol acyl- transferase and α-glucosidase. Pellitorine exhibits anti-inflammatory, antibacterial, antimycobacterial and larvicidal properties. Pellitorine is used in research on inflammations, infections, diabetes and cancers. [91], [92]

Piperundecalidine
Molecular formula: C23H29NO3
Structural formula:


[93]



Piperundecalinide is an alkaloid. It belongs to the family of Phenylpropenes. It is found in fruits of Pippali (Piper longum) and many herbs.  [94]

Piperundecalinide belongs to the class of organic compounds known as benzodioxoles. Piperundecalinide exists as a solid that is insoluble in water. Within the cell piperundecalinide is located in the cell membrane. Outside the body piperundecalinide can be found in herbs and spices. Piperundecalinide exhibits anti-inflammatory activity and inhibits oxidative stress. [95]


Piperlongumine (PL)
Molecular formula: C17H19NO5
Structural formula:











Piperlongumine (PL) is a constituent of the fruit of the Pippali (Piper longum). Piperlongumine shows anti-inflammatory, antioxidant and antitumor properties. [96]

Recently piperlongumine and its derivatives were synthesized. They all were found to show anti-inflammatory activity. However of these derivatives piperlongumine was the most potent anti-inflammatory agent. [97]

Fibroblast-like synoviocytes (FLS) play a key role in the development of rheumatoid arthritis (RA). Myeloid derived suppressor cells (MDSCs) can suppress T cell responses and play an important role in the regulation of autoimmune arthritis. A study showed that piperlongumine reduced the arthritis score and histopathologic lesions in collagen-induced arthritis (CIA) in mice. Piperlongumine (PL) also reduced the levels of serum anti-collagen II antibodies (anti C II), tumor necrosis factor-α (TNF-α), interleukin (IL)-1 β, interleukin (IL)-23 and interleukin (IL)-17 in collagen-induced arthritis in mice. Additionally piperlongumine (PL) reduced secretion of IL-1 β, interleukin (IL)-23 and interleukin (IL)-17 by TNF-α-stimulated human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Piperlongumine significantly inhibited the migration and invasion of TNF-α-stimulated human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). These results suggest that piperlongumine may be a candidate for the treatment of rheumatoid arthritis (RA).  [98]

Piperlongumine suppresses the ability of proliferation, invasion and cell migration (formation of metastasis) of oral cancer cells. It also increases the chemosensitivity and radiosensitivity of oral cancers. Thus piperlongumine can be an effective therapeutic agent for oral cancer. [99]

APR-246 is a novel anticancer compound under trial for the treatment of refractory hematological malignancies and prostate cancers. It is also tried for the treatment of head and neck squamous cell carcinoma (HNSCC). Piperlongumine is found to synergize APR-246. Administration of piperlongumine along with APR-246 significantly suppresses glutathione S-transferase activity resulting in the accumulation of reactive oxygen species (ROS), depletion of glutathione (GSH) and elevation of oxidized glutathione (GSSG) in cancer cells. This results in DNA damage of cancer cells and cancer cell apoptosis. [100]

A study showed that piperlongumine inhibited the proliferation of all B-cell acute lymphoblastic leukemia (B-ALL) but not normal B-cells. The effect was dose and time dependent. Regardless of glucocorticoid resistance, piperlongumine induced apoptosis in B-cell acute lymphoblastic leukemia (B-ALL) via elevation of reactive oxygen species (ROS). Piperlongumine did not sensitize most of B-cell acute lymphoblastic leukemia (B-ALL) to dexamethasone. [101]

Piperlongumine inhibits Burkitt lymphoma but leaves normal cells undamaged. [102]

Piperlongumine induces the DNA damage, apoptosis of breast cancer cells and inhibits the proliferation of breast cancer cells. Piperlongumine also arrests the tumor angiogenesis and formation of metastasis of breast cancer.  [103]

Piperlongumine was known to sensitize breast cancers to radiation. To validate this concept the researchers cultured breast cancer MDA-MB-231 cells. The result of the study showed that piperlongumine at a non-cytotoxic concentration enhanced the radio-sensitivity of MDA-MB-231 cells.  [104]    

Piperlongumine was found to be effective to arrest triple negative breast cancer. This activity was attributed to the activation of mitochondrial apoptotic pathway. The effect was dependent on the concentration of piperlongumine and duration of the treatment. [105]

By raising intracellular levels of reactive oxygen species (ROS) piperlongumine kills high-grade glioma (HGG) without damaging normal brain cells. Therefore piperlongumine can be considered a novel therapeutic option for the treatment of high-grade glioma (HGG).  [106]

A study showed that piperlongumine selectively killed glioblastoma multiforme cells via accumulating reactive oxygen species in the cancer cells, leaving the normal cells unharmed. [107]

In an in vivo setting, piperlongumine significantly reduced atherosclerotic plaque formation as well as proliferation and activation of nuclear kappa B (NF-κB) factor. [108]

At the concentration of 100μg/ml piperlongumine caused 30% inhibition of platelet aggregation. At the concentration of 200μg/ml piperlongumine inhibited the platelet aggregation induced by arachidonic acid (100%), collagen (59%), adenosine diphospate (ADP 52%) but not induced by thrombin. Acetyl salicylic acid (aspirin) a well-known cyclooxygenase inhibitor greatly increased the effect of piperlongumine on arachidonic acid-induced platelet aggregation.  [109]   

In yet another study on rabbits, piperlongumine, depending on concentration, significantly inhibited platelet aggregation induced by thromboxane (A2) receptor agonist U46619 but only slightly inhibited the platelet aggregation induced by thrombin. [110]

Piperlongumine suppressed the growth of lung cancer cells. Most of 2-halogenated piperlongumine showed more potent antitumor activity than the natural compound as it suppressed the tumor growth by 48.58 percent at a dose of 2mg/kg body weight. This activity was attributed to the ability of these compounds to elevate reactive oxygen species (ROS) in tumor cells. [111]

Researchers showed that piperlongumine inhibited the growth of colon cancer cells in time and concentration dependent manner. At concentration below 10 μM (micrometer) piperlongumine was not toxic to normal colon-mucosa cells. Even after exposure up to 24 hours piperlongumine was not toxic to normal cells of the colon-mucosa. [112]

By activating AMPK phosphorylation piperlongumine shows cytotoxic activity against cultured HepG2 cells. [113]

Pancreatic cancer is one of the most deadly cancers with 95% mortality. The poor response to currently available therapies has drawn attention to alternative therapeutic strategies. The use of reactive oxygen species (ROS)-inducing agents has emerged as an innovative and effective strategy for the treatment of various cancers. By elevating reactive oxygen species (ROS) and causing DNA damage, piperlongumine induces apoptosis in pancreatic cancer cells.  [114]

In an experimental study, lupus-prone MRL-Fas (Ipr) female mice were treated by intraperitoneal injection of piperlongumine at a dose of 2.4mg/kg bodyweight for 10 days. The treatment significantly attenuated proteinuria and glomerulonephritis. The improvement was accompanied by decreased serum levels of nephritogenic anti-dsDNA antibodies, interleukin (IL)-6, interleukin (IL)-17, interleukin (IL)-23 and TNF- α. This study sheds new light on the immune-modulatory role of piperolongumine.  [115]

In prostate cancer cell line elevated NF- κB activity had been demonstrated. This was found in androgen-independent prostate cancers with metastasis. Piperlongumine inhibited NF- κB activity and aggressive growth of prostate cancer cells. Piperlongumine also inhibited the formation of metastasis of prostate cancers. [116]

Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis. Recent investigations show that piperlongumine induces rapid depletion of the androgen receptor in prostate cancer cells. This study suggests that piperlongumine may offer opportunities for both prevention and treatment of prostate cancer. [117]  

A study showed that piperlongumine selectively inhibited the growth of human ovarian cancer cells. Piperlongumine induced apoptosis in ovarian cancer cells. In vertebrates the DNA replication occurs during synthesis (S) phase (G2 Phase or Gap 2 phase) resulting in cell growth. Piperlongumine arrested the cell growth of ovarian cancer cells in G2 phase that resulted in cell death. Combination of piperlongumine with cisplatin or paclitaxel had synergistic antigrowth effect on ovarian cancer cells. [118]

Piperlongumine is selectively toxic to cancer cells in vitro and in vivo. By inducing oxidative stress in cancer cells, causing DNA damage and apoptosis, piperlongumine kills cancer cells. [119], [120]

Piperlongumine blocks the nuclear factor κB (NF- κB) pathway in inflammation activated by tumor necrosis factor-α (TNF-α) and various other cancer promoters. Additionally piperlongumine also shows activity against COX-2 and interleukin-6. Thus by potent anti-inflammatory activity piperlongumine exhibits anticancer property. [121]

Retrofractamide-A
Molecular formula: C20H25NO3
Structural formula:




Retrofractamide A belongs to the class of organic compounds known as benzodioxoles. Retrofractamide A is a neutral solid that is insoluble in water. Retrofractamide A is soluble in chloroform, benzene, ether, methanol and ethanol. Within the cell Retrofractamide A is present in the cell membrane. Outside of the human body retrofractamide A can be found in herbs and spices such as black pepper. [122]

Pergumidiene
Molecular formula: C27H39NO3
Structural formula:

 [123]


Pergumidiene was first isolated from Marichi (Piper nigrum). Later it was shown to be present in many piper species such as Piper longum, Piper cubeba. Pergumidiene showed antibacterial activity against Staphylococcus aureus, Streptococcus mutans and antifungal activity against Candida albicans and Saccharomyces cerevisiae. [124]

Brachystamide-B
Molecular formula: C26H37NO3
Structural formula:





Pharmacological properties of Brachystamide B are similar to other phytochemicals of Pippali (Piper longum) [125]

Longamide 
Molecular formula: C7H6Br2N2O2
Structural formula:





Longamide belongs to the class of organic compounds known as carboxidimic acids. Longamide exists as a solid insoluble in water. Within the cells longamide is located in the cell membrane. Outside the human body longamide can be found in many herbs and spices such as Pippali (Piper longum), Marichi (Piper nigram).   [126]

Longamide shows cytotoxic activity. Longamide is used to treat adenocarcinoma of the lung and human prostate cancer. [127]

Dehydropipernonaline
Molecular formula: C21H25NO3
Structural formula:

 [128]


Dehydropipernonaline, an amide was isolated from Pippali (Piper longum) Dehydropipernonaline has coronary vasodilating activity. [129]

Piperidine
Molecular formula: (CH2)5NH
Structural formula:





Piperidine is a colourless, water miscible liquid. Its odor is described as objectionable or that of typical amines or animal like. The name comes from Piper which is the Latin word for pepper

Piperidine was first obtained in 1850 by the Scottish chemist Thomas Anderson and later in 1852 by the French chemist Auguste Cahours who named it ‘piperidine’. Both chemists obtained piperidine by reacting piperine with nitric acid.    

Piperidine and its derivatives are used in the synthesis for new drugs and chemicals:

Icaridin (Insect repellent)

Selective serotonin reuptake inhibitors (SSRIs)

Neurostimulents and nootropics:

Methylphenidate, Ethylphenidate, Pipradrol, Desoxypipradrol

Opiods:

Dipipanone, Fentanyl and its analogs, Loperamide, Pethedine, Prodine

Antipsychotic medications:

Droperidol, Haloperidol, Melperone, Mesoridazine, Risperidone, Thioridazine


Anticholinergic chemicals and weapons:

Ditran, N-Methyl-3-piperidyl benzilate

Selective estrogen receptor modulators (SERM)

Raloxiphen

Vasodilators:

Minoxidil

Piperidine is also used in the manufacture of flavours and fragrance agents.
Piperidine is also used in chemical degradation reactions such as the sequencing of DNA in the cleavage of particular modified nucleotides.

Piperidine is listed as a precursor of Narcotic Drugs and Psychotropic Substances due to its use in the manufacture of ‘Angel Dust’, ‘Sherms’, ‘Wet’ etc. [PCP-(1-(1-phenylcyclohexyl)piperidine] [130]

Tetrahydropiperine (THP).

Molecular formula: C17H23NO3

Structural formula:






Tetrahydropiperine is an off-white solid with low melting point and characteristic odor. Tetrahydropiperine is insoluble in water but soluble in chloroform. Tetrahydropiperine is a natural topical permeation enhancer. Is therefore used in cosmetic preparations for better penetration and to enhance drug absorption.

Tetrahydropiperine can be used to treat febrile convulsions, epilepsy and to relieve pain. 
In agriculture Tetrahydropiperine is used to control insects. [132]

Sarmentine
Molecular formula: C14H23NO
Structural formula:



Sarmentine is a natural amide isolated from the fruit of Piper species. It is a potent herbicide. Hence it is used more in agriculture. Sarmentine has some structural similarity to crotonoyl-Co A, the substrate of enoyl-ACP reductase, a key enzyme in the early steps of fatty acid stnthesis. This activity has still remained unattended by researchers for its use in clinical medicine. [134]

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Comments

Unknown said…
Pellitorine isolated from the herb of Astragalus membranaceus Bge. var. mongholicus. It may be an effective skin-lightening agent. Calycosin

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