Piper longum L.

P. longum is one of the famous three acrids (trikatu), the others being P. nigrum and Zingiber officinale. It is known in Sanskrit as Pippali, Mdgadhi, Капа and Krsna (Warrier et al. 2007d).

Effect on Digestive Efficiency

To study the impact of P. longum on gut microbiota Peterson et al. (2019) applied in vitro anaerobic cultivation of human fecal microbiota, followed by 16S r.R.N.A. sequencing to study the modulatory effects of the herb. P. longum was found to possess substantial power to modulate fecal bacterial communities to include potential prebiotic and beneficial repressive effects. Glycosyl hydrolase gene representation is strongly modulated by P. longum, suggesting that polysaccharide substrates present in it provide selective benefits to gut communities. The experimental data suggest that substrates present in P. longum may encourage beneficial alterations in gut communities, thereby altering their collective metabolism to contribute to digestive efficiency. This study validates the ayurvedic use of P. longum to correct “lowering of abdominal fire”.

Antibacterial Activity

Singh and Rai (2013) evaluated the antibacterial activity of various solvent extracts of fruits of P. longum against different Gram-positive and Gram-negative bacteria using the disk diffusion method. The petroleum ether extract was resistant towards all the tested bacterial strains while the ethyl acetate extract was highly active. Among all the Gram-positive bacteria, Staphylococcus aureus was highly sensitive, with inhibition zone 24.33 mm in the presence of 500 mg/ml ethyl acetate extract, while in case of Gram-negative bacterial strains Pseudomonas aeruginosa and Vibrio cholerae were highly sensitive. Hexane extract was least inhibitory towards all the bacterial strains.

Anti-Inflammatory Activity

Guineensine is a dietary N-isobutylamide present in P. longum and shown to inhibit cellular endo- cannabinoid uptake. Considering the role of endocannabinoids in inflammation and pain reduction, Reynoso-Moreno et al. (2017) evaluated guineensine in mouse models of acute and inflammatory pain and endotoxemia. Significant dose-dependent anti-inflammatory effects like inhibition of inflammatory pain, inhibition of edema formation and acute analgesia were observed. Moreover, guineensine inhibited pro-inflammatory cytokine production in endotoxemia. Both hypothermia and analgesia were blocked by the CB, receptor inverse agonist rimonabant, but the pronounced hypolocomotion was CB1 receptor (Cannabinoid receptor type l)-independent. A screening of 45 CNS-related receptors, ion channels and transporters revealed apparent interactions of guineensine with the dopamine transporter DAT, 5HT2A and sigma receptors. The potent pharmacological effects of guineensine might relate to the reported anti-inflammatory effects of P. longum.

Anti-inflammatory activity of oil isolated from P. longum dried fruits was studied by Kumar et al. (2009) in rats, using the carrageenan-induced right hind paw edema method. The oil inhibited carrageenan-induced rat paw edema. The anti-inflammatory activity was comparable to that of ibu- profen. The fruit decoction also showed anti-inflammatory activity against carrageenan-induced rat paw edema (Sharma and Singh 1980).

Anti-Cancer Effect

Guo et al. (2019) prepared three extracts of P. longum using reflux, ultrasonic and supercritical fluid extraction techniques. Active compounds were isolated by a bioassay-guided method and antiinflammatory activity, anti-proliferation activity and cytotoxicity were evaluated. The anti-inflammatory activity and cytotoxicity of supercritical fluid extracts were stronger than those of the other two extracts. Supercritical fluid extract and piperine were found to reduce colony formation, inhibit cell migration and promote apoptosis through increasing cleaved RA.R.R (Poly (ADP-ribose) polymerase) and the ratio of Bax/Bcl-2.

Ovadje et al. (2014) assessed and validated the anticancer potential of ethanol extract of P. longum against human cancer cells (the malignant melanoma cell line G-361, human colorectal cancer cell lines HT-29 and HCT116, ovarian adenocarcinoma cell line OVCAR-3, pancreatic adenocarcinoma cell line BxPC-3 and normal-derived colon mucosa NCM460 cell line). Following treatment with the extract, cell viability was assessed using a water-soluble tetrazolium salt and apoptosis induction was observed following nuclear staining. The in vivo effect of the extract was studied using Balb/C mice and CD-I nu/nu immunocompromised mice.

Results indicated that ethanol extract of P. longum selectively induces caspase-independent apoptosis in cancer cells, without affecting non-cancerous cells. This is achieved by targeting the mitochondria, leading to the dissipation of the mitochondrial membrane potential and increase in R.O.S. production. Release of the apoptosis-inducing factor (A.I.F.) and endonuclease G from isolated mitochondria confirms the mitochondria as a potential target of P. longum. In vivo studies indicate that oral administration is able to halt the growth of colon cancer tumors in immunocompromised mice, without associated toxicity. These results demonstrate that P. longum is a potentially safe and non-toxic alternative in cancer therapy (Ovadje et al. 2014).

Piperine (1-Piperoylpiperidine), the main component of P. longum, is an alkaloid with a long history of medicinal use. It exhibits a variety of biochemical and pharmaceutical activities, including che- mopreventive activities, without significant cytotoxic effects on normal cells, at least at doses of <250 pg/ml. The term chemoprevention refers to natural agents with the ability to interfere with tumorigen- esis and metastasis, or at least, attenuate the cancer-related symptoms (Zadorozhna et al. 2019).

Reports on the antibacterial, anti-inflammatory and anticancer activities justify the use of P. longum in the treatment of pllha (splenomegaly) and yakrt (hepatomegaly). Agnimandya or “lowering of abdominal fire” is a term used to describe a reduction in digestive efficiency. Dietary piperine, by favorably stimulating digestive enzymes of pancreas, enhances the digestive capacity and significantly reduces gastrointestinal food transit time (Srinivasan 2007).

Plumbago zeylanica L.

Agni, Vahni, Hutasa, Dahana and Sikhi are the various Sanskrit names of Citraka, a component of numerous ayurvedic formulations (Figure 5.6). In Kerala, red-flowered P. indica is used as Citraka, whereas in North India, white-flowered P. zeylanica is preferred. The blue-colored Plumbago (P. auriculata Lam. syn. P. capensis Thunb.) is native to South Africa and is not used in Kerala as a medicinal plant (Warrier et al. 2007d).

Hemorrhoids are vascular structures in the anal canal that get swollen or inflamed. They often result in pain and swelling in the area of the anus. External hemorrhoids often result in pain and swelling in the area of the anus (Schubert et al. 2009). P. zeylanica possesses many properties that are helpful in the treatment of hemorrhoids.

Checker et al. (2009) studied the anti-inflammatory effects of plumbagin (5-hydroxy-2-methyl-l, 4-naphthoquinone) isolated from P. zeylanica. Plumbagin inhibited T-cell proliferation in response to polyclonal mitogen concanavalin A (Con A) by blocking cell cycle progression. It also suppressed expression of early and late activation markers CD69 and CD25 respectively, in activated T-cells.

At these immunosuppressive doses, plumbagin did not reduce the viability of lymphocytes. The inhibition of T-cell proliferation by plumbagin was accompanied by a decrease in the levels of Con A- induced IL-2, IL-4, IL-6 and IFN-gamma cytokines. Similar immunosuppressive effects of plumbagin on cytokine levels were observed in vivo. To characterize the mechanism of inhibitory action of plumbagin, the mitogen-induced IicBa degradation and nuclear translocation of NF-kB was studied in lymphocytes. Plumbagin completely inhibited Con А-induced 1кВа degradation and NF-кВ activation.

Shaikh et al. (2016) evaluated the in vivo and in vitro anti-inflammatory potential of P. zeylanica. The extracts prepared using water, ethanol and hexane were evaluated in vitro for COX-1 and 2 inhibition and antioxidant activities. Results showed that P. zeylanica inhibited COX-2 activity more as compared to COX-1. The ethanol extract of P. zeylanica demonstrated effective DPPFI, OH and superoxide radical scavenging activity as well. The results obtained justify the use of P. zeylanica as an anti-inflammatory single herb remedy in the ayurvedic treatment of hemorrhoids.

Increased microvascular density has been reported in hemorrhoidal tissue, suggesting that neovascularization might be another important phenomenon of hemorrhoidal disease (Lohsiriwat 2012). Chung et al. (2004) reported that endoglin (CD105), which is one of the binding sites of TGF-fl and is a proliferative marker for neovascularization, was expressed in more than half of hemorrhoidal tissue specimens compared to none taken from the normal anorectal mucosa. Moreover, these investigators found that microvascular density increased in hemorrhoidal tissue especially when thrombosis and stromal vascular endothelial growth factors (V.E.G.F.) were present. Han et al. (2005) also demonstrated that there was a higher expression of angiogenesis-related protein such as V.E.G.F. in hemorrhoids.

While studying the growth-inhibiting property of plumbagin derived from P. zeylanica on human prostate cancer PC-3M-luciferase cells, Hafeez et al. (2013) observed that plumbagin-caused inhibition of the growth and metastasis of PC-3M cells, accompanying inhibition of the expression of angiogenesis markers CD31 and VEGF.

The roots of P. zeylanica are recommended in Ayurveda as appetizer and digestive. It has been established that the feeding of P. zeylanica root stimulates the proliferation of coliform bacteria in mice. Supporting data on the above inference was adduced by using a special dilution method of obtaining bacterial counts. The data were statistically analyzed and the increase in coliform bacteria due to P. zeylanica feeding was shown to be significant at the 5% level. This coliform proliferation action of P. zeylanica is similar to that of Mexaform, a drug used to counteract the action of antibiotics. The authors therefore suggested that the claims that P. zeylanica is a digestive-stimulant and an appetizer is most probably due to its action as an intestinal flora normalizer (Iyengar and Pendse 1966).

P. zeylanica was evaluated for its wound-healing activity in rats. Wound-healing activity was studied using excision and incision wound models in rats following topical application of 10% w/v extract in saline. The herb was found to possess significant wound-healing activity (Reddy et al. 2002).

Medicines for hemorrhoids need to have the ability to control bacterial infections. Kaewbumrung and Panichayupakaranant (2014) reported that extraction and a one-step purification of the crude extract of P. indica using silica-gel vacuum chromatography provided a plumbagin derivative-rich P. indica root extract. Antibacterial activities of the standardized extract and three naphthoquinones, plumbagin, elliptinone and 3, З'-biplumbagin, against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis were evaluated using the microdilution assay. The bactericidal activities of the extract against these bacteria were much stronger than those of elliptinone and 3, З'-biplumbagin and almost equal to those of plumbagin.

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