Article

Piper betel leaf extract: Anticancer benefits and bio-guided fractionation to identify active principles for prostate cancer management

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Abstract

Plant extracts, a concoction of bioactive non-nutrient phytochemicals, have long served as the most significant source of new leads for anticancer drug development. Explored for their unique medicinal properties, the leaves of Piper betel, an evergreen perennial vine, are a reservoir of phenolics with antimutagenic, antitumor, and antioxidant activities. Here we show that oral feeding of betel leaf extract (BLE) significantly inhibited the growth of human prostate xenografts implanted in nude mice compared to vehicle-fed controls. To gain insights into the 'active principles', we performed a bioactivity-guided fractionation of methanolic BLE employing solvents of different polarity strengths using classical column chromatography. This approach yielded 15 fractions, which were then pooled to 10 using similar retention factors on thin-layer chromatographs. Bioactivity assays demonstrated that one fraction in particular, F2, displayed a 3-fold better in vitro efficacy to inhibit proliferation of prostate cancer cells than the parent BLE. The presence of phenols, hydroxychavicol (HC) and chavibetol (CHV), was confirmed in F2 by NMR, HPLC, and mass spectroscopy. Further, the HC containing F2 sub-fraction was found to be ~8-fold more potent than the F2 sub-fraction that contained CHV, in human prostate cancer PC-3 cells as evaluated by the MTT assay. Removing CHV from F2 remarkably decreased the IC50 of this fraction, indicating that HC is perhaps the major bioactive constituent, which is present to an extent of 26.59% in BLE. These data provide evidence that HC is a potential candidate for prostate cancer management and warrants further preclinical evaluation.

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... Other betel phytochemicals include allylpyrocatechol (APC; 2hydroxychavicol), 4-hydroxycatechol, b-caryophyllene, methyl eugenol, carotenes, starch, diastases, and an essential oil containing hydroxychavicol (18,19). Hydroxychavicol, a phenolic compound quantitatively present at approximately 26% in betel leaves, has been shown to exert antiproliferative activity in prostate cancer (20). Hydroxychavicol has also been shown to impede cell-cycle progression of prostate cancer and oral KB carcinoma cells (20)(21)(22). ...
... Hydroxychavicol, a phenolic compound quantitatively present at approximately 26% in betel leaves, has been shown to exert antiproliferative activity in prostate cancer (20). Hydroxychavicol has also been shown to impede cell-cycle progression of prostate cancer and oral KB carcinoma cells (20)(21)(22). Several reports indicate hydroxychavicol as an antimutagenic agent (12,23) as well as an effective inhibitor of cyclooxygenase (COX), platelet calcium signaling, and thromboxane B2 production (21). Other studies suggest that hydroxychavicol also known as APC possesses antiulcerogenic activity (24) and has been shown to alleviate indomethacin-induced stomach ulceration leading to gastric cancer (25). ...
... Chavibetol (CHV), along with hydroxychavicol, acts as a radioprotectant (25), and exhibits substantial immunomodulatory and free radical scavenging activities (25). We have shown that CHV synergizes with hydroxychavicol to exert antiproliferative activity against human prostate cancer PC-3 cells (20). Betel leaf contains large amounts of safrole, which is rapidly degraded in the human body into dihydroxychavicol and eugenol, the antimutagenic agents, which are then excreted via the urine (26,27). ...
Article
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Plants contain a much greater diversity of bioactive compounds than any man-made chemical library. Heart-shaped Piper betel leaves are magnificent reservoirs of phenolic compounds with antiproliferative, antimutagenic, antibacterial and antioxidant properties. Widely consumed in South Asian countries, the glossy leaf contains a multitude of biophenolics such as hydroxychavicol, eugenol, chavibetol, and piperols. Convincing data underscore the remarkable chemotherapeutic and chemopreventive potential of betel leaves against a variety of cancer types. The leaf constituents modulate an extensive array of signaling molecules such as transcription factors as well as reactive oxygen species (ROS) to control multiple nodes of various cellular proliferation and death pathways. Herein, we provide an overall perspective on the cancer-fighting benefits of the phenolic phytochemicals in betel leaves and a comprehensive overview of the mechanisms responsive to dose-driven ROS-mediated signaling cascades conscripted by bioactive phenolics to confer chemotherapeutic and chemopreventive advantages. Intriguingly, these ROS-triggered responses are contextual and may either elicit a protective xenohormetic antioxidant response to pre-malignant cells to constitute a chemopreventive effect or generate a curative chemotherapeutic response by pro-oxidatively augmenting the constitutively elevated ROS levels in cancer cells to tip the balance in favor of selective apoptosis induction in cancer cells while sparing normal ones. In conclusion, this review provides an update on how distinct ROS levels exist in normal versus cancer cells and how these levels can be strategically modulated and exploited for therapeutic gains. We emphasize the yet untapped potential of the evergreen vine, betel leaf, for chemopreventive and chemotherapeutic management of cancer.
... We have recently reported the bioactive constituents of Piper betel leaf extract (BLE), and its significant antiproliferative activity in in vitro and in vivo prostate cancer models (Paranjpe et al., 2013). Our study concluded that the phenolic compound, hydroxychavicol (HC) is the most abundant phytochemical in betel leaves that majorly contributed to the antiproliferative efficacy of BLE. ...
... The fractions 4-22 were found to contain pure HC and thus were pooled and concentrated under vacuum. HC was further characterized by spectral analysis for both quantitation and >99% purity via HPLC using similar method as described earlier (Paranjpe et al., 2013). ...
... However, despite this quenching upon HC treatment, there was a slight increase in ROS levels ( Figure 2C) suggesting a mitochondrial and NOX independent induction of oxidative stress. This could most likely be attributed to the presence of catechol group in HC, known for imparting prooxidant property (Mira et al., 2002;Paranjpe et al., 2013). We then asked if the cell death observed upon treatment with HC was dependent on its ROS-generation activity. ...
... A wide range of double bond specific groups in C=O and C=C was observed in the region from 2,000 to 1,500. Lastly, the region from 1700-600 show finger print that is reminiscent of phenyl propanoid eugenol[27,28]. ...
... More importantly, our results highlight the potential of using betel leaf extract as a potent anti-fungal agent for farming and perhaps also food storage against different types of molds. Food spoilage is a major agricultural problem accounting for heavy losses; therefore it is necessary to make the process commercially viable and efficacious against various pathogens and food spoilage organisms[31,32].Ali et al., 2010); antibacterial (Sharma et al 2009) hydrodistillation anti-bacterial (Basak and Guha, 2015) Concoction-boiling extraction anti-cancer (Gundala et al., 2014) Eugenol ethanol or watersoxhlet extraction Streptococcus mutans (Deshpande and Kadam, 2013) solvent extraction: methanol, ethyl acetate and petroleum ether Streptococcus mutans (Deshpande and Kadam, 2015) hydro-distillation anti-bacterial (Sugumaran et al., 2011) Hydroxychavicol and Eugenol methanolic extract anti-cancer (Paranjpe et al., 2013) liquid-liquid and supercritical fluid extraction Comparison of extraction methods(Singtongratana et al., 2013) Summary of bio-active extraction procedures from Piper betle ...
... A wide range of double bond specific groups in C=O and C=C was observed in the region from 2,000 to 1,500. Lastly, the region from 1700-600 show finger print that is reminiscent of phenyl propanoid eugenol [27,28]. ...
... Amides (25, 26, 30, and 31) have antitumour properties (Tang et al., 2010). P. betle contains a bioactive compounds with strong effect on prostate cancer management (Paranjpe et al., 2013;Yadav et al., 2014). Hydroxychavicol and its analogues synthesized from P. betle have been shown to have antiproliferative activity against prostate cancer PC-3 cells and cervical cancer HeLa cells (Yadav et al., 2014). ...
... This justifies the potentials of hydroxychavicol and its analogues as anti-cancer agents. Extracts of P. betle had strong activity in mice implanted with human prostate xenografts when fed orally (Paranjpe et al., 2013). Piperdine, a bioactive compound isolated from P. nigrum inhibited HEp2 cells (human epithelial cells of larynx) at a concentration of 5 μg/ml (Reshmi et al., 2010). ...
Article
This article reviews new discoveries related to the phytochemistry and biological activities of bioactive compounds from Piper species. It outlines the anticancer, anti-parasitic, and antimicrobial activities of Piper species in relation to drug discovery. The use of bioactive compounds from medicinal plants as therapeutic agents has been an important area in biomedical and natural product research. Piper species are effective medicinal plants used in folk medicine. They have traditionally been used to treat stomach ache, rheumatoid arthritis, diarrhoea and other general infections, and their efficacy has been attributed to their bioactive compounds. Bioactive compounds and extracts from Piper species have been examined and found to be of clinical importance for both malignant and non-malignant diseases. They have displayed pronounced efficacy as anticancer, antitumour and antimicrobial agents in various pharmacological studies. They have been reported to possess anti-inflammatory, antioxidant, antibacterial, antifungal, and antimalarial activities. The alkaloids piperine, piperlongumine, guineensine, chabamide and pellitorine, which have been isolated from most Piper species, are able to inhibit the growth of cancer cell lines inducing apoptosis and acting as nuclear export inhibitors. These bioactive compounds can improve the effectiveness of chemotherapeutic drugs with minimal systemic toxicity to normal cells in cancer therapy. Pinoresinol, guineensine and other bioactive compounds from this species exhibited strong antimicrobial efficacy against various microorganisms including pathogenic Vibrio strains, which are often involved in host cell invasion during Vibrio cholera infection. The anticancer, antimicrobial and antimalarial properties of Piper species are compiled to support further exploration of their bioactive compounds for drug discovery. Biomedical and pharmacological discoveries concerning their anticancer and antimicrobial properties are highlighted here for further clinical applications, which could pave the way for the proper therapeutic use of bioactive compounds and extracts from this plant species.
... Regarding the safety, recently our group have demonstrated that the methanolic leaf extract of GT is safe and non-toxic, when analysed using both in vitro and in vivo experimental models 8 . Subsequently we also identified that the active principle constituent vitexin exhibits cholinesterase inhibitory, anti-amyloidogenic and neuroprotective effects against Aβ [25][26][27][28][29][30][31][32][33][34][35] induced neurotoxicity in N2A cells 9 . However the leaf of the plant has not been scientifically explored against human cancer, so far. ...
... Most importantly, both P1 & P2 exhibited increased cytotoxicity in A549 cells, when compared with BGT. These findings are supported by earlier reports wherein cytotoxicity effect of purified piper petal leaf extract was higher than their crude extract 35 . Hence the increased cytotoxicity of P1 and P2 may be due to the enrichment of active principles in both P1 & P2. ...
Article
Full-text available
Lung cancer is the leading cause of cancer related deaths both in developed and developing countries. Since majority of the existing therapeutic methods harms both normal and malignant cells, a viable alternative is to switch into safe and beneficial traditional medicinal plants. Hence the present study was framed to identify selective anti-lung cancer agents from the medicinal plant Grewia tiliaefolia (GT). Cell viability experiments showed that benzene extract of GT (BGT) leaf effectively inhibited the growth of A549 cells, while being non-toxic to normal human lung L132 and PBMC cells. Ames and comet assays demonstrated that BGT is of non-mutagenic and non-genotoxic nature in untransformed cells. The hematological and histopathological profiles of the in vivo acute and sub-acute toxicity studies demonstrated that BGT is safe and tolerable. Importantly, western blot analysis and Annexin V-FITC staining confirmed that BGT promotes mitochondrial dependent apoptotic cell death in A549 cells by arresting cell cycle at G2/M phase. Bio-assay guided fractionation revealed the presence of phytosteols (β-sitosterol and daucosterol) which significantly inhibited the growth of A549 cells both alone and in combination. This study warrants that these phytosterols in alone or in combination can be considered as safe and potential drug candidates for lung cancer treatment.
... Piper betle L (Piperaceae) are generally named as betel leaf. It is one of many medicinal plants that have become popular in cancer studies [5]. Studies have shown that leaf extract of P. betle possess phenolic compounds such as hydroxychavicol, chavibetol and eugenol [5,6]. ...
... It is one of many medicinal plants that have become popular in cancer studies [5]. Studies have shown that leaf extract of P. betle possess phenolic compounds such as hydroxychavicol, chavibetol and eugenol [5,6]. In addition, it has been noted that leaf extract of P. betle exhibits antioxidant activity, as revealed through DPPH, hydroxyl, nitric oxide and superoxide anion radical scavenging activities, as well as ferric reducing antioxidant power (FRAP) assay. ...
Article
Purpose: To determine the antioxidant and anticancer effects of Piper betle (P. betle) leaf extract on human breast cancer MCF-7 cells, and to develop transdermal patches containing the extract. Methods: The leaf extract of P. betle was prepared by maceration method, and its antioxidant activity was evaluated using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Cytotoxicity and suppression of cell migration (indices of anticancer activity) were also assessed in MCF-7 cells by sulforhodamine B (SRB) and wound healing assays, respectively. Transdermal patches were developed using the casting method, and the resultant patches were evaluated with regard to their physical appearance and mechanical properties before and after a stability test. Results: The extract exhibited antioxidant activity with half-maximal inhibitory concentration (IC50) of 30.0 ± 0.1 µg/mL. It also showed cytotoxicity with an IC50 of 114.3 ± 14.9 µg/mL, and significantly suppressed the migration of MCF-7 cells at a dose of 25 µg/mL. Based on desirable characteristics, patch base formulations containing 4.2 % pectin, 0.4 % hydroxyl propyl methylcellulose (HPMC), 0.4 % polyvinyl pyrrolidine K-90 (PVP-K90) and 3 % propylene glycol (PG) were selected for incorporation into the extract. Conclusion: Leaf extract of P. betle exhibits potential anti-breast cancer properties. A transdermal patch containing 0.03 % of the extract can be successfully developed for treatment of breast cancer.
... Studies show that various plant possesses concoction of bioactive compounds to act as anticarcinogenic and anti-proliferative towards cancer cells for anticancer drug development [64][65] [66]. Antioxidant activities in plant also contributed to the positive correlation to the inhibition of cancer cell growth [67]. ...
... Paranjpe et al. investigated the properties on Piper betle leaf extract against prostate cancer by identifying the active principle of the Piper betle extract [67]. In vivo research was done on 6-week-old male BALB/c nude mice. ...
... One such study demonstrated that HC has a greater effect than crude PBL water extract on HT-29 cells (Ng et al., 2014). Bio-guided fractioning revealed that the fraction containing about 95% of total HC, in comparison to other fractions of PBL extract, exerted the highest cytotoxic effect on prostate cancer cells (Paranjpe et al., 2013). Polyphenols such as curcumin, gingerols, and capsaicin are active compounds from turmeric, ginger, and red chili, respectively, and these compounds have entered clinical trials as prospective chemotherapeutic agents (Sung et al., 2012). ...
Article
This study aims to elucidate the antiproliferative mechanism of hydroxychavicol (HC). Its effects on cell cycle, apoptosis, and the expression of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (MAPK) in HT-29 colon cancer cells were investigated. HC was isolated from Piper betle leaf (PBL) and verified by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and gas chromatography-mass spectrometry (GC-MS). The cytotoxic effects of the standard drug 5-fluorouracil (5-FU), PBL water extract, and HC on HT-29 cells were measured after 24, 48, and 72 h of treatment. Cell cycle and apoptosis modulation by 5-FU and HC treatments were investigated up to 30 h. Changes in phosphorylated JNK (pJNK) and P38 (pP38) MAPK expression were observed up to 18 h. The half maximal inhibitory concentration (IC 50) values of HC (30 μg/mL) and PBL water extract (380 μg/mL) were achieved at 24 h, whereas the IC 50 of 5-FU (50 μmol/L) was obtained at 72 h. Cell cycle arrest at the G 0 /G 1 phase in HC-treated cells was observed from 12 h onwards. Higher apoptotic cell death in HC-treated cells compared to 5-FU-treated cells (P<0.05) was observed. High expression of pJNK and pP38 MAPK was observed at 12 h in HC-treated cells, but not in 5-FU-treated HT-29 cells (P<0.05). It is concluded that HC induces cell cycle arrest and apoptosis of HT-29 cells, with these actions possibly mediated by JNK and P38 MAPK.
... Betel leaf contains phenols, hydroxychavicol and chavibetol. It has antimutagenic and antioxidant activities (Paranjpe et al., 2013). Betel leaves were purchased from UK based ethnic shops in the cities of Leicester, Birmingham and London and the concentration of arsenic in betel leaves was 0.107 mg/kg (Al-Rmalli et al., 2011). ...
... The presence of necrotic cells along with early apoptotic cells suggested that these cells resulted from an apoptotic process rather than necrotic process [30] or it may be due to the incomplete process of apoptosis [31]. The presence of increased necrotic cell in the present study may result after the apoptotic process or incomplete process of apoptosis due to increased or decreased concentrations of extract or it may be due to the complex action of neem oil extract. ...
Article
Full-text available
Objective: To find the cytotoxic and apoptotic effects of neem oil extract on the selected cancerous (A-549, PC-3 and DU-145) and noncancerous (NIH3T3 and CCD-18Co) cell lines. Methods: Viability and cytotoxic effect induced by the extract was measured by using MTT assay and apoptotic effect of the extract was evaluated by using Hoechst 33342 and propidium iodide dual staining through a fluorescent microscope and activity of caspases 3, 8 and 9 through colorimetric assay kits. Results: The results showed that neem oil extract significantly reduced the viability in all selected cancer cells treated with varying concentrations of extract as compared with untreated cells and had less effect on noncancerous cell lines. It significantly increased the percentage of necrotic and apoptotic cells, and caspases 3, 8 and 9 activities in all cancer cells treated with extract as compared with untreated cells whereas no effect on noncancerous cell lines. It suggested that neem oil extract exerted a higher cytotoxic effect on cancer cells than normal cells and lower concentration induced apoptosis only in cancer cells. One of the apoptosis-inducing mechanism was through the activation of caspases signaling pathways. Conclusion: Conclusively, it implies that neem oil extract may contain one or more potential agents that can be used as a safe and effective anticancer therapy. © 2018, Hainan Medical University. E-edition Published by Wolters Kluwer India Pvt. Ltd. All rights reserved.
... The leaves of Piper betel contain a large number of bioactive molecules like polyphenols, alkaloids, steroids, saponins and tannins (Kumar et al. 2010, Haslan et al. 2015. The leaf extract has also been reported to exhibit biological capabilities of detoxification, antioxidant, antimutagenic and anticancer suggesting the chemopreventive potential of Piper betle against various ailments including liver fibrosis and prostate cancer (Paranjpe et al. 2013;Young et al. 2007). ...
Article
Hydroxychavicol (HC), a major phenolic derivative isolated from the leaves of Piper betle L. is well known for its antibacterial, antifungal and antimutagenic properties. The present study evaluated the in vivo antitumor activity of HC against Ehrlich Ascites Carcinoma (EAC) cells in Swiss albino mice and in silico interaction of HC with the receptors involved in the cancer. Hydroxychavicol (200 and 400 mg/kg bw) was orally administered for 21 consecutive days and was effective in inhibiting the tumor growth in ascitic mouse model. HC consistently reduced the tumor volume, viable cell count, lipid peroxidation and elevated the life span of HC treated mice. Besides the hematological profiles, SGOT and SGPT levels reverted back to normal and oxidative stress markers GSH, SOD and CAT also increased in HC treated groups. In silico docking analysis revealed that HC possessed potent antagonist activity against all the cancer targets demonstrating its inhibitory activity.
... The leaves also contain the enzymes like diastase and catalase besides a significant amount of several essential amino acids including lysine, histidine and arginine [1,2,[4][5][6] . Most of the previous studies on Betel leaf concentrated more on the components present in betel leaf extract [7][8][9][10][11][12] . There is a large scope in determining an appropriate extraction technique that extracts the phyto-components from betel leaves. ...
Article
Full-text available
The present study aims at finding out the optimum parameters for the extraction of components from Betel leaves possessing medicinal applications using ethanol solvent by Soxhlet apparatus. The optimum conditions for the extract were calculated based on the extract yield by varying four parameters: material quantity (A: 2–4 g), solvent quantity (B: 250–300 ml), mantle temperature (C: 65–75 °C) and extraction time (D: 1–3 hours) and optimized using a four factor three level Box–Behnken response surface design (BBD) coupled with desirability function methodology. Results showed that temperature and extraction time had significant effect on yield of extract. Optimum conditions for highest yield of extract (10.94%) are as follows: material quantity (2 g), solvent quantity (281.4 ml), temperature (72 °C) and time (3 hours). The extract at the maximum yield condition was analyzed for phytocomponents by FTIR and GC–MS. The results indicated the presence of Hydroxy chavicol (69.46%), 4-Chromanol (24%) and Eugenol (4.86%), which possess wide application including as antioxidant, anti-inflammatory, anti-platelet and antithrombotic, antibacterial and antifungal agents.
... , antimicrobial (Arambewela, Kumaratunge, & Dias, 2005;Nalina & Rahim, 2007;Patel & Mohan, 2017;Prakash et al., 2010), antiplaque (Pandita, Varghese, Mantri, & Kachwala, 2010), antimalarial (Al-Adhroey, Nor, Al-Mekhlafi, Amran, & Mahmud, 2011), and anticancer (Paranjpe et al., 2013) and cytotoxic (Atiya et al., 2017;Atiya, Sinha, & Lal, 2018) activities of P. betle leaves. The leaf extracts also showed anti-allergic (Wirotesangthong, Inagaki, Tanaka, Thankijcharoenpath, & Nagai, 2008), gastroprotective (Bhattacharya, Chaudhuri, Chattopadhyay, & Bandyopadhyay, 2007), immunomodulatory (Kanjwani, Marathe, Chiplunlar, & Sathaye, 2008), anti-inflammatory (Ganguly, Mula, Chattopadhyay, & Chatterjee, 2007), and chemopreventive (Young et al., 2007) properties. ...
Article
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Rationale: Piper betle leaf, used as masticatory in South Asia, is also medicinally important. Objective: This work was done to analyze phytochemical composition of two solvent fractions (chloroform and ethyl acetate) of the aqueous extracts obtained from eight varieties of P. betle leaves and to identify the active components against β-glucuronidase by chemometric analysis. Results: Twenty-four phenolic compounds, in addition to different organic acids, fatty acids, amino acids, sugars, and polyols, were identified from the solvent fractions. The extracts inhibited the enzyme β-glucuronidase. Piceatannol was the most active constituent against the enzyme (activity 12 times higher than that of silymarin), Chlorogenic acid also inhibited β-glucuronidase (activity 4.4 times higher when compared to silymarin). 2,2'-Diphenyl-1-picrylhydrazyl and superoxide free radical scavenging activities of both the fractions of eight varieties of P. betle leaf extracts showed very strong antioxidant potentiality. Conclusion: The findings validated some medicinal properties of the said leaves. Practical applications: Edible leaves of Piper betle are medicinally and economically important. Leaves of different local varieties are reported to be used for the treatment of different diseases. The leaves have many biological properties, hepatoprotection being one of them. A large number of rural population is economically dependent on the cultivation of betel vine. But with a rapid change in lifestyle, the chewing habit of P. betle is decreasing ultimately affecting the livelihood of farmers dependent on betel cultivation. Knowledge on β-glucuronidase inhibitory activity and the mechanism for hepatoprotection of different P. betle varieties may validate the medicinal properties of betel, which would increase consumption of these leaves.
... This is due to an additional of hydroxy group in aromatic rings which may increase the antioxidants properties. There are also some study reported that hydroxychavicol quantitatively present at approximately 26% in betel leaves which has been shown can exert the antiproliferative activity in prostat cancer [3]. This compound also convincely inhibit the cyclooxygenerase (COX), platelet calcium signalling and thromboxane B2 production also anti ulcerogenic activity [4]. ...
Conference Paper
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The objective of this review was to investigate the effect of some parameters on extraction yield, Hyroxychavicol (HC) and Eugenol (EU) from Piper Betel L. There were some extraction procedures applied either by conventional or advanced like conventional aqueous or solvent (maceration, digestion, etc), hydro-distillation, soxhlet, ultrasound, sub-critical water and supercritical fluid extraction. The experiments were usually conducted by carried out different extraction parameters such as particle sizes, raw material to solvent ratio, time of extraction, temperature, type of solvent including concentration and pH of solvent and others The highly influence factor were selected based on chemical state (i.e temperature and solvent condition) and physical state (particle size and raw material or vessel condition) to evaluate the performance of extraction process. The dominant factor to achieve high yield of Hyroxychavicol (HC) and Eugenol (EU) was also explained in this paper.
... The PB leaf showed dose dependent suppression of dimethylbenzanthracene induced mutagenesis in Salmonella Typhimurium strain TA98 with metabolic activation (Amonkar et al., 1986;Paranjpe et al., 2013). ...
... India supports nearly 55000 ha of betel cultivation (Das et al. 2016). Betel leaf is known for its medicinal properties which include anti-bacterial, anti-fungal, anti-inflammatory, hepatoprotective, anti-cancer and anti-leishmanial effects (Nadkarni & Nadkarnai 2007, Misra et al. 2009, Kumar et al. 2010, Paranjpe et al. 2013. Furthermore, betel leaf chewing is considered as an effective method of drug delivery through buccal mucosa (Shojaei 1998). ...
Article
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There are very few studies on endophyte communities of freshly consumed leaves. This is vital as some endophytes which continue to survive in detached leaves belong to mycotoxin producing genera. We studied the endophyte community of betel leaf, which is eaten fresh by a huge population, especially in Asia. Young and mature leaves of betel vine were screened for their endophyte assemblage. In addition, mature leaves collected during dry and wet seasons and those stored in the market were studied for endophyte presence. The entire leaf was infected with endophytes. Though endophyte colonization frequency (CF %) increased with leaf age, their species composition did not vary. The CF% of most of the endophytes was low (0.7 % - 8.7 %) while that of Colletotrichum sp. 1 was high irrespective of leaf age or season (46 % - 78.67 %). The CF% of Fusarium pallidoroseum increased with leaf age and storage period; the presence of F. mangiferae increased with storage time. The two Fusarium endophytes isolated from betel leaf produce an array of mycotoxins including beauvericin, enniatin, nivalenol, fusarenon X, equisetin, HT2 toxin, diacetoxyscirpenol and neosolaniol. This study underscores the importance of investigating the endophyte communitiesof leafy vegetables, especially those having relatively longer shelf life.
... The betel leaves are mainly used as mouth freshener and is also well known for curing many communicable and non-communicable diseases like cold, cough, bronchial asthma, rheumatism, stomachalgia and used to treat other diseases like bad breath, boils and abscesses, conjunctivitis, constipation, swelling of gums, cuts and injuries (Gundala et al., 2014) [12] . It is also found that betel has significant anti proliferative activity in vitro and in vivo prostate cancer models (Paranjpeet al., 2013) [23] . Studies have evidenced that some potential phytochemicals of the betel vine leaf extract such as hydroxychavicol (Chang et al., 2002;Jeng et al., 2004) [5,16] , ursolic acid (Kassi et al., 2007;Yamai et al., 2009;Yu et al., 2010;Shao et al., 2011) [18,40,41,35] , chlorogenic acid (Rakshit et al., 2010) [28] , and eugenol (Ghosh et al., 2005;Pisano et al., 2007;Manikandan et al., 2010;Jaganathan et al., 2011) [9,24,22,14] can induce apoptosis in tumour cells confirming the chemopreventive effect. ...
Article
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Piper betle L., (family- Piperaceae) commonly known as the betel vine is an important medicinal and recreational plant in Southeast Asia. Betel vine is a dioecious, evergreen, perennial creeper with glossy heart shaped leaves. The present study was executed to identify the suitable integrated nitrogen management on leaf yield, quality and economy of betel vine (Piper betle L.) cultivars in new alluvial zone of West Bengal. The field experiment was conducted at Horticulture Research Station, Mondouri, Bidhan Chandra Krishi Viswavidyalaya, Nadia, West Bengal during the 2017-2018. The experiment was laid out in Rnadomized Block Design, replicated thrice with eight treatments of integrated nitrogen management. It was noted that treatments in combination with inorganic and organic sources of nitrogen produced better results than the treatments with sole application of organic source of nitrogen. The application of nitrogen from mustard oil cake and urea in 1:1 ratio (T1) produced maximum leaf yield/ vine (86.45 leaves/ vine/ year), projected leaf yield (63.22 lakhs/ ha/ year), chlorophyll content of the leaves (52.30 SPAD value), Ascorbic acid content of leaves (3.07 mg/100g), essential oil content ( 65.50 mg/100g) and ß Carotene content of leaves (7.28 mg/100g) in Simurali Deshi (V1). Maximum fresh weight (261.25 g) and dry weight (42.01 g) of 100 leaves were found in Halisahar Sanchi (V₃). Among all the sources of nitrogen Mustard oil cake 50% + Urea 50% (T₁) showed highest benefit and cost ratio in all the three cultivars.
... Sirih Merah was reported to contain biophenolics such as hydroxychavicol, eugenol, chavibetol, piperol (Gundala and Aneja, 2014). Some of these compound has been shown to exert antimutagenic (Chang et al., 2002), antiproliferative activity in prostate cancer (Paranjpe et al., 2013), enhance tumor growth by downregulation of NF-κB pathway (Sarkar et al., 2008), and also eliminate cancerous cells without harming normal cells (Guha, 2006). *Corresponding author e-mail: ririsjenie@gmail.com ...
Article
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Breast cancer is one type of cancer with a high mortality rate due to its metastatic property. Red betel leaves (Piper crocatum Ruiz and Pav) has been known as herbal medicine containing biophenolic, such as apigenin and luteolin derivatives which has cytotoxic activity toward cancer cells. This study is intended to explore the inhibitory effect of Piper crocatum leaves methanolic extract (PCM) on cell proliferation and migration by using 4T1 cells as model of metastatic breast cancer. By using MTT assay, PCM performed cytotoxic activity in a dose dependent manner with IC50 value of 120 μg/mL. Wound healing assay revealed that migration inhibitory activity of PCM on 4T1 cells at the concentration of 30 µg/mL. In conclusion, PCM perform cytotoxic effect and antimigration activity toward metastatic breast cancer cells. Keywords : breast cancer cells, Piper crocatum Ruiz & Pav, cytotoxic, cell mgration
... It induces the cell cycle arrest and apoptosis of oral KB carcinoma cells (Chang et al., 2002). In another study, significant inhibition of growth of human prostate xenograft was also observed with oral doses of betel leaf extract in mice (Paranjpe et al., 2013). From these studies, it can be suggested that betel leaf and its components possess potential anticancer effects. ...
Article
Betel leaf (Piper betle L.) is a commercial crop, which is traditionally consumed in the raw state as a mouth freshener and stimulant in Southeast Asia since antiquity. It possesses various functional and medicinal properties, such as antimicrobial, antioxidant, anti-diabetic, anti-carcinogenic etc. The leaf contains essential oil, which has a unique aroma contributing flavour and fragrance. This essential oil is a mixture of concentrated phytochemicals, among which the major components are estragole, chavicol, chavibetol, ß-cubebene, and caryophyllene. In different scientific researches, betel leaf extracts or essential oil were described for its numerous beneficial functional properties, contributed by these bioactive compounds. However, some health hazards may occur, when the leaf is consumed along with areca nut and tobacco. This review article provides an overview of the current status of betel leaf and its essential oil for its utilization as a bioactive ingredient in the food system. Citation: Roy, A. and Guha, P. 2021. Traditional and functional uses of betel leaf (Piper betle L.) pertaining to food sector: a review. Journal of Postharvest Technology, 9 (1): 72-85.
... [13] It is used to treat alcoholism, bronchitis, asthma, leprosy, dyspepsia, and antioxidative property. [14] Pterospermum acerifolium (L.) Willd (Sterculiaceae) is generally recognized as Kanakchampa, traditionally used for hemostasis, inflammation, ear pain, stomach ache, blood troubles, smallpox, leucorrhea, leprosy, ulcer, and tumors and as an antihyperglycemic agent, laxative, and anthelmintic. [15] Saraca indica (Caesalpiniaceae), Ashoka in Bengali, is useful as a heart tonic, hypoglycemic agent, in the treatment of abdominal pain, tumors, AIDS, inflammation, and cancer. ...
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The aim of the present study was to evaluate anthelmintic activity on Tubifex tubifex worm of methanol extract of Macaranga denticulata (Muell. Arg.) leaves and in silico molecular docking used for six phytoconstituents namely 3-acetylaleuritolic acid, oleanolic acid, macarangin, scopoletin, β-sitosterol, stigmasterol isolated from M. denticulata, to identify whether these compounds interact with tubulin. M. denticulata leaves extract exhibited strong anthelmintic activity in vitro. Where it paralyzed (10.22±0.69min) and produced death (19.43±0.80 min) of the Tubifex tubifex at 10 mg/ml dose and the standard, Levamisole (3.3±0.38min and 6.5±0.76min) at 1 mg/ml. A wide range of docking score found during molecular docking by Schrodinger. 3-acetylaleuritolic acid, oleanolic acid, macarangin, scopoletin, β-sitosterol, stigmasterol showed the docking score-5.733,-3.951,-7.584,-6.115,-8.307-, and 8.021 respectively. Among all the compounds, β-sitosterol showed highest docking score. So, β-sitosterol is the best compounds as anthelmintic drug, as it possessed higher value in Molecular docking. Methanol extract of M. Denticulata leaves showed well anthelmintic activity. Further in vivo investigation need to identify that isolated compounds from M. denticulata have anthelmintic activity.
... It can be consumed in the form of fresh leaves or in the form of concoction. Hence, betel leaf is widely studied for its medicinal properties such as anti-tumor, antimutagenic, anti-oxidant; anti-inflammatory, etc 26 . It is also used in the form of extracts or single isolated molecules. ...
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Our present study aims at analyzing and comparing the antioxidant, anti-inflammatory and phytochemical property of betel leaves from two different domains of Karnataka that includes the Western Ghats and the Northern region. Initially, the ethanol extracts of all four samples (two from each domain) were prepared and checked for their anti-inflammatory and antioxidant activity. As a result, the betel leaf extract from the western region showed good antioxidant activity and a significant anti-inflammatory activity when compared with the standard Gallic acid. In connection to this, the phytochemical content such as Alkaloids, Tannins, Flavonoids, and Phenols showed positive in all four extracts, but the quantification studies showed that the extracts from the Western Ghats had a higher quantity of alkaloids and phenols when compared to the samples from northern regions. These results imply that the presence of functionally important groups depends on the composition of the soil in which they grow in. Hence having good biologically important activity in them can prove beneficial for their role towards formulating a cost-effective lead drug from the extracts with no side effects.
... [13] It is used to treat alcoholism, bronchitis, asthma, leprosy, dyspepsia, and antioxidative property. [14] Pterospermum acerifolium (L.) Willd (Sterculiaceae) is generally recognized as Kanakchampa, traditionally used for hemostasis, inflammation, ear pain, stomach ache, blood troubles, smallpox, leucorrhea, leprosy, ulcer, and tumors and as an antihyperglycemic agent, laxative, and anthelmintic. [15] Saraca indica (Caesalpiniaceae), Ashoka in Bengali, is useful as a heart tonic, hypoglycemic agent, in the treatment of abdominal pain, tumors, AIDS, inflammation, and cancer. ...
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Background: Piper Betle, Pterospermum acerifolium, Saraca indica, Argyreia speciosa, and Rhaphidophora glauca are medicinal plants commonly used as traditional medicine for the treatment of various diseases. To examine, whether organic extracts of these plants possess thrombolytic properties with minimal or no toxicity is our main aim of the study. Materials and Methods: In vitro thrombolytic model was used to check the clot lysis effects using streptokinase (SK) as a positive control and water as a negative control. Cytotoxicity was screened by brine shrimp lethality bioassay using vincristine sulfate (VS) as positive control. Results: Among herbal drugs, different organic extracts of P. betle, P. acerifolium, S. indica, A. speciosa, and R. glauca showed significant (P < 0.05 and P < 0.0001) clot lysis activity viz., 31.58% ±0.76%, 40.50% ±0.94%, 49.70% ±1.69%, 35.81% ±0.86%, and 43.80% ±0.91%, respectively, compared to reference drug SK (79.32% ±1.629%). In brine shrimp cytotoxic assay, mortality achieved by the extracts showed lethal concentration 50 (LC50) values 274.64 ± 3.46, 215.60 ± 4.59, 478.40 ± 6.98, 233.37 ± 2.56, and 209.32 ± 1.98 μg/ml, respectively, with reference to VS (LC50,0.05 ± 0.34). Conclusion: In this study, S. indica, R. glauca, and P. acerifolium possessed effective thrombolytic activity. Further studies can be undertaken to identify certain structure of the ingredients in the extracts and to elucidate the precise mechanism of action. SUMMARY Five Bangladesh medicinal plants, named Piper betle, Pterospermum acerifolium, Saraca indica, Argyreia speciosa, and Rhaphidophora glauca were subjected to comparative antithrombotic and toxicity based analysis. In comparative study, Saraca indica showed highest clot lysis (49.70 ± 1.69%) activity among the other plant with lowest toxicity (LC50: 478.40 ± 6.98) Abbreviations Used: h: Hour; min: Minutes; sec: Second; kg: Kilogram; g: Gram; μg: Microgram; L: Liter; mL: Millilitre; μL: Micro liter; μg/mL: Microgram per Milliliter; mg/kg: Milligram per kilogram; %: Percent; °C: Degree Celsius; et al.: et alliori (and others); w/w: Weight by Weight; v/v: Volume by Volume; SEM: Standard Error Mean; LC50: lethal concentration at 50%
... Chlorogenic acid another bioactive agent of betle leaves which selectively removes carcinogenic cells. The major chemo-preventive cell signalling mechanisms including activation of caspases, inhibition of cyclin, MMPs, COX, NFKB etc. has been shown in figure 2 [19,16,20,21,15] . ...
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Plants contain a higher amount of biological compounds that are usually used in distinct types of health issues. Piper betle is one among the various therapeutically active herbal plants and known to possess a diverse range of secondary metabolites. It belongs to the Piperaceae or pepper family and commonly used in chewing agents to provoke offensive breath. Heart-shaped betle leaves contain several types of phytochemical compounds with antimutagenic, antiproliferative, antibacterial, and antioxidant properties. The betle plants are usually consumed in south Asian countries. Recent studies showed the remarkable role of such herbal drugs in chemoprevention against several types of cancer. Present review describes the potential of piper to modulate a diverse range of signaling molecules including transcription factors and reactive oxygen species (ROS) to regulate the multiple functions of several cellular processes including proliferation and death pathways
... It is prepared using a variety of Rosa species including Rosa centifolia, belonging to family Rosaceae. Traditionally, it has been used as a cooling tonic to fight fatigue, dysmenorrhea, hyperacidity, lethargy, fluid retention, and heat-related conditions [97]. It is used as a memory enhancer and blood purifier. ...
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Natural products and traditional ethnomedicines are of great effect in therapeutics. Such types of medicine have been practiced in certain areas of the world to treat different health conditions. This pilot investigation aims to review the cumulative health effect of addendums used in betel quid such as areca nut, lime, and tobacco-associated betel quid chewing and without tobacco-associated chewing. This review shows that betel leaf extract and its essential oil could inhibit growth of microbes and damage different gram-positive and gram-negative bacteria as well as various fungus species. Some studies concluded that the combination of Piper leaves essential oil with antibiotics have potential effect on oral microorganisms. Long-term consumption of betel quid with tobacco is known to cause cancer, chromosomal aberrations, and pharynx tumors. However, consumption of betel leaf without tobacco has health benefits because of ethnomedicinal properties. Its essential is oil utilized as raw material for perfumes and mouth fresheners manufacturing. Scientific researches on this plant revealed that it possesses many beneficial activities to be used for developing novel drugs. However, compounds of betel leaves have beneficial natural antioxidant. Chewing and intake of leaves have effect on moving parts of salivary gland which is the main step of digestion. Its components also act as heartbeat regulators in relaxing the blood vessels to reduce hypertension. So this review discussed the natural compounds of betel leaves which is used as traditional medicine to further develop drug discovery.
... A wide range of double bond specific groups in C=O and C=C was observed in the region from 2,000 to 1,500. Lastly, the region from 1700-600 show finger print that is reminiscent of phenyl propanoid eugenol [27,28]. ...
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Piper betle (Linn) commonly called as betel leaf is a widely cultivated plant in the Indian subcontinent. The traditional Indian ayurvedic document describes several of its medicinal properties including as an effective antifungal agent. The present study was conducted to evaluate the secondary metabolite that contributes to its antifungal activity. Invitro studies were performed on molds and yeasts on antifungal using fractions obtained from ethyl acetate, hexane and ethanol-methanol extracts by well-diffusion technique. Ethyl acetate extracts showed highest anti-fungal activity. Using biophysical techniques such as Nuclear Magnetic Resonance and Fourier transform infrared spectroscopy techniques; we identified the molecule as derivative of the phenyl propanoid family akin eugenol. The molecule can be readily purified using a 2 step solvent extraction procedure along with silica column chromatography. These findings reveal the antifungal and possible commercial potential of the plant extract and its potential in agriculture against pest management and food spoilage.
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Betelvine (Piper betel L.) is cultivated for its deep green heart shaped leaf for (15-20) million Indian and 2 billion foreign consumers annually. The crop provides Rs (6 000-7 000) million of national income per year and at the same time leaves worth Rs (30-40) million is exported to other countries. The leaves are not only used directly for chewing purposes but also possesses antioxidant, anti-inflammatory, anti-apoptotic, anti-cancer and anti-microbial properties. Besides, the leaves also contain eugenol rich essential oil (1%-3%) which is the source for medicine, stimulant, antiseptic, tonic and other ayurvedic formulations. The essential oil also contains chavibetol, caryophyllene and methyl eugenol which are the potent source for preparation in ayurvedic medicine and herbal products. Cost of betelvine essential oil is 10$ per 5 mL. In spite of its great economical and medicinal importance betelvine is still neglected by the researchers for proper characterization and authentication for selection of elite landraces. Lack of awareness among people, use of same planting material for many generations, existing of many synonyms for a single landraces, no proper characterization of available landraces are some of the significant constraints for its commercialization. Our review endeavours a complete advance in the research on betelvine, existing lacunae for its proper characterization and commercial cultivation. It also attempts to provide a comprehensive account on biotechnological interventions made in betelvine aimed at complementing conventional programmes for improvement of this nutraceutically important cash crop.
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Betelvine is prone to several fungal diseases including leaf spots, foot and root rot caused by Fusarium spp. due to humid conditions prevailing in fields. In the present study, a potent antagonistic bacterial endophyte and a virulent fungal pathogen were selected after rigorous screening of isolates from different betelvine varieties to provide an efficient biocontrol strategy in cultivation of betelvine. Wild varieties of crops are a rich source of untapped endophytes. Of the four betelvine varieties used for isolations and screening, the wild variety was richest in endophytic populations. Using 16S rRNA sequencing, the selected antagonist was identified as Bacillus sp. (NBRI-W9). The pathogen, virulent against cultivated varieties, was identified as Fusarium sp. (NBRI-PMSF12) using ITS 1 and 2 region sequencing. Under in vitro and field conditions, NBRI-W9 was able to induce early rooting, provide plant growth promotion, increase leaf size and yield (leaf number) and provide biocontrol against the Fusarium sp. infection. NBRI-W9 treatments showed bacterial colonization on the leaf surface preferably in the vicinity of pearl glands and the collenchyma region in scanning electron microscope (SEM) studies. NBRI-W9 was observed to directly enter the leaf by degrading cell walls and colonize the subcellular layers. SEM analysis showed direct confrontation of NBRI-W9 with Fusarium on the leaf surface and in the collenchyma region as one of the probable modes of biocontrol.
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Background/aims: The objective of this study was to elucidate the underlying antioxidant mechanism of aqueous extract of Piper betle (PB) in aging rats. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway involving phase II detoxifying and antioxidant enzymes plays an important role in the antioxidant system by reducing electrophiles and reactive oxygen species through induction of phase II enzymes and proteins. Methods: Genes and proteins of phase II detoxifying antioxidant enzymes were analyzed by QuantiGenePlex 2.0 Assay and Western blot analysis. Results: PB significantly induced genes and proteins of phase II and antioxidant enzymes, NAD(P)H quinone oxidoreductase 1, and catalase in aging mice (p < 0.05). The expression of these enzymes were stimulated via translocation of Nrf2 into the nucleus, indicating the involvement of ARE, a cis-acting motif located in the promoter region of nearly all phase II genes. Conclusions: PB was testified for the first time to induce cytoprotective genes through the Nrf2/ARE signaling pathway, thus unraveling the antioxidant mechanism of PB during the aging process.
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The effective potentiality of anticancerous drugs, namely, cisplatin, etoposide and vinblastine, as well as the ethanolic extract of Piper betle L. leaves, is evaluated (concentrations used: 0.001, 0.01, 0.1, 1.0 and 10.0 µM for vinblastine; 25, 50, 75, 100, 125 and 150 µM for other test materials) on germinating grass pea (Lathyrus sativus L.) seedlings in relation to radicle length and mitotic index. Furthermore, inhibition in the frequency of dividing polyploid cells induced due to prior treatments of colchicine (0.5%, 8 h) and in vitro callus growth are also assessed following treatments with different concentrations of the test materials. The objective of the present study is to determine the effectivity of the test materials on a plant species with the view to develop a plant system (convenient to use and cost effective) as a model for preliminary screening of novel anticancerous drugs as well as plant extract(s) possessing such potentiality for further exploration.
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A rapid ultra performance liquid chromatography electrospray ionisation tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and validated for identification and characterization of phytoconstituents with simultaneous quantitative determination of three major bioactive phenolics namely allylpyrocatechol-3,4-diacetate, eugenyl acetate and eugenol from thirteen landraces of Piper betle leaf extracts. Among the 29 phytoconstituents detected, 19 were identified and characterized based on their fragmentation pattern obtained via MS/MS by means of collision-induced-dissociation (CID) and by comparison of their retention time with authentic standards or by previously reported literature. The proposed method was fully validated in terms of linearity, LOD, LOQ, precision, stability and recovery. All calibration curves showed a good linear relationship (r2 ≥ 0.9981). The precision evaluated by an intra- and inter-day study showed RSD ≤ 1.0% and good accuracy with overall recovery in the range from 96.14–98.46% (RSD ≤ 1.6%) for all analytes. The quantitative results showed that there were remarkable differences in the contents of the major bioactive phenolics in all the thirteen landraces of P. betle. The developed UPLC-ESI-MS/MS method was found to be simple, precise, sensitive and accurate. Hence, it can be reliably utilized as a quality control method for P. betle or derived herbal formulations. In vitro antimicrobial activity of the crude extract of P. betle landraces was also evaluated, and all extracts tested exhibited antifungal activity but none of the extracts were found to be active against bacteria even at 500 μg mL−1 concentration.
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We have recently demonstrated that hydroxychavicol is a major constituent and the most active biophenolic of Piper betel leaves with significant antiproliferative activity in the micro molar range. Herein we present the design, synthesis and evaluation of fifteen novel hydroxychavicol analogs with varying antiproliferative activities in cancer cell lines from two representative tissue types, namely, the prostate and cervix that show very encouraging results compared to the parent compounds. Our long range goal is to develop a structure-activity guided relationship to gain mechanistic insights into novel molecular targets of this class of bioactive molecules for rational drug development. Cytotoxicity-guided experimentation on these novel analogs yielded the following structural factors as the key activity regulators: 1) unlike the hydroxyl substituent at position-4, the position-3 hydroxyl is vital for enhanced activity 2) acetoxyl groups are dispensable for activity as corroborated earlier by others 3) allylic double bonds at 2'C-3'C serve to positively influence antiproliferative activity 4) long saturated side chains at 1'-position negatively regulate antiproliferative activity and 5) maneuvering position-4 with a benzyl group positively impacted the biological activity profile. Most amphiphilic compounds showed moderate to good therapeutic potential as expected on the basis of medicinal chemistry principles. Intriguingly, the most active compound with ten-fold higher activity than the parent molecule was realized by sheer serendipity to employ a silica gel based rearrangement that was further explored using nuclear magnetic resonance spectroscopy and density functional theory calculations. This is the first report to describe strategies for optimal synthesis of a novel series of 15 analogs based upon hydroxychavicol, a simple phytochemical of immense anticancer potential.
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Piper betle L. is a popular medicinal plant in Asia, and extracts of the plant leaf are used for several therapeutics. It is known for its rich source of phenolic compounds, including hydroxychavicol. Hydroxychavicol is an allylbenzene that has gained much attention due to its anticancer properties. The current study quantified and purified hydroxychavicol from P. betle L. and predicted its anticancer competence through in silico and cytotoxicity studies. Leaf samples of 22 P. betle L. accessions from different locations of Tamil Nadu, India, were analyzed using reverse phase-high performance liquid chromatography for quantification of hydroxychavicol. The highest quantity of hydroxychavicol was obtained from the accession BV22 (89.2%). Chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of hydroxychavicol using SwissADME satisfied the physicochemical property guidelines of Lipinski's Rule of Five, ensuring its drug-likeness behavior. Molecular docking studies confirmed the interaction of hydroxychavicol with all 16 tested cancer targets. In Vitro MTT assay of hydroxychavicol in bone cancer cell lines (MG63) also demonstrated the anticancer competency, indicating the requirement to formulate the molecule as a drug in treating various types of cancers.
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Betelvine (Piper betle) leaves are known for its medicinal properties since 600 AD practiced in Ayurvedic system of medicine. It is a cash crop for many Southeast Asian countries and is, therefore, also known as “Green Gold.” Widely consumed as masticator, betelvine leaves are a rich source of phenolic compounds having antiproliferative, antimutagenic, antibacterial, and antioxidant properties. The Piper betel leaf (PBL) extract is used as an antiseptic in cuts and wounds, is used as a diuretic, helps in digestion, and treats boils, conjunctivitis, stomach problems, hysteria, itches, leucorrhea, and ringworm. Also, the PBL extract is used as adjunct in Ayurvedic medicines, and the essential oil obtained from the betelvine leaves has antimicrobial and antiprotozoal activities. The high amounts of phenolic compounds present in betelvine leaf extract are of antioxidant nature which plays a key role to serve several medicinal properties. Apart from these medicinal properties reported since Ayurvedic times, modern researches have proved them to bear anticancer properties too. The compounds that confer the anticancer activity to betelvine leaves include antioxidant compounds such as eugenol, hydroxychavicol, β-carotene, and ascorbic acid, all of which are known for scavenging free radicals, thereby preventing cellular damages. In the present chapter, we have discussed the advances in betelvine research in the field of cancer as a cancer suppressor, killing agent for cancer cells, as nutraceutical and other medicinal properties helpful in cancer therapy.
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Quinone methides (QMs) are considered to be highly reactive intermediates because of their aromatization both in chemical and biological systems. Being highly accessible, quinone methides (QMs) have been widely exploited and their concurrent use has been manifested for the synthesis of tertiary and quaternary carbon centers of bioactives, drugs and drug-like molecules. In this feature article, the synthetic routes, structure-reactivity relationships and synthetic applications of quinone methides are discussed. Formation of the intermediates during bioactivation of different chemical entities and possible chemical manifestations leading to their toxicity in biological systems are also covered.
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HeLa cells are broadly used for in-vitro studies in bringing out the medicinal value of plants against some dreadful diseases. From time immemorial, it is well proven that plant extracts play a vital role in treating many diseases including cancer. The plant extract contains copious varied phenolic compounds and flavonoids that are majorly responsible for its medicinal properties. In our study we have focused on the extraction of betel quid (betel leaves, areca nut and slaked lime in an appropriate proportion) using the solvent hexane. The hexane extract of the betel quid was evaluated for in vitro studies of apoptosis of HeLa cells. The results revealed that hexane extract of the betel quid at the maximum concentration of 200 µg/mL was very effective and only 20.89 % of cells were viable. The cytotoxic effect against HeLa cells was significant with IC50 of 96.33μg/ml. Further studies can be done on concentrating the bioactive compounds responsible for the anticancer activity. The bioactive active compounds can be formulated in the treatment of cancer in the upcoming research.
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Medicinal plants are one of the most important resources for developing new lead therapeutic compounds used in various traditional medicines worldwide for thousands of years due to the presence of natural bioactive components, which help in preventing various human diseases. Piper betle Linn belongs to the Piperaceae family, commonly known as Betel and Paan. Betel leaves possess several bioactivities, and these are used in traditional medicinal systems. Syzygium aromaticum L. (Cloves) is a tree belonging to the Myrtaceae family. Closed flowering buds are used as a spice in food preparations all over the world. Eugenol is an active compound of both plants (Piper betle and Syzygium aromaticum). Hence, we attempted to study the effect of the methanolic extracts of Piper betle and Syzygium aromaticum, along with their active component, eugenol, using an in-vitro approach. The in-vitro cytotoxicity was assessed against lung adenocarcinoma cell lines (A549) using the MTT and SRB assays, and the type of cell death was characterized by differential staining. The results showed that the plant extracts, as well as eugenol, showed good anticancer potential in-vitro.
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Piper betle leaves possess several ethnomedicinal properties and are immensely used in traditional medicinal practices in regions of Asian and African subcontinents. However, their effects in treating skeletal complications are least known. In this study, we evaluated cellular and molecular effects of betel leaf extract (BLE) and its major phytoconstituent, hydroxychavicol (HCV) in promoting osteogenesis in vitro and alleviating glucocorticoid induced osteoporosis (GIO) in vivo. Both BLE and HCV markedly stimulated osteoblast differentiation of C3H10T1/2 cells with increased expression of RUNX2 and osteopontin through the GSK-3β/β-catenin-signaling pathway. Also, oral administration of BLE and HCV in GIO rats resulted in restoration of bone mass and tissue microarchitecture. Thus, with our findings we conclude that BLE and HCV promote osteogenesis of C3H10T1/2 cells via the GSK-3β/β-catenin pathway and alleviate GIO in rats.
Chapter
Since time immemorial, Piper betle Linn. (betel vine or paan) has been an integral part of various traditional and folk medicines of Southeast Asian countries. The betel leaves are the most valued plant parts routinely used as chewing agent and known to prevent halitosis. Betel vine leaves possess numerous medicinal benefits, such as relieving indigestion, bronchitis, constipation, congestion, and cough. Betel vine leaves are mostly consumed as a part of betel quid, which consists of areca nut (Areca catechu Linn.), tobacco (Nicotiana tabacum Linn.), and slaked lime, a concoction with potent carcinogenic properties. Routine consumption of betel quid is associated with oral cancer, and scientific analyses have attributed that both tobacco and areca nut as carcinogenic, while slaked lime as a promoter of carcinogenesis. Conversely, betel vine leaves are devoid of carcinogenic effects and in turn known to possess cancer preventive effects that can negate carcinogens present in the quid. The aim of the chapter is to provide the information on betel vine’s cancer preventive effects and the mechanisms involved. Moreover, it also highlighted the various phytoconstituents that promote beneficial role of betel vine leaves against different cancers.
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The aim of the study was carried out to identification of possible bioactive compounds and to analyse the pharmacognostic evaluation and of ethanolic extracts of Syzygium cumini (L.) and Syzygium aromaticum (L.) by GC-MS method, the mass spectrum and peak values were matched with national institute of standard technology (NIST) library. There are bio active compounds from each plant extract were identified and analysed of their potential activities of their compounds were pharmacognostic valuable and further investigation need for the production improved novel drugs and lead to therapeutic use for various infectious diseases .
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Piper betle L. (synonym: Piper betel Blanco), or betel vine, an economically and medicinally important cash crop, belongs to the family Piperaceae, often known as the green gold. The plant can be found all over the world and is cultivated primarily in South East Asian countries for its beautiful glossy heart-shaped leaves, which are chewed or consumed as betel quid and widely used in Chinese and Indian folk medicine, as carminative, stimulant, astringent, against parasitic worms, conjunctivitis, rheumatism, wound, etc., and is also used for religious purposes. Hydroxychavicol is the most important bioactive compound among the wide range of phytoconstituents found in essential oil and extracts. The pharmacological attributes of P. betle are antiproliferation, anticancer, neuropharmacological, analgesic, antioxidant, antiulcerogenic, hepatoprotective, antifertility, antibacterial, antifungal and many more. Immense attention has been paid to nanoformulations and their applications. The application of P. betle did not show cytotoxicity in preclinical experiments, suggesting that it could serve as a promising therapeutic candidate for different diseases. The present review comprehensively summarizes the botanical description, geographical distribution, economic value and cultivation, ethnobotanical uses, preclinical pharmacological properties with insights of toxicological, clinical efficacy, and safety of P. betle. The findings suggest that P. betle represents an orally active and safe natural agent that exhibits great therapeutic potential for managing various human medical conditions. However, further research is needed to elucidate its underlying molecular mechanisms of action, clinical aspects, structure–activity relationships, bioavailability and synergistic interactions with other drugs.
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Piper betel Linn. (Family: Piperaceae) is an evergreen perennial vine, native to Southeast Asian countries. Due to its great nutritive, medicinal and economic value it is termed as "Green Gold" in India. Since ages, leaves of P. betel have been used as medicine either alone or as adjuvant to other medicine due to various pharmacological activities such as antioxidant, antimicrobial, anti-inflamma-tory, antidiabetic, hypo-lipidemic, antiplatelet etc. Chemically, leaves of betel vine are reservoir of phenolic compounds. Eugenol and hydroxychavicol are two chief phenolic biomarker compounds isolated from different extracts of P. betel L. leaves. Through understanding of the molecular mechanisms through which the phenolic biomarker exerts free radical scavenging activity, hypolipidemic activity, antibacterial activity, antifungal and cytotoxic effects may help various researchers for understanding structural-activity relationship and new drug development. Therefore, in the present review briefly summarizes the current state of knowledge regarding the possible mechanism behind all the pharmacological activities of hydroxychavicol, a phenolic biomarker isolated from P. betel leaves. Abstract Abbreviations
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Piper betle L. is one of the important plants in the Asiatic region which ranks second to coffee and tea in terms of daily consumption. Though the plant is known for abuse, in recent years several reports have been published on the effects of the plant extract and chemical constituents on different biological activities in vitro and in vivo. The leaf extract, fractions and purified compounds are found to play a role in oral hygiene, anti-diabetic, cardiovascular, anti-inflammatory/ immunomodulatory, anti-ulcer, hepato-protective and anti-infective, etc. Patents were also awarded for some of the biological activities like anti-inflammatory, anti-cancer and immunomodulatory associated with leaf extracts and purified compounds. The active compounds isolated from leaf and other parts are hydroxychavicol, hydroxylchavicol acetate, allypyrocatechol, chavibetol, piperbetol, methylpiperbetol, piperol A and piperol B. Phenol-rich leaves of P. betle show high antioxidant activities. A number of biologically active compounds from P. betle have potential for use as medicines, neutraceuticals and industrial compounds. Since the traditional use of P. betle involves chewing, it offers possibilities of use in drug delivery through buccal mucosa bypassing the gastric route.
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Natural products from medicinal plants, either as pure compounds or as standardized extracts, provide unlimited opportunities for new drug leads because of the unmatched availability of chemical diversity. Due to an increasing demand for chemical diversity in screening programs, seeking therapeutic drugs from natural products, interest particularly in edible plants has grown throughout the world. Botanicals and herbal preparations for medicinal usage contain various types of bioactive compounds. The focus of this paper is on the analytical methodologies, which include the extraction, isolation and characterization of active ingredients in botanicals and herbal preparations. The common problems and key challenges in the extraction, isolation and characterization of active ingredients in botanicals and herbal preparations are discussed. As extraction is the most important step in the analysis of constituents present in botanicals and herbal preparations, the strengths and weaknesses of different extraction techniques are discussed. The analysis of bioactive compounds present in the plant extracts involving the applications of common phytochemical screening assays, chromatographic techniques such as HPLC and, TLC as well as non-chromatographic techniques such as immunoassay and Fourier Transform Infra Red (FTIR) are discussed.
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The concept of growing crops for health rather than for food or fiber is slowly changing plant biotechnology and medicine. Rediscovery of the connection between plants and health is responsible for launching a new generation of botanical therapeutics that include plant-derived pharmaceuticals, multicomponent botanical drugs, dietary supplements, functional foods and plant-produced recombinant proteins. Many of these products will soon complement conventional pharmaceuticals in the treatment, prevention and diagnosis of diseases, while at the same time adding value to agriculture. Such complementation can be accelerated by developing better tools for the efficient exploration of diverse and mutually interacting arrays of phytochemicals and for the manipulation of the plant's ability to synthesize natural products and complex proteins. This review discusses the history, future, scientific background and regulatory issues related to botanical therapeutics.
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Various epidemiologic and experimental in vivo and in vitro studies have suggested that polyphenols derived from fruits, vegetables and beverages might decrease the risk of developing lifestyle diseases, such as cardiovascular disorders and cancer. Apples are a major dietary source of polyphenols. Here we investigated the antitumor activity of apple polyphenols (APs) and procyanidins, namely condensed tannins, both in vitro and in vivo studies. APs and procyanidins inhibited the growth of transplanted B16 mouse melanoma cells and BALB-MC.E12 mouse mammary tumor cells, and increased the survival rate of the host mice-transplanted B16 cells. Among the APs, the apple procyanidins specifically, rather than other polyphenols such as chlorogenic acid, (−)-epicatechin, phloridzin and procyanidin B2, had a major effect on cell proliferation and induced apoptosis in vitro. The apple procyanidins increased mitochondrial membrane permeability and cytochrome c release from mitochondria and activated caspase-3 and caspase-9 within the tumor cells. In addition, we separated eight procyanidin fractions according to the degree of polymerization using normal-phase chromatography, and detected strong anti-tumor activity in the procyanidin pentamer and higher degree fractions. Our results indicate that the oral administration of apple procyanidins inhibits the proliferation of tumor cells by inducing apoptosis through the intrinsic mitochondrial pathway.
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Alcoholic extract of Piper betle (Piper betle L.) leaves was recently found to induce apoptosis of CML cells expressing wild type and mutated Bcr-Abl with imatinib resistance phenotype. Hydroxy-chavicol (HCH), a constituent of the alcoholic extract of Piper betle leaves, was evaluated for anti-CML activity. Here, we report that HCH and its analogues induce killing of primary cells in CML patients and leukemic cell lines expressing wild type and mutated Bcr-Abl, including the T315I mutation, with minimal toxicity to normal human peripheral blood mononuclear cells. HCH causes early but transient increase of mitochondria-derived reactive oxygen species. Reactive oxygen species-dependent persistent activation of JNK leads to an increase in endothelial nitric oxide synthase-mediated nitric oxide generation. This causes loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose polymerase leading to apoptosis. One HCH analogue was also effective in vivo in SCID mice against grafts expressing the T315I mutation, although to a lesser extent than grafts expressing wild type Bcr-Abl, without showing significant bodyweight loss. Our data describe the role of JNK-dependent endothelial nitric oxide synthase-mediated nitric oxide for anti-CML activity of HCH and this molecule merits further testing in pre-clinical and clinical settings.
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Eating five servings of fruits and vegetables per day! This is what is highly recommended and heavily advertised nowadays to the general public to stay fit and healthy! Drinking green tea on a regular basis, eating chocolate from time to time, as well as savoring a couple of glasses of red wine per day have been claimed to increase life expectancy even further! Why? The answer is in fact still under scientific scrutiny, but a particular class of compounds naturally occurring in fruits and vegetables is considered to be crucial for the expression of such human health benefits: the polyphenols! What are these plant products really? What are their physicochemical properties? How do they express their biological activity? Are they really valuable for disease prevention? Can they be used to develop new pharmaceutical drugs? What recent progress has been made toward their preparation by organic synthesis? This Review gives answers from a chemical perspective, summarizes the state of the art, and highlights the most significant advances in the field of polyphenol research.
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Piper betle Linn. is a traditional plant associated with the Asian and southeast Asian cultures. Its use is also recorded in folk medicines in these regions. Several of its medicinal properties have recently been proven. Phytochemical analysis showed the presence of mainly terpenes and phenols in betel leaves. These constituents vary in the different cultivars of Piper betle. In this paper we have attempted to profile eight locally available betel cultivars using the recently developed mass spectral ionization technique of direct analysis in real time (DART). Principal component analysis has also been employed to analyze the DART MS data of these betel cultivars. The results show that the cultivars of Piper betle could be differentiated using DART MS data.
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The longstanding, successful use of herbal drug combinations in traditional medicine demands that we find a rationale for their comparative pharmacological and therapeutic superiority to isolated single constituents. The synergistic efficacy of these combinations can be evaluated and verified by Berenbaum's isobole method, followed by clinical studies performed in comparison with synthetic standard drugs. There are many examples of mono- and multi-extract combinations used presently, which exhibit synergistic efficiency based on multi-target mechanisms of action. Among the natural products, gallocatechins of green tea and curcuminoids of ginger are the presently favoured polyphenols for a possible future use in co-medication with antibiotics and standard anticancer drugs. The main targets were found to be COX 1+2, NF-κB, and membrane glycoproteins that belong to the ATP-binding cassette (ABC) transporter family.
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Every year nearly 200,000 men in the United States are diagnosed with prostate cancer (PCa), and another 29,000 men succumb to the disease. Within certain regions of the world population based studies have identified a possible role for green tea in the prevention of certain cancers, especially PCa. One constituent in particular, epigallocatechin-3-gallate also known as EGCG has been shown in cell culture models to decrease cell viability and promote apoptosis in multiple cancer cell lines including PCa with no effect on non-cancerous cell lines. In addition, animal models have consistently shown that standardized green tea polyphenols when administered in drinking water delay the development and progression of PCa. Altogether, three clinical trials have been performed in PCa patients and suggest that green tea may have a distinct role as a chemopreventive agent. This review will present the available data for standardized green tea polyphenols in regard to PCa chemoprevention that will include epidemiological, mechanism based studies, safety, pharmacokinetics, and applicable clinical trials. The data that has been collected so far suggests that green tea may be a promising agent for PCa chemoprevention and further clinical trials of participants at risk of PCa or early stage PCa are warranted.
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With emerging trends in the incidence of cancer of various organ sites, additional approaches are needed to control human malignancies. Intervention or prevention of cancer by dietary constituents, a strategy defined as chemoprevention, holds great promise in our conquest to control cancer, because it can be implemented on a broader population base with less economic burden. Consistent with this, several epidemiological studies have shown that populations that consume diets rich in fruits and vegetables have an overall lower cancer incidence. Based on these encouraging observations, research efforts from across the globe have focused on identifying, characterizing, and providing scientific basis to the efficacy of various phytonutrients in an effort to develop effective strategy to control various human malignancies. Cancer induction, growth, and progression are multi-step events and numerous studies have demonstrated that various dietary agents interfere with these stages of cancer, thus blocking malignancy. Fruits and vegetables represent untapped reservoir of various nutritive and nonnutritive phytochemicals with potential cancer chemopreventive activity. Grapes and grape-based products are one such class of dietary products that have shown cancer chemopreventive potential and are also known to improve overall human health. This review focuses on recent advancements in cancer chemopreventive and anticancer efficacy of grape seed extract and other grape-based products. Overall, completed studies from various scientific groups conclude that both grapes and grape-based products are excellent sources of various anticancer agents and their regular consumption should thus be beneficial to the general population.
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Research and practice in nutrition relate to food and its constituents, often as supplements. In food, however, the biological constituents are coordinated. We propose that "thinking food first"' results in more effective nutrition research and policy. The concept of food synergy provides the necessary theoretical underpinning. The evidence for health benefit appears stronger when put together in a synergistic dietary pattern than for individual foods or food constituents. A review of dietary supplementation suggests that although supplements may be beneficial in states of insufficiency, the safe middle ground for consumption likely is food. Also, food provides a buffer during absorption. Constituents delivered by foods taken directly from their biological environment may have different effects from those formulated through technologic processing, but either way health benefits are likely to be determined by the total diet. The concept of food synergy is based on the proposition that the interrelations between constituents in foods are significant. This significance is dependent on the balance between constituents within the food, how well the constituents survive digestion, and the extent to which they appear biologically active at the cellular level. Many examples are provided of superior effects of whole foods over their isolated constituents. The food synergy concept supports the idea of dietary variety and of selecting nutrient-rich foods. The more we understand about our own biology and that of plants and animals, the better we will be able to discern the combinations of foods, rather than supplements, which best promote health.
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In the present investigation, we determined the chemotherapeutic efficacy of 9-bromonoscapine (Br-Nos), a more potent noscapine analog, on MCF10A, spontaneously immortalized human normal breast epithelial cells and MCF10A-CSC3, cigarette smoke condensate (CSC)-transformed cells. The results from cytogenetic analysis showed that Br-Nos induced polyploidy and telomeric association in MCF10A-CSC3 cells, while MCF10A cells remained unaffected. Our immunofluorescence data further demonstrated that MCF10A-CSC3 cells were susceptible to mitotic catastrophe on exposure to Br-Nos and failed to recover after drug withdrawal. MCF10A-CSC3 cells exhibited Br-Nos-induced aberrant multipolar spindle formation, which irreversibly impaired the alignment of replicated chromosome to the equatorial plane and finally culminated in cell death. Although MCF10A cells upon Br-Nos treatment showed bipolar spindles with some uncongressed chromosomes, these cells recovered fairly well after drug withdrawal. Our flow-cytometry analysis data reconfirmed that MCF10A-CSC3 cells were more susceptible to cell death compared to MCF10A cells. Furthermore, our results suggest that decreased levels of cdc2/cyclin B1 and cdc2 kinase activity are responsible for Br-Nos-induced mitotic cell arrest leading to cell death in MCF10A-CSC3 cells. This study thus explores the underlying mechanism of Br-Nos-induced mitotic catastrophe in CSC-transformed MCF10A-CSC3 cells and its potential usefulness as a chemotherapeutic agent for prevention of cigarette smoke-induced breast cancer growth.
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The longstanding, successful use of herbal drug combinations in traditional medicine makes it necessary to find a rationale for the pharmacological and therapeutic superiority of many of them in comparison to isolated single constituents. This review describes many examples of how modern molecular-biological methods (including new genomic technologies) can enable us to understand the various synergistic mechanisms underlying these effects. Synergistic effects can be produced if the constituents of an extract affect different targets or interact with one another in order to improve the solubility and thereby enhance the bioavailability of one or several substances of an extract. A special synergy effect can occur when antibiotics are combined with an agent that antagonizes bacterial resistance mechanisms. The verification of real synergy effects can be achieved through detailed pharmacological investigations and by means of controlled clinical studies performed in comparison with synthetic reference drugs. All the new ongoing projects aim at the development of a new generation of phytopharmaceuticals which can be used alone or in combination with synthetic drugs or antibiotics. This new generation of phytopharmaceuticals could lend phytotherapy a new legitimacy and enable their use to treat diseases which have hitherto been treated using synthetic drugs alone.
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Epidemiological studies have shown marked variations in prostate cancer incidence and mortality across different geographic regions, leading to the rising interest in the role of nutrition in prostate cancer risk. There is also a large body of evidence that a diverse diet, rich in vegetables, can reduce the risk of prostate cancer. In this review, the role of various kinds of vegetables and their bioactive compounds associated with prostate cancer risk, and the underlying mechanisms of these associations are summarized. There is accumulating evidence to support the consumption of lycopene, in particular tomato and tomato-based products, as protective factors against prostate cancer. Evidence on the protective role of beta-carotene was inconsistent from cohort and case-control studies. Evidence on the effect of pulses or soy consumption on prostate cancer risk was limited but suggestive of decreased risk with increased pulses or soy consumption. However, the role of vitamin C, vitamin E, allium vegetables, and cruciferous vegetables on prostate cancer risk remains to be determined due to limited evidence. Although the impact on prostate cancer risk differs among various vegetables and their constituent nutrients, the overall benefits of plant based diet on cancer prevention and other diet-related diseases should be promoted.
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The effect of betel leaf extract and some of its constituents, eugenol, hydroxychavicol, beta-carotene and alpha-tocopherol, on benzo[a]pyrene-induced forestomach neoplasia in male Swiss mice was examined. Betel leaf and its constituents decreased the number of papillomas per animal with the maximum protection, considering molar dosage, exhibited by beta-carotene and alpha-tocopherol. Except for beta-carotene, eugenol, hydroxychavicol and alpha-tocopherol increased the levels of reduced glutathione in the liver while glutathione S-transferase activity was enhanced by all except eugenol. Of seven sources, Banarasi betel leaves showed the maximum amounts of beta-carotene and alpha-tocopherol.
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Effects of topically applied betel leaf extract (BLE) and its constituents. beta-carotene, alpha-tocopherol, eugenol and hydroxychavicol on 7,12-dimethylbenz(a)anthracene (DMBA) induced skin tumors were evaluated in two strains of mice. BLE, beta-carotene and alpha-tocopherol, significantly inhibited the tumor formation by 83, 86, 86% in Swiss mice and 92, 94 and 89% in male Swiss bare mice respectively. Hydroxychavicol showed 90% inhibition in Swiss bare mice at 24 weeks of treatment. Eugenol showed minimal protection in both strains of mice. The mean latency period and survivors in BLE, beta-carotene, alpha-tocopherol and hydroxychavicol treated groups were remarkably high as compared to DMBA alone treated group. Intraperitoneal injection of betal leaf constituents showed a significant effect on both glutathione and glutathione S-transferase levels in the Swiss mouse skin.
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In folklore medicine, extracts of the leaves of the subtropical plant Catharanthus roseus (L.) G. Don (sometimes known as Madagascar periwinkle) were reputed to be useful in the treatment of diabetes. This review describes how attempts to verify the antidiabetic properties of the extracts led instead to the discovery and isolation of two complex indole alkaloids, vinblastine and vincristine, which are used in the clinical treatment of a variety of cancers. The two alkaloids, although structurally almost identical, nevertheless differ markedly in the type of tumors that they affect and in their toxic properties. These and related alkaloids have been the subject of many pharmacological and biochemical investigations both in vivo and in vitro in the search for improved cancer treatments. A model system used in these studies, a transplantable lymphoma in Noble strain rats designated Nb2 node, has serendipitously led to the development of a highly sensitive and specific bioassay for lactogenic hormones.