Cancer Protective Role of Selected Dietary Polyphenols via Modulating Keap1/Nrf2/ARE and Interconnected Signaling Pathways.

The Kelch-like ECH associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway is considered a master regulator of the cellular response against oxidative stress. Numerous studies have investigated the role of Keap1/Nrf2/ARE in the different stages of cancer development. A comprehensive literature search using the Google Scholar, PubMed and Science Direct databases was performed to retrieve information related to the cancer protective role of 21 selected dietary polyphenols via modulation of Keap1/Nrf2/ARE and interconnected signaling pathways/proteins (MAPK/ERK1/2, PI3K/Akt, PKD, JNKs, AMPK, NF-κB). Information on the anti-inflammatory and cytoprotective effects caused by the selected dietary polyphenols following Keap1/Nrf2/ARE modulation was also collected. The majority of the studies analyzed in this review demonstrated the cancer protective role of the selected polyphenols mostly in-vitro. Limited work was performed in-vivo and only one of the selected polyphenols was subjected to a clinical trial. It is hoped that this review will encourage further in-vivo studies to confirm the cancer protective role of methyleugenol, carnosol, and catechin, as well as further clinical trials to unambiguously establish whether the consumption of dietary polyphenols impacts on the incidence and progression of cancers in humans.

Supplementation of syringic acid-rich Phrynium pubinerve leaves imparts protection against allergic inflammatory responses by downregulating iNOS, COX-2, and NF-κB expressions.

Background: The present study was designed to characterize the role of ethanolic leaf extract of Phrynium pubinerve Blume (EPP) supplement in attenuating allergic inflammation, encouraged by the presence of syringic acid in it, as this phenolic acid is reportedly promising in suppressing serum immunoglobulin E (IgE) and inflammatory cytokine levels. Materials and methods: HPLC-DAD dereplication analysis was performed to determine the presence of the vital polyphenolic metabolites. The efficacy of EPP against lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 cells was evaluated by measuring its inhibitory effects on NO and ROS/RNS production. The expressions of major inflammation-associated molecules (iNOS, COX-2, NF-κB, IL-6, and TNF-α) in RAW 264.7 cells were assessed through Western blot. Physiological and behavioral changes, BMI, and different biochemical parameters in mice blood serum were investigated in the toxicological assays. Formaldehyde-induced paw edema test in mice was conducted using established animal model. TDI-induced allergic model in mice was carried out to determine different allergy-like symptoms, and differential white blood cell (WBC) counts in blood and bronchoalveolar lavage (BAL) fluid. The intermolecular interaction analysis of the identified major metabolite of EPP with H1R and iNOS was studied by molecular docking. Results: HPLC-DAD analysis showed the presence of syringic acid (89.19 mg/100 g EPP) and a few other compounds. LPS-induced NO generation was reduced by EPP in a concentration-dependent manner, showing IC50 of 28.20 ± 0.27 µg/mL. EPP exhibited a similar inhibitory effect on ROS/RNS production with IC50 of 29.47 ± 2.19 µg/mL. Western blotting revealed that EPP significantly downregulated the expressions of iNOS, COX-2, NF-κB, IL-6, and TNF-α in RAW 264.7 cells when challenged with LPS. The toxicological assays confirmed the dosage and organ-specific safety of EPP. In the formaldehyde-induced paw edema test, EPP caused a 66.41% reduction in mice paw volume at 500 mg/kg dose. It ameliorated TDI-induced allergy-like symptoms and decreased different inflammatory WBCs in mice's blood and BAL fluid in a dose-dependent manner. Finally, syringic acid demonstrated mentionable intermolecular binding affinity towards H1R (-6.6 Kcal/moL) and iNOS (-6.7 Kcal/moL). Conclusions: Collectively, considerable scientific reasoning was obtained in favor of the suppressive potential of EPP against allergic inflammatory responses that are proposed to be exerted via the downregulation of iNOS, COX-2, and NF-κB expressions, H1R antagonism and suppression of cytokines, such as IL-6, and TNF-α.

Crosstalk between xanthine oxidase (XO) inhibiting and cancer chemotherapeutic properties of comestible flavonoids- a comprehensive update.

Gout is an inflammatory disease caused by metabolic disorder or genetic inheritance. People throughout the world are strongly dependent on ethnomedicine for the treatment of gout and some receive satisfactory curative treatment. The natural remedies as well as established drugs derived from natural sources or synthetically made exert their action by mechanisms that are closely associated with anticancer treatment mechanisms regarding inhibition of xanthine oxidase, feedback inhibition of de novo purine synthesis, depolymerization and disappearance of microtubule, inhibition of NF-ĸB activation, induction of TRAIL, promotion of apoptosis, and caspase activation and proteasome inhibition. Some anti-gout and anticancer novel compounds interact with same receptors for their action, e.g., colchicine and colchicine analogues. Dietary flavonoids, i.e., chrysin, kaempferol, quercetin, fisetin, pelargonidin, apigenin, luteolin, myricetin, isorhamnetin, phloretinetc etc. have comparable IC50 values with established anti-gout drug and effective against both cancer and gout. Moreover, a noticeable number of newer anticancer compounds have already been isolated from plants that have been using by local traditional healers and herbal practitioners to treat gout. Therefore, the anti-gout plants might have greater potentiality to become selective candidates for screening of newer anticancer leads.

Evaluation of the mechanism of action of albendazole on adult rat lungworm (Angiostrongyluscantonensis).

Albendazole is considered the anthelmintic of choice for the management of rat lungworm disease (neuroangiostrongyliasis), due to its broad spectrum of nematocidal activity and its ability to cross the blood-brain barrier. Albendazole binds to ß-tubulins, preventing their polymerization into microtubules, thereby corrupting the cascade of cell division at metaphase, which ultimately leads to the death of individual cells and eventually the death of the parasite. Inhibition of microtubule formation will also hinder the axoplasmic transport system, affecting the neuronal activities of the parasite. While this mechanism has been explicated in other parasitic and non-parasitic nematodes, it has never been evaluated in Angiostrongylus cantonensis. This study evaluates the antimitotic effects of albendazole sulphoxide (active metabolite) on the microtubules of adult A. cantonensis using the tubulin polymerization assay and measures its effects on worm viability using the colorimetric MTT assay. Three different concentrations of albendazole (62.5 µM, 250 µΜ, and 1 mM) were evaluated. We saw a statistically significant dose-dependent reduction in the band intensity of polymerized tubulins (or microtubules) (P = 0.019), suggesting that albendazole imparts its antimitotic effect in a dose-dependent manner. Similarly, our MTT assay showed a dose-dependent decrease in formazan intensity (proportional to cell viability), suggesting that the rate of nematocidal activity of albendazole is also proportional to its concentration. In compiling the results from both these experiments, a correlation between the microtubule assembly and worm viability is evident.

Altersolanol B, a fungal tetrahydroanthraquinone, inhibits the proliferation of estrogen receptor-expressing (ER+) human breast adenocarcinoma by modulating PI3K/AKT, p38/ERK MAPK and associated signaling pathways.

The present study focused on the apoptosis-inducing effects and cellular signal-modulating properties of altersolanol B (AB), a minor fungal tetrahydroanthraquinone (THAQ) metabolite, in the estrogen receptor positive (ER+) human breast adenocarcinoma cell line, MCF-7. AB demonstrated approximately 4-fold greater antiproliferative activity in ER+ MCF-7 cells (IC50 5.5 µM) compared to the ER-negative (triple-negative) MDA-MB-231 (IC50 21.3 µM). The viability of normal breast fibrocystic epithelial cells, MCF-10A, was unaffected. AB induced intrinsic apoptosis in MCF-7 cells; it triggered the activation of caspase 9 and poly (ADP-ribose) polymerase (PARP), upregulated the expression of pro-apoptotic Bax, and downregulated the expression of anti-apoptotic Bcl-2. AB induced cell cycle arrest at G0/G1, as indicated by the downregulation of key checkpoint proteins operating at the G0/G1 phase of the cell cycle (cyclin D1, CDK4 and CDK2). The observed increase in p21Waf1/Cip1 and p53 expression may facilitate cell cycle arrest, and the subsequent induction of apoptosis. AB lacked significant effects on intracellular ROS levels, while it down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2), and the Nrf2-dependent antioxidant enzyme, heme oxygenase-1. The compound disrupted AKT signaling through the downregulation of phospho-AKT and phospho-FOXO1, and the upregulation of PTEN, a phosphatase and tumor suppressor that negatively regulates the PI3K/AKT pathway. AB also disrupted the phosphorylation of AKT-controlled eukaryotic translation initiation factor, 4E-BP1, and GSK-3ß, both of which are aberrantly regulated in human cancer. The AB-dependent downregulation of NF-κB was corroborated by the inhibition of TNFα-induced NF-κB activity as monitored in a luciferase reporter. The NF-κB inhibitory activity of AB was 3-fold more potent than that of the standard inhibitor, N-p-Tosyl-l-phenylalanine chloromethyl ketone. In addition to reducing the pro-survival effects of NF-кB, the inhibition of AKT phosphorylation by AB may also lead to FOXO1-mediated growth arrest and apoptosis. AB upregulated the expression of phospho-MKK4 and phospho-p38, and downregulated the expression of phospho-MEK1/2 and phospho-ERK1/2 indicating opposing effects on the two important oncogenic signaling cascades that are aberrantly activated in many cancers. AB disrupted both the AKT and ERK1/2 signaling pathways leading to apoptosis in ER+ MCF-7 cells through mitochondria-associated mechanisms coupled with the potent inhibition of NF-кB activation. The clinical limitations of multi-agent combination therapy that targets multiple pathways in cancer may potentially be circumvented by using a single molecule, such as AB, that inhibits both AKT and ERK1/2 signaling. Our preliminary study suggested that the THAQ pharmacophore, with its disrupted conjugated ring system and relative redox inactivity, may possess greater mechanistic advantage against ER+ breast cancer when compared to the fully conjugated ring systems of the anthraquinone that possess intrinsic redox activity and DNA interacting ability. This study supports the continued investigation of THAQs as lead molecules in anticancer drug discovery and development.

Regulation of the redox signaling and inflammation by Terminalia myriocarpa leaves and the predictive interactions of it's major metabolites with iNOS and NF-ĸB.

ETHNOPHARMACOLOGICAL RELEVANCE: The present study was designed to investigate the regulation of the redox signaling and inflammation by ethanolic leaf extract of Terminalia myriocarpaVan Heurck & Müller (ETM), inspired by the reported antioxidant potential of the plant bark and the anti-edema effect of the same genus. MATERIALS AND METHODS: HPLC-DAD dereplication study was conducted to detect the major polyphenolic secondary metabolites. In-vitro DPPH free radical scavenging assay, nitric oxide (NO) scavenging assay, Fe2+ ion chelating ability assay and reducing power assay were conducted to evaluate the antioxidant capacity. The molecular mechanism of anti-inflammation was investigated via assessing the NO and NF-ĸB inhibiting properties in different cell lines. In-vivo carrageenan and histamine-induced edema tests were conducted using established animal models. Pro-inflammatory proteins iNOS and NF-κB were docked against the major metabolites of ETM in the in-silico study. RESULTS: HPLC dereplication analysis revealed the presence of considerable amount of ellagic acid, where methyl-(S)-flavogallonate was previously reported in T. myriocarpa. Significant antioxidant activity was found in every in- vitro redox assay conducted. NO was reduced in RAW 264.7 cells, showing 83.67 ± 4.18% inhibitory activity at the highest tested concentration. TNF-α induced NF-κB was also observed to be reduced in 293/NF-кB-luc cells with an inhibitory activity of 66.23 ± 0.81% at the highest dose tested. In-vivo carrageenan-induced edema test demonstrated significant anti-inflammatory activity (p < 0.05; p < 0.01) at both doses of 250 and 500 mg/kg with 60.10% highest reduction in rat paw volume. Using same doses, histamine-induced edema test exhibited mentionable anti-inflammatory potential (p < 0.05; p < 0.01) with 67.91% highest reduction in rat paw volume. Moreover, ellagic acid and methyl-(S)-flavogallonate showed significant binding affinity with iNOS (-8.5 and -8.7 Kcal/moL, respectively) and NF-κB (-7.3 and -7.3 Kcal/moL, respectively). CONCLUSION: Mentionable basis was found on behalf of the anti-inflammatory and antioxidant potentials of ETM which might be correlated with its NF-ĸB inhibiting properties.

Molecular Docking and Molecular Dynamics Simulation Studies of Triterpenes from Vernonia patula with the Cannabinoid Type 1 Receptor.

A molecular docking approach was employed to evaluate the binding affinity of six triterpenes, namely epifriedelanol, friedelin, α-amyrin, α-amyrin acetate, ß-amyrin acetate, and bauerenyl acetate, towards the cannabinoid type 1 receptor (CB1). Molecular docking studies showed that friedelin, α-amyrin, and epifriedelanol had the strongest binding affinity towards CB1. Molecular dynamics simulation studies revealed that friedelin and α-amyrin engaged in stable non-bonding interactions by binding to a pocket close to the active site on the surface of the CB1 target protein. The studied triterpenes showed a good capacity to penetrate the blood-brain barrier. These results help to provide some evidence to justify, at least in part, the previously reported antinociceptive and sedative properties of Vernonia patula.

Antinociceptive and sedative activity of Vernonia patula and predictive interactions of its phenolic compounds with the cannabinoid type 1 receptor.

When tested in the acetic acid-induced writhing and formalin-induced paw-licking tests, the ethanol extract of Vernonia patula (VP) aerial parts showed significant antinociceptive activity. In neuropharmacological tests, it also significantly delayed the onset of sleep, increased the duration of sleeping time, and significantly reduced the locomotor activity and exploratory behaviour of mice. Five phenolic compounds, namely gallic acid, vanillic acid, caffeic acid, quercetin and kaempferol, were detected in VP following HPLC-DAD analysis. The presence of these phenolic compounds in VP provides some support for the observed antinociceptive and sedative effects. A computational study was performed to predict the binding affinity of gallic acid, vanillic acid, caffeic acid, quercetin and kaempferol towards the cannabinoid type 1 (CB1) receptor. Caffeic and vanillic acid showed the highest probable ligand efficiency indices towards the CB1 target. Vanillic acid displayed the best blood-brain barrier penetration prediction score. These findings provide some evidence for the traditional use of VP to treat pain.

Molecular Phylogenetics and Biological Potential of Fungal Endophytes From Plants of the Sundarbans Mangrove.

The Sundarbans forest in Bangladesh is the world's largest mangrove. It is a unique ecosystem where living organisms face extreme challenges to compete for survival. Such competition results in the production of bioactive molecules which are useful for agriculture and human health. In this study, eighty fungal endophytes from nine mangrove plants growing in a region, as yet unexplored, of the Sundarbans were isolated by surface sterilisation and pure culture techniques. Among the eighty isolates subjected to a preliminary antimicrobial screening using an agar plug diffusion assay, only fifteen showed some promising activity. These were subsequently identified by polymerase chain reaction of their ITS gene. Extracts prepared from the identified isolates were screened for antimicrobial, antioxidant, cytotoxic and α-glucosidase inhibitory activities. Their total polyphenol and flavonoid content and their FRAP value were also determined. All endophytes are reported for the first time in the plants under investigation.

Ficus hispida Bark Extract Prevents Nociception, Inflammation, and CNS Stimulation in Experimental Animal Model.

Background. Ficus hispida is traditionally used in the ailment of pain, inflammation, and neurological disorders. The present study set out to evaluate the in vivo antinociceptive, anti-inflammatory, and sedative activity of the ethanol extract of Ficus hispida bark (EFHB). Methods. The antinociceptive activity of EFHB was evaluated by using acetic acid induced writhing, formalin, hot plate, and tail immersion methods in Swiss albino mice. Its anti-inflammatory activity was assessed by using carrageenan and histamine induced rat paw oedema test in Wister rats. The central stimulating activity was studied by using pentobarbital induced hypnosis, hole cross, and open field tests in Swiss albino mice. Results. EFHB demonstrated antinociceptive activity both centrally and peripherally. It showed 62.24% of writhing inhibition. It significantly inhibited licking responses in early (59.29%) and late phase (71.61%). It increased the reaction time to the thermal stimulus in both hot plate and tail immersion. It inhibited the inflammation to the extent of 59.49%. A substantial increase in duration of sleep up to 60.80 min and decrease of locomotion up to 21.70 at 400 mg/kg were also observed. Conclusion. We found significant dose dependent antinociceptive, anti-inflammatory, and sedative properties of EFHB in experimental animal models.

Anti-Inflammatory and Antioxidant Activity of Acalypha hispida Leaf and Analysis of its Major Bioactive Polyphenols by HPLC.

PURPOSE: Inflammation and oxidative stress can lead to different chronic diseases including cancer and atherosclerosis. Many medicinal plants have the potential to show as anti-inflammatory activity. Present investigation was performed to investigate anti-inflammatory, antioxidant activity, and quantification of selected bioactive plant polyphenols of the ethanol (EAH) and aqueous (AAH) extracts of Acalypha hispida (Euphorbiaceae) leaves. METHODS: Anti-inflammatory activity was evaluated by carragenan and histamine induced rat paw edema models while antioxidant capacity was evaluated by DPPH free radical scavenging, Fe+2 chelating ability, reducing power, NO scavenging, total phenolic and total flavonoid content assay. Identification and quantification of bioactive polyphenols was done by HPLC. RESULTS: At the doses of 200 and 400 mg/kg, both EAH and AAH showed statistically significant inhibition of paw volume in the anti-inflammatory activity test. Both the extracts showed DPPH scavenging (IC50: 14 and 17 µg/ml, respectively), Fe+2 ion chelating (IC50: 40 and 46 µg/ml, respectively), NO scavenging activity (65.49 and 60.66% inhibition at 100 µg/ml), and concentration dependent reducing power ability. For EAH and AAH, flavonoid content was 126.30 and 149.72 mg QE/g dry extract, while phenolic content was 130.51 and 173.80 mg GAE/g dry extract, respectively. HPLC analysis of EAH and AAH indicated the presence of high content of ellagic acid along with other phenolic constituents. CONCLUSION: High content of ellagic acid along with other phenolic constituents might have played an important role in the observed anti-inflammatory and antioxidant activity.

Investigation of the Key Pharmacological Activities of Ficus racemosa and Analysis of Its Major Bioactive Polyphenols by HPLC-DAD.

Objective. Oxidative stress leads to numerous physiological disorders including infectious diseases, inflammation, and cancer. The present study was carried out to investigate antioxidant, antibacterial, and cytotoxic activity of methanol crude extract of leaves and fruits of the Ficus racemosa (LCME and FCME, resp.) and to analyse its major bioactive polyphenols by HPLC-DAD. Methods. Antioxidant capacity of the extracts was evaluated by DPPH free radical scavenging, reducing power, total phenolic, total flavonoid, total tannin content assay, superoxide radical, hydroxyl radical, and hydrogen peroxide scavenging assay. Identification and quantification of bioactive polyphenols were done by HPLC-DAD method. Antibacterial activity was tested by "disc diffusion" method. Brine shrimp lethality assay was carried out to check the cytotoxic potential. Result. Both LCME and FCME showed DPPH scavenging ability and concentration dependent reducing power activity. They had phenolic content, flavonoid content, and tannin content. Both the extracts showed superoxide radical scavenging ability, hydroxyl radical scavenging ability, and hydrogen peroxide scavenging ability. HPLC analysis of LCME and FCME indicated the presence of significant amount of gallic acid along with other phenolic constituents. Conclusion. Significant amount of gallic acid along with other phenolic constituents might have played an important role in the observed antioxidant, antibacterial, and cytotoxic activity.

Ethnomedicinal survey of various communities residing in Garo Hills of Durgapur, Bangladesh.

BACKGROUND: Garo Hills represents one of earliest human habitation in Bangladesh preserving its ancient cultures due to the geographic location. It is situated in the most northern part of Durgapur sub-district having border with Meghalaya of India. Durgapur is rich in ethnic diversity with Garo and Hajong as the major ethnic groups along with Bangalee settlers from the mainstream population. Thus the ethnomedicinal practice in Garo Hills is considered rich as it encompasses three different groups. Present survey was undertaken to compile the medicinal plant usage among the various communities of the Garo Hills. METHODS: The ethnomedicinal data was collected through open and focussed group discussions, and personal interviews using semi-structured questionnaire. A total of 185 people were interviewed, including the three community people and their traditional health practitioners (THPs). The usage of the plants were further analysed and are presented as use value (UV), informant consensus factor (ICF) and fidelity level (FL). RESULTS: A total of 71 plants from 46 families and 64 genera were documented during our survey. Gastrointestinal disorders represented the major ailment category with the use of 36 plant species followed by dermatological problems (25 species). The ICF ranged from 0.90 to 0.99, with an average value of 0.96. Leaves (41) were the principle source of medication followed by fruits (27). Trees (33) were the major plant type used in the ethnobotanical practice. A total of 25 plants showed high FL (70.91 to 100 %) with 12 plants showing maximum FL (100 %). A number of the plants appear to have unique ethnomedicinal uses. CONCLUSION: Present investigation revealed a rich traditional practice in the studied region, which provides primary health care to the local community. This compilation of the ethnobotanical knowledge can help researchers to identify the uses of various medicinal plants that have a long history of use.

In-vitro anthelmintic activity of three Bangladeshi plants against Paramphistomum cervi and Haemonchus contortus.

BACKGROUND: Conventional plant-based therapies act as an important therapeutic tool for the treatment of worm infections all over the world and continuous evaluation of medicinal plants to find new potential lead compounds should be carried out. METHODS: In-vitro analysis was conducted to evaluate the probable anthelmintic effect of crude aqueous and hydroalcoholic extracts of Ananas sativus leaves, Erythrina variegata barks and Alocasia indica rootstocks, against adult Paramphistomum cervi (Trematoda) and Haemonchus contortus (Nematode). RESULTS: Among all three concentrations (25, 50, and 100 mg/mL), the hydroalcoholic leaf extract of A. sativus exhibited paralysis and death time ranged between 7.26 to 26.76 min and 15.40 to 35.55 min respectively for P. cervi while that for H. contortus was 14.70 to 42.43 min and 23.43 to 56.34 min, respectively. Moreover, aqueous extract exhibited paralysis and death time ranged between 7.66 to 28.72 min and 18.30 to 33.00 min, respectively, for P. cervi whereas paralysis and death time ranged between 23.34 to 37.88 min and 31.08 to 58.30 min respectively for H. contortus. Both extracts of E. variegata bark and A. indica tuber showed comparatively less significant anthelmintic activity. All results were statistically significant (p < 0.001). CONCLUSIONS: A. sativus leaf displayed favorable anthelmintic activity on both P. cervi and H. contortus, whereas E. variegata barks and A. indica rootstocks showed insignificant result.