Identifying druggable targets from active constituents of Azadirachta indica A. Juss. for non-small cell lung cancer using network pharmacology and validation through molecular docking.

INTRODUCTION: Azadirachta indica A. Juss. is a well-known medicinal plant that has been used traditionally to cure various ailments in every corner of the globe. There are many in vitro and in vivo experimental evidences in connection with the bioactivity of the extracts of this plant. Lung cancer is the deadliest form of cancer and contributes to the most cancer related deaths. The mode of action of anticancer components of this plant is still to be established explicitly. OBJECTIVE: The objective of this study is to identify druggable targets of active constituents of A. indica A. Juss. for non-small cell lung cancer (NSCLC) using network pharmacology and validation of activity through molecular docking analysis. METHODOLOGY: Targets of all the active phytochemicals from A. indica were predicted and genes related to NSCLC were retrieved. A protein-protein interaction (PPI) network of the overlapping genes were prepared. Various databases and servers were employed to analyse the disease pathway enrichment analysis of the clustered genes. Validation of the gene/protein activity was achieved by performing molecular docking, and ADMET profiling of selected phytocompounds was performed. RESULT: Gene networking revealed three key target genes as EGFR, BRAF and PIK3CA against NSCLC by the active components of A. indica. Molecular docking and ADMET analysis further validated that desacetylnimbin, nimbandiol, nimbin, nimbinene, nimbolide, salannin and vepinin are the best suited anti- NSCLC among all the phytocompounds present in this plant. CONCLUSION: The present study has provided a better understanding of the pharmacological effects of active components from A. indica and its potential therapeutic effect on NSCLC.

Natural Flavonoids in the Prevention and Treatment of Lung Cancer: A Pharmacological Aspect.

Deadly disease cancer has many types; among them, lung cancer is responsible for the highest number of cancer mortality. Existing therapies as well as drugs for treating lung cancer are not effective and are often associated with innumerable side effects and toxicities. For these reasons, researchers have been working on developing novel anti-cancer medicines from plants and other natural sources that have a high safety profile. Natural flavonoids are a polyphenolic group of phytochemicals extracted from plants and other plant-derived compounds. Natural flavonoids are gaining popularity due to their unique and priceless medicinal properties, including anticancer properties. Several researchers have already declared that flavonoids possess the ability to treat different cancers, particularly lung cancer. The bioactivity of natural flavonoids is mainly due to their structural diversity. Natural flavonoids fight against lung cancer by regulating redox homeostasis, upregulating apoptosis, pro-apoptotic factors, and survival genes, arresting cell cycle progression, autophagy, reducing cell proliferation and invasiveness, maintaining inflammation response, downregulating anti-apoptotic factors, and targeting lung cancer signaling pathways. Flavonoids can act alone or synergistically with other agents to treat lung cancer. Due to these reasons, it is possible to use natural flavonoids as pharmaceutical leads to prevent and treat lung cancer.

Ethnomedicinal, Phytochemical and Nutra-pharmaceutical Potentials of Indian Arrowroot (Curcuma angustifolia Roxb).

Indian Arrowroot (Curcuma angustifolia Roxb) belonging to the Zingiberaceae family is widely distributed in India and some parts of Nepal, Thailand, Bangladesh and Pakistan. It is traditionally used as medicine for treating various diseases and also used as food. Few data are available about its application in pharmacology and therapeutics. Literature search for related contents, keywords such as "Curcuma angustifolia Roxb", "traditional food", "ethnomedicine", "pharmacology", "phytochemicals", "pharmacological activities" were used in search engines including PubMed, Google Scholar, Scopus, ScienceDirect, and Semantic Scholar. Secondary metabolites found in Indian Arrowroot include essential oils, alkaloids, flavonoids, terpenoids, phytosterols, terpenes, phenols, and others. Pharmacological activities such as antioxidant, antiinflammatory, anti-proliferative, anti-ulcerogenic, hepatoprotective, and anti-cancerous activities have been shown by Indian Arrowroot (Curcuma angustifolia Roxb). The presence of nutritional value and pharmaceutical potential gained demand in the various food production industries and pharmacology research. It may play a vital role in future studies of Curcuma angustifolia Roxb as ethnomedicine and further exploitation in pharmacological studies.

Acteoside (Verbascoside): A Prospective Therapeutic Alternative against Hepatocellular Carcinoma by Inhibiting the Expression of AXL, FGFR, BRAF, TIE2 and RAF1 Targets.

AIM: Hepatocellular carcinoma (HCC) is the world's second leading cause of cancerrelated mortality and the fifth most prevalent cancer overall. Several synthetic and plant-based remedies are in practice to treat diverse liver disorders. Because of their minimal side effects and protective characteristics, plant phenolics have the potential to become alternative therapeutics, replacing currently existing HCC medications. The present study identifies the plant phenolics as having the capacity to inhibit HCC with low side effects and cost efficiency. BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality, despite the proven effectiveness of screening programs for at-risk individuals, the majority of patients have disease progression or tumor characteristics that preclude curative therapies at the time of diagnosis. Acteoside (Verbascoside) is a naturally occurring phenylethanoid glycoside found throughout the plant kingdom. Acteoside is a physiologically active chemical with the number of pharmacological and protective effects against various liver illnesses. OBJECTIVES: Currently used HCC medications have a variety of side effects. Plant-based chemicals offer the possibility of treating HCC with minimal side effects. The work is targeted to find the best phytochemical (plant phenolic) lead molecule for future drug development research against Hepatocellular carcinoma. METHODS: The targets were selected based on an analysis of relevant literature, and the 3D structures of the selected receptors were obtained in. pdb format from the RCSB-Protein data bank (PDB, http://www.rscb.org/pdb). Based on a review of the literature, sixty plant secondary metabolites, or plant phenolics, were selected. The ligand structures were obtained and downloaded in.sdf format from the NCBI PubChem chemicals database (https://pubchem.ncbi.nlm.nih.gov/). Molecular docking between the receptor and ligands was accomplished using the Molegro Virtual Docker 6.0 (MVD) software. RESULTS: The target RAF1, BRAF chain 1, TIE2 chain 2 FGFR1, FGFR2, AXL, and FGFR4 showed the best binding effectiveness with acteoside compared to their respective positive control. RET chain 1 and BRAF chain 2 acteoside showed prominent binding efficacy after Curcumin, and Epigallocatechingallate, respectively, against positive control. Present findings clearly point towards the potentiality of acteoside in inhibiting various HCC targets. CONCLUSION: Acteoside may be used as a prominent lead molecule in the future treatment of hepatic cancer with its multifaceted binding efficiencies against various target proteins.

Effect of acetone fraction of Ottelia alismoides on the G2/M cell cycle arrest and apoptosis in the human carcinoma cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: The North-eastern parts of India have immense therapeutic floras, Ottelia alismoides is an aquatic plant that has been in use for a long time in traditional medicine for treating diseases like cancer, tuberculosis, diabetes, febrifuge, hemorrhoids, and rubefacient. In lung and skin carcinoma cells with a high rate of proliferation and metastasis including drug resistance and non-specific target activity, generates important challenges towards their treatment strategy. Thus, finding novel therapeutic targets to treat lung and skin cancer progression is essential to enhance the patients' survival with treatment. AIM OF THE STUDY: The purpose of this study was to evaluate the apoptotic potential of acetone extract of O. alismoides (L.) Pers. (OA-AC) and to identify the compounds responsible for this effect, HRLC-MS-QTOF analysis of the extract has been undertaken along with in-silico molecular docking analysis of the identified compounds. MATERIALS AND METHODS: A549 and A431 cells were treated with acetone extract of O. alismoides (OA-AC) at 24 h and 48 h exposure and cell cycle phase distribution was evaluated and also apoptosis induction activity was evaluated by OA-EtBr staining and Mitochondrial outer membrane potential assay. Western blotting was performed for the evaluation of apoptotic protein expression. At last, the HR-LCMS of OA-AC was analyzed to identify the compounds responsible for the apoptotic activity of the extract. RESULTS: The cell cycle phase distribution analysis in A549 and A431 cells at 24hrs exposure with 10 µg/mL and 25 µg/mL of OA-AC showed a potent arrest or blockage at the G2/M phase of the cell cycle with reduced expression of cyclin B and p-Cdc2. At 48 h exposure, apoptosis was observed in these cancer cells with elevated expression of Bax, p21 and cleaved caspase 3 and reduced expression of the Bcl2. CONCLUSION: AO-EtBr staining of these cancer cells reveals that the death induced by OA-AC was apoptotic in nature with depolarization of mitochondrial membrane due to loss or damage of the mitochondrial membrane. The HRLC-MS-QTOF analysis of OA-AC depicted 14 major isolable compounds and molecular docking analysis displayed 4 compounds that might act as an inhibitor of cyclin B for G2/M phase arrest that leads to apoptotic induction in the cells.

Molecular docking analysis of flupenthixol and desmethylastemizole with the apoptotic regulator proteins CFLAR and TRAF2 linked to lung carcinoma.

It is known that molecular changes in apoptotic genes due to mutation may cause disruption of apoptotic pathway resulting in an abrupt increase in cell proliferation. Therefore, it is of interest to identify compounds that could potentially replenish the changes in the apoptotic pathway, resulted from mutation. The gene network analysis using the Network Analyzer Plugin of Cytoscape (3.5.1) shows CFLAR and TRAF2 as influential genes in the apoptotic pathway. Mutation in these genes brings loss in apoptotic property of a cell and thus increases the cell proliferating activity. Thus, data on the molecular docking analysis of four natural compounds from Ottelia alismoides (L.) Pers with the two target proteins were reported. Flupenthixol and desmethylastemizole was found to be two efficient ligand molecules based on ligand-target interaction. In stereochemical quality assessment, the Ramachandran plot analysis of receptors indicates the better stereochemical characteristics for receptor-ligand interaction.

Naturally Occurring Calanolides: Occurrence, Biosynthesis, and Pharmacological Properties Including Therapeutic Potential.

Calanolides are tetracyclic 4-substituted dipyranocoumarins. Calanolide A, isolated from the leaves and twigs of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens, is the first member of this group of compounds with anti-HIV-1 activity mediated by reverse transcriptase inhibition. Calanolides are classified pharmacologically as non-nucleoside reverse transcriptase inhibitors (NNRTI). There are at least 15 naturally occurring calanolides distributed mainly within the genus Calophyllum, but some of them are also present in the genus Clausena. Besides significant anti-HIV properties, which have been exploited towards potential development of new NNRTIs for anti-HIV therapy, calanolides have also been found to possess anticancer, antimicrobial and antiparasitic potential. This review article provides a comprehensive update on all aspects of naturally occurring calanolides, including their chemistry, natural occurrence, biosynthesis, pharmacological and toxicological aspects including mechanism of action and structure activity relationships, pharmacokinetics, therapeutic potentials and available patents.

Plant utilization against digestive system disorder in Southern Assam, India.

ETHNOPHARMACOLOGICAL RELEVANCE: Being one of the most common types of life threatening diseases in Southern Assam, India, the digestive system disorders (DSD) have gained much attention in recent decades. Traditional beliefs and inadequate income of mass population result in the use of alternative phytotherapies to treat the diseases. AIM OF THE STUDY: The present paper documents the medicinal knowledge and utilization of plants for treatment of digestive system disorders in Southern Assam, India by Disease Consensus Index (DCI). It also determines the most suitable plant species used to treat digestive system disorders in the study area. MATERIALS AND METHODS: The study was based on ethnomedicinal field survey covering a period of 1 year from 2014-2015. The ethnomedicinal information was collected by using semi-structured questionnaires from different traditional Bengali people having knowledge on medicinal plants. Collected data were analyzed by calculating DCI. RESULTS: During the survey, 29 informants were interviewed and a total of 49 plants under 46 genera belonging to 33 families were listed. Data analysis revealed that Litsea glutinosa, Momordica charantia, Andrographis paniculata, Lawsonia inermis, Cleome viscosa, Psidium guajava, Ageratum conyzoides, Cuscuta reflexa, Cynodon dactylon and Carica papaya are the most prominent plants among the people of Southern Assam for treating DSD. CONCLUSION: This explorative survey emphasizes the need to preserve and document the traditional healing practices for managing DSD inviting for more imminent scientific research on the plants to determine their efficacy as well as safety. With the help of statistical analysis (DCI), we propose 10 priority plants for DSD in present work. Systematic pharmacological study with these plants may contribute significant result.

Ethnomedicinal plants used by traditional healers of North Tripura district, Tripura, North East India.

ETHNOPHARMACOLOGICAL RELEVANCE: Information about ethnomedicinal plants used by traditional healers in Tripura, India is very much limited. As there is rapid erosion of traditional knowledge in the state, needs has arisen to document the diversity of medicinal plants, their preparation and associated diseases. AIM OF THE STUDY: Attempts have been made to explore the herbal medicines used by the traditional healers belonging to the various communities in North Tripura district of Tripura, India and document the associated traditional knowledge on the utilisation of medicinal plants. MATERIALS AND METHODS: The study was based on ethnomedicinal field survey covering a period of 1 year from February 2012 to February 2013. The ethnomedicinal information was collected by using semi-structured questionnaires from different healers and knowledge holders. Collected data were analysed through informant consensus factor, Index of Specialisation and Relative frequency of citation to determine culturally significant plants. RESULTS: A total of 75 species of plants under 68 genera belonging to 43 families were collected during the study for the treatment of 15 disease categories. Leaves were the most frequently used plant parts and most of the medicines were prepared in the form of extract and administered orally. FIC values of the present study indicated that there was a high agreement in the use of plants in the treatment of digestive system disorders and respiratory system disorders among the healers. Plants having high ISu are Justicia adhatoda, Pajanelia longifolia, Catharanthus roseus etc. CONCLUSION: The present study highlighted certain species having higher priority indices for further phytochemical investigation. Counselling of traditional health practitioners should be taken into consideration in order to smooth continuation and extension of traditional medical knowledge and practice for ensuring safe and effective therapy.