Therapeutic importance of Kigelia africana subsp. africana: an alternative medicine.

AIM: To summarise a detailed up-to-date review of the traditional uses, phytoconstituents, and pharmacological activities of various parts of Kigelia africana. MATERIALS AND METHODS: Google Scholar, PubMed, PubChem, Elsevier, King Draw, indianbiodiversity.org. RESULT: The phytochemical analysis of Kigelia africana subsp. africana has revealed the presence of approximately 145 compounds extracted from different parts of the plant. These bioactive extracts of the plant possess anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antineoplastic, and anti-urolithic activities. Due to its anti-inflammatory, antioxidant, and immune-booster properties, Kigelia can prove to be an essential source of drugs for treating various disorders. CONCLUSION: Knowledge of the phytoconstituents, non-medicinal and medicinal traditional uses, pharmacological activities, and products obtained from Kigelia is described in this review with the hope that the updated findings will promote research on its biological pathways.

Traditional medicinal importance of Kigelia africana subsp. africanaPhytoconstituents present in extracts from different parts of the plantPharmacological activities of phytochemicals extracted from KigeliaAnti-inflammatory and antioxidant role in preventing oxidative stressPotential as ethnopharmacological therapeutic in treating respiratory ailmentsToxicity evaluation of Kigelia africana subsp. africana.

Evaluating the role of MEN1 gene expression and its clinical significance in breast cancer patients.

BACKGROUND: Breast cancer is a multifactorial disease which involves number of molecular factors that are critically involved in proliferation of breast cancer cells. MEN1 gene that is traditionally known for its germline mutations in neuroendocrine tumors is associated with high risk of developing breast cancer in females with MEN1 syndrome. However, the paradoxical role of MEN1 is reported in sporadic breast cancer cases. The previous studies indicate the functional significance of MEN1 in regulating breast cells proliferation but its relevance in development and progression of breast cancer is still not known. Our study targets to find the role of MEN1 gene aberration and its clinical significance in breast cancer. METHODS: Breast tumor and adjacent normal tissue of 142 sporadic breast cancer patients were collected at the time of surgery. The expression analysis of MEN1 mRNA and protein was done through RT-PCR, immunohistochemistry and western blotting. Further to find the genetic and epigenetic alterations, automated sequencing and MS-PCR was performed respectively. Correlation between our findings and clinical parameters was determined using appropriate statistical tests. RESULTS: MEN1 expression was found to be significantly increased in the breast tumor tissue with its predominant nuclear localization. The elevated expression of MEN1 mRNA (63.38% cases) and protein (60.56% cases) exhibited a significant association with ER status of the patients. Most of the cases had unmethylated (53.52%) MEN1 promoter region, which can be a key factor responsible for dysregulated expression of MEN1 in breast cancer cases. Our findings also revealed the significant association of MEN1 mRNA overexpression with Age and lymph node status of the patients. CONCLUSION: Our results indicate upregulated expression of MEN1 in sporadic breast cancer patients and it could be critically associated with development and advancement of the disease.

Identification and characterization of a novel begomovirus, Withania leaf curl virus associated with leaf curl disease of Withania somnifera.

Begomovirus is the largest genus of the family Geminiviridae with wide host range and responsible for a considerable amount of economic damage to many important crops globally. Withania somnifera (Indian ginseng) is an important medicinal plant with high demand in pharmaceutical industries worldwide. During the routine survey in 2019, typical characteristic viral symptoms such as severe leaf curling, downward rolling of the leaves, vein clearing, and poor growth of Withania plants with 17-20% disease incidence were observed in Lucknow, India. Typical symptoms, abundant presence of whiteflies, PCR and RCA based detection indicated the amplification of ~ 2.7 kb and suspected the causal pathogen to be a begomovirus, associated with a betasatellite (~ 1.3 kb). Transmission electron microscopy revealed the presence of twinned particles of ~ 18-20 nm in diameter. Full genome sequencing (2758 bp) of the virus and its analysis showed only 88% sequence identity with the begomovirus sequences present in the database. Hence, based on the nomenclature guidelines we concluded that the virus associated with the present disease of W. somnifera is a novel begomovirus and its name is proposed as Withania leaf curl virus.

Phytocompounds targeting epigenetic modulations: an assessment in cancer.

For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.

Is heparan sulfate a target for inhibition of RNA virus infection?

Heparan sulfate (HS) is a linear polysaccharide attached to a core protein, forming heparan sulfate proteoglycans (HSPGs) that are ubiquitously expressed on the surface of almost all mammalian cells and the extracellular matrix. HS orchestrates the binding of various signal molecules to their receptors, thus regulating many biological processes, including homeostasis, metabolism, and various pathological processes. Due to its wide distribution and negatively charged properties, HS is exploited by many viruses as a cofactor to attach to host cells. Therefore, inhibition of the interaction between virus and HS is proposed as a promising approach to mitigate viral infection, including SARS-CoV-2. In this review, we summarize the interaction manners of HS with viruses with focus on significant pathogenic RNA viruses, including alphaviruses, flaviviruses, and coronaviruses. We also provide an overview of the challenges we may face when using HS mimetics as antivirals for clinical treatment. More studies are needed to provide a further understanding of the interplay between HS and viruses both in vitro and in vivo, which will favor the development of specific antiviral inhibitors.

Identification of plant-based hexokinase 2 inhibitors: combined molecular docking and dynamics simulation studies.

Cancer cells ferment glucose, even under aerobic conditions, following a phenomenon known as the 'Warburg effect.' Hexokinase 2 (HK2) catalyzes the crucial step of phosphorylation of glucose for subsequent utilization in glycolysis and other pathways. HK2 has been proposed as a potential therapeutic target for anti-cancer therapy because of its enhanced expression in glucose-dependent tumors. Here, we have employed structure-based virtual screening using in-house library to identify potential phytoconstituents which could inhibit the HK2 activity. The initial hits were selected based on their binding affinity towards HK2 using the molecular docking approach. Subsequently, the filters for physicochemical properties, PAINS patterns and PASS evaluation were applied to find potential hits against HK2. Finally, we have identified epigallocatechin gallate (EGCG) and quercitrin, two natural compounds with appreciable binding affinity, efficiency and specificity towards the HK2 binding pocket. Both compounds were found to be binding preferentially to the HK2 active site and showed a decent set of drug-like properties. All-atom molecular dynamics (MD) simulations for 100 ns were carried out to see the conformational dynamics, complexes stability and interaction mechanism of HK2 with EGCG and quercitrin. MD simulation results showed that HK2 forms stable protein-ligand complexes with EGCG and quercitrin with consistency throughout the trajectory. Overall, these findings suggest that EGCG and quercitrin might be further exploited as promising scaffolds in the drug development process against HK2..Communicated by Ramaswamy H. Sarma.

Phytocompounds Targeting Metabolic Reprogramming in Cancer: An Assessment of Role, Mechanisms, Pathways, and Therapeutic Relevance.

The metabolism of cancer is remarkably different from that of normal cells and confers a variety of benefits, including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefits. In the continued search for safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and attempt to make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the pharmacological interactions of phytocompounds with major metabolic pathways and evaluate the role of phytocompounds in the regulation of growth signaling and transcriptional programs involved in the metabolic transformation of cancer. Lastly, we examine the potential of these compounds in the clinical management of cancer along with limitations and challenges.

Anticancer potential of andrographolide from Andrographis paniculata (Burm.f.) Nees and its mechanisms of action.

ETHNOPHARMACOLOGICAL RELEVANCE: Synthetic drugs used for cancer treatment have side effects that may be immunosupressive, can cause liver, kidney and cardiac toxicity, and infertility and ovarian failure, among others. Thus, herbal drugs could be used in the cancer treatment as an adjuvant therapy. Andrographis paniculata (Burm.f.) Nees (AP) is one of the traditional herbs used in different alternative medicinal systems such as Ayurveda, Unani, Chinese, Malayi, Siddha, etc. for the treatment of various disorders and diseases including cancer. AIM OF THE STUDY: The aim of writing this review is to highlight the medicinal importance of AP and its main phytoconstituent andrographolide (AG). The main emphasis was given on the anticancer activity of AG, its proposed mechanisms of action, novel approaches used to improve its biopharmaceutical properties with the perspective of evidence-based research, and its development as an adjuvant therapy for cancer treatment in future. MATERIALS AND METHODS: Literature survey was conducted and research papers were retrieved from different databases such as Pubmed, Google Scholar, ACS, Wiley online library, ScienceDirect, Springer, and Scopus during 1970-2020. Research articles, review articles, and short communications, etc. were used for this purpose. The papers were selected on the basis of exclusion and inclusion criteria. RESULTS: Different anticancer mechanisms of AG have been reportedly proven such as cell cycle arrest, apoptosis, NF-κß inhibition, antiangiogenesis, cytokine inhibition, etc. whereas its pharmacokinetic properties showed its highly protein bound nature, Cyt P400 (CYP) inhibition, low aqueous solubility, poor oral bioavailability, etc. Different novel formulations of AG have been investigated to increase its bioavailability for better efficacy. CONCLUSION: This review can provide knowledge about the potential applicability of AP or AG as an adjuvant therapy in cancer treatment. Further research is needed before making any conclusion about the efficacy in humans as an adjuvant therapy in cancer.

Silibinin induces metabolic crisis in triple-negative breast cancer cells by modulating EGFR-MYC-TXNIP axis: potential therapeutic implications.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment modalities and poor prognosis. Metabolic reprogramming in cancer is considered a hallmark of therapeutic relevance. Here, we report disruption of metabolic reprogramming in TNBC cells by silibinin via modulation of EGFR-MYC-TXNIP signaling. Metabolic assays combined with LC-MS-based metabolomics revealed inhibition of glycolysis and other key biosynthetic pathways by silibinin, to induce metabolic catastrophe in TNBC cells. Silibinin-induced metabolic suppression resulted in decreased cell biomass, proliferation, and stem cell properties. Mechanistically, we identify EGFR-MYC-TXNIP as an important regulator of TNBC metabolism and mediator of inhibitory effects of silibinin. Highlighting the clinical relevance of our observations, the analysis of METABRIC dataset revealed deregulation of EGFR-MYC-TXNIP axis in TNBC and association of EGFRhigh -MYChigh -TXNIPlow signature with aggressive glycolytic metabolism and poor disease-specific and metastasis-free survival. Importantly, combination treatment of silibinin or 2-deoxyglucose (glycolysis inhibitor) with paclitaxel synergistically inhibited proliferation of TNBC cells. Together, our results highlight the importance of EGFR-MYC-TXNIP axis in regulating TNBC metabolism, demonstrate the anti-TNBC activity of silibinin, and argue in favor of targeting metabolic vulnerabilities of TNBC, at least in combination with mainstay chemotherapeutic drugs, to effectively treat TNBC patients.

In silico and in vitro Studies on Begomovirus Induced Andrographolide Biosynthesis Pathway in Andrographis Paniculata for Combating Inflammation and Cancer.

Andrographolide and neoandrographolide are major bioactive molecules of Andrographis paniculata, a well-known medicinal plant. These molecules exhibited varying degrees of anti-inflammatory and anticancer activities in-vitro and in-vivo. Role of begomovirus protein C2/TrAP in biosynthesis of andrographolide was identified through molecular modeling, docking and predicted results were substantiated by in vitro studies. Homology molecular modeling and molecular docking were performed to study the binding conformations and different bonding behaviors, in order to reveal the possible mechanism of action behind higher accumulation of andrographolide. It was concluded that C2/TrAP inhibit the activation of SNF1-Related Protein Kinase-1 (SnRK1) in terpenoid pathway and removes the negative regulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) by SnRK1, leading to higher accumulation of andrographolide and neoandrographolide in begomovirus infected plants. The binding site residues of SnRK1 docked with C2/TrAP were found to be associated with ATP binding site, substrate binding site and activation loop. Predicted results were also validated by HPTLC. This study provides important insights into understanding the role of viral protein in altering the regulation of biosynthesis of andrographolide and could be used in future research to develop biomimetic methods for increasing the production of such phytometabolites having anti-cancerous and anti-inflammatory properties.

Eclipta yellow vein virus enhances chlorophyll destruction, singlet oxygen production and alters endogenous redox status in Andrographis paniculata.

The infection of Eclipta yellow vein virus [EcYVV-IN, Accession No. KC476655], recently reported for the first time, on Andrographis paniculata was studied for redox-mediated alteration mechanism in infected plants. A. paniculata, an important medicinal plant, is used in traditional Indian, Chinese and modern system of medicine. Andrographolide, one of the foremost components of this plant, is known for its varied pharmacological properties. Our investigation provides insight into the effect of virus-induced changes in the singlet oxygen quenching due to the alteration in pigment content (chlorophyll and carotenoids) as well as activation of plant secondary metabolism along with defense activation leading to changes in enzymatic and non-enzymatic redox status. Due to infection, a reduction in carotenoid content was observed which leads to reduced quenching of singlet oxygen. An increased level of enzymatic (SOD and APX) and non-enzymatic antioxidant (DPPH, FRAP, RP, NO, TAC and TP) activities were also observed in virus-infected plants with a positive correlation (>0.9). However, CAT activity was diminished which could be either due to its proteolytic degradation or inactivation by superoxide anions (O(2-.)), NO or peroxynitrite radicals. A significant (p < 0.05) increase in total phenolic content was observed in the infected plants while no considerable difference was seen in the total flavonoid content. Our results highlighted the alteration in redox status caused by virus-induced biotic stress on the plants and could be useful for understanding the after effects of viral infection This study could also be helpful in developing biomimetic methods for improving the production of secondary metabolites of pharmaceutical importance.