Kaempferol and Apigenin suppresses the stemness properties of TNBC cells by modulating Sirtuins.

Sirtuins (SIRTs) overexpression serves as a potential therapeutic target for TNBC because it is associated with bioactivities of cancer stem cells (CSCs), resistance to chemotherapy, and metastasis. Irrespective of the availability of synthetic SIRT inhibitors, new SIRT inhibitors with enhanced potency and lesser side effects serve as current unmet needs. Therefore, bioactive dietary compounds; kaempferol (KMP) and apigenin (API) were investigated for their anti-SIRTs potential. We observed KMP and API inhibits cellular proliferation by DNA damage and S-phase cell cycle arrest in TNBC Cells. They also suppress stemness properties in TNBCs as observed in experiments of mammosphere formation and clonogenic potential. Our mechanistic approach indicated that KMP and API inhibited SIRT3 and SIRT6 proteins, as evidenced by our in silico and in vitro experiment. Collectively, our studies suggest that KMP and API are promising candidates to be further developed as sirtuin modulators against TNBCs.

Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow.

In the past two decades, the treatment of metastatic colorectal cancer (mCRC) has been revolutionized as multiple cytotoxic, biological, and targeted drugs are being approved. Unfortunately, tumors treated with single targeted agents or therapeutics usually develop resistance. According to pathway-oriented screens, mCRC cells evade EGFR inhibition by HER2 amplification and/or activating Kras-MEK downstream signaling. Therefore, treating mCRC patients with dual EGFR/HER2 inhibitors, MEK inhibitors, or the combination of the two drugs envisaged to prevent the resistance development which eventually improves the overall survival rate. In the present study, we aimed to screen potential phytochemical lead compounds that could multi-target EGFR, HER2, and MEK1 (Mitogen-activated protein kinase kinase) using a computer-aided drug design approach that includes molecular docking, endpoint binding free energy calculation using MM-GBSA, ADMET, and molecular dynamics (MD) simulations. Docking studies revealed that, unlike all other ligands, apigenin and kaempferol exhibit the highest docking score against all three targets. Details of ADMET analysis, MM/GBSA, and MD simulations helped us to conclusively determine apigenin and kaempferol as potentially an inhibitor of EGFR, HER2, and MEK1 apigenin and kaempferol against mCRC at a systemic level. Additionally, both apigenin and kaempferol elicited antiangiogenic properties in a dose-dependent manner. Collectively, these findings provide the rationale for drug development aimed at preventing CRC rather than intercepting resistance.

Emerging role of sirtuins in breast cancer metastasis and multidrug resistance: Implication for novel therapeutic strategies targeting sirtuins.

Sirtuins (SIRTs), a class III histone deacetylases (HDACs) that require NAD+ as a cofactor and include SIRT1-7 proteins in mammals. Accumulative evidence has established that every sirtuin possesses exclusive and poised biology, implicating their role in the regulation of multifaceted biological functions leading to breast cancer initiation, progression, and metastasis. This article provides an outline of recent developments in the role of sirtuins in breast cancer metastasis and development of multidrug resistance (MDR). In addition, we have also highlighted the impending prospects of targeting SIRTs to overcome MDR to bring advancement in breast cancer management. Further, this review will focus on strategies for improving the activity and efficacy of existing cancer therapeutics by combining (adjuvant treatment/therapy) them with sirtuin inhibitors/modulators. All available as well as newly discovered synthetic and dietary sirtuin inhibitors, activators/modulators have been extensively reviewed and compiled to provide a rationale for targeting sirtuins. Further, we discuss their potential in developing future therapeutics against sirtuins proposing their use along with conventional chemotherapeutics to overcome the problem of breast cancer metastasis and MDR.

Bioactive Pigments from Isolated Bacteria and Its Antibacterial, Antioxidant and Sun Protective Application Useful for Cosmetic Products.

Bacterial pigments are the unique and sustainable source of bioactive colour compounds used in cosmetics, food, textiles, printing and pharmaceutical products. Here, we report the pigment-producing isolates and their biological activities that could be benefited for different industries including cosmeceuticals. In this study, a total of 19 pigment-producing bacteria were isolated and purified from collected soil and water samples. The colour production ability of purified bacteria was observed up to 5 transfers. Of the 19 isolates, two isolates lost colour production ability in subsequent transfers. Crude pigments extracted from the remaining 17 isolates showed sunscreen activity in the range of 0.4-8.34. However, only 6 of them showed significant antibacterial and antioxidant activities. In the media optimization experiment, these 6 bacteria showed optimum growth in neutral to alkaline pH, while optimum temperatures for growth were different for different bacteria. One isolate produces the promising pigment, out of all six potential pigments. It is stable up to 5 transfers, having antioxidant and antibacterial activity with Sun protective activity; the strain was identified using 16srRNA gene sequencing and obtained accession number as MK770403 (probable strain is Staphylococcus xylosus) from National Center for Biotechnology Information (NCBI) database. The results of this study suggested that these bioactive pigments can further be developed and used as antibacterial, antioxidant and sun-protective ingredients in cosmeceuticals.

c-Myc-Dependent Cell Competition in Human Cancer Cells.

Cell Competition is an interaction between cells for existence in heterogeneous cell populations of multicellular organisms. This phenomenon is involved in initiation and progression of cancer where heterogeneous cell populations compete directly or indirectly for the survival of the fittest based on differential gene expression. In Drosophila, cells having lower dMyc expression are eliminated by cell competition through apoptosis when present in the milieu of cells having higher dMyc expression. Thus, we designed a study to develop c-Myc (human homolog) dependent in vitro cell competition model of human cancer cells. Cells with higher c-Myc were transfected with c-myc shRNA to prepare cells with lower c-Myc and then co-cultured with the same type of cells having a higher c-Myc in equal ratio. Cells with lower c-Myc showed a significant decrease in numbers when compared with higher c-Myc cells, suggesting "loser" and "winner" status of cells, respectively. During microscopy, engulfment of loser cells by winner cells was observed with higher expression of JNK in loser cells. Furthermore, elimination of loser cells was prevented significantly, when co-cultured cells were treated with the JNK (apoptosis) inhibitor. Above results indicate elimination of loser cells in the presence of winner cells by c-Myc-dependent mechanisms of cell competition in human cancer cells. This could be an important mechanism in human tumors where normal cells are eliminated by c-Myc-overexpressed tumor cells. J. Cell. Biochem. 118: 1782-1791, 2017. © 2016 Wiley Periodicals, Inc.

Frequent inoculations with radiation attenuated sporozoite is essential for inducing sterile protection that correlates with a threshold level of Plasmodia liver-stage specific CD8+ T cells.

Whole sporozoite vaccine (WSV) is shown to induce sterile protection that targets Plasmodium liver-stage infection. There are many underlying issues associated with induction of effective sterile protracted protection. In this study, we have addressed how the alterations in successive vaccine regimen could possibly affect the induction of sterile protection. We have demonstrated that the pattern of vaccination with RAS (radiation attenuated sporozoites) induces varying degrees of protection among B6 mice. Animals receiving four successive doses generated 100% sterile protection. However, three successive doses, though with the same parasite inoculum as four doses, could induce sterile protection in ∼50% mice. Interestingly, mice immunized with the same 3 doses, but with longer gap, could not survive the challenge. We demonstrate that degree of protection correlates with the frequencies of IFN-γ+ and multifunctional (IFN-γ+ CD107a+) CD8+ TEM cells present in liver. The failure to achieve protective threshold frequency of these cells in liver might make the host more vulnerable to parasite infection during infectious sporozoite challenge.

Gene expression study of phase I and II metabolizing enzymes in RPTEC/TERT1 cell line: application in in vitro nephrotoxicity prediction.

1. The phase I and II metabolizing enzymes of kidneys play an important role in the metabolism of xenobiotic as well as endogenous compounds and proximal tubules of kidney constitute high concentration of these metabolizing enzymes compared with the other parts. 2. It has been shown previously that differential enzyme expression among human and rodent/non-rodent species can be a roadblock in drug discovery and development process. Currently, proximal tubule cell lines of human origin such as RPTEC/TERT1 and HK-2 are used to understand the pathophysiology of kidney diseases, therapeutic efficacy of drugs, and nephrotoxicity of compounds. 3. The purpose of the present study is to understand the metabolic enzymes present in RPTEC/TERT1 and HK-2 cell lines that would help to interpret and predict probable in vitro behavior of the molecule being tested. 4. We analyzed the expression of phase I and II metabolizing enzymes of RPTEC/TERT1 and HK-2 cell lines. We found equal expression of CYP1B1, 2J2, 3A4, 3A5, UGT1A9, SULT2A1 and GSTA, higher expression of 2B6, 2D6, 4A11, 4F2, 4F8, 4F11, UGT2B7, SULT1E1 in RPTEC/TERT1 and absence of GSTT in RPTEC/TERT1 compared to HK-2 at mRNA level. Such differences can affect the outcome of in vitro nephrotoxicity prediction.

Renaissance in phytomedicines: promising implications of NGS technologies.

MAIN CONCLUSION: Medicinal plant research is growing significantly in faith to discover new and more biologically compatible phytomedicines. Deposition of huge genome/trancriptome sequence data assisted by NGS technologies has revealed the new possibilities for producing upgraded bioactive molecules in medicinal plants. Growing interest of investors and consumers in the herbal drugs raises the need for extensive research to open the facts and details of every inch of life canvas of medicinal plants to produce improved quality of phytomedicines. As in agriculture crops, knowledge emergence from medicinal plant's genome/transcriptome, can be used to assure their amended quality and these improved varieties are then transported to the fields for cultivation. Genome studies generate huge sequence data which can be exploited further for obtaining information regarding genes/gene clusters involved in biosynthesis as well as regulation. This can be achieved rapidly at a very large scale with NGS platforms. Identification of new RNA molecules has become possible, which can lead to the discovery of novel compounds. Sequence information can be combined with advanced phytochemical and bioinformatics tools to discover functional herbal drugs. Qualitative and quantitative analysis of small RNA species put a light on the regulatory aspect of biosynthetic pathways for phytomedicines. Inter or intra genomic as well as transcriptomic interactive processes for biosynthetic pathways can be elucidated in depth. Quality management of herbal material will also become rapid and high throughput. Enrichment of sequence information will be used to engineer the plants to get more efficient phytopharmaceuticals. The present review comprises of role of NGS technologies to boost genomic studies of pharmaceutically important plants and further, applications of sequence information aiming to produce enriched phytomedicines. Emerging knowledge from the medicinal plants genome/transcriptome can give birth to deep understanding of the processes responsible for biosynthesis of medicinally important compounds.

Cell Competition: Roles and Importance as a Central Phenomenon.

Cell competition is a type of short-range cell-cell interaction first observed in Drosophila melanogaster. In two heterogeneous cell populations, cells that have a higher fitness level would have a competitive advantage and grow at the cost of neighbor cells that have comparatively lower fitness. This interaction is due to differences in expression levels of a specific protein in the two cell populations, and it is known as cell competition. In this review, we have studied recent findings of cell competition in different biological processes in Drosophila as well as mammalian systems. The purpose of this review is to collate important studies of competitive cell interactions, and to understand its roles and importance as a central phenomenon. This review provides evidence of the relevance of cell competition in various physiological and pathological conditions, such as size control in organ development, stem cell maintenance, tissue repair, organ regeneration, aging, formation of memory, and cancer.

In silico screening of alleged miRNAs associated with cell competition: an emerging cellular event in cancer.

Cell competition is identified as a crucial phenomenon for cancer and organ development. There is a possibility that microRNAs (miRNAs) may play an important role in the regulation of expression of genes involved in cell competition. In silico screening of miRNAs is an effort to abridge, economize and expedite the experimental approaches to identification of potential miRNAs involved in cell competition, as no study has reported involvement of miRNAs in cell competition to date. In this study, we used multiple screening steps as follows: (i) selection of cell competition related genes of Drosophila through a literature survey; (ii) homology study of selected cell competition related genes; (iii) identification of miRNAs that target conserved cell competition-related genes through prediction tools; (iv) sequence conservation analysis of identified miRNAs with human genome; (v) identification of conserved cell competition miRNAs using their expression profiles and exploration of roles of their homologous human miRNAs. This study led to the identification of nine potential cell competition miRNAs in the Drosophila genome. Importantly, eighteen human homologs of these nine potential Drosophila miRNAs are well reported for their involvement in different types of cancers. This confirms their probable involvement in cell competition as well, because cell competition is well justified for its involvement in cancer initiation and maintenance.

Integrated blood and organ profile analysis to evaluate ameliorative effects of kaempferol on 5-fluorouracil-induced toxicity.

Colorectal cancer (CRC) treatment strategies encompass a triad of medical interventions: surgery, radiotherapy, and chemotherapy. Among these, the use of chemotherapy, specifically 5-fluorouracil (5-FU), has become a cornerstone in CRC management. However, it is imperative to explore novel approaches that harness the synergistic potential of chemotherapy agents alongside adjunctive compounds to mitigate the severe adverse effects that often accompany treatment. In light of this pressing need, this study focuses on evaluating Kaempferol (KMP) in combination with 5-FU in a DMH-induced CRC animal model, scrutinizing its impact on haematological indices, organ health, and gastrointestinal, hepatotoxic, and nephrotoxic effects. Remarkably, KMP demonstrated haemato-protective attributes and exerted an immunomodulatory influence, effectively counteracting 5-FU-induced damage. Furthermore, organ assessments affirm the safety profile of the combined treatments while suggesting KMP's potential role in preserving the structural integrity of the intestine, and spleen. Histopathological assessments unveiled KMP's capacity to ameliorate liver injury and mitigate CRC-induced renal impairment. These multifaceted findings underscore KMP's candidacy as a promising adjunctive therapeutic option for CRC, underlining the pivotal need for personalized therapeutic strategies that concurrently optimize treatment efficacy and safeguard organ health. KMP holds tremendous promise in elevating the paradigm of CRC management.

Methyl jasmonate mediates upregulation of bacoside A production in shoot cultures of Bacopa monnieri.

Methyl jasmonate (MJ) enhances the production of a range of secondary metabolites including triterpenoid saponins in a variety of plant species. Here, it enhanced production of bacoside A, a valuable triterpenoid saponin having nootropic therapeutic activity in in vitro shoot cultures of Bacopa monnieri, the only known source of bacoside A. The highest yield was with 50 µM MJ giving 4.4 mg bacoside A/g dry wt; an 1.8-fold increase (compared to control) after 1 week.

Elicitor mediated enhancement of shoot biomass and lupeol production in Hemidesmus indicus (L.) R. Br. ex. Schult. and Tylophora indica (Burm. F.) Merrill using yeast extract and salicylic acid.

Hemidesmus indicus (L.) R. Br. ex Schult. and Tylophora indica (Burm. F.) Merrill shoot cultures were treated with different concentrations of yeast extract (YE; 25-200 mg/L) and salicylic acid (SA; 50-200 µM), and their effect on lupeol production was assessed. The maximum dry weight (DW) biomass was recorded when H. indicus shoots were treated with SA (50 µM) and T. indica shoots with YE (200 mg/L). Highest lupeol yield (335.40 ± 0.04 µg/g DW) was obtained in H. indicus shoots after treatment with 50 µM of SA for 3 weeks. Whereas in T. indica, maximum lupeol content (584.26 ± 8.14 µg/g DW) was recorded by giving treatment with 25 µM of SA for 6 weeks.

Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism.

Metabolic alterations are one of the hallmarks of cancer, which has recently gained great attention. Increased glucose absorption and lactate secretion in cancer cells are characterized by the Warburg effect, which is caused by the metabolic changes in the tumor tissue. Cancer cells switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis due to changes in glucose degradation mechanisms, a process known as "metabolic reprogramming". As a result, proteins involved in mediating the altered metabolic pathways identified in cancer cells pose novel therapeutic targets. Hypoxic tumor microenvironment (HTM) is anticipated to trigger and promote metabolic alterations, oncogene activation, epithelial-mesenchymal transition, and drug resistance, all of which are hallmarks of aggressive cancer behaviour. Angiogenesis, erythropoiesis, glycolysis regulation, glucose transport, acidosis regulators have all been orchestrated through the activation and stability of a transcription factor termed hypoxia-inducible factor-1 (HIF-1), hence altering crucial Warburg effect activities. Therefore, targeting HIF-1 as a cancer therapy seems like an extremely rational approach as it is directly involved in the shift of cancer tissue. In this mini-review, we present a brief overview of the function of HIF-1 in hypoxic glycolysis with a particular focus on novel therapeutic strategies currently available.

Apigenin and kaempferol as novel renoprotective agent against cisplatin-induced toxicity: an in vitro study.

Cisplatin is one of the highly consumed and potent antineoplastic drugs. However, its side effects in normal tissues, notably nephrotoxicity, is a major stumbling block and dose-limiting factor. Renoprotective approaches are being developed, however, the protective benefits are usually only partial implying the need for combinatorial strategies. Therefore, in this study, we investigated the nephroprotective efficacy of apigenin and kaempferol as dietary supplements against cisplatin-induced renal injury using human embryonic kidney (HEK-293) cells as our in vitro model. Our findings from MTT data, morphology studies, comet and ROS analysis suggest that CIS 11.36 µM + API 12.5 µg/mL and CIS 11.36 µM + KMP 25 µg/mL protects against cisplatin-induced nephrotoxicity. Results of western blot analysis further suggest the involvement of NGAL in the API and KMP mediated nephroprotection. Collectively, our studies suggest that API and KMP are promising candidates to be further developed as renoprotective agents against cisplatin-induced toxicity.

Identification of potential therapeutic targets associated with diagnosis and prognosis of colorectal cancer patients based on integrated bioinformatics analysis.

Colorectal cancer (CRC) is the most common malignancy of digestive system with significant mortality rate. CRC patients with comparable clinical symptoms or at similar stages of the disease have different outcomes. This underlying clinical result is almost inevitably due to genetic heterogeneity. Therefore, the current study aimed to highlight gene signatures during CRC and unveil their potential mechanisms through bioinformatic analysis. The gene expression profiles (GSE28000, GSE33113, GSE44861, and GSE37182) were downloaded from the Gene Expression Omnibus database, and the differential expressed genes (DEGs) were identified in normal tissues and tumor tissue samples of CRC patients. In total, 8931 DEGs were identified in CRC, including 411 up-regulated genes and 166 down-regulated genes. Further, a protein-protein interaction network was constructed and the highly related genes were clustered using the Molecular Complex Detection algorithm (MCODE) to retrieve the core interaction in different genes' crosstalk. The screened hub genes were subjected to functional enrichment analysis. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell division, cell cycle, and cell proliferation; the down-regulated DEGs were significantly enriched in BP, including cellular homeostasis, detoxification, defense response, intracellular signaling cascade. Additionally, KEGG pathway analysis displayed the up-regulated DEGs were enriched in the cell cycle, TNF signaling, chemokine signaling pathway, while the down-regulated DEGs were enriched in NF-kB signaling, mineral reabsorption. Furthermore, the overall survival and expression levels of hub genes were detected by the UALCAN database and were further validated using Human Protein Atlas database. Taken together the identified DEGs (MT2A, CCNB1, DLGAP5, CCNA2, CXCL2, and RACGAP1) enhance our understanding of the molecular pathways that underpin CRC pathogenesis and could be exploited as molecular targets and diagnostic biomarkers for CRC therapy.

Identification of natural inhibitors against prime targets of SARS-CoV-2 using molecular docking, molecular dynamics simulation and MM-PBSA approaches.

The recently emerged COVID-19 has been declared a pandemic by the World Health Organization as to date; no therapeutic drug/vaccine is available for the treatment. Due to the lack of time and the urgency to contain the pandemic, computational screening appears to be the best tool to find a therapeutic solution. Accumulated evidence suggests that many phyto-compounds possess anti-viral activity. Therefore, we identified possible phyto-compounds that could be developed and used for COVID-19 treatment. In particular, molecular docking was used to prioritize the possible active phyto-compounds against two key targets namely RNA dependent RNA polymerase (RdRp) and main protease (Mpro) of SARS-CoV-2. In this study, an antiviral drug- Remdesivir (RdRp inhibitor) and Darunavir (Mpro inhibitor) are used as reference drugs. This study revealed that phyto-molecules- Mulberroside-A/C/E/F, Emblicanin A, Nimbolide, and Punigluconin showed high binding affinity against RdRp while Andrographolides, Mulberrosides, Anolignans, Chebulic acid, Mimusopic acid, and Punigluconin showed better binding affinity against Mpro as compared with the reference drug. Furthermore, ADME profiles validated the drug-likeness properties of prioritized phyto-compounds. Besides, to assess the stability, MD simulations studies were performed along with reference inhibitors for Mpro (Darunavir) and RdRp (Remdesivir). Binding free energy calculations (MM-PBSA) revealed the estimated value (ΔG) of Mpro_Darunavir; Mpro_Mulberroside E; RdRp_Remdesivir and RdRp_Emblicanin A were -111.62 ± 6.788, -141.443 ± 9.313, 30.782 ± 5.85 and -89.424 ± 3.130 kJmol-1, respectively. Taken together, the study revealed the potential of these phyto-compounds as inhibitors of RdRp and Mpro inhibitor that could be further validated against SARS-CoV-2 for clinical benefits.Communicated by Ramaswamy H. Sarma.

Andrographolide: a new plant-derived antineoplastic entity on horizon.

Plant-derived natural products occupy an important position in the area of cancer chemotherapy. Molecules such as vincristine, vinblastine, paclitaxel, camptothecin derivatives, epipodophyllotoxin, and so forth, are invaluable contributions of nature to modern medicine. However, the quest to find out novel therapeutic compounds for cancer treatment and management is a never-ending venture; and diverse plant species are persistently being studied for identification of prospective anticancer agents. In this regard, Andrographis paniculata Nees, a well-known plant of Indian and Chinese traditional system of medicines, has drawn attention of researchers in recent times. Andrographolide, the principal bioactive chemical constituent of the plant has shown credible anticancer potential in various investigations around the globe. In vitro studies demonstrate the capability of the compound of inducing cell-cycle arrest and apoptosis in a variety of cancer cells at different concentrations. Andrographolide also shows potent immunomodulatory and anti-angiogenic activities in tumorous tissues. Synthetic analogues of the compound have also been created and analyzed, which have also shown similar activities. Although it is too early to predict its future in cancer chemotherapy, the prologue strongly recommends further research on this molecule to assess its potential as a prospective anticancer agent.

Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis.

BACKGROUND: Sulforaphane (SFN) is a naturally occurring organosulfur compound found in cruciferous vegetables such as broccoli, brussels sprouts and cabbage. SFN is known for its multiple therapeutic properties, such as HDAC inhibitory, chemo preventive and anti-cancer effects. Cisplatin (CIS) has limited effect against metastatic triple-negative breast cancer (TNBC). Additionally, CIS impose severe side effects to normal cells, and later TNBC cells develops resistance. Studies suggest that the overexpression of sirtuins (SIRTs) promotes CIS resistance and metastasis by activating epithelial-to-mesenchymal transition (EMT) pathway in TNBC. PURPOSE: In view of the above information, we investigated the therapeutic efficacy of SFN, in combination with CIS against TNBC metastasis and CIS resistance. METHODS: The anti-cancerous effect of SFN-CIS combination on human TNBC cell lines was demonstrated by utilizing MTT assay and, apoptosis and cell cycle assay followed by FACS analysis. The synergistic effect of SFN-CIS combination on the experimental metastasis was demonstrated by utilizing migration, invasion, chemotaxis, mammosphere and colony formation assay on human TNBC MDA-MB-231 and MDA-MB-468 cells. The role of SIRTs-mediated EMT signaling axis in the metastasis and chemoresistance was investigated by western blotting technique as well as sirtuin activity tests. This was further validated by using Chromatin immunoprecipitation (ChIP) analysis. RESULTS: We found that SFN-CIS combination synergistically inhibits cellular growth of MDA-MB-231 and MDA-MB-468 cells. More importantly, SFN was found to protect normal kidney cells from CIS-induced toxicity. Further, SFN-CIS combination was found to synergistically inhibit metastatic-events via significantly altering EMT markers which was further associated with the suppression of SIRTs functions in TNBC cells. ChIP analysis validated that SFN-CIS combination suppresses EMT mechanism through altered chromatin modifications at E-cadherin promoter resulting in its re-expression. CONCLUSION: The results of the current study suggests that CIS when supplemented with SFN, inhibits metastasis and stemness potential of TNBC cells by down regulating SIRTs-mediated EMT cascade. Overall this study affirms that, this novel combination could be a promising strategy against SIRT-mediated TNBC metastasis and CIS-resistance.

Binding Insight of Anti-HIV Phytocompounds with Prime Targets of HIV: A Molecular Dynamics Simulation Analysis.

BACKGROUND: Despite intense efforts, AIDS is difficult to tackle by current anti-retroviral therapy (ART) due to its side effects; therefore, there is an urgent need to discover potential, multitarget and low-cost anti-HIV compounds. OBJECTIVE: We have shown that few phytocompounds can potentially inhibit the prime targets of HIV namely GP120 envelope protein, reverse transcriptase, protease, integrase and ribonulcease. In this study, top ranked prioritized compounds were subjected to Molecular Dynamics (MD) simulation in order to study the conformational dynamics and integrity of crucial interaction in the receptor sites. METHODS: The system was built for selected protein-ligand complex using TIP3P water model and OPLS_2005 force field. Trajectories were recorded up to 20 ns simulation time in Desmond module of Schrödinger software. RESULTS: As a result of a comprehensive analysis of molecular properties and dynamics of the complexes, it has been concluded that Chebulic acid, Curcumin and Mulberroside C could be developed as envelope glycoprotein GP120 inhibitor, reverse transcriptase inhibitor and protease inhibitor respectively. However, the fluctuation of Chebulic acid with respect to integrase and ribonuclease protein was higher during the simulation. CONCLUSION: These findings can aid in the designing of the structural properties for more effective anti-HIV compounds against the given targets.