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.

Meticulous assessment of natural compounds from NPASS database for identifying analogue of GRL0617, the only known inhibitor for SARS-CoV2 papain-like protease (PLpro) using rigorous computational workflow.

The latest global outbreak of 2019 respiratory coronavirus disease (COVID-19) is triggered by the inception of novel coronavirus SARS-CoV2. If recent events are of any indicators of the epidemics of past, it is undeniable to state a fact that the SARS-CoV2 viral infection is highly transmissible with respect to its previously related SARS-CoV's. Papain-like protease (PLpro) is an enzyme that is required by the virus itself for replicating into the host system; and it does so by processing its polyproteins into a functional replicase complex. PLpro is also known for downregulating the genes responsible for producing interferons, an essential family of molecules produced in response to viral infection, thus making this protein an indispensable drug target. In this study, PLpro inhibitors were identified through high throughput structure-based virtual screening approach from NPASS natural product library possessing ~ 35,000 compounds. Top five hits were scrutinised based on structural aromaticity and ability to interact with a key active site residue of PLpro, Tyr268. For second level of screening, the MM-GBSA End-Point Binding Free Energy Calculation of the docked complexes was performed, which identified Caesalpiniaphenol A as the best hit. Caesalpiniaphenol A not only possess a double ring aromatic moiety but also has lowest minimum binding energy, which is at par with the control GRL0617, the only known inhibitor of SARS-CoV2 PLpro. Details of the Molecular Dynamics (MD) simulation and ADMET analysis helped to conclusively determine Caesalpiniaphenol A as potentially an inhibitor of SARS-CoV2 PLpro.

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.

Influence of cyanobacterial inoculants, elevated carbon dioxide, and temperature on plant and soil nitrogen in soybean.

Climate change affects nitrogen dynamics in crops and diazotrophic microorganisms with carbon dioxide (CO2 ) sequestering potential such as cyanobacteria can be promising options. The interactions of three cyanobacterial formulations (Anabaena laxa, Calothrix elenkinii and Anabaena torulosa-Bradyrhizobium japonicum biofilm) on plant and soil nitrogen in soybean, were investigated under elevated CO2 and temperature conditions. Soybean plants were grown inside Open Top Chambers under ambient and elevated (550 ± 25 ppm) CO2 concentrations and elevated temperature (+2.5-2.8°C). Interactive effect of elevated CO2 and cyanobacterial inoculation through A. laxa and Anabaena torulosa-B. japonicum biofilm led to improved growth, yield, nodulation, nitrogen fixation, and seed N in soybean crop. Nitrogenase activity in nodules increased in A. laxa and biofilm treatments, with an increase of 55% and 72%, respectively, over no cyanobacterial inoculation treatment. Although high temperature alone reduced soil microbial biomass carbon, dehydrogenase activity, and soil available N, the combined effect of CO2 and temperature were stimulatory; cyanobacterial inoculation further led to an increase under all the conditions. The highest seed N uptake (758 mg plant-1 ) was recorded with cyanobacterial biofilm inoculation under elevated CO2 with control temperature conditions. The positive interactions of elevated CO2 and cyanobacterial inoculation, particularly through A. laxa and A. torulosa-B. japonicum biofilm inoculation highlights their potential in counteracting the negative impact of changing climate along with enhancing plant and soil N in soybean.

Prevalence and the risk factors of gastro-esophageal reflux disease in medical students.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a commonly prevalent gastrointestinal disorder in adults. Very few studies on magnitude of GERD in student community have been done and there is none so far from India. Rigorous MBBS curriculum makes medical students prone for reflux symptoms. Hence, this study was conducted to determine the prevalence of GERD in medical students and the potential risk factors associated with it. METHODS: This was a cross sectional observational study conducted on medical students in a premier medical college of India. All participants were interviewed for GERD symptoms using the validated questionnaire on frequency scale for the symptoms of GERD. Additional 11 questions include enquiries on medical history and lifestyle factors. RESULTS: Of the 600 students, 150 (25%) had GERD symptoms. Of these, 88 (58.6%) had mild, 58 (38.6%) moderate, and 4 (2.7%) severe reflux symptoms. Fifty eight (38.6%) of students with GERD had associated dyspepsia. On univariate analysis higher BMI, final years of MBBS course, use of NSAID or alcohol, inadequate sleep, sleeping within one hour of taking dinner, missing breakfast regularly and quick eating were significantly associated with GERD (p < 0.05). CONCLUSIONS: Prevalence of symptoms of GERD in medical students is 25%, majority had mild symptoms. Associated dyspeptic symptoms were present in 38.6%. Factors predisposing to GERD in them are higher BMI, final years of MBBS course, use of NSAID, inadequate sleep, sleeping within one hour of taking dinner, missing breakfast on regular basis and quick eating.

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.

Apolipoprotein E3 functionalized lipid-drug conjugated nanoparticles of Levetiracetam for enhanced delivery to the brain: In-vitro cell line studies and in-vivo study.

A significant portion of brain-tumor patients suffer from 'brain-tumor-related epilepsy (BTE)' which results in depression, anxiety and hampered quality of life. Conventional anti-epileptic drugs indicate negative interaction with other drugs augmenting the poor outcome of overall therapy. Levetiracetam (LVM) has evidenced effectiveness for BTE but its hydrophilicity restricts the passage into blood-brain barrier. The majority of lipid nanoparticles fails to load hydrophilic drug sufficiently. Therefore, lipid-drug conjugates (LDC) were synthesized using stearic acid via amide bond formation confirmed by FTIR and NMR. The nanoparticles of synthesized LDC were prepared by solvent injection method followed by functionalization with Apolipoprotein E3 (ApoE3@LDC-NP). The nanoparticles were characterized by DSC, XRD, particle size (131.6 ± 1.24 nm), zeta potential (-15.6 ± 0.09 mV), and for storage stability. In-vitro release study indicated initial burst release of 20 ± 0.63 % followed by sustained release up to 30 h (66 ± 1.40 %) for ApoE3@LDC-NP. The cell-line study on HEK293 indicated no significant cytotoxic effect and greater cell uptake through U87MG cell line. The pharmacokinetic and bio-distribution study indicated 2.5-fold greater brain-targeting of ApoE3@LDC-NP as compared to LVM solution. It proved safe in the haemolysis study and exhibited the absence of tissue necrosis. Thus, ApoE3@LDC-NP might be a promising approach for effective brain-targeting of LVM for improved clinical response in BTE.

Global Food Production and Distribution Analysis using Data Mining and Unsupervised Learning.

BACKGROUND: Today's food industry is extensive and complicated, encompassing anything from subsistence agriculture to multinational food corporations. The mobility of food and food elements in food systems has a major impact on biodiversity preservation and the overall sustainability of our fragile global ecosystem. Identifying the human and livestock consumption patterns across regions and territories will optimize the dietary standards of the habitually undernourished and the expanding population without substantially increasing the amount of land under cultivation. Food preservation is the basis for economic advancement and social sustainability, so the food industry, both local and global, is fundamental to everyone. As a primary mechanism for ensuring global food preservation, there is currently a strong emphasis on accelerating food supply and decreasing waste. Thus, analyzing the production and distribution of food supply will boost economic sustainability. METHODOLOGY: In this paper, we present a quantitative analysis of global and regional food supply to reveal the flow of food and feed products in various parts of the world. Using data mining and machine learning-based approaches, we seek to quantify the production and distribution of food elements. The study aims to employ artificial intelligence-based methods to comprehend the shift and change in supply and consumption patterns with timely distribution to meet the global food instability. The method involves using statistical-based approaches to identify the hidden factors and variables. Feature engineering is used to uncover the interesting features in the dataset, and various clustering-based algorithms, like K-Means, have been utilized to group and identify the similar and most notable features. RESULT AND DISCUSSION: The concept of data mining and machine learning-based algorithms has helped us in identifying the global food production and distribution subsystem. The identified elements and their relationship can help stakeholders in regulating various external and internal factors, including urbanization, urban food needs, the economic, political and social framework, food demand, and supply flows. The exploratory analysis helps in establishing the efficiency and dynamism of food supply and distribution systems. CONCLUSION: The outcome demonstrates a pattern indicating the flow of currently grown crops into various endpoints. Few countries with massive populations have shown tremendous growth in their production capacity. Despite the fact that only a few countries produce a large portion of food and feed crops, still it is insufficient to feed the estimated global population. Significant changes in many people's socioeconomic conditions, as well as radical dietary changes, will also be required to boost agricultural credit and economic foundations.

Nanovaccines: A game changing approach in the fight against infectious diseases.

The field of nanotechnology has revolutionised global attempts to prevent, treat, and eradicate infectious diseases in the foreseen future. Nanovaccines have proven to be a valuable pawn in this novel technology. Nanovaccines are made up of nanoparticles that are associated with or prepared with components that can stimulate the host's immune system. In addition to their delivery capabilities, the nanocarriers have been demonstrated to possess intrinsic adjuvant properties, working as immune cell stimulators. Thus, nanovaccines have the potential to promote rapid as well as long-lasting humoral and cellular immunity. The nanovaccines have several possible benefits, including site-specific antigen delivery, increased antigen bioavailability, and a diminished adverse effect profile. To avail these benefits, several nanoparticle-based vaccines are being developed, including virus-like particles, liposomes, polymeric nanoparticles, nanogels, lipid nanoparticles, emulsion vaccines, exomes, and inorganic nanoparticles. Inspired by their distinctive properties, researchers are working on the development of nanovaccines for a variety of applications, such as cancer immunotherapy and infectious diseases. Although a few challenges still need to be overcome, such as modulation of the nanoparticle pharmacokinetics to avoid rapid elimination from the bloodstream by the reticuloendothelial system, The future prospects of this technology are also assuring, with multiple options such as personalised vaccines, needle-free formulations, and combination nanovaccines with several promising candidates.

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.

Males of the parasitoid wasp, Nasonia vitripennis, can identify which fly hosts contain females.

The reproductive success of a male is limited by the number of females it can mate with. Thus, males deploy elaborate strategies to maximize access to females. In Nasonia, which are parasitoids of cyclorrhaphous flies, such reproductive strategies are thought to be restricted to competition among males for access to females in the natal patch. This study investigates whether additional strategies are present, especially the capability to identify which fly hosts contain adult females inside. Behavioural assays revealed that only one out of the four species, N. vitripennis, can distinguish which hosts specifically have adult female wasps, indicating a species-specific reproductive strategy. Results of gas chromatography-mass spectrometry analyses and behavioural data suggest that female-signature cuticular hydrocarbons (CHCs) are used as chemical cues, possibly emanating from within the host puparium. Further assays indicated that N. vitripennis males can also detect differences in the intensities of female-signature CHCs, giving them the capability to seek out hosts with maximum number of females. This study uncovers a previously unknown reproductive strategy in one of the most widely studied parasitoid wasps.

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.

Delta variant (B.1.617.2) of SARS-CoV-2: Mutations, impact, challenges and possible solutions.

Since commencement of COVID-19 pandemic, several SARS-CoV-2 variants have emerged amid containment efforts via vaccination. The Delta variant (B.1.617.2), discovered in October 2020, was designated as a VOC by the WHO on May 11, 2021. The enhanced transmissibility of Delta variant has been associated with critical mutations such as D614G, L452R, P681R, and T478K in the S-protein. The increased affinity of the S-protein and ACE2 has been postulated as a key reason for decreased vaccine efficacy. As per evidence, the Delta variant possesses increased transmissibility and decreased vaccine efficacy compared to other VOCs like Alpha and Beta. This has led to concerns regarding the acquisition of novel mutations in the Delta variant and outbreaks in vulnerable communities, including vaccinated people. In this mini-review of Delta variant, we have explained its evolution and characteristics, the impact of spike mutations on infectivity and immune evasion, and measures to combat future outbreaks.

Co-infection of Hepatitis B and Hepatitis C among HIV-infected patients: A cross-sectional study from tertiary care hospital of eastern Nepal.

INTRODUCTION: This study was conducted with an objective to analyze prevalence and risk factors associated with co-infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) in HIV-positive patients with reference to their CD4+ T cell status. MATERIALS AND METHODS: HIV-positive patients visiting the HIV clinic for CD4+ T cells testing at B.P. Koirala Institute of Health Sciences were tested for Hepatitis B and Hepatitis C. Data regarding age, gender, mode of HIV transmission, duration of HIV diagnosis, antiretroviral therapy status, antiretroviral therapy duration, hepatitis B or C status, and CD4+ T cells count were collected via face-to-face interview, and hospital records. The data were entered in Microsoft Excel 2019 v16.0 (Microsoft, WA, USA) and statistical analysis was performed by using statistical package for social sciences, IBM SPSS® v21 (IBM, Armonk, New York). RESULTS: Out of 474 HIV-positive patients, HIV-HBV, HIV-HCV, and HIV-HBV-HCV co-infections were seen in 2.95% (14/474), 18.14% (86/474), and 2.53% (12/474) respectively. The primary route of infection was intra-venous drug use (IVDU) in those co-infected with HBV only (8, 57.14%), HCV only (46, 53.49%), and both HBV and HCV (8, 66.67%). HIV patients infected via IVDU were 2.40 times more likely to have HIV-HCV co-infection as compared to those infected via sexual route (AOR 2.40, 95% CI: 1.49,3.86). Similarly, HIV patients with CD4+ T cells count less than 350 cells/mm3 were more likely to have HIV-HBV-HCV co-infection as compared to those with CD4 count equal to and more than 350 cells/mm3 (AOR 13.84, 95% CI: 2.90,66.10). CONCLUSION: HIV-positive patients are at high risk of hepatitis B and/or hepatitis C co-infection. Intravenous drug use, and lower CD4+T cells count are the most important risk predictors of co-infection. All HIV-positive patients should be carefully screened with hepatitis B and hepatitis C tests during their follow-up.

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.

Identification of crucial hub genes and potential molecular mechanisms in breast cancer by integrated bioinformatics analysis and experimental validation.

Breast cancer (BC) is a malignancy that affects a large number of women around the world. The purpose of the current study was to use bioinformatics analysis to uncover gene signatures during BC and their potential mechanisms. The gene expression profiles (GSE29431, GSE10810, and GSE42568) were retrieved from the Gene Expression Omnibus database, and the differential expressed genes (DEGs) were identified in normal tissues and tumour tissue samples from BC patients. In total, 296 DEGs were identified in BC, including 46 upregulated genes and 250 downregulated genes. GO and KEGG pathway analysis were performed. A PPI network of the DEGs was also constructed. GO analysis results showed that upregulated DEGs were significantly enriched in biological processes (BP), including cell division, mitotic cell cycle, chromosome separation, and cell division. MF analysis showed that upregulated DEGs controlled the microtubule cytoskeleton, the microtubule organising center, the cytoskeleton, and the chromosome-centric region. KEGG analysis revealed the upregulated DEGs mainly regulated p53 signaling, while the downregulated DEGs were enriched in the AMPK signalling pathway and PPAR signalling pathway. Moreover, five hub genes with a high degree of stability were identified, including NUSAP1, MELK, CENPF, TOP2A, and PPARG. Experimental validation showed that all five hub genes had the same expression trend as predicted. The overall survival and expression levels of hub genes were detected by Kaplan-Meier-plotter and the UALCAN database and were further validated using the Human Protein Atlas database. Taken together, the identified key genes enhance our understanding of the molecular pathways that underpin BC pathogenesis. As a result, our novel findings could be used as molecular targets and diagnostic biomarkers in the treatment of BC. This study is based on empirical evidence, making it an appealing read for the global scientific community.

A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition.

Sirtuin 1 (SIRT1) is a NAD-dependent deacetylase that is critically involved in diverse cellular processes including metabolic disease, cancer, and possibly aging. Despite extensive studies on SIRT1 function, how SIRT1 levels are regulated remains relatively unknown. Here, we report that the nuclear bile acid receptor farnesoid X receptor (FXR) inhibits microRNA-34a (miR-34a) in the liver, which results in a positive regulation of SIRT1 levels. Activation of FXR by the synthetic agonist GW4064 decreases hepatic miR-34a levels in normal mice, and consistently, hepatic miR-34a levels are elevated in FXR-null mice. FXR induces expression of small heterodimer partner (SHP), an orphan nuclear receptor and transcriptional corepressor, which in turn results in repression of p53, a key activator of the miR-34a gene, by inhibiting p53 occupancy at the promoter. MiR-34a decreased SIRT1 levels by binding to the 3'-untranslated region of SIRT1 mRNA, and adenovirus-mediated overexpression of miR-34a substantially decreased SIRT1 protein levels in mouse liver. Remarkably, miR-34a levels were elevated, and SIRT1 protein levels were reduced in diet-induced obese mice, and FXR activation in these mice reversed the miR-34a and SIRT1 levels, indicating an intriguing link among FXR activation, decreased miR-34a, and subsequently, increased SIRT1 levels. Our study demonstrates an unexpected role of the FXR/SHP pathway in controlling SIRT1 levels via miR-34a inhibition and that elevated miR-34a levels in obese mice contribute to decreased SIRT1 levels. Manipulation of this regulatory network may be useful for treating diseases of aging, such as metabolic disease and cancer.

Terminal and broadcast reliability analysis of direct 2-D symmetric torus network.

Reliability analysis is one of the crucial issues for any scalable optical interconnection network. Torus is a highly scalable optical interconnect for data centre networks. The traditional torus network has XY routing algorithm. We have proposed a novel optimised routing algorithm. This paper focuses on the time-dependent and time-independent analysis for both terminal and broadcast reliabilities of the torus network using XY and optimised routing algorithm under various network sizes ( N × N where N = 8 , 16 , 32 , 64 ). The results are evaluated and compared considering nodes failures in MATLAB.

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.