Screening of miRNAs as prognostic biomarkers and their associated hub targets across Hepatocellular carcinoma using survival-based bioinformatics approach.

BACKGROUND: The hepatocellular carcinoma (HCC) incident rate is gradually increasing yearly despite all the research and efforts taken by scientific communities and governing bodies. Approximately 90% of all liver cancer cases belong to HCC. Usually, HCC patients approach the treatment in the late stages of this malignancy which becomes the primary cause of high mortality rate. The knowledge about molecular pathogenesis of HCC is limited and needs more attention from researchers to identify the driver genes and miRNAs, which causes to translate this information into clinical practice. Therefore, the key regulators identification of miRNA-mRNA regulatory network is essential to identify HCC-associated genes. METHODOLOGY: We extracted microRNA (miRNA) and messenger RNA (mRNA) expression datasets of normal and tumor HCC patient samples from UCSC Xena followed by identifying differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs). Univariate and multivariate cox-proportional hazard models were utilized to identify DEMs having significant association with overall survival (OS). Kaplan-Meier (KM) plotter was used to validate the presence of prognostic DEMs. A risk-score model was used to evaluate the effectiveness of KM-plotter validated DEMs combination on risk of samples. Target DEGs of prognostic miRNAs were identified via sources such as miRTargetLink and miRWalk followed by their validation in an external microarray cohort and enrichment analysis. RESULTS: 562 DEGs and 388 DEMs were identified followed by seven prognostic miRNAs (i.e., miR-19a, miR-19b, miR-30d-5p, miR-424-5p, miR-3677-5p, miR-3913-5p, miR-7705) post univariate, multivariate, risk-score model evaluation and KM-plotter analyses. ANLN, MRO, CPEB3 were their targets and were also validated in GSE84005 dataset. CONCLUSIONS: The findings of this study decipher that most significant miRNAs and their identified target genes have association with apoptosis, inflammation, cell cycle regulation and cancer-related pathways, which appear to contribute to HCC pathogenesis and therefore, the discovery of new targets.

Uncovering the role of aquaporin and chromobox family members as potential biomarkers in head and neck squamous cell carcinoma via integrative multiomics and in silico approach.

Head and neck squamous cell carcinoma (HNSC) is a diverse group of tumors arising from oral cavity, oropharynx, larynx, and hypopharynx squamous epithelium, posing significant morbidity. Aquaporins (AQPs) are membrane proteins forming water channels, some associated with carcinomas. Chromobox (CBX) family is known to modulate physiological and oncological processes. In our study, we analyzed AQPs and CBXs having significant expression followed by their prognostic and mutational assessment. Next, we performed enrichment and tumor infiltration analysis followed by HPA validation. Lastly, we established a 3-node miRNA-TF-mRNA regulatory network and performed protein-protein docking of the highest-degree subnetwork motif between TF and mRNA. Significant upregulation of CBX3/2 and downregulation of AQP3/5/7 correlated with poor overall survival (OS) in HNSC patients. The most significant pathway, GO-BP, GO-MF, and GO-CC terms associated with AQP3 and CBX3 were passive transport by aquaporins, response to vitamin, glycerol channel activity, and condensed chromosome, centromeric region. AQP3 negatively correlated with [Formula: see text] T cells, positively with [Formula: see text] T cells and B cells, and negatively with tumor purity, whereas CBX3 positively correlated with [Formula: see text] T cells, negatively with [Formula: see text] T cells and B cells, and positively with tumor purity. Three-node miRNA-TF-mRNA regulatory network revealed a highest-degree subnetwork motif comprising one TF (SMAD3), one miRNA (miR-423-5p), and one mRNA (AQP3). Protein-protein interaction studies suggested a direct interaction between AQP3 and Smad3 proteins. We concluded that AQP3 and CBX3 hold potential as treatment strategies and individual prognostic biomarkers, while further protein-protein interaction studies of AQP3 could offer insights into its interactions with Smad3 proteins.

Identification of potential therapeutic targets for COVID-19 through a structural-based similarity approach between SARS-CoV-2 and its human host proteins.

Background: The COVID-19 pandemic caused by SARS-CoV-2 has led to millions of deaths worldwide, and vaccination efficacy has been decreasing with each lineage, necessitating the need for alternative antiviral therapies. Predicting host-virus protein-protein interactions (HV-PPIs) is essential for identifying potential host-targeting drug targets against SARS-CoV-2 infection. Objective: This study aims to identify therapeutic target proteins in humans that could act as virus-host-targeting drug targets against SARS-CoV-2 and study their interaction against antiviral inhibitors. Methods: A structure-based similarity approach was used to predict human proteins similar to SARS-CoV-2 ("hCoV-2"), followed by identifying PPIs between hCoV-2 and its target human proteins. Overlapping genes were identified between the protein-coding genes of the target and COVID-19-infected patient's mRNA expression data. Pathway and Gene Ontology (GO) term analyses, the construction of PPI networks, and the detection of hub gene modules were performed. Structure-based virtual screening with antiviral compounds was performed to identify potential hits against target gene-encoded protein. Results: This study predicted 19,051 unique target human proteins that interact with hCoV-2, and compared to the microarray dataset, 1,120 target and infected group differentially expressed genes (TIG-DEGs) were identified. The significant pathway and GO enrichment analyses revealed the involvement of these genes in several biological processes and molecular functions. PPI network analysis identified a significant hub gene with maximum neighboring partners. Virtual screening analysis identified three potential antiviral compounds against the target gene-encoded protein. Conclusion: This study provides potential targets for host-targeting drug development against SARS-CoV-2 infection, and further experimental validation of the target protein is required for pharmaceutical intervention.

Nitric oxide as a double-edged sword in pulmonary viral infections: Mechanistic insights and potential therapeutic implications.

In the face of the global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), researchers are tirelessly exploring novel therapeutic approaches to combat coronavirus disease 2019 (COVID-19) and its associated complications. Nitric oxide (NO) has appeared as a multifaceted signaling mediator with diverse and often contrasting biological activities. Its intricate biochemistry renders it a crucial regulator of cardiovascular and pulmonary functions, immunity, and neurotransmission. Perturbations in NO production, whether excessive or insufficient, contribute to the pathogenesis of various diseases, encompassing cardiovascular disease, pulmonary hypertension, asthma, diabetes, and cancer. Recent investigations have unveiled the potential of NO donors to impede SARS-CoV- 2 replication, while inhaled NO demonstrates promise as a therapeutic avenue for improving oxygenation in COVID-19-related hypoxic pulmonary conditions. Interestingly, NO's association with the inflammatory response in asthma suggests a potential protective role against SARS-CoV-2 infection. Furthermore, compelling evidence indicates the benefits of inhaled NO in optimizing ventilation-perfusion ratios and mitigating the need for mechanical ventilation in COVID-19 patients. In this review, we delve into the molecular targets of NO, its utility as a diagnostic marker, the mechanisms underlying its action in COVID-19, and the potential of inhaled NO as a therapeutic intervention against viral infections. The topmost significant pathway, gene ontology (GO)-biological process (BP), GO-molecular function (MF) and GO-cellular compartment (CC) terms associated with Nitric Oxide Synthase (NOS)1, NOS2, NOS3 were arginine biosynthesis (p-value = 1.15 x 10-9) regulation of guanylate cyclase activity (p-value = 7.5 x 10-12), arginine binding (p-value = 2.62 x 10-11), vesicle membrane (p-value = 3.93 x 10-8). Transcriptomics analysis further validates the significant presence of NOS1, NOS2, NOS3 in independent COVID-19 and pulmonary hypertension cohorts with respect to controls. This review investigates NO's molecular targets, diagnostic potentials, and therapeutic role in COVID-19, employing bioinformatics to identify key pathways and NOS isoforms' significance.

Exploring the role of miR-200 family in regulating CX3CR1 and CXCR1 in lung adenocarcinoma tumor microenvironment: implications for therapeutic intervention.

Lung adenocarcinoma (LUAD) is the most common malignant subtype of lung cancer (LC). miR-200 family is one of the prime miR regulators of epithelial-mesenchymal transition (EMT) and worst overall survival (OS) in LC patients. The study aimed to identify and validate the key differentially expressed immune-related genes (DEIRGs) regulated by miR-200 family which may serve for therapeutic aspects in LUAD tumor microenvironment (TME) by affecting cancer progression, invasion, and metastasis. The study identified differentially expressed miRNAs (DEMs) in LUAD, consisting of hsa-miR-200a-3p and hsa-miR-141-5p, respectively. Two highest-degree subnetwork motifs identified from 3-node miRNA FFL were: (i) miR-200a-3p-CX3CR1-SPIB and (ii) miR-141-5p-CXCR1-TBX21. TIMER analysis showed that the expression levels of CX3CR1 and CXCR1 were significantly positively correlated with infiltrating levels of M0-M2 macrophages and natural killer T (NKT) cells. The OS of LUAD patients was significantly affected by lower expression levels of hsa-miR-200a-3p, CX3CR1 and SPIB. These DEIRGs were validated using the human protein atlas (HPA) web server. Further, we validated the regulatory role of hsa-miR-200a-3p in an in-vitro indirect co-culture model using conditioned media from M0, M1 and M2 polarized macrophages (THP-1) and LUAD cell lines (A549 and H1299 cells). The results pointed out the essential role of hsa-miR-200a-3p regulated CX3CL1 and CX3CR1 expression in progression of LC TME. Thus, the study augments a comprehensive understanding and new strategies for LUAD treatment where miR-200 family regulated immune-related genes, especially chemokine receptors, which regulate the metastasis and invasion of LUAD, leading to the worst associated OS.

Integrative multiomics and weighted network approach reveals the prognostic role of RPS7 in lung squamous cell carcinoma pathogenesis.

Lung cancer is one of the most commonly occurring malignant cancers with the highest rate of mortality globally. Difference between lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) and their treatment strategies according to genetic markers may be helpful in reducing the cancer progression and increasing the overall survival (OS) in patients. LUSC is known for comparatively less typical onco-drivers, target therapy resistance, marked genomic complexity, and a reasonably higher mutation rate. The mRNA-seq data and clinical information of LUAD and LUSC cohorts from UCSC Xena comprising 437 and 379 patient samples were extracted. Differential expression and weighted network analyses revealed 47 and 18 hub differentially expressed genes (DEGs) corresponding to LUAD and LUSC cohorts. These hub DEGs were further subjected to protein-protein interaction network (PPIN) and OS analyses. Lower mRNA expression levels of both RPS15A and RPS7 worsened the OS of LUSC patients. Additionally, both these prognostic biomarkers were validated via external sources such as UALCAN, cBioPortal, TIMER, and HPA. RPS7 had higher mutation frequency compared to RPS15A and showed significant negative correlations with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, and macrophages. Our findings provided novel insights into biomarker discovery and the critical role of ribosomal biogenesis especially smaller ribosomal subunit in pathogenesis of LUSC.

Comprehensive multiomics and in silico approach uncovers prognostic, immunological, and therapeutic roles of ANLN in lung adenocarcinoma.

The anillin actin-binding protein (ANLN) is immensely overexpressed in cancers, including lung cancer (LC). Phytocompounds have gained interest due to their broader potential and reduced unwanted effects. Screening numerous compounds presents a challenge, but in silico molecular docking is pragmatic. The present study aims to identify the role of ANLN in lung adenocarcinoma (LUAD), along with identification and interaction analysis of anticancer and ANLN inhibitory phytocompounds followed by molecular dynamics (MD) simulation. Using a systematic approach, we found that ANLN is significantly overexpressed in LUAD and mutated with a frequency of 3.73%. It is linked with advanced stages, clinicopathological parameters, worsening of relapse-free survival (RFS), and overall survival (OS), pinpointing its oncogenic and prognostic potential. High-throughput screening and molecular docking of phytocompounds revealed that kaempferol (flavonoid aglycone) interacts strongly with the active site of ANLN protein via hydrogen bonds, Vander Waals interactions, and acts as a potent inhibitor. Furthermore, we discovered that ANLN expression was found to be significantly higher (p) in LC cells compared to normal cells. This is a propitious and first study to demonstrate ANLN and kaempferol interactions, which might eventually lead to removal of rout from cell cycle regulation posed by ANLN overexpression and allow it to resume normal processes of proliferation. Overall, this approach suggested a plausible biomarker role of ANLN and the combination of molecular docking subsequently led to the identification of contemporary phytocompounds, bearing symbolic anticancer effects. The findings would be advantageous for pharmaceutics but require validation using in vitro and in vivo methods. HIGHLIGHTS: • ANLN is significantly overexpressed in LUAD. • ANLN is implicated in the infiltration of TAMs and altering plasticity of TME. • Kaempferol (potential ANLN inhibitor) shows important interactions with ANLN which could remove the alterations in cell cycle regulation, imposed by ANLN overexpression eventually leading to normal process of cell proliferation.

Investigating the link between miR-34a-5p and TLR6 signaling in sepsis-induced ARDS.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6 and an antagonizing effect on STAT6 to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03700-1.

Investigating the role of Kinesin family in lung adenocarcinoma via integrated bioinformatics approach.

Lung cancer is the leading cause of mortality from cancer worldwide. Lung adenocarcinoma (LUAD) is a type of non-small cell lung cancer (NSCLC) with highest prevalence. Kinesins a class of motor proteins are shown to be involved in carcinogenesis. We conducted expression, stage plot and survival analyses on kinesin superfamily (KIF) and scrutinized the key prognostic kinesins. Genomic alterations of these kinesins were studied thereafter via cBioPortal. A protein-protein interaction network (PPIN) of selected kinesins and 50 closest altering genes was constructed followed by gene ontology (GO) term and pathway enrichment analyses. Multivariate survival analysis based on CpG methylation of selected kinesins was performed. Lastly, we conducted tumor immune infiltration analysis. Our results found KIF11/15/18B/20A/2C/4A/C1 to be significantly upregulated and correlated with poor survival in LUAD patients. These genes also showed to be highly associated with cell cycle. Out of our seven selected kinesins, KIFC1 showed the highest genomic alteration with highest number of CpG methylation. Also, CpG island (CGI) cg24827036 was discovered to be linked to LUAD prognosis. Therefore, we deduced that reducing the expression of KIFC1 could be a feasible treatment strategy and that it can be a wonderful individual prognostic biomarker. CGI cg24827036 can also be used as a therapy site in addition to being a great prognostic biomarker.

Global and local evolutionary dynamics of Dengue virus serotypes 1, 3, and 4.

Evolutionary studies on Dengue virus (DENV) in endemic regions are necessary since naturally occurring mutations may lead to genotypic variations or shifts in serotypes, which may lead to future outbreaks. Our study comprehends the evolutionary dynamics of DENV, using phylogenetic, molecular clock, skyline plots, network, selection pressure, and entropy analyses based on partial CprM gene sequences. We have collected 250 samples, 161 in 2017 and 89 in 2018. Details for the 2017 samples were published in our previous article and that of 2018 are presented in this study. Further evolutionary analysis was carried out using 800 sequences, which incorporate the study and global sequences from GenBank: DENV-1 (n = 240), DENV-3 (n = 374), and DENV-4 (n = 186), identified during 1944-2020, 1956-2020, and 1956-2021, respectively. Genotypes V, III, and I were identified as the predominant genotypes of the DENV-1, DENV-3, and DENV-4 serotypes, respectively. The rate of nucleotide substitution was found highest in DENV-3 (7.90 × 10-4 s/s/y), followed by DENV-4 (6.23 × 10-4 s/s/y) and DENV-1 (5.99 × 10-4 s/s/y). The Bayesian skyline plots of the Indian strains revealed dissimilar patterns amongst the population size of the three serotypes. Network analyses showed the presence of different clusters within the prevalent genotypes. The data presented in this study will assist in supplementing the measures for vaccine development against DENV.

Breast Cancer Prognostic Hub Genes Identified by Integrated Transcriptomic and Weighted Network Analysis: A Road Toward Personalized Medicine.

Breast cancer (BC) is the second-most common type and among the leading causes of worldwide cancer-related deaths. There is marked person-to-person variability in susceptibility to, and phenotypic expression and prognosis of BC, a predicament that calls for personalized medicine and individually tailored therapeutics. In this study, we report new observations on prognostic hub genes and key pathways involved in BC. We used the data set GSE109169, comprising 25 pairs of BC and adjacent normal tissues. Using a high-throughput transcriptomic approach, we selected data on 293 differentially expressed genes to establish a weighted gene coexpression network. We identified three age-linked modules where the light-gray module strongly correlated with BC. Based on the gene significance and module membership features, peptidase inhibitor 15 (PI15) and KRT5 were identified as our hub genes from the light-gray module. These genes were further verified at transcriptional and translational levels across 25 pairs of BC and adjacent normal tissues. Their promoter methylation profiles were assessed based on various clinical parameters. In addition, these hub genes were used for Kaplan-Meier survival analysis, and their correlation with tumor-infiltrating immune cells was investigated. We found that PI15 and KRT5 may be potential biomarkers and potential drug targets. These findings call for future research in a larger sample size, which could inform diagnosis and clinical management of BC, thus paving the way toward personalized medicine.

Combined Multiomics and In Silico Approach Uncovers PRKAR1A as a Putative Therapeutic Target in Multi-Organ Dysfunction Syndrome.

Despite all epidemiological, clinical, and experimental research efforts, therapeutic concepts in sepsis and sepsis-induced multi-organ dysfunction syndrome (MODS) remain limited and unsatisfactory. Currently, gene expression data sets are widely utilized to discover new biomarkers and therapeutic targets in diseases. In the present study, we analyzed MODS expression profiles (comprising 13 sepsis and 8 control samples) retrieved from NCBI-GEO and found 359 differentially expressed genes (DEGs), among which 170 were downregulated and 189 were upregulated. Next, we employed the weighted gene co-expression network analysis (WGCNA) to establish a MODS-associated gene co-expression network (weighted) and identified representative module genes having an elevated correlation with age. Based on the results, a turquoise module was picked as our hub module. Further, we constructed the PPI network comprising 35 hub module DEGs. The DEGs involved in the highest-confidence PPI network were utilized for collecting pathway and gene ontology (GO) terms using various libraries. Nucleotide di- and triphosphate biosynthesis and interconversion was the most significant pathway. Also, 3 DEGs within our PPI network were involved in the top 5 significantly enriched ontology terms, with hypercortisolism being the most significant term. PRKAR1A was the overlapping gene between top 5 significant pathways and GO terms, respectively. PRKAR1A was considered as a therapeutic target in MODS, and 2992 ligands were screened for binding with PRKAR1A. Among these ligands, 3 molecules based on CDOCKER score (molecular dynamics simulated-based score, which allows us to rank the binding poses according to their quality and to identify the best pose for each system) and crucial interaction with human PRKAR1A coding protein and protein kinase-cyclic nucleotide binding domains (PKA RI alpha CNB-B domain) via active site binding residues, viz. Val283, Val302, Gln304, Val315, Ile327, Ala336, Ala337, Val339, Tyr373, and Asn374, were considered as lead molecules.

Unravelling hub genes as potential therapeutic targets in lung cancer using integrated transcriptomic meta-analysis and in silico approach.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Smoking has been identified as the main contributing cause of the disease's development. The study aimed to identify the key genes in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the two major types of LC. Meta-analysis was performed with two datasets GSE74706 and GSE149507 obtained from Gene Expression Omnibus (GEO). Both the datasets comprised samples from cancerous and adjacent non-cancerous tissues. Initially, 633 differentially expressed genes (DEGs) were identified. To understand the underlying molecular mechanism of the identified genes, pathway enrichment, gene ontology (GO) and protein-protein interaction (PPI) analyses were done. A total of 9 hub genes were identified which were subjected to mutation study analysis in LC patients using cBioPortal. These  9 genes (i.e. AURKA, AURKB, KIF23, RACGAP1, KIF2C, KIF20A, CENPE, TPX2 and PRC1) have shown overexpression in LC patients and can be explored as potential candidates for prognostic biomarkers. TPX2 reported a maximum mutation of 4%. This was followed with high throughput screening and docking analysis to identify the potential drug candidates following competitive inhibition of the AURKA-TPX2 complex. Four compounds, CHEMBL431482, CHEMBL2263042, CHEMBL2385714, and CHEMBL1206617 were identified. The results signify that the selected 9 genes can be explored as biomarkers in disease prognosis and targeted therapy. Also, the identified 4 compounds can be further analyzed as promising therapeutic candidates.Communicated by Ramaswamy H. Sarma.

Unravelling the role of telomere shortening with ageing and their potential association with diabetes, cancer, and related lifestyle factors.

Telomeres are often considered as the 'ageing clock' that determines the lifespan at the cellular level, forming the ends of a chromosome, which shorten each time the cell divides itself to the point where they become so short the cell is unable to divide itself further. Telomere length alteration is often linked with lifestyle factors such as age, obesity, exposure to pesticides and pollution, depression, unhealthy diet, lack of exercise, and stress. The current review discusses the mechanism of telomere shortening in relation to ageing and lifestyle factors in general and its association with chronic diseases like diabetes which may influence the health and lifespan of an individual by increasing telomere shortening. Accelerated or excessive telomere shortening is also associated with the early onset of age-related disorders globally and, hence, reduced lifespan of individuals. Upregulated Telomerase activity and reactivation of telomeres is observed in > 70 % of cancer patients by TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, making it a useful marker in diagnosis and prognosis of various cancers. The study presents a systematic review of the unregulated Telomere activity with progression of various cancer and extrapolation of suitable pathways and prognostic information correlated with mRNA levels of TERT, which are critical among thymic epithelial tumors (TETs). In most cancers, unlimited proliferation is due to the reactivation of reverse transcriptase gene TERT. All these observations are comprehensively presented in the paper and might be useful for researchers working in the field of telomere dynamics and finding the correlation of age shortening with mRNA expression profiling.

Mathematical modeling in perspective of vector-borne viral infections: a review.

Background: Viral diseases are highly widespread infections caused by viruses. These viruses are passing from one human to other humans through a certain medium. The medium might be mosquito, animal, reservoir and food, etc. Here, the population of both human and mosquito vectors are important. Main body of the abstract: The main objectives are here to introduce the historical perspective of mathematical modeling, enable the mathematical modeler to understand the basic mathematical theory behind this and present a systematic review on mathematical modeling for four vector-borne viral diseases using the deterministic approach. Furthermore, we also introduced other mathematical techniques to deal with vector-borne diseases. Mathematical models could help forecast the infectious population of humans and vectors during the outbreak. Short conclusion: This study will be helpful for mathematical modelers in vector-borne diseases and ready-made material in the review for future advancement in the subject. This study will not only benefit vector-borne conditions but will enable ideas for other illnesses.

miR-495-3p regulates sphingolipid metabolic reprogramming to induce Sphk1/ceramide mediated mitophagy and apoptosis in NSCLC.

Sphingolipid metabolism is the forefront area of cancer research, but the underlying mechanisms are not fully explored yet. Sphingolipid metabolites [ceramide, sphingosine-1-phosphate (S1P)] are critical players in cell growth and apoptosis. Sphk1 is a key enzyme, catalyzing the phosphorylation of sphingosine to S1P, favoring cell proliferation and survival. Contrarily, ceramide induces cell cycle arrest and apoptosis. Sphk1 also exerts regulatory roles in numerous cellular processes, wherein microRNAs (miRNAs) play a momentous role. However, miR-mediated regulation of Sphk1 in Non-small cell lung cancer (NSCLC), continues to be elusive. miR-495 is highly downregulated and worsens NSCLC prognosis. The present study demonstrates Sphk1 upregulation and poor prognosis in NSCLC. However, miR-495-3p directly targets Sphk1, and possesses tumor-suppressive roles by decreasing cell proliferation, wound healing, colony formation, LDH-A activity, and inducing G0/G1 phase cell cycle arrest upon restoration. Besides, we also found ceramide accretion upon Sphk1 inhibition, leading to mitochondrial dysregulation. We found a cogent upregulation of Drp-1, PARK2 and LC3ß, along with degradation of PINK1 and Mfn2, demonstrating an imbalance in mitochondrial fission/fusion and induction of mitophagy, even during PINK1 deficiency. Later, we found a reduction in mitochondrial energy homeostasis, mitochondrial membrane potential, increased ROS generation and ultimately initiation of apoptosis, upon miR-495-3p overexpression. Overall, we showed that miR-495-3p reprograms sphingolipid rheostat towards ceramide by targeting Sphk1 and induces lethal mitophagy to suppress NSCLC tumorigenesis. The study identified a miR-mediated mechanism of sphingolipid reprogramming that could be beneficial in designing novel therapeutic strategies for NSCLC.

Integrated transcriptomic and regulatory network analyses uncovers the role of let-7b-5p, SPIB, and HLA-DPB1 in sepsis.

Sepsis has affected millions of populations of all age groups, locations, and sexes worldwide. Immune systems, either innate or adaptive are dysregulated due to the infection. Various biomarkers are present to date, still sepsis is a primary cause of mortality. Globally, post-operative body infections can cause sepsis and septic shock in ICU. Abnormal antigen presentation to T-cells leads to a dysregulated immune system. miRNAs are sparkly evolved as biomarkers due to their high sensitivity and efficiency. In this work, we analyzed high-throughput mRNA data collected from Gene Expression Omnibus (GEO) and linked it to significant miRNAs and TFs using a network-based approach. Protein-protein interaction (PPI) network was constructed using sepsis-specific differentially expressed genes (DEGs) followed by enrichment analyses and hub module detection. Sepsis-linked decrease transcription of the classical HLA gene such as HLA-DPB1 and its interplay with miR-let-7b-5p and transcription factor SPIB was observed. This study helped to provide innovative targets for sepsis.

miR-16-5p regulates aerobic glycolysis and tumorigenesis of NSCLC cells via LDH-A/lactate/NF-κB signaling.

BACKGROUND AND AIM: Cancer cells exhibit Warburg effect, characterized by increased glycolysis followed by fermentative conversion of pyruvate to lactate. Upregulation of Lactate Dehydrogenase-A (LDH-A) is elucidated to be a dominant molecular mediator of the phenomenon. Also, microRNA (miRNA) dysregulation participates in malignant progression and dissemination in several cancers. miR-16-5p is considerably reduced in lung cancers (LC), suggesting its tumor-suppressive role. However, its role in the regulation of aerobic glycolysis remains unknown. Our study aims to identify the regulatory roles of miR-16-5p/LDH-A in Non-small cell lung cancer (NSCLC). MAIN METHODS: We evaluated the differential expression of LDH-A and its prognostic potential in NSCLC tissues using online databases. We performed Tissue analysis using Immunohistochemistry (IHC); In-vitro cellular analysis including transient transfection, cellular proliferation, migration, and colony forming analysis. We also performed cell survival, metabolic, cell cycle, apoptotic, ROS generation and Immunocytochemistry (ICC) analyses to identify the role of miR-16-5p/LDH-A in aerobic glycolysis and tumorigenesis of NSCLC. KEY FINDINGS: We have identified that miR-16-5p directly targets LDH-A by binding to the complementary binding regions present in its 3'-UTR region, leading to degradation, sequentially leading to reduced lactate accumulation, glucose uptake and ATP levels. Our study also demonstrated the role of lactate accumulation in promoting NSCLC tumorigenesis via activation of NF-κB signaling pathway. However, miR-16-5p mediated targeting of LDH-A downregulates the expression of NF-κB associated genes, along with increased ROS generation, apoptosis, and cell cycle arrest. SIGNIFICANCE: In conclusion, our findings identify miR-16-5p/LDH-A/lactate/NF-κB as an important link between metabolism and NSCLC cells tumorigenesis.

Differential Gene Expression and Weighted Correlation Network Dynamics in High-Throughput Datasets of Prostate Cancer.

Precision oncology is an absolute need today due to the emergence of treatment resistance and heterogeneity among cancerous profiles. Target-propelled cancer therapy is one of the treasures of precision oncology which has come together with substantial medical accomplishment. Prostate cancer is one of the most common cancers in males, with tremendous biological heterogeneity in molecular and clinical behavior. The spectrum of molecular abnormalities and varying clinical patterns in prostate cancer suggest substantial heterogeneity among different profiles. To identify novel therapeutic targets and precise biomarkers implicated with prostate cancer, we performed a state-of-the-art bioinformatics study, beginning with analyzing high-throughput genomic datasets from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) suggests a set of five dysregulated hub genes (MAF, STAT6, SOX2, FOXO1, and WNT3A) that played crucial roles in biological pathways associated with prostate cancer progression. We found overexpressed STAT6 and SOX2 and proposed them as candidate biomarkers and potential targets in prostate cancer. Furthermore, the alteration frequencies in STAT6 and SOX2 and their impact on the patients' survival were explored through the cBioPortal platform. The Kaplan-Meier survival analysis suggested that the alterations in the candidate genes were linked to the decreased overall survival of the patients. Altogether, the results signify that STAT6 and SOX2 and their genomic alterations can be explored in therapeutic interventions of prostate cancer for precision oncology, utilizing early diagnosis and target-propelled therapy.