Structure-Based Virtual Screening Identifying Novel FOXM1 Inhibitors as the Lead Compounds for Glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. OBJECTIVE: In this research, the objective was to perform structure-based in silico screening with the aim of identifying natural compounds proficient in targeting the DNA-binding domain (DBD) of the FOXM1 protein. METHODS: In this study, in silico tools were employed for screening a hundred naturally occurring compounds capable of targeting the FOXM1 protein. Through molecular docking analysis and pharmacokinetic profiling, five compounds were found to be promising candidates for extensive interaction with the FOXM1 protein. Further, these compounds were validated for the stability of the FOXM1-natural compound complex using molecular dynamics (MD) simulations. RESULTS: Four compounds, such as Withaferin A, Bryophyllin A, Silybin B, Sanguinarine and Troglitazone (control compound), emerged as promising candidates with substantial interactions with FOXM1, suggesting their potential as a protein inhibitor based on molecular docking investigations. After MD simulation analysis, the FOXM1- Bryophyllin A complex was found to maintain the highest stability, and the other three ligands had moderate but comparable binding affinities over a period of 100 ns. CONCLUSION: This study provides valuable insights into four promising FOXM1 inhibitors that have the ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based designing strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.

Computational exploration of FOXM1 inhibitors for glioblastoma: an integrated virtual screening and molecular dynamics simulation study.

In this study, a comprehensive investigation of a set of phytochemicals to identify potential inhibitors for the Forkhead box protein M1 (FOXM1) was conducted. FOXM1 is overexpressed in glioblastoma (GBM) cells and plays a crucial role in cell cycle progression, proliferation, and invasion. FOXM1 inhibitors have shown promising results in preclinical studies, and ongoing clinical trials are assessing their efficacy in GBM patients. However, there are limited studies on the identification of novel compounds against this attractive therapeutic target. To address this, the NPACT database containing 1,574 phytochemicals was used, employing a hierarchical multistep docking approach, followed by an estimation of relative binding free energy. By fixing user-defined XP-dock and MM-GBSA cut-off scores of -6.096 and -37.881 kcal/mol, the chemical space was further narrowed. Through exhaustive analysis of molecular binding interactions and various pharmacokinetics profiles, we identified four compounds, namely NPACT00002, NPACT01454, NPACT00856, and NPACT01417, as potential FOXM1 inhibitors. To assess the stability of protein-ligand binding in dynamic conditions, 100 ns Molecular dynamics (MD) simulations studies were performed. Furthermore, Molecular mechanics with generalized Born and surface area solvation (MM-GBSA) based binding free energy estimations of the entire simulation trajectories revealed a strong binding affinity of all identified compounds towards FOXM1, surpassing that of the control drug Troglitazone. Based on extensively studied multistep docking approaches, we propose that these molecules hold promise as FOXM1 inhibitors for potential therapeutic applications in GBM. However, experimental validation will be necessary to confirm their efficacy as targeted therapies.Communicated by Ramaswamy H. Sarma.

Severe Disease Burden and the Mitigation Strategy in the Arsenic-Exposed Population of Kaliprasad Village in Bhagalpur District of Bihar, India.

The present study was carried out in the village Kaliprasad of Bhagalpur district of Bihar to know the arsenic exposure effect in the exposed population. A total of n = 102 households were studied, and their water and biological samples such as urine and hair were collected and analyzed in a graphite furnace atomic absorption spectrophotometer (GF-AAS). The assessment of arsenic-exposed village population reveals that the villagers were suffering from serious health-related problems such as skin manifestations (hyperkeratosis and melanosis in their palm and soles), breathlessness, general body weakness, mental disorders, diabetes, hypertension (raised blood pressure), hormonal imbalance, neurological disorders, and few cancer cases. About 77% of household hand pump water had arsenic level more than the WHO recommended level of 10 µg/L, with highest level of 523 µg/L. Moreover, in 60% individual's urine samples, arsenic concentration was very high with maximum 374 µg/L while in hair 64% individuals had arsenic concentration above the permissible limit with maximum arsenic concentration of 11,398 µg/kg. The hazard quotient (HQ) was also calculated to know the arsenic risk percentage in children as 87.11%, in females as 83.15%, and in males as 82.27% by groundwater. This has surpassed the threshold value of 1 × 10 - 6 for carcinogenic risk (CR) in children, female, and male population group in the village. Hence, the exposed population of Kaliprasad village are at very high risk of the disease burden.

Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer.

Brain cancer is known as one of the deadliest cancers globally. One of the causative factors is the imbalance between oxidative and antioxidant activities in the body, which is referred to as oxidative stress (OS). As part of regular metabolism, oxygen is reduced by electrons, resulting in the creation of numerous reactive oxygen species (ROS). Inflammation is intricately associated with the generation of OS, leading to the increased production and accumulation of reactive oxygen and nitrogen species (RONS). Glioma stands out as one of the most common malignant tumors affecting the central nervous system (CNS), characterized by changes in the redox balance. Brain cancer cells exhibit inherent resistance to most conventional treatments, primarily due to the distinctive tumor microenvironment. Oxidative stress (OS) plays a crucial role in the development of various brain-related malignancies, such as glioblastoma multiforme (GBM) and medulloblastoma, where OS significantly disrupts the normal homeostasis of the brain. In this review, we provide in-depth descriptions of prospective targets and therapeutics, along with an assessment of OS and its impact on brain cancer metabolism. We also discuss targeted therapies.

Lead phytochemicals and marine compounds against ceruloplasmin in cancer targeting.

In silico docking studies serve as a swift and efficient means to sift through a vast array of natural and synthetic small molecules, aiding in the identification of potential inhibitors for cancer biomarkers. One such biomarker, ceruloplasmin (CP), has been implicated in various tumor types due to its overexpression, earning it recognition as a marker of aggressive tumors. This study focused on pinpointing inhibitors for the CP -Myeloperoxidase (MPO) interaction site, a complex formation known to impede HOCl production, a crucial process for inducing apoptotic cell death in tumor cells. The initial phase of our investigation involved in silico docking studies, which screened a diverse library of phytochemicals and marine compounds. Through this process, we identified several promising drug candidates based on their binding affinities. Subsequently, these candidates underwent rigorous filtration based on Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Finally, we subjected the selected compounds to molecular dynamics (MDs) simulation to further assess their viability. Lycoperoside F, a steroidal alkaloid glycoside derived from tomatoes (Lycopersicon esculentum), stood out with notable interactions at the binding site. Another noteworthy compound was Xyloglucan (XG) oligosaccharides, predominantly found in the primary cell walls of higher plants. During the subsequent MDs simulations, these interactions were accompanied by highly stable root mean square deviation (RMSD) plots, signifying the consistency and robustness of the observed MDs behavior. XG oligosaccharides demonstrated the highest binding affinity with CP, reaffirming their potential as strong candidates. Additionally, Ardimerin digallate, known as a retroviral ribonuclease H inhibitor for HIV-1 and HIV-2, displayed favorable interactions at the MPO interaction site. Given that promising drug candidates must meet stringent criteria, including non-toxicity, effectiveness, specificity, stability and potency, these phytochemicals have the potential to progress to in vitro studies as CP inhibitors. Ultimately, this could contribute to the suppression of tumor growth, marking a significant step in cancer treatment research.Communicated by Ramaswamy H. Sarma.

Differentially Expressed Genes, miRNAs and Network Models: A Strategy to Shed Light on Molecular Interactions Driving HNSCC Tumorigenesis.

Head and neck squamous cell carcinoma (HNSCC) is among the most common cancer worldwide, accounting for hundreds thousands deaths annually. Unfortunately, most patients are diagnosed in an advanced stage and only a percentage respond favorably to therapies. To help fill this gap, we hereby propose a retrospective in silico study to shed light on gene-miRNA interactions driving the development of HNSCC. Moreover, to identify topological biomarkers as a source for designing new drugs. To achieve this, gene and miRNA profiles from patients and controls are holistically reevaluated using protein-protein interaction (PPI) and bipartite miRNA-target networks. Cytoskeletal remodeling, extracellular matrix (ECM), immune system, proteolysis, and energy metabolism have emerged as major functional modules involved in the pathogenesis of HNSCC. Of note, the landscape of our findings depicts a concerted molecular action in activating genes promoting cell cycle and proliferation, and inactivating those suppressive. In this scenario, genes, including VEGFA, EMP1, PPL, KRAS, MET, TP53, MMPs and HOXs, and miRNAs, including mir-6728 and mir-99a, emerge as key players in the molecular interactions driving HNSCC tumorigenesis. Despite the heterogeneity characterizing these HNSCC subtypes, and the limitations of a study pointing to relationships that could be context dependent, the overlap with previously published studies is encouraging. Hence, it supports further investigation for key molecules, both those already and not correlated to HNSCC.

Crosstalk between long noncoding RNA and microRNA in Cancer.

miRNAs and lncRNAs play a central role in cancer-associated gene regulations. The dysregulated expression of lncRNAs has been reported as a hallmark of cancer progression, acting as an independent prediction marker for an individual cancer patient. The interplay of miRNA and lncRNA decides the variation of tumorigenesis that could be mediated by acting as sponges for endogenous RNAs, regulating miRNA decay, mediating intra-chromosomal interactions, and modulating epigenetic components. This paper focuses on the influence of crosstalk between lncRNA and miRNA on cancer hallmarks such as epithelial-mesenchymal transition, hijacking cell death, metastasis, and invasion. Other cellular roles of crosstalks, such as neovascularization, vascular mimicry, and angiogenesis were also discussed. Additionally, we reviewed crosstalk mechanism with specific host immune responses and targeting interplay (between lncRNA and miRNA) in cancer diagnosis and management.

Wetland functional assessment and uncertainty analysis using fuzzy α-cut-based modified hydrogeomorphic approach.

Wetlands are significant ecosystems which perform several functions such as ground water recharge, flood control, carbon sequestration, and pollution reduction. Accurate evaluation of wetland functions is challenging, due to uncertainty associated with variables such as vegetation, soil, hydrology, land use, and landscape. Uncertainty is due to the factors such as the cost of evaluating quality parameters, measurement, and human errors. This study proposes an innovative framework based on modified hydrogeomorphic approach (HGMA) using fuzzy α-cut technique. HGMA has been used for wetland functional assessment and α-cut technique is used to characterize uncertainty corresponding to the input variables and wetland functions. The most uncertain variables were found to be the density of wetlands and basin count in the landscape assessment area with the scores of 4.38% and 3.614% respectively. Among the functions, the highest uncertainty is found in functional capacity index (FCI) corresponding to water storage (1.697%) and retain particulate (1.577%). The quantified uncertainty can help the practitioners to make informed decisions regarding planning best management practices for preserving and restoring the wetland functionality.

Early epigenetic markers for precision medicine.

Changes in DNA methylation levels, changes in histones, and noncoding RNA functions (ncRNAs) are common among different diseases and epigenetic component mutations. The ability to distinguish between the roles of drivers and passengers in epigenetic changes will allow to identify diseases where epigenetics could influence diagnosis, prediction and treatment. In addition, by examining the interaction between epigenetic components and other pathways of disease, a combination intervention approach will be developed. A comprehensive study of the association of specific cancer types or the cancer genome atlas project has revealed frequent mutations in genes encoded by the epigenetic components. These include mutations in DNA methylase and demethylase, the cytoplasm and the change of cytoplasm, as well as genes involved in the restoration of chromatins and the structure of chromosomes, also, the metabolic genes isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) affect histone and DNA methylation, disrupting the architecture of the 3D genome, but also affect the metabolic genes IDH1 and IDH2. Repeated DNA elements also cause cancer. In the 21st century, epigenetic research has rapidly accelerated, causing legitimate excitement and hope, and causing a certain level of excitement. New epigenetic tools can be used as prevention, diagnosis and therapeutic markers. Drug development targets specific epigenetic mechanisms that regulate gene expression and promotes gene expression. The development and use of epigenetic tools is an appropriate and effective method for treating various diseases clinically.

Arsenic causing gallbladder cancer disease in Bihar.

In recent times Gallbladder cancer (GBC) incidences increased many folds in India and are being reported from arsenic hotspots identified in Bihar. The study aims to establish association between arsenic exposure and gallbladder carcinogenesis. In the present study, n = 200 were control volunteers and n = 152 confirmed gallbladder cancer cases. The studied GBC patient's biological samples-gallbladder tissue, gallbladder stone, bile, blood and hair samples were collected for arsenic estimation. Moreover, n = 512 gallbladder cancer patients blood samples were also evaluated for the presence of arsenic to understand exposure level in the population. A significantly high arsenic concentration (p < 0.05) was detected in the blood samples with maximum concentration 389 µg/L in GBC cases in comparison to control. Similarly, in the gallbladder cancer patients, there was significantly high arsenic concentration observed in gallbladder tissue with highest concentration of 2166 µg/kg, in gallbladder stones 635 µg/kg, in bile samples 483 µg/L and in hair samples 6980 µg/kg respectively. Moreover, the n = 512 gallbladder cancer patient's blood samples study revealed very significant arsenic concentration in the population of Bihar with maximum arsenic concentration as 746 µg/L. The raised arsenic concentration in the gallbladder cancer patients' biological samples-gallbladder tissue, gallbladder stone, bile, blood, and hair samples was significantly very high in the arsenic exposed area. The study denotes that the gallbladder disease burden is very high in the arsenic exposed area of Bihar. The findings do provide a strong link between arsenic contamination and increased gallbladder carcinogenesis.

Glutamatergic neurotransmission: A potential pharmacotherapeutic target for the treatment of cognitive disorders.

In the mammalian brain, glutamate is regarded to be the primary excitatory neurotransmitter due to its widespread distribution and wide range of metabolic functions. Glutamate plays key roles in regulating neurogenesis, synaptogenesis, neurite outgrowth, and neuron survival in the brain. Ionotropic and metabotropic glutamate receptors, neurotransmitters, neurotensin, neurosteroids, and others co-ordinately formulate a complex glutamatergic network in the brain that maintains optimal excitatory neurotransmission. Cognitive activities are potentially synchronized by the glutamatergic activities in the brain via restoring synaptic plasticity. Dysfunctional glutamate receptors and other glutamatergic components are responsible for the aberrant glutamatergic activity in the brain that cause cognitive impairments, loss of synaptic plasticity, and neuronal damage. Thus, controlling the brain's glutamatergic transmission and modifying glutamate receptor function could be a potential therapeutic strategy for cognitive disorders. Certain drugs that regulate glutamate receptor activities have shown therapeutic promise in improving cognitive functions in preclinical and clinical studies. However, several issues regarding precise functional information of glutamatergic activity are yet to be comprehensively understood. The present article discusses the scope of developing glutamatergic systems as prospective pharmacotherapeutic targets to treat cognitive disorders. Special attention has been given to recent developments, challenges, and future prospects.

Neuropharmacological interventions of quercetin and its derivatives in neurological and psychological disorders.

Quercetin is a naturally occurring bioactive flavonoid abundant in many plants and fruits. Quercetin and its derivatives have shown an array of pharmacological activities in preclinical tests against various illnesses and ailments. Owing to its protective role against oxidative stress and neuroinflammation, quercetin is a possible therapeutic choice for the treatment of neurological disorders. Quercetin and its derivatives can modulate a variety of signal transductions, including neuroreceptor, neuroinflammatory receptor, and redox signaling events. The research on quercetin and its derivatives in neurology-related illnesses mainly focused on the targets, such as redox stress, neuroinflammation, and signaling pathways; however, the function of quercetin and its derivatives on specific molecular targets, such as nuclear receptors and proinflammatory mediators are yet to be explored. Findings showed that various molecular targets of quercetin and its derivatives have therapeutic potential against psychological and neurodegenerative disorders.

Insights into intricacies of the Latent Membrane Protein-1 (LMP-1) in EBV-associated cancers.

Numerous lymphomas, carcinomas, and other disorders have been associated with Epstein-Barr Virus (EBV) infection. EBV's carcinogenic potential can be correlated to latent membrane protein 1 (LMP1), which is essential for fibroblast and primary lymphocyte transformation. LMP1, a transmembrane protein with constitutive activity, belongs to the tumour necrosis factor receptor (TNFR) superfamily. LMP1 performs number of role in the life cycle of EBV and the pathogenesis by interfering with, reprogramming, and influencing a vast range of host cellular activities and functions that are getting well-known but still poorly understood. LMP1, pleiotropically perturbs, reprograms and balances a wide range of various processes of cell such as extracellular vesicles, epigenetics, ubiquitin machinery, metabolism, cell proliferation and survival, and also promotes oncogenic transformation, angiogenesis, anchorage-independent cell growth, metastasis and invasion, tumour microenvironment. By the help of various experiments, it is proven that EBV-encoded LMP1 activates multiple cell signalling pathways which affect antigen presentation, cell-cell interactions, chemokine and cytokine production. Therefore, it is assumed that LMP1 may perform majorly in EBV associated malignancies. For the development of novel techniques toward targeted therapeutic applications, it is essential to have a complete understanding of the LMP1 signalling landscape in order to identify potential targets. The focus of this review is on LMP1-interacting proteins and related signalling processes. We further discuss tactics for using the LMP1 protein as a potential therapeutic for cancers caused by the EBV.

Expression analysis and regulation of GLI and its correlation with stemness and metabolic alteration in human brain tumor.

GLI gene-mediated hedgehog (Hh) signaling pathway plays a substantial role in brain cancer development and growth including glioblastoma multiforme (GBM), lower-grade glioma (LGG), and medulloblastoma (MB). GLI2 and GLI3 gene expression levels are extremely enhanced in these cancers with poor patient survival. Moreover, GLI genes are correlated with stemness-related factors SOX2, SOX9, POU5F1, and NANOG that work as the driving factors for brain cancer stem cells (CSCs) progression. It's critical to find new ways to combat this deadly malignancy and CSCs. Using in silico approaches, our study explored the role of GLI genes (GLI1, GLI2, and GLI3), the primary transcription factors of the sonic hedgehog (SHH) signaling pathway, in GBM, LGG, MB, and glioblastoma stem-like cells (GSCs). Additionally, we found strong association of angiogenic-related gene VEGFA, metabolic genes ENO1, ENO2, and pluripotency-related genes SOX2, SOX9, NANOG, POU5F1 with GLI genes, suggesting their role in brain tumor initiation and progression. We also studied their transcriptional network and functional category enrichment analysis about brain tumor development to find a better therapeutic strategy against brain cancer and their stem cells. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03419-5.

Identification and validation of potent inhibitor of Escherichia coli DHFR from MMV pathogen box.

The present study is conducted to find the solution of rising antimicrobial resistance (AMR) in Escherichia coli which is a pathogen responsible for fatal systemic infections in human and animals. The enzyme dihydrofolate reductase (DHFR) is found in all organisms. In this study DHFR of E. coli (ec-DHFR) and human DHFR (h-DHFR) is targeted by novel chemical entities (NCE) from the Pathogen box of Medicines for Malaria Venture, Switzerland (MMV) using molecular modelling. The in-silico studies were further validated by in-vitro assays. The virtual screening of 400 MMV compounds was conducted using PyRx standard tool followed by manual docking of selected compounds by Autodock vina and Ligplot program. The in-silico studies showed good binding energy and strong hydrogen bond in docking of MMV675968 with ec-DHFR and no hydrogen bond with h-DHFR. This was further validated by the Molecular dynamic studies that revealed high binding free energy in ec-DHFR and in-vitro assays that produced good synergy in combination study of MMV675968 with last line (meropenem) and last resort (colistin) antibiotics. The extensive MD simulation and energetic analysis thus concludes that MMV675968 targets ec-DHFR. The combination studies were conducted with MMV675968 and FDA approved drugs against a panel of multidrug resistant Escherichia coli isolates. The synergistic results obtained in combination studies concluded that in-vitro data is consistent with in-silico data and that MMV675968 is a potential lead for future process of antimicrobial drug development against the multidrug resistance E. coli.Communicated by Ramaswamy H. Sarma.

Molecular mechanism(s) of regulations of cancer stem cell in brain cancer propagation.

Brain tumors are most often diagnosed with solid neoplasms and are the primary reason for cancer-related deaths in both children and adults worldwide. With recent developments in the progression of novel targeted chemotherapies, the prognosis of malignant glioma remains dismal. However, the high recurrence rate and high mortality rate remain unresolved and are closely linked to the biological features of cancer stem cells (CSCs). Research on tumor biology has reached a new age with more understanding of CSC features. CSCs, a subpopulation of whole tumor cells, are now regarded as candidate therapeutic targets. Therefore, in the diagnosis and treatment of tumors, recognizing the biological properties of CSCs is of considerable significance. Here, we have discussed the concept of CSCs and their significant role in brain cancer growth and propagation. We have also discussed personalized therapeutic development and immunotherapies for brain cancer by specifically targeting CSCs.

Polycystic Ovary Syndrome: An Updated Overview Foregrounding Impacts of Ethnicities and Geographic Variations.

Polycystic ovary syndrome (PCOS) is one of the most common heterogeneous conditions of the endocrine reproductive system in women of childbearing age. Hyperandrogenism and oligomenorrhea are the two core characteristics of PCOS, a complicated and multifaceted illness. The condition is also linked to several major side effects, which include type 2 diabetes, early atherosclerosis, infertility, and endometrial cancer. There are few facts and statistics available on PCOS prevalence internationally due to the significant degree of geographic and ethnic variance and inconsistency caused by different diagnosis standards. Limited (n = 179) explorations have been made in the context of the prevalence of this complicated illness so far, and out of these, only 55 studies have discussed its association with race and/or ethnicity. However, those studies remain restricted due to the small sample size, biased selection, and the lack of comparative studies. Variations in PCOS prevalence frequency also arise due to different diagnostic criteria, as well as racial and ethnic differences, associated lifestyle factors, and subsequent illnesses that affect the accuracy of the diagnosis. The main objective behind this systematic review is to provide comprehensive epidemiological data on PCOS that is organized geographically. This evidence-based study also provides an overview of the clinical management of PCOS to instigate further research on this complex endocrinological condition and the subsequent development of preventive treatment strategies.

Effect of Environmental Stressors, Xenobiotics, and Oxidative Stress on Male Reproductive and Sexual Health.

This article examines the environmental factor-induced oxidative stress (OS) and their effects on male reproductive and sexual health. There are several factors that induce OS, i.e. radition, metal contamination, xenobiotic compounds, and cigarette smoke and lead to cause toxicity in the cells through metabolic or bioenergetic processes. These environmental factors may produce free radicals and enhance the reactive oxygen species (ROS). Free radicals are molecules that include oxygen and disbalance the amount of electrons that can create major chemical chains in the body and cause oxidation. Oxidative damage to cells may impair male fertility and lead to abnormal embryonic development. Moreover, it does not only cause a vast number of health issues such as ageing, cancer, atherosclerosis, insulin resistance, diabetes mellitus, cardiovascular diseases, ischemia-reperfusion injury, and neurodegenerative disorders but also decreases the motility of spermatozoa while increasing sperm DNA damage, impairing sperm mitochondrial membrane lipids and protein kinases. This chapter mainly focuses on the environmental stressors with further discussion on the mechanisms causing congenital impairments due to poor sexual health and transmitting altered signal transduction pathways in male gonadal tissues.

In Silico Analysis of CatSper Family Genes and APOB Gene Regulation in Male Infertility.

Sperm concentration and sperm motility are the two major causes of male infertility. Having spermatozoa in semen without motility or flagellum tail defect is a major concern needed to be investigated. The CatSper genes are the novel family of four sperm-specific Ca2+-permeable channels which plays an important role in sperm motility, acrosome reaction, sperm, and oocyte fusion. CatSper1, CatSper2, and CatSper3 are very well-studied genes for their role in asthenozoospermia, but the association of these genes with metabolic genes is still unstudied. Another unrevealed aspect is how ROS alter the function of CatSper genes. Among the Catsper family genes, the role of CatSper4 gene must be explored more. In this study, we have used the in silico approach to find the connection between the CatSper family gene with glycolytic genes and also the involvement of CATSPER4 protein in sperm flagellum using the STRING database. Connection of CATSPER1 protein with lipid metabolic gene is also found in Reactome database, and after that gene ontology of these genes was done by using DAVID and Enrichr databases. This analysis showed a strong interaction between CATSPER1, CATSPER2, and CATSPER3 protein with glycolytic protein (i.e., GAPDHS and PGK2), and CATSPER4 protein shows strong relation in the function of sperm flagellum. We also found a novel gene, i.e., APOB contributing to sperm motility. Gene ontology showed the role of APOB and glycolytic proteins in sperm motility. Enrichr analysis showed the association of APOB and glycolytic proteins in asthenozoospermia and CATSPER4 protein with sperm flagellum. Elsevier Pathway Collection also showed proteins involved in male infertility (i.e., GAPDHS). Therefore, we report the role of the CatSper4 gene in sperm tail function and the APOB novel gene involved in sperm motility. Understanding the molecular mechanism(s) of regulations of the CatSper family gene will help us to develop new therapeutic approaches in infertile males.

Bacteriospermia and Male Infertility: Role of Oxidative Stress.

Male infertility is one of the major challenging and prevalent diseases having diverse etiologies of which bacteriospermia play a significant role. It has been estimated that approximately 15% of all infertility cases are due to infections caused by uropathogens and in most of the cases bacteria are involved in infection and inflammation leading to the development of bacteriospermia. In response to bacterial load, excess infiltration of leukocytes in the urogenital tract occurs and concomitantly generates oxidative stress (OS). Bacteria may induce infertility either by directly interacting with sperm or by generating reactive oxygen species (ROS) and impair sperm parameters such as motility, volume, capacitation, hyperactivation. They may also induce apoptosis leading to sperm death. Acute bacteriospermia is related with another clinical condition called leukocytospermia and both compromise male fertility potential by OS-mediated damage to sperm leading to male infertility. However, bacteriospermia as a clinical condition as well as the mechanism of action remains poorly understood, necessitating further research in order to understand the role of individual bacterial species and their impact in male infertility.