'Intracytoplasmic sperm injection (ICSI) paradox' and 'andrological ignorance': AI in the era of fourth industrial revolution to navigate the blind spots.

The quandary known as the Intracytoplasmic Sperm Injection (ICSI) paradox is found at the juncture of Assisted Reproductive Technology (ART) and 'andrological ignorance' - a term coined to denote the undervalued treatment and comprehension of male infertility. The prevalent use of ICSI as a solution for severe male infertility, despite its potential to propagate genetically defective sperm, consequently posing a threat to progeny health, illuminates this paradox. We posit that the meteoric rise in Industrial Revolution 4.0 (IR 4.0) and Artificial Intelligence (AI) technologies holds the potential for a transformative shift in addressing male infertility, specifically by mitigating the limitations engendered by 'andrological ignorance.' We advocate for the urgent need to transcend andrological ignorance, envisaging AI as a cornerstone in the precise diagnosis and treatment of the root causes of male infertility. This approach also incorporates the identification of potential genetic defects in descendants, the establishment of knowledge platforms dedicated to male reproductive health, and the optimization of therapeutic outcomes. Our hypothesis suggests that the assimilation of AI could streamline ICSI implementation, leading to an overall enhancement in the realm of male fertility treatments. However, it is essential to conduct further investigations to substantiate the efficacy of AI applications in a clinical setting. This article emphasizes the significance of harnessing AI technologies to optimize patient outcomes in the fast-paced domain of reproductive medicine, thereby fostering the well-being of upcoming generations.

Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling.

Recent mounting evidence has revealed extensive genetic heterogeneity within tumors that drive phenotypic variation affecting key cancer pathways, making cancer treatment extremely challenging. Diverse cancer types display resistance to treatment and show patterns of relapse following therapy. Therefore, efforts are required to address tumor heterogeneity by developing a broad-spectrum therapeutic approach that combines targeted therapies. Inflammation has been progressively documented as a vital factor in tumor advancement and has consequences in epigenetic variations that support tumor instigation, encouraging all the tumorigenesis phases. Increased DNA damage, disrupted DNA repair mechanisms, cellular proliferation, apoptosis, angiogenesis, and its incursion are a few pro-cancerous outcomes of chronic inflammation. A clear understanding of the cellular and molecular signaling mechanisms of tumor-endorsing inflammation is necessary for further expansion of anti-cancer therapeutics targeting the crosstalk between tumor development and inflammatory processes. Multiple inflammatory signaling pathways, such as the NF-κB signaling pathway, JAK-STAT signaling pathway, MAPK signaling, PI3K/AKT/mTOR signaling, Wnt signaling cascade, and TGF-ß/Smad signaling, have been found to regulate inflammation, which can be modulated using various factors such as small molecule inhibitors, phytochemicals, recombinant cytokines, and nanoparticles (NPs) in conjugation to phytochemicals to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy to restrict malignant progression and improve the efficacy of cancer therapy. siRNA-and shRNA-loaded NPs have been observed to downregulate STAT3 signaling pathways and have been employed in studies to target tumor malignancies. This review highlights the pathways involved in the interaction between tumor advancement and inflammatory progression, along with the novel approaches of nanotechnology-based drug delivery systems currently used to target inflammatory signaling pathways to combat cancer.

Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer.

Head and neck cancer is the sixth most common cancer across the globe. This is generally associated with tobacco and alcohol consumption. Cancer in the pharynx majorly arises through human papillomavirus (HPV) infection, thus classifying head and neck squamous cell carcinoma (HNSCC) into HPV-positive and HPV-negative HNSCCs. Aberrant, mesenchymal-epithelial transition factor (c-MET) signal transduction favors HNSCC progression by stimulating proliferation, motility, invasiveness, morphogenesis, and angiogenesis. c-MET upregulation can be found in the majority of head and neck squamous cell carcinomas. c-MET pathway acts on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K), alpha serine/threonine-protein kinase (Akt), mitogen-activated protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. c-MET also establishes a crosstalk pathway with epidermal growth factor receptor (EGFR) and contributes towards chemoresistance in HNSCC. In recent years, the signaling communications of c-MET/HGF in metabolic dysregulation, tumor-microenvironment and immune modulation in HNSCC have emerged. Several clinical trials have been established against c-MET/ hepatocyte growth factor (HGF) signaling network to bring up targeted and effective therapeutic strategies against HNSCC. In this review, we discuss the molecular mechanism(s) and current understanding of c-MET/HGF signaling and its effect on HNSCC.

Reactive Oxygen Species in the Reproductive System: Sources and Physiological Roles.

Reactive oxygen species (ROS) are oxygen-containing molecules which are reactive in nature and are capable of independent existence in the body. ROS comprise mostly of free radicals that contain at least one unpaired electron. Endogenous sources are the foremost birthplaces of ROS, which include mitochondrial electron transport chain, endoplasmic reticulum and peroxisome. Conversely, numerous enzymatic pathways such as xanthine oxidase and cyclooxygenase systems are among the prominent generators of cellular ROS. Major sources of ROS in the female reproductive tract include Graafian follicles, follicular fluid, fallopian tube, peritoneal cavity and endometrium. On the contrary, leukocytes, immature spermatozoa and varicocele are the key originators of ROS in the male reproductive system. For the sake of maintaining a proper oxidative balance, cells have evolved a variety of antioxidative molecules. From the physiological perspective, ROS and antioxidants are actively involved in the regulation of myriad female reproductive processes, such as cyclic luteal and endometrial changes, follicular development, ovulation, fertilization, embryonic implantation, maintenance of pregnancy and parturition. Similarly, physiological amounts of ROS are crucial in the accomplishment of various male reproductive functions as well, which include spermatozoa maturation, capacitation, hyperactivation and acrosome reaction. This chapter highlights the birthplaces of ROS in the female and male reproductive tract along with mechanisms of their production. This chapter will also put forward specific physiological roles of these reactive molecules in upholding the structural integrity and functionality of both the reproductive systems.

Pathological Roles of Reactive Oxygen Species in Male Reproduction.

Reactive oxygen species (ROS) are free radicals that have at least one unpaired electron and play specific roles in the human body. An imbalance of ROS and antioxidant levels gives rise to a condition called oxidative stress. High levels of ROS in the male reproductive tract can interfere with its normal functioning and can even pose as toxic to the sperm, inhibiting sperm functioning (including motility) and metabolism. Oxidative stress resulting from ROS and lipid peroxidation is one of the major causes of male infertility including infertility in varicocele patients. These may cause DNA and peroxidative damage and apoptosis. Production of ROS in excess also leads to erectile dysfunction (ED). In recent years, studies have also linked oxidative stress with the development, progress, and therapy response of prostate cancer patients. The present study summarizes the pathological roles of ROS in male reproductive problems such as infertility, ED, and prostate cancer and also provide an insight into the probable mechanism through which ROS exert their pathological impact.

Oxidative Stress and Idiopathic Male Infertility.

Idiopathic male infertility (IMI) refers to the condition where semen quality declines, but exact causatives are not identified. This occurs in almost 30-40% of infertile men. Traditional semen analyses are extensively used for determining semen quality, but these bear critical shortcomings such as poor reproducibility, subjectivity, and reduced prediction of fertility. Oxidative stress (OS) has been identified as the core common mechanism by which various endogenous and exogenous factors may induce IMI. Male oxidative stress infertility (MOSI) is a term used to describe infertile males with abnormal semen parameters and OS. For the treatment of MOSI, antioxidants are mostly used which counteract OS and improve sperm parameters with appropriate combinations, dosage, and duration. Diagnosis and management of male infertility have witnessed a substantial improvement with the advent in the omics technologies that address at genetic, molecular, and cellular levels. Incorporation of oxidation-reduction potential (ORP) can be a useful clinical biomarker for MOSI. Moreover, various modulations of male fertility status can be achieved via stem cell and next-generation sequencing (NGS) technologies. However, several challenges must be overcome before the advanced techniques can be utilized to address IMI, including ethical and religious considerations, as well as the possibility of genetic abnormalities. Considering the importance of robust understanding of IMI, its diagnosis, and possible advents in management, the present article reviews and updates the available information in this realm, emphasizes various facets of IMI, role of OS in its pathophysiology, and discusses the novel concept of MOSI with a focus on its diagnostic and therapeutic aspects.

Role of Infection and Leukocytes in Male Infertility.

Male infertility is considered as a multifactorial complex reproductive illness, and male urogenital infection and inflammation are crucial etiologies contributing up to 35% of all cases. Mostly triggered by sexually transmitted diseases and uropathogens, chronic manifestation of such infection may cause irreversible infertility in the male. Male urogenital infection involves bacterial, viral, protozoal, and fungal infections many of which remain asymptomatic most of the time and are passed to the sexual partner leading to fertilization failure, pregnancy loss, and even development of illness in the offspring. The abundance of leukocytes in semen can be used as an indicator of urogenital infection. Its contribution in male infertility can be as high as 30% and the clinical condition is referred to as leukocytospermia. Seminal bacterial load together with increased leukocytes contribute to the impairment of male fertility parameters such as, sperm motility, DNA integrity, acrosome reaction, and damage sperm molecular structure. Pathophysiology of bacteriospermia-induced impairment of male infertility is probably mediated by the involvement of bacterial pathogens in the intrinsic apoptotic pathway resulting in sperm death, whereas that of seminal leukocytes operates through excessive generation of ROS. Although the application of antibiotics forms the frontline therapeutic approach, the growing resistance to antibiotics poses a concern in the management of microbes-induced male urogenital infection. Complementary and alternative medicine may offer additional management options in combating such infections. On the other hand, both broad spectrum antibiotics and antioxidant therapy have showed promising results in the management of infertile men with leukocytospermia. Use of herbal medicine may also play a promising role in the management of such patients. However, recent molecular biology techniques have noted the association of elevated levels of IL-8 with both the Chlamydial infection of the male urogenital tract as well as the clinical condition of leukocytospermia. On the basis of such common pathogenesis, further research involving advanced molecular techniques may pave the way towards the development of better diagnostic tools in the clinical management of male urogenital infection and leukocytospermia.

Oxidative Stress and Varicocele-Associated Male Infertility.

Despite being regarded as one of the most common causes of male subfertility, the pathophysiology of varicocele remains largely unknown. Recently, oxidative stress (OS) is proposed to be the mediator in how varicocele may negatively impact fertility. The imbalance of reactive oxygen species (ROS) and seminal antioxidants results in damage to sperm DNA and lipid membrane. There is evidence demonstrating higher OS level in men with varicocele which is also positively correlated with clinical grading of varicocele. Moreover, a number of studies have revealed the negative correlation between OS and conventional semen parameters. Furthermore, various interventions have shown their potential in alleviating OS in men with varicocele-associated infertility. Although direct evidence on improving pregnancy rate is not available at the moment, varicocelectomy has demonstrated promising results in relieving OS. Oral antioxidants represent another option with a favourable safety profile. The supplement can be used alone or as adjunct to varicocelectomy. However, most of the studies are hampered by heterogenous dose regime and high-level evidence is lacking.

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.

Arsenic-Induced Sex Hormone Disruption: An Insight into Male Infertility.

Arsenic (As) is one of the most potent natural as well as anthropogenic metalloid toxicants that have various implications in the everyday life of humans. It is found in several chemical forms such as inorganic salt, organic salt, and arsine (gaseous form). Although it is mostly released via natural causes, there are many ways through which humans come in contact with As. Drinking water contamination by As is one of the major health concerns in various parts of the world. Arsenic exposure has the ability to induce adverse health effects including reproductive problems. Globally, around 15% of the couples are affected with infertility, of which about 20-30% are attributed to the male factor. Arsenic affects the normal development and function of sperm cells, tissue organization of the gonads, and also the sex hormone parameters. Stress induction is one of the implications of As exposure. Excessive stress leads to the release of glucocorticoids, which impact the oxidative balance in the body leading to overproduction of reactive oxygen species (ROS). This may in turn result in oxidative stress (OS) ultimately interfering with normal sperm and hormonal parameters. This study deals with As-induced OS and its association with sex hormone disruption as well as its effect on sperm and semen quality.

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.

Metabolic Dysregulation and Sperm Motility in Male Infertility.

Nowadays, about 14% of couples have difficulty in conceiving, and half of the cases are attributed to men. Asthenozoospermia or poor sperm motility is considered as the cause of infertility in males which is most common. Even though energy metabolism is considered the main reason for the etiology of asthenospermia, few attempts are made to determine the pathway of its metabolic potential. Recognition of cellular as well as molecular pathways that lead to reduced sperm motility may lead to the implementation of new therapeutic strategies to eliminate low sperm motility in people with asthenozoospermia. This review article discusses the key causes of decreased sperm motility and some of the muted genes and metabolic causes of the same.

Pathogenesis of Viral Infections and Male Reproductive Health: An Evidence-Based Study.

Viruses, being intracellular obligate parasites, can cause several congenital and sexually transmitted diseases. Depending on the site of infection, viruses can adopt various pathogenic mechanisms for their survival and to escape the host immune response. The male reproductive system is one of the attainable targets of many viruses including immunodeficiency virus (HIV), Zika virus (ZIKV), adenovirus, cytomegalovirus (CMV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and infection with such viruses may cause serious health issues. Leydig cells and seminiferous tubules are the prime sites of mammalian testis for viral infection. The azoospermic condition is a common symptom of viral infection, wherein the hypothalamic-pituitary-testicular (HPT) axis can be disrupted, leading to decreased levels of luteinizing hormone (LH). Furthermore, oxidative stress (OS) is a major contributing factor to viral infection-associated male infertility. The likelihood of direct and indirect infection, as well as sex-based variability in the vulnerability pattern to viral infections, has been observed. However, there appears to be a long-term impact of viral infection on male reproductive performance due to testicular tissue pathogenicity - a process that requires thorough investigation. The present study aimed to explore how the viruses affect the male reproductive system, including their distribution in tissues and body fluids, possible targets as well as the effects on the endocrine system. We used the major electronic databases such as MEDLINE and SCOPUS. Google Scholar was also consulted for additional literature search related to the topic. Obtained literatures were sorted based on the content. The articles that reported the pathogenesis of viruses on male reproductive health and were published in the English language were included in the present study.

Natural Products as the Modulators of Oxidative Stress: An Herbal Approach in the Management of Prostate Cancer.

Prostate cancer is the most commonly diagnosed and frequently occurred cancer in the males globally. The current treatment strategies available to treat prostate cancer are not much effective and express various adverse effects. Hence, there is an urgent need to identify novel treatment that can improve patient outcome. From times immemorial, natural products are highly recognized for novel drug development for various diseases including cancer. Cancer cells generally maintain higher basal levels of reactive oxygen species (ROS) when compared to normal cells due to its high metabolic rate. However, initiation of excess intracellular ROS production can not be tolerated by the cancer cells and induce several cell death signals which are in contrast to normal cells. Therefore, small molecules of natural origin that induce ROS can potentially kill cancer cells in specific and provide a better opportunity to develop a novel drug therapy. In this review, we elaborated various classes of medicinal compounds and their mechanism of killing prostate cancer cells through direct or indirect ROS generation. This can generate a novel thought to develop promising drug candidate to treat prostate cancer patients.

Heat Shock Factors in Protein Quality Control and Spermatogenesis.

Proper regulation of cellular protein quality control is crucial for cellular health. It appears that the protein quality control machinery is subjected to distinct regulation in different cellular contexts such as in somatic cells and in germ cells. Heat shock factors (HSFs) play critical role in the control of quality of cellular proteins through controlling expression of many genes encoding different proteins including those for inducible protein chaperones. Mammalian cells exert distinct mechanism of cellular functions through maintenance of tissue-specific HSFs. Here, we have discussed different HSFs and their functions including those during spermatogenesis. We have also discussed the different heat shock proteins induced by the HSFs and their activities in those contexts. We have also identified several small molecule activators and inhibitors of HSFs from different sources reported so far.

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.

Interplay of Oxidants and Antioxidants in Mammalian Embryo Culture System.

One principal purpose of assisted reproductive technology (ART) is to produce viable and good quality embryos. However, a variety of environmental factors may induce epigenetic changes in the embryo. Moreover, laboratory conditions including the culture media may also affect embryo development. Therefore, media change is an important factor in maintaining proper oxidant/antioxidant balance during embryo culture. Alterations in the oxidant/antioxidant balance are related to various cellular responses such as an increase in the level of reactive oxygen species (ROS) and consequent lipid peroxidation (LPO), DNA damage, and apoptosis. The current study focuses on the role of external factors on embryo culture and the ability of antioxidants to enhance in vitro fertilization (IVF) outcomes. Indeed, an optimization of media culture by the addition of enzymatic and nonenzymatic antioxidants in animal models and human embryos in ART has been updated in this study, with an emphasis on comparing the available results and their possible reasons.

Oxidative Stress-Induced Male Infertility: Role of Antioxidants in Cellular Defense Mechanisms.

Male infertility is linked to several environmental and mutagenic factors. Most of these factors, i.e., lifestyle, radiations, and chemical contaminations, work on the fundamental principles of physics, chemistry, and biology. Principally, it may induce oxidative stress (OS) and produce free radicals within the cells. The negative effect of OS may enhance the reactive oxygen species (ROS) levels in male reproductive organs and impair basic functions in a couple's fertility. Evidence suggests that infertile men have significantly increased ROS levels and a reduced antioxidant capacity compared with fertile men. Although, basic spermatic function and fertilizing capacity depend on a delicate balance between physiological activity of ROS and antioxidants to protect from cellular oxidative injury in sperm, that is essential to achieve pregnancy. The ideal oxidation-reduction (REDOX) equilibrium requires a maintenance of a range of ROS concentrations and modulation of antioxidants. For this reason, the chapter focuses on the effects of ROS in sperm functions and the current concepts regarding the benefits of medical management in men with diminished fertility and amelioration of the effect to improve sperm function. Also, this evidence-based study suggests an increasing rate of infertility that poses a global challenge for human health, urging the need of health care professionals to offer a correct diagnosis, comprehension of the process, and an individualized management of the patients.

Biological databases and tools for neurological disorders.

Computational approach to study of neuronal impairment is rapidly evolving, as experiments and intuition alone could not explain the complexity of brain system. The increase in an overwhelming amount of new data from both theory and computational modeling necessitate the development of databases and tools for analysis, visualization, and interpretation of neuroscience data. To ensure the sustainability of this development, consistent update and training of young professionals are imperative. For this purpose, relevant articles, chapters, and modules are essential to keep abreast of developments. Therefore, this article seeks to outline the biological databases and analytical tools along with their applications. It's envisaged that knowledge along this line would be a "training recipe" for young talents and guide for professionals and researchers in neuroscience.

Reactive Nitrogen Species and Male Reproduction: Physiological and Pathological Aspects.

Reactive nitrogen species (RNS), like reactive oxygen species (ROS), are useful for sustaining reproductive processes such as cell signaling, the regulation of hormonal biosynthesis, sperm capacitation, hyperactivation, and acrosome reaction. However, endogenous levels of RNS beyond physiological limits can impair fertility by disrupting testicular functions, reducing gonadotropin production, and compromising semen quality. Excessive RNS levels cause a variety of abnormalities in germ cells and gametes, particularly in the membranes and deoxyribonucleic acid (DNA), and severely impair the maturation and fertilization processes. Cell fragmentation and developmental blockage, usually at the two-cell stage, are also connected with imbalanced redox status of the embryo during its early developmental stage. Since high RNS levels are closely linked to male infertility and conventional semen analyses are not reliable predictors of the assisted reproductive technology (ART) outcomes for such infertility cases, it is critical to develop novel ways of assessing and treating oxidative and/or nitrosative stress-mediated male infertility. This review aims to explicate the physiological and pathological roles of RNS and their relationship with male reproduction.