Blood-testis barrier: a review on regulators in maintaining cell junction integrity between Sertoli cells.

The blood-testis barrier (BTB) is formed adjacent to the seminiferous basement membrane. It is a distinct ultrastructure, partitioning testicular seminiferous epithelium into apical (adluminal) and basal compartments. It plays a vital role in developing and maturing spermatocytes into spermatozoa via reorganizing its structure. This enables the transportation of preleptotene spermatocytes across the BTB, from basal to adluminal compartments in the seminiferous tubules. Several bioactive peptides and biomolecules secreted by testicular cells regulate the BTB function and support spermatogenesis. These peptides activate various downstream signaling proteins and can also be the target themself, which could improve the diffusion of drugs across the BTB. The gap junction (GJ) and its coexisting junctions at the BTB maintain the immunological barrier integrity and can be the "gateway" during spermatocyte transition. These junctions are the possible route for toxicant entry, causing male reproductive dysfunction. Herein, we summarize the detailed mechanism of all the regulators playing an essential role in the maintenance of the BTB, which will help researchers to understand and find targets for drug delivery inside the testis.

Cadmium as a male reproductive toxicant and natural and non-natural ways to tackle it: a review.

Cadmium (Cd) is a naturally occurring environmental pollutant, a toxic substance that causes oxidative stress. According to epidemiological studies, the data suggested that environmental and occupational Cd exposure may be related to several diseases and severe testicular damage. However, studies are going on to explore the mechanism of Cd-induced male reproductive toxicity and its treatment strategies. Currently, researchers are focusing on naturally occurring bioactive compounds, plant extracts, and biochemical, which have better efficacy, less toxicity, and high bioavailability. This review focuses on the mechanistic effect of Cd on testicular toxicity and different categories of compounds having a beneficial impact on Cd-induced male reproductive toxicity. Some potent bioactive antioxidants are quercetin, caffeic acid phenethyl ester, cyanidin-3-O-glucoside, curcumin, and silymarin. In comparison, plant extracts are Costus afer leaf methanol extract, methanol root extract of Carpolobia lutea, red carrot methanolic extract, Panax ginseng extract, and biochemicals including melatonin, progesterone, glutamine, L-carnitine, and selenium. Advanced and more detailed studies are needed on these compounds to explore their mechanism in attenuating Cd-induced testicular toxicity and can be potential therapeutics in the future.

Novel biomolecules in targeted cancer therapy: a new approach towards precision medicine.

Cancer is a major threat to human life around the globe, and the discovery of novel biomolecules continue to be an urgent therapeutic need that is still unmet. Precision medicine relies on targeted therapeutic strategies. Researchers are better equipped to develop therapies that target proteins as they understand more about the genetic alterations and molecules that cause progression of cancer. There has been a recent diversification of the sorts of targets exploited in treatment. Therapeutic antibody and biotechnology advancements enabled curative treatments to reach previously inaccessible sites. New treatment strategies have been initiated for several undruggable targets. The application of tailored therapy has been proven to have efficient results in controlling cancer progression. Novel biomolecules like SMDCs, ADCs, mABs, and PROTACS has gained vast attention in the recent years. Several studies have shown that using these novel technology helps in reducing the drug dosage as well as to overcome drug resistance in different cancer types. Therefore, it is crucial to fully untangle the mechanism and collect evidence to understand the significance of these novel drug targets and strategies. This review article will be discussing the importance and role of these novel biomolecules in targeted cancer therapies.

Protective effects of macromolecular polyphenols, metals (zinc, selenium, and copper) - Polyphenol complexes, and different organs with an emphasis on arsenic poisoning: A review.

For the potential health benefits and nutritional value, polyphenols are one of the secondary metabolites of plants that have received extensive research. It has anti-inflammatory and cytotoxicity-reducing properties in addition to a high antioxidant content. Macromolecular polyphenols and polysaccharides are biologically active natural polymers with antioxidant and anti-inflammatory potential. Arsenic is an ecologically toxic metalloid. Arsenic in drinking water is the most common way people come into contact with this metalloid. While arsenic is known to cause cancer, it is also used to treat acute promyelocytic leukemia (APL). The treatment's effectiveness is hampered by the adverse effects it can cause on the body. Oxidative stress, inflammation, and the inability to regulate cell death cause the most adverse effects. Polyphenols and other macromolecules like polysaccharides act as neuroprotectants by mitigating free radical damage, inhibiting nitric oxide (NO) production, lowering A42 fibril formation, boosting antioxidant levels, and controlling apoptosis and inflammation. To prevent the harmful effects of toxins, polyphenols and pectin lower oxidative stress, boost antioxidant levels, improve mitochondrial function, control apoptosis, and suppress inflammation. Therefore, it prevents damage to the heart, liver, kidneys, and reproductive system. This review aims to identify the effects of the polyphenols in conjugation with polysaccharides as an ameliorative strategy for arsenic-induced toxicity in various organs.

Non-small cell lung carcinoma (NSCLC): Implications on molecular pathology and advances in early diagnostics and therapeutics.

Continuous revision of the histologic and stage-wise classification of lung cancer by the World Health Organization (WHO) provides the foundation for therapeutic advances by promoting molecular targeted and immunotherapies and ensuring accurate diagnosis. Cancer epidemiologic data provide helpful information for cancer prevention, diagnosis, and management, supporting health-care interventions. Global cancer mortality projections from 2016 to 2060 show that cancer will overtake ischemic heart diseases (IHD) as the leading cause of death (18.9 million) immediately after 2030, surpassing non-small cell lung cancer (NSCLC), which accounts for 85 percent of lung cancers. The clinical stage at the diagnosis is the main prognostic factor in NSCLC therapies. Advanced early diagnostic methods are essential as the initial stages of cancer show reduced mortality compared to the advanced stages. Sophisticated approaches to proper histological classification and NSCLC management have improved clinical efficiency. Although immune checkpoint inhibitors (ICIs) and targeted molecular therapies have refined the therapeutic management of late-stage NSCLC, the specificity and sensitivity of cancer biomarkers should be improved by focusing on prospective studies, followed by their use as therapeutic tools. The liquid biopsy candidates such as circulating tumor cells (CTCs), circulating cell-free tumor DNA (cfDNA), tumor educated platelets (TEP), and extracellular vesicles (EVs) possess cancer-derived biomolecules and aid in tracing: driver mutations leading to cancer, acquired resistance caused by various generations of therapeutic agents, refractory disease, prognosis, and surveillance.

A review on immunological aspects in male reproduction: An immune cells and cytokines.

The male reproductive system, particularly the male gamete, offers a unique barrier to the immune system. The growing germ cells in the testis need to be shielded from autoimmune damage. Hence the testis has to establish and sustain an immune-privileged milieu. Sertoli cells create this safe space, protected by the blood-testis barrier. Cytokines are a type of immune reaction that can positively and negatively affect male reproductive health. Inflammation, disease, and obesity are just a few physiological conditions for which cytokines mediate signals. They interact with steroidogenesis, shaping the adrenals and testes to produce the hormones needed for survival. In particular pathological condition, including autoimmune disorders, contains high levels of the same cytokines in semen that play an essential role in the immunomodulation of the male gonad. This review focuses on understanding the immunological role of cytokines in the control and development of male reproduction. Also, in maintaining male reproductive health and diseases linked with their aberrant function in the testis.

Evolving strategies and application of proteins and peptide therapeutics in cancer treatment.

Several proteins and peptides have therapeutic potential and can be used for cancer therapy. By binding to cell surface receptors and other indicators uniquely linked with or overexpressed on tumors compared to healthy tissue, protein biologics enhance the active targeting of cancer cells, as opposed to the passive targeting of cells by conventional small-molecule chemotherapeutics. This study focuses on peptide medications that exist to slow or stop tumor growth and the spread of cancer, demonstrating the therapeutic potential of peptides in cancer treatment. As an alternative to standard chemotherapy, peptides that selectively kill cancer cells while sparing healthy tissue are developing. A mountain of clinical evidence supports the efficacy of peptide-based cancer vaccines. Since a single treatment technique may not be sufficient to produce favourable results in the fight against cancer, combination therapy is emerging as an effective option to generate synergistic benefits. One example of this new area is the use of anticancer peptides in combination with nonpeptidic cytotoxic drugs or the combination of immunotherapy with conventional therapies like radiation and chemotherapy. This review focuses on the different natural and synthetic peptides obtained and researched. Discoveries, manufacture, and modifications of peptide drugs, as well as their contemporary applications, are summarized in this review. We also discuss the benefits and difficulties of potential advances in therapeutic peptides.

Molecular mechanisms augmenting resistance to current therapies in clinics among cervical cancer patients.

Cervical cancer (CC) is the fourth leading cause of cancer death (~ 324,000 deaths annually) among women internationally, with 85% of these deaths reported in developing regions, particularly sub-Saharan Africa and Southeast Asia. Human papillomavirus (HPV) is considered the major driver of CC, and with the availability of the prophylactic vaccine, HPV-associated CC is expected to be eliminated soon. However, female patients with advanced-stage cervical cancer demonstrated a high recurrence rate (50-70%) within two years of completing radiochemotherapy. Currently, 90% of failures in chemotherapy are during the invasion and metastasis of cancers related to drug resistance. Although molecular target therapies have shown promising results in the lab, they have had little success in patients due to the tumor heterogeneity fueling resistance to these therapies and bypass the targeted signaling pathway. The last two decades have seen the emergence of immunotherapy, especially immune checkpoint blockade (ICB) therapies, as an effective treatment against metastatic tumors. Unfortunately, only a small subgroup of patients (< 20%) have benefited from this approach, reflecting disease heterogeneity and manifestation with primary or acquired resistance over time. Thus, understanding the mechanisms driving drug resistance in CC could significantly improve the quality of medical care for cancer patients and steer them to accurate, individualized treatment. The rise of artificial intelligence and machine learning has also been a pivotal factor in cancer drug discovery. With the advancement in such technology, cervical cancer screening and diagnosis are expected to become easier. This review will systematically discuss the different tumor-intrinsic and extrinsic mechanisms CC cells to adapt to resist current treatments and scheme novel strategies to overcome cancer drug resistance.

Insights into the Scenario of SARS-CoV-2 Infection in Male Reproductive Toxicity.

COVID-19 has become a significant public health concern that has catastrophic consequences for society. Some preliminary evidence suggests that the male reproductive system may be an infection target for SARS-CoV-2. SARS-CoV-2 may be transmitted sexually, according to preliminary research. Testicular cells exhibit a high level of the angiotensin-converting enzyme 2 (ACE2) receptor, which enhances the entry of the SARS-CoV-2 into host cells. Some instances of COVID-19 have been documented to exhibit hypogonadism during the acute stage. Furthermore, systemic inflammatory reactions triggered by SARS-CoV-2 infection may cause oxidative stress (OS), which has been shown to have profoundly deleterious consequences on testicular functioning. This work gives a clear picture of how COVID-19 may affect male reproductive systems and calls attention to the many unanswered questions about the mechanisms by which this virus can be linked to men's health and fertility.

Role of Metabolism and Metabolic Pathways in Prostate Cancer.

Prostate cancer (PCa) is the common cause of death in men. The pathophysiological factors contributing to PCa are not well known. PCa cells gain a protective mechanism via abnormal lipid signaling and metabolism. PCa cells modify their metabolism in response to an excessive intake of nutrients to facilitate advancement. Metabolic syndrome (MetS) is inextricably linked to the carcinogenic progression of PCa, which heightens the severity of the disease. It is hypothesized that changes in the metabolism of the mitochondria contribute to the onset of PCa. The studies of particular alterations in the progress of PCa are best accomplished by examining the metabolome of prostate tissue. Due to the inconsistent findings written initially, additional epidemiological research is required to identify whether or not MetS is an aspect of PCa. There is a correlation between several risk factors and the progression of PCa, one of which is MetS. The metabolic symbiosis between PCa cells and the tumor milieu and how this type of crosstalk may aid in the development of PCa is portrayed in this work. This review focuses on in-depth analysis and evaluation of the metabolic changes that occur within PCa, and also aims to assess the effect of metabolic abnormalities on the aggressiveness status and metabolism of PCa.

A Systematic Role of Metabolomics, Metabolic Pathways, and Chemical Metabolism in Lung Cancer.

Lung cancer (LC) is considered as one of the leading causes of cancer-associated mortalities. Cancer cells' reprogrammed metabolism results in changes in metabolite concentrations, which can be utilized to identify a distinct metabolic pattern or fingerprint for cancer detection or diagnosis. By detecting different metabolic variations in the expression levels of LC patients, this will help and enhance early diagnosis methods as well as new treatment strategies. The majority of patients are identified at advanced stages after undergoing a number of surgical procedures or diagnostic testing, including the invasive procedures. This could be overcome by understanding the mechanism and function of differently regulated metabolites. Significant variations in the metabolites present in the different samples can be analyzed and used as early biomarkers. They could also be used to analyze the specific progression and type as well as stages of cancer type making it easier for the treatment process. The main aim of this review article is to focus on rewired metabolic pathways and the associated metabolite alterations that can be used as diagnostic and therapeutic targets in lung cancer diagnosis as well as treatment strategies.

Crosstalk between COVID-19 Infection and Kidney Diseases: A Review on the Metabolomic Approaches.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory disorder. Various organ injuries have been reported in response to this virus, including kidney injury and, in particular, kidney tubular injury. It has been discovered that infection with the virus does not only cause new kidney disease but also increases treatment difficulty and mortality rates in people with kidney diseases. In individuals hospitalized with COVID-19, urinary metabolites from several metabolic pathways are used to distinguish between patients with acute kidney injury (AKI) and those without. This review summarizes the pathogenesis, pathophysiology, treatment strategies, and role of metabolomics in relation to AKI in COVID-19 patients. Metabolomics is likely to play a greater role in predicting outcomes for patients with kidney disease and COVID-19 with varying levels of severity in the near future as data on metabolic profiles expand rapidly. Here, we also discuss the correlation between COVID-19 and kidney diseases and the available metabolomics approaches.

The Implication of Mechanistic Approaches and the Role of the Microbiome in Polycystic Ovary Syndrome (PCOS): A Review.

As a complex endocrine and metabolic condition, polycystic ovarian syndrome (PCOS) affects women's reproductive health. These common symptoms include hirsutism, hyperandrogenism, ovulatory dysfunction, irregular menstruation, and infertility. No one knows what causes it or how to stop it yet. Alterations in gut microbiota composition and disruptions in secondary bile acid production appear to play a causative role in developing PCOS. PCOS pathophysiology and phenotypes are tightly related to both enteric and vaginal bacteria. Patients with PCOS exhibit changed microbiome compositions and decreased microbial diversity. Intestinal microorganisms also alter PCOS patient phenotypes by upregulating or downregulating hormone release, gut-brain mediators, and metabolite synthesis. The human body's gut microbiota, also known as the "second genome," can interact with the environment to improve metabolic and immunological function. Inflammation is connected to PCOS and may be caused by dysbiosis in the gut microbiome. This review sheds light on the recently discovered connections between gut microbiota and insulin resistance (IR) and the potential mechanisms of PCOS. This study also describes metabolomic studies to obtain a clear view of PCOS and ways to tackle it.

Implications of cancer stem cells in diabetes and pancreatic cancer.

This review provides a detailed study of pancreatic cancer (PC) and the implication of different types of cancers concerning diabetes. The combination of anti-diabetic drugs with other anti-cancer drugs and phytochemicals can help prevent and treat this disease. PC cancer stem cells (CSCs) and how they migrate and develop into malignant tumors are discussed. A detailed explanation of the different mechanisms of diabetes development, which can enhance the pancreatic CSCs' proliferation by increasing the IGF factor levels, epigenetic modifications, DNA damage, and the influence of lifestyle factors like obesity, and inflammation, has been discussed. It also explains how cancer due to diabetes is associated with high mortality rates. One of the well-known diabetic drugs, metformin, can be combined with other anti-cancer drugs and prevent the development of PC and has been taken as one of the prime focus in this review. Overall, this paper provides insight into the relationship between diabetes and PC and the methods that can be employed to diagnose this disease at an earlier stage successfully.

The pathophysiological and immunological background of the monkeypox virus infection: An update.

In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over 10 000 confirmed cases in over 50 countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated MPX to the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that causes smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this reemerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current MPX epidemic.

Exploring the Regulatory Role of ncRNA in NAFLD: A Particular Focus on PPARs.

Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven to play a significant role in the pathogenesis of virtually all acute and chronic liver disorders. Recent studies demonstrated the medical applications of miRNA in various phases of hepatic pathology. PPARs play a major role in regulating many signaling pathways involved in various metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, encompassing a spectrum spanning from mild steatosis to severe non-alcoholic steatohepatitis (NASH). PPARs were found to be one of the major regulators in the progression of NAFLD. There is no recognized treatment for NAFLD, even though numerous clinical trials are now underway. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC), and its frequency increases as obesity and diabetes become more prevalent. Reprogramming anti-diabetic and anti-obesity drugs is an effective therapy option for NAFLD and NASH. Several studies have also focused on the role of ncRNAs in the pathophysiology of NAFLD. The regulatory effects of these ncRNAs make them a primary target for treatments and as early biomarkers. In this study, the main focus will be to understand the regulation of PPARs through ncRNAs and their role in NAFLD.

The mechanism of action of non-coding RNAs in placental disorders.

Placental complication arises due to various risk factors occurring during the pregnancy period, leading to an increased morbidity rate. Placenta related disorders are one of primary reason for pregnancy related complications and the clinical incidences are seen to be on the rise. Most of the common disorders associated with placenta are pre-eclampsia, recurrent spontaneous abortions, intra-uterine growth restriction etc. Several studies have been done to understand the genetics and immunological attributes leading to the development of placenta associated complications. In the recent years, studies were able to establish and identify ncRNAs found specifically in foetal tissues such as the placenta. The aberrant expression patterns of ncRNA associated with placenta has been linked to disorders such as pre-eclampsia. Since ncRNA play a major role in regulating biological processes like trophoblast growth, migration and invasion, their aberrant expression could very well lead to complications like spontaneous pregnancy loss. This review article focuses on the association of ncRNAs - miRNAs, lncRNAs, CircRNAs in placenta associated complications as well as the different ncRNA based therapies. Deciphering the exact mechanism involved in the regulation and development of placenta through ncRNA will help in using it as a biomarker for early diagnosis. Understanding the therapeutic opportunities of ncRNAs in placental disorders will result in better treatment strategies.

Letrozole: Pharmacology, toxicity and potential therapeutic effects.

The highly active estrogen metabolism and receptor protein expression are to blame for the elevated breast cancer (BC) rate in post-menopausal women. Letrozole is a powerful endocrine medication that targets and inhibits the aromatase, often known as an aromatase inhibitor (AI). It aids in the adjuvant, neoadjuvant, and metastatic treatment of HR+ breast cancer because it can boost FSH production for ovulation induction. It has recently been used in infertile pre-menopausal women. The main advantages of utilizing letrozole to enhance follicle development may be wasted in current infertility treatments. We went into great length in this review about the pharmacokinetics, pharmacodynamics, and distinct adverse effects of the drug on the heart, kidney, liver, embryo, bone, and ovary. It also causes apoptosis, necrosis, and fibrosis, which all result in the demise of cancer cells. Its central and peripheral effects on follicle formation, estrogen production in the ovaries, and their clinical implications are explored in detail in this work.

Misuse of Cardiac Lipid upon Exposure to Toxic Trace Elements-A Focused Review.

Heavy metals and metalloids like cadmium, arsenic, mercury, and lead are frequently found in the soil, water, food, and atmosphere; trace amounts can cause serious health issues to the human organism. These toxic trace elements (TTE) affect almost all the organs, mainly the heart, kidney, liver, lungs, and the nervous system, through increased free radical formation, DNA damage, lipid peroxidation, and protein sulfhydryl depletion. This work aims to advance our understanding of the mechanisms behind lipid accumulation via increased free fatty acid levels in circulation due to TTEs. The increased lipid level in the myocardium worsens the heart function. This dysregulation of the lipid metabolism leads to damage in the structure of the myocardium, inclusive fibrosis in cardiac tissue, myocyte apoptosis, and decreased contractility due to mitochondrial dysfunction. Additionally, it is discussed herein how exposure to cadmium decreases the heart rate, contractile tension, the conductivity of the atrioventricular node, and coronary flow rate. Arsenic may induce atherosclerosis by increasing platelet aggregation and reducing fibrinolysis, as exposure interferes with apolipoprotein (Apo) levels, resulting in the rise of the Apo-B/Apo-A1 ratio and an elevated risk of acute cardiovascular events. Concerning mercury and lead, these toxicants can cause hypertension, myocardial infarction, and carotid atherosclerosis, in association with the generation of free radicals and oxidative stress. This review offers a complete overview of the critical factors and biomarkers of lipid and TTE-induced cardiotoxicity useful for developing future protective interventions.

Molecular Crosstalk between the Immunological Mechanism of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Oral Cancer.

Oral cancer is a significant non-communicable disease affecting both emergent nations and developed countries. Squamous cell carcinoma of the head and neck represent the eight major familiar cancer types worldwide, accounting for more than 350,000 established cases every year. Oral cancer is one of the most exigent tumors to control and treat. The survival rate of oral cancer is poor due to local invasion along with recurrent lymph node metastasis. The tumor microenvironment contains a different population of cells, such as fibroblasts associated with cancer, immune-infiltrating cells, and other extracellular matrix non-components. Metastasis in a primary site is mainly due to multifaceted progression known as epithelial-to-mesenchymal transition (EMT). For the period of EMT, epithelial cells acquire mesenchymal cell functional and structural characteristics, which lead to cell migration enhancement and promotion of the dissemination of tumor cells. The present review links the tumor microenvironment and the role of EMT in inflammation, transcriptional factors, receptor involvement, microRNA, and other signaling events. It would, in turn, help to better understand the mechanism behind the tumor microenvironment and EMT during oral cancer.