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.

Arsenic-induced prostate cancer: an enigma.

Arsenic exhibits varying degrees of toxicity depending on its many chemical forms. The carcinogenic properties of arsenic have already been established. However, the precise processes underlying the development of diseases following acute or chronic exposure to arsenic remain poorly known. Most of the existing investigation has focused on studying the occurrence of cancer following significant exposure to elevated levels of arsenic. Nevertheless, multiple investigations have documented diverse health consequences from prolonged exposure to low levels of arsenic. Inorganic arsenic commonly causes lung, bladder, and skin cancer. Some investigations have shown an association between arsenic in drinking water and prostate cancer, but few investigations have focused on exploring this connection. There is currently a lack of relevant animal models demonstrating a clear link between inorganic arsenic exposure and the development of prostate cancer. Nevertheless, studies using cellular model systems have demonstrated that arsenic can potentially promote the malignant transformation of human prostate epithelial cells in vitro. The administration of elevated levels of arsenic has been demonstrated to elicit cell death in instances of acute experimental exposure. Conversely, in cases of chronic exposure, arsenic prompts cellular proliferation and sustains cellular viability, thereby circumventing the constraints imposed by telomere shortening and apoptosis. Furthermore, cells consistently exposed to the stimulus exhibit an augmented ability to invade surrounding tissues and an enhanced potential to form tumors. This review aims to portray mechanistic insights into arsenic-induced prostate cancer.

Assessment of metabolic responses following silica nanoparticles in zebrafish models using 1H NMR analysis.

Silica nanoparticles (SNPs) are widely explored as drug carriers, gene delivery vehicles, and as nanoparticles intended for bone and tissue engineering. SNPs are highly evident through various clinical trials for a wide range of biomedical applications. SNPs are biocompatible and promising nanoparticles for next-generation therapeutics. However, despite the well-established importance of SNPs, metabolomics methods for the SNPs remain elusive which renders its maximal clinical translation. We applied 1H nuclear magnetic resonance (1H NMR) spectroscopy to investigate the metabolomics profile in Zebrafish (Danio rerio) exposed to SNPs. Zebrafish were exposed to the SNPs (10.0, 25.0, and 50.0 µg/mL) for 72 h and whole-body samples were subjected for targeted profiling. Pattern recognition of 1H NMR spectral data depicted alterations in the metabolomic profiles between control and SNPs exposed zebrafish. We found that tryptophane, lysine, methionine, phenylalanine, tyrosine, sn-glycero-3-phosphocholine (G3PC), and o-phosphocholine were decreased. The metabolic expression of niacinamide, nicotinamide adenine dinucleotide (NAD+), citrate, adenosine triphosphate (ATP), and xanthine were increased in zebrafish with SNPs treatment. We are report for the first time on metabolite alterations and phenotypic expression in zebrafish via 1H NMR. These results demonstrate that SNPs can adversely affect the significant metabolic pathways involved in energy, amino acids, cellular membrane, lipids, and fatty acid metabolisms. Metabolomics profiling may be able to detect metabolic dysregulation in SNPs-treated zebrafish and establish a foundation for further toxicological studies.

Does gut brain axis has an impact on Parkinson's disease (PD)?

Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.

Association of Biochemical Parameters and Screening for Mutations in the MCU Gene in Alzheimer's Disease Patients.

The most prevalent form of dementia, Alzheimer's disease (AD) is a chronic illness that is on the rise among the geriatric population. Even though research into its biochemical, genetic, and cytogenetic pathways has advanced, its aetiology is still unclear and complex. In this study, we recruited sixty-eight participants diagnosed with AD where the cytogenetic, biochemical parameters and genetic mutations were analysed. Our results revealed chromosomal aberrations such as aneuploidies in the peripheral blood of Alzheimer's disease patients. Biochemical parameters revealed no statistical significance in the study though a pattern could be observed in the serum levels. Further few novel mutations at the c.21 C > T, c.56G > A were observed in the MCU gene of mitochondrial calcium uniporter. All these findings reveal the need for a larger cohort study to gain a better and more detailed understanding of the aetiology of Alzheimer's disease.

Association Study Between Kynurenine 3-Monooxygenase (KMO) Gene and Parkinson's Disease Patients.

The influence of various risk factors such as aging, intricate cellular molecular processes, and lifestyle factors like smoking, alcohol consumption, caffeine intake, and occupational factors has received increased focus in relation to the risk and development of Parkinson's disease (PD). Limited research has been conducted on the assessment of lifestyle impact on kynurenine 3-monooxygenase (KMO) gene in PD. A total of 164 subjects, including 82 PD cases and 82 healthy individuals, were recruited based on specific inclusion and exclusion criteria. The severity of PD and clinical assessment were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling. Sanger sequencing was performed to analyse the KMO gene in the recruited subjects, and case-control studies were conducted. The UPDRS assessment revealed significant impairments in smell, tremors, walking, and posture instability in the late-onset PD cohorts. The HY scaling indicated a higher proportion of late-onset cohorts in stage 2. Moreover, both alcoholic and non-alcoholic groups showed significantly increased levels of 3-HK in late-onset PD. Gene analysis identified missense variants at position g.241593373 T > A (rs752312199) and intronic variants at positions g.241592623A > G (rs640718), g.241592800C > A (rs990388262), g.241592802A > C (rs1350160268), g.241592808 T > C (rs1478255936), and g.241592812G > T (rs948928931). The alterations in the KMO gene were found to influence the levels of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). Genomic analysis revealed a high prevalence of missense mutations in the late-onset PD groups, leading to a decline in 3-HK levels in patients. This leads to the reduction of the progression of disease in late-onset groups which shows that this mutation may lead to the protective effect on the PD subjects. This study suggests the use of KYNA and 3-HK as potential biomarkers in analysing the progression of disease. This study is limited by its small sample size. To overcome this limitation, a larger study involving in greater number of participants is needed to thoroughly investigate the KMO gene and KP metabolites, to enhance our understanding of Parkinson's disease progression, and to enhance diagnostic capabilities.

Piperlongumine: the amazing amide alkaloid from Piper in the treatment of breast cancer.

Piperlongumine (PL), an alkaloid found primarily in the fruits and roots of the plant Piper longum L. (Piperaceae), is a natural compound that exhibits potent activity against various cancer cell proliferation. The most frequently caused malignancy in women globally, breast cancer (BC), has been demonstrated to be significantly inhibited by PL. Apoptosis, cell cycle arrest, increased ROS generation, and changes in the signalling protein's expression are all caused by the numerous signalling pathways that PL impacts. Since BC cells resist conventional chemotherapeutic drugs (doxorubicin, docetaxel etc.), researchers have shown that the drugs in combination with PL can exhibit a synergistic effect, greater than the effects of the drug or PL alone. Recently, techniques for drug packaging based on nanotechnology have been employed to improve PL release. The review has presented an outline of the chemistry of PL, its molecular basis in BC, its bioavailability, toxicity, and nanotechnological applications. An attempt to understand the future prospects and direction of research about the compound has also been discussed.

Molecular insight into renal cancer and latest therapeutic approaches to tackle it: an updated review.

Renal cell carcinoma (RCC) is one of the most lethal genitourinary cancers, with the highest mortality rate, and may remain undetected throughout its development. RCC can be sporadic or hereditary. Exploring the underlying genetic abnormalities in RCC will have important implications for understanding the origins of nonhereditary renal cancers. The treatment of RCC has evolved over centuries from the era of cytokines to targeted therapy to immunotherapy. A surgical cure is the primary treatment modality, especially for organ-confined diseases. Furthermore, the urologic oncology community focuses on nephron-sparing surgical approaches and ablative procedures when small renal masses are detected incidentally in conjunction with interventional radiologists. In addition to new combination therapies approved for RCC treatment, several trials have been conducted to investigate the potential benefits of certain drugs. This may lead to durable responses and more extended survival benefits for patients with metastatic RCC (mRCC). Several approved drugs have reduced the mortality rate of patients with RCC by targeting VEGF signaling and mTOR. This review better explains the signaling pathways involved in the RCC progression, oncometabolites, and essential biomarkers in RCC that can be used for its diagnosis. Further, it provides an overview of the characteristics of RCC carcinogenesis to assist in combating treatment resistance, as well as details about the current management and future therapeutic options. In the future, multimodal and integrated care will be available, with new treatment options emerging as we learn more about the disease.

Assessment of tRNAThr and tRNAGln Variants and Mitochondrial Functionality in Parkinson's Disease (PD) Patients of Tamil Nadu Population.

Parkinson's disease (PD) is speculated with genetic and environmental factors. At molecular level, the mitochondrial impact is stated to be one of the causative reasons for PD. In this study, we investigated the mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels along with mitochondrial tRNA alterations among three age categories of PD. By determining the genetic and organellar functionality using molecular techniques, the ROS levels were reported to be high with decreased MMP and ATP in the late-onset age group than in other two age categories. Likewise, the tRNA significancy in tRNAThr and tRNAGln was noticed with C4335T and G15927A mutations in late-onset and early-onset PD groups respectively. Therefore, from the findings, ageing has shown a disruption in tRNA metabolism leading to critical functioning of ATP synthesis and MMP, causing oxidative stress in PD patients. These physiological outcomes show that ageing has a keen role in the divergence of mitochondrial function, thereby proving a correlation with ageing and maintenance of mitochondrial homeostasis in PD.

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.

Cancer chemoresistance and its mechanisms: Associated molecular factors and its regulatory role.

Cancer therapy has advanced from tradition chemotherapy methods to targeted therapy, novel drug delivery mechanisms, combination therapies etc. Although several novel chemotherapy strategies have been introduced, chemoresistance still remains as one of the major barriers in cancer treatments. Chemoresistance can lead to relapse and hinder the development of improved clinical results for cancer patients, and this continues to be the major hurdle in cancer therapy. Anticancer drugs acquire chemoresistance through different mechanisms. Understanding these mechanisms is crucial to overcome and increase the efficiency of the cancer therapies that are employed. The potential molecular pathways behind chemoresistance include tumor heterogeneity, elevated drug efflux, multidrug resistance, interconnected signaling pathways, and other factors. To surpass this limitation, new clinical tactics are to be introduced. This review aims to compile the most recent information on the molecular pathways that regulate chemoresistance in cancers, which will aid in development of new therapeutic targets and strategies.

Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics?

Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.

Molecular mechanisms of alcohol's effects on the human body: A review and update.

Alcohol consumption has been linked to numerous negative health outcomes although it has some beneficial effects on moderate dosages, the most severe of which being alcohol-induced hepatitis. The number of people dying from this liver illness has been shown to climb steadily over time, and its prevalence has been increasing. Researchers have found that alcohol consumption primarily affects the brain, leading to a wide range of neurological and psychological diseases. High-alcohol-consumption addicts not only experienced seizures, but also ataxia, aggression, social anxiety, and variceal hemorrhage that ultimately resulted in death, ascites, and schizophrenia. Drugs treating this liver condition are limited and can cause serious side effects like depression. Serine-threonine kinases, cAMP protein kinases, protein kinase C, ERK, RACK 1, Homer 2, and more have all been observed to have their signaling pathways disrupted by alcohol, and alcohol has also been linked to epigenetic changes. In addition, alcohol consumption induces dysbiosis by changing the composition of the microbiome found in the gastrointestinal tract. Although more studies are needed, those that have been done suggest that probiotics aid in keeping the various microbiota concentrations stable. It has been argued that reducing one's alcohol intake may seem less harmful because excessive drinking is a lifestyle disorder.

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.

Recent advances in understanding brain cancer metabolomics: a review.

Regardless of the significant progress made in surgical techniques and adjuvant therapies, brain tumors are a major contributor to cancer-related morbidity and mortality in both pediatric and adult populations. Gliomas represent a significant proportion of cerebral neoplasms, exhibiting diverse levels of malignancy. The etiology and mechanisms of resistance of this malignancy are inadequately comprehended, and the optimization of patient diagnosis and prognosis is a challenge due to the diversity of the disease and the restricted availability of therapeutic options. Metabolomics refers to the comprehensive analysis of endogenous and exogenous small molecules, both in a targeted and untargeted manner, that enables the characterization of an individual's phenotype and offers valuable insights into cellular activity, particularly in the context of cancer biology, including brain tumor biology. Metabolomics has garnered attention in current years due to its potential to facilitate comprehension of the dynamic spatiotemporal regulatory network of enzymes and metabolites that enables cancer cells to adapt to their environment and foster the development of tumors. Metabolic changes are widely acknowledged as a significant characteristic for tracking the advancement of diseases, treatment efficacy, and identifying novel molecular targets for successful medical management. Metabolomics has emerged as an exciting area for personalized medicine and drug discovery, utilizing advanced analytical techniques such as nuclear magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) to achieve high-throughput analysis. This review examines and highlights the latest developments in MRS, MS, and other technologies in studying human brain tumor metabolomics.