Rosolic acid as a novel activator of the Nrf2/ARE pathway in arsenic-induced male reproductive toxicity: An in silico study.

Male reproductive toxicity as a result of arsenic exposure is linked with oxidative stress and excessive generation of reactive oxygen species (ROS). It leads to an imbalance between ROS production and antioxidant defense mechanisms ultimately resulting in male infertility. The nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor that responds to cellular stressors controlling the oxidative state, mitochondrial dysfunction, inflammation, and proteostasis. This study aims to investigate the potential of Rosolic acid (ROA) to act as a novel Nrf2 activator by mitigating oxidative stress to combat arsenic-induced male reproductive toxicity. The protein and ligands were prepared in the BIOVIA Discovery Studio, followed by protein-ligand docking using auto dock vina integrated with the PyRx-Virtual Screening Tool. Then the ADME properties were analyzed using the SwissADME tool to get a clear idea about the physicochemical properties, lipophilicity, water solubility, pharmacokinetics, and drug likeliness of ROA. It was followed by molecular dynamics simulation (MDS) studies using GROMACS. The 3D and 2D interaction maps revealed the interactions of Keap 1 with ROA. Keap1-ROA complex was found to have a binding energy of -7.8 kcal/mol. ROA showed 0 violations for Lipinski and 0 alerts each for PAINS and Brenk and a bioavailability score of 0.55. The BOILED-Egg representation showcases that ROA is predicted as passively crossing the blood-brain barrier (BBB). The MDS described 2FLU-ROA as a stable system. This work portrays that ROA can be a potent Nrf2 activator by exhibiting an inhibitory activity against the Keap1 protein and thus mitigating oxidative stress in arsenic-induced male reproductive toxicity.

Anti-sperm Antibodies as an Increasing Threat to Male Fertility: Immunological Insights, Diagnostic and Therapeutic Strategies.

It is a fact that sperm possess antigenic properties. Substantial scientific research suggests that specific antibodies that attach to sperm antigens can induce infertility in both humans and other species. Antisperm antibodies (ASA) represent a significant etiology of infertility in humans, leading to immunoinfertility. The association between ASA and infertility is multifaceted. The observation of sperm agglutination, although not conclusive for the diagnosis of immunological infertility, may suggest the presence of ASA. Nevertheless, ASA may also manifest in the lack of any sperm agglutination. Managing ASA from an andrological perspective depends on the underlying cause and the specific approaches healthcare professionals adopt. The precise etiology of male infertility resulting from ASA remains unclear. Current research has examined the impact of ASA and its prevalence among infertile males to understand the relationship between ASA and changes in semen parameters. However, the findings have been inconclusive. Numerous techniques have been documented for the management of immunoinfertility. This review examines the importance of ASA in the context of infertility, encompassing the postulated mechanisms underlying the development of ASA, the various assays employed for detecting them, and the available treatments.

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.

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.

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms.

Because the overexpression of histone deacetylase enzymes (HDACs) has been linked to numerous diseases, including various cancers and neurodegenerative disorders, HDAC inhibitors have emerged as promising therapeutic agents. However, most HDAC inhibitors lack both subclass and isoform selectivity, which leads to potential toxicity. Unlike classical hydroxamate HDAC inhibitors, slow-binding HDAC inhibitors form tight and prolonged bonds with HDAC enzymes. This distinct mechanism of action improves both selectivity and toxicity profiles, which makes slow-binding HDAC inhibitors a promising class of therapeutic agents for various diseases. Therefore, the development of slow-binding HDAC inhibitors that can effectively target a wide range of HDAC isoforms is crucial. This Perspective provides valuable insights into the potential and progress of slow-binding HDAC inhibitors as promising drug candidates for the treatment of various diseases.

The mechanistic insights of the antioxidant Keap1-Nrf2 pathway in oncogenesis: a deadly scenario.

The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2 protein is crucial in preserving tissue integrity by safeguarding cells against metabolic, xenobiotic and oxidative stress. Due to its various functions, Nrf2 is a potential pharmacological target for reducing the incidence of diseases such as cancer. However, mutations in Keap1-Nrf2 are not consistently favored in all types of cancer. Instead, they seem to interact with specific driver mutations of tumors and their respective tissue origins. The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway mutations are a powerful cancer adaptation that utilizes inherent cytoprotective pathways, encompassing nutrient metabolism and ROS regulation. The augmentation of Nrf2 activity elicits significant alterations in the characteristics of neoplastic cells, such as resistance to radiotherapy and chemotherapy, safeguarding against apoptosis, heightened invasiveness, hindered senescence, impaired autophagy and increased angiogenesis. The altered activity of Nrf2 can arise from diverse genetic and epigenetic modifications that instantly impact Nrf2 regulation. The present study aims to showcase the correlation between the Keap1-Nrf2 pathway and the progression of cancers, emphasizing genetic mutations, metabolic processes, immune regulation, and potential therapeutic strategies. This article delves into the intricacies of Nrf2 pathway anomalies in cancer, the potential ramifications of uncontrolled Nrf2 activity, and therapeutic interventions to modulate the Keap1-Nrf2 pathway.

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.

Epicardial adipose tissue and cardiac lipotoxicity: A review.

Epicardial adipose tissue (EAT) has morphological and physiological contiguity with the myocardium and coronary arteries, making it a visceral fat deposit with some unique properties. Under normal circumstances, EAT exhibits biochemical, mechanical, and thermogenic cardioprotective characteristics. Under clinical processes, epicardial fat can directly impact the heart and coronary arteries by secreting proinflammatory cytokines via vasocrine or paracrine mechanisms. It is still not apparent what factors affect this equilibrium. Returning epicardial fat to its physiological purpose may be possible by enhanced local vascularization, weight loss, and focused pharmacological therapies. This review centers on EAT's developing physiological and pathophysiological dimensions and its various and pioneering clinical utilities.

HPV-associated cancers: insights into the mechanistic scenario and latest updates.

Cancer and related diseases are the second leading cause of death worldwide. The human papillomavirus (HPV) is an infectious agent that can be spread mainly through sexual contact and has been linked to several malignancies in both sexes. HPV is linked to almost all cases of cervical cancer. It is also linked to many head and neck cancer (HNC) cases, especially oropharyngeal cancer. Also, some HPV-related cancers, like vaginal, vulvar, penile, and anal cancers, are related to the anogenital area. Over the past few decades, testing for and preventing cervical cancer has improved, but anogenital cancers are still harder to confirm. HPV16 and HPV18 have been extensively researched due to their significant carcinogenic potential. The products of two early viral genes, E6 and E7, have been identified as playing crucial roles in cellular transformation, as emphasized by biological investigations. The complete characterization of numerous mechanisms employed by E6 and E7 in undermining the regulation of essential cellular processes has significantly contributed to our comprehension of HPV-induced cancer progression. This review focuses on the various types of cancers caused by HPV infection and also sheds light on the signaling cascades involved in the same.

Frustration shapes multi-channel Kondo physics: a star graph perspective.

We study the overscreened multi-channel Kondo (MCK) model using the recently developed unitary renormalisation group technique. Our results display the importance of ground state degeneracy in explaining various important properties like the breakdown of screening and the presence of local non-Fermi liquids (NFLs). The impurity susceptibility of the intermediate coupling fixed point Hamiltonian in the zero-bandwidth (or star graph) limit shows a power-law divergence at low temperature. Despite the absence of inter-channel coupling in the MCK fixed point Hamiltonian, the study of mutual information between any two channels shows non-zero correlation between them. A spectral flow analysis of the star graph reveals that the degenerate ground state manifold possesses topological quantum numbers. Upon disentangling the impurity spin from its partners in the star graph, we find the presence of a local Mott liquid arising from inter-channel scattering processes. The low energy effective Hamiltonian obtained upon adding a finite non-zero conduction bath dispersion to the star graph Hamiltonian for both the two and three-channel cases displays the presence of local NFLs arising from inter-channel quantum fluctuations. Specifically, we confirm the presence of a local marginal Fermi liquid in the two channel case, whose properties show logarithmic scaling at low temperature as expected. Discontinuous behaviour is observed in several measures of ground state entanglement, signalling the underlying orthogonality catastrophe associated with the degenerate ground state manifold. We extend our results to underscreened and perfectly screened MCK models through duality arguments. A study of channel anisotropy under renormalisation flow reveals a series of quantum phase transitions due to the change in ground state degeneracy. Our work thus presents a template for the study of how a degenerate ground state manifold arising from symmetry and duality properties in a multichannel quantum impurity model can lead to novel multicritical phases at intermediate coupling.

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.

Unlocking the mystery associated with infertility and prostate cancer: an update.

Male-specific reproductive disorders and cancers have increased intensely in recent years, making them a significant public health problem. Prostate cancer (PC) is the most often diagnosed cancer in men and is one of the leading causes of cancer-related mortality. Both genetic and epigenetic modifications contribute to the development and progression of PC, even though the exact underlying processes causing this disease have yet to be identified. Male infertility is also a complex and poorly understood phenomenon believed to afflict a significant portion of the male population. Chromosomal abnormalities, compromised DNA repair systems, and Y chromosome alterations are just a few of the proposed explanations. It is becoming widely accepted that infertility shares a link with PC. Much of the link between infertility and PC is probably attributable to common genetic defects. This article provides an overview of PC and spermatogenic abnormalities. This study also investigates the link between male infertility and PC and uncovers the underlying reasons, risk factors, and biological mechanisms contributing to this association.

Dynamic correlations in the conserved Manna sandpile.

We study dynamic correlations for current and mass, as well as the associated power spectra, in the one-dimensional conserved Manna sandpile. We show that, in the thermodynamic limit, the variance of cumulative bond current up to time T grows subdiffusively as T^{1/2-µ} with the exponent µ≥0 depending on the density regimes considered and, likewise, the power spectra of current and mass at low frequency f varies as f^{1/2+µ} and f^{-3/2+µ}, respectively. Our theory predicts that, far from criticality, µ=0 and, near criticality, µ=(ß+1)/2ν_{⊥}z>0 with ß, ν_{⊥}, and z being the order parameter, correlation length, and dynamic exponents, respectively. The anomalous suppression of fluctuations near criticality signifies a "dynamic hyperuniformity," characterized by a set of fluctuation relations, in which current, mass, and tagged-particle displacement fluctuations are shown to have a precise quantitative relationship with the density-dependent activity (or its derivative). In particular, the relation, D_{s}(ρ[over ¯])=a(ρ[over ¯])/ρ[over ¯], between the self-diffusion coefficient D_{s}(ρ[over ¯]), activity a(ρ[over ¯]) and density ρ[over ¯] explains a previous simulation observation [Eur. Phys. J. B 72, 441 (2009)10.1140/epjb/e2009-00367-0] that, near criticality, the self-diffusion coefficient in the Manna sandpile has the same scaling behavior as the activity.

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.