Chronic stress-mediated dysregulations in inflammatory, immune and oxidative circuitry impairs the therapeutic response of methotrexate in experimental autoimmune disease models.

Chronic stress is significantly implicated in the worsening of autoimmune disorders, contributing to elevated inflammation and diminished therapeutic efficacy. Here, in this study, we investigated the detrimental impact of an 8-week chronic unpredictable stress (CUS) protocol on the progression of arthritis and psoriasis using collagen-induced arthritis (CIA) and imiquimod (IMQ)-induced psoriasis rat models, respectively. Our objective was to elucidate how prolonged stress exacerbates disease severity and impairs the effectiveness of treatment drug. Following the induction of CIA and IMQ, rats were subjected to an 8-week CUS paradigm designed to simulate chronic stress conditions. Moreover, after 5 weeks of CUS, methotrexate (MTX; 2 mg/kg, administered once weekly for 3 weeks, intraperitoneally) was introduced as a therapeutic intervention. The severity of CUS-induced effects and the therapeutic impairment of MTX in arthritis and psoriasis rats were assessed through pathological examination of joint and epidermal tissues, respectively. Additionally, we measured various pro-inflammatory cytokine levels, including NF-κB (nuclear factor kappa B), IFN-γ (interferon-gamma), TNF-α (tumour necrosis factor alpha), IL (interleukin)-1ß, IL-6, IL-17 and IL-23 using enzyme-linked immunosorbent assay (ELISA), analysed immune cells through complete haematological profiling and evaluated oxidative stress markers. Our findings revealed that CUS significantly aggravated the pathological features of both arthritis and psoriasis. Prolonged stress exposure led to heightened inflammatory responses, increased oxidative stress and more severe tissue damage. Moreover, the therapeutic efficacy of MTX was notably reduced in stressed rats compared to non-stressed, underscoring the detrimental effects of chronic stress on treatment outcomes. Taken together, our results emphasize the importance of considering chronic stress as a critical factor in the management of autoimmune diseases.

Evidence-based neuroprotective potential of nonfeminizing estrogens: In vitro and in vivo studies.

Menopause weakens the brain's structural integrity and increases its susceptibility to a range of degenerative and mental illnesses. 17ß estradiol (17ßE2) exhibits potent neuroprotective properties. Exogenous estrogen supplementation provides neuroprotection, but the findings presented by the Million Women Study (MWS) and the Women's Health Initiative (WHI), as well as the increased risk of endometrial cancer, breast cancer and venous thromboembolism associated with estrogen use, have cast doubt on its clinical use for neurological disorders. Thus, the objective of our review article is to compile all in vitro and in vivo studies conducted till date demonstrating the neuroprotective potential of nonfeminizing estrogens. This objective has been achieved by gathering various research and review manuscripts from different records such as PubMed, Embase, Scopus, Google Scholar, Web of Science and OVID, using different terms like 'estrogen deficiency, 17ß estradiol, non-feminising estrogens, and brain disorder'. However, recent evidence has revealed the contribution of numerous non-estrogen receptor-dependent pathways in neuroprotective effects of estrogen. In conclusion, synthetic nonfeminizing estrogens that have little or no ER binding but are equally powerful (and in some cases more potent) in delivering neuroprotection are emerging as viable and potential alternatives.

Personalized treatment approach for HER2-positive metastatic breast cancer.

Breast cancer (BC) is a leading global concern for women, with 30% being HER2-positive cases linked to poorer outcomes. Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Although these therapies have improved MBC management and patient outcomes, resistance can develop, reducing effectiveness. Personalized strategies based on tumor characteristics offer hope for better responses and longer outcomes. This review outlines insights into MBC patients responding well to anti-HER2 treatments, even across multiple treatment regimen. Recent immunotherapy, locoregional therapy, and liquid biopsy breakthroughs are covered, suggesting ways to increase long-term responders. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics.

Modeling and characterization of gas coupled ultrasonic transducers at low pressures and temperatures and implications for sonic anemometry on Mars.

A sonic anemometer targeted at wind speed measurements on the surface of Mars is described. This environment requires transducer operation in 4-10 mbar CO2 at temperatures between 143 and 293 K (-130 °C and 20 °C, respectively). Over these ranges, transducer pressure and temperature sensitivity could be a source of measurement error. To investigate this, four candidate transducers were tested using transmission mode ultrasonic testing and impedance measurements: two narrowband piezoelectric transducers, a broadband capacitive transducer, and a micromachined capacitive ultrasound transducer. A system model was used for comparison and interpretation, and implications for a sonic anemometer were examined. Variation of transducer characteristics, including diffraction effects, across 2-10 mbar in CO2 and 190-293 K (-83 °C-20 °C) result in ±2.3% error in wind speed measurement and ±1.1% error in speed of sound measurement for the worst case but only ±0.14% error in wind and ±0.07% error in speed of sound for the best transducer operated off resonance. The acoustic conditions on Mars are similar to those in Earth's stratosphere at 30-42 km of altitude. Hence, testing was also conducted in dry air over the same range of pressures and temperatures with relevance to a secondary application of the instrument as a stratospheric anemometer for high altitude balloon missions on Earth.

Terra incognita of glial cell dynamics in the etiology of leukodystrophies: Broadening disease and therapeutic perspectives.

Neuroglial cells, also known as glia, are primarily characterized as auxiliary cells within the central nervous system (CNS). The recent findings have shed light on their significance in numerous physiological processes and their involvement in various neurological disorders. Leukodystrophies encompass an array of rare and hereditary neurodegenerative conditions that were initially characterized by the deficiency, aberration, or degradation of myelin sheath within CNS. The primary cellular populations that experience significant alterations are astrocytes, oligodendrocytes and microglia. These glial cells are either structurally or metabolically impaired due to inherent cellular dysfunction. Alternatively, they may fall victim to the accumulation of harmful by-products resulting from metabolic disturbances. In either situation, the possible replacement of glial cells through the utilization of implanted tissue or stem cell-derived human neural or glial progenitor cells hold great promise as a therapeutic strategy for both the restoration of structural integrity through remyelination and the amelioration of metabolic deficiencies. Various emerging treatment strategies like stem cell therapy, ex-vivo gene therapy, infusion of adeno-associated virus vectors, emerging RNA-based therapies as well as long-term therapies have demonstrated success in pre-clinical studies and show promise for rapid clinical translation. Here, we addressed various leukodystrophies in a comprehensive and detailed manner as well as provide prospective therapeutic interventions that are being considered for clinical trials. Further, we aim to emphasize the crucial role of different glial cells in the pathogenesis of leukodystrophies. By doing so, we hope to advance our understanding of the disease, elucidate underlying mechanisms, and facilitate the development of potential treatment interventions.

The pandemic's unseen wounds: COVID-19's profound effects on mental health.

Objective: This review aims to explore the impact of the COVID-19 pandemic on mental health, with a focus on the physiological and psychological consequences, including comorbidities. The goal is to understand the direct and indirect populations affected by mental distress and identify potential interventions. Methodology: A comprehensive literature search was conducted using various databases, including Google Scholar, ResearchGate, ScienceDirect, PubMed, PLoS One, and Web of Science. The search utilized relevant keywords to investigate the direct and indirect impacts of COVID-19 on mental health. The selected articles were critically evaluated and analyzed to identify key findings and insights. Main findings: Mental health, being an intrinsic component of overall well-being, plays a vital role in physiological functioning. The COVID-19 pandemic, caused by the emergence of the novel SARS-CoV-2 virus, has had a devastating global impact. Beyond the respiratory symptoms, individuals recovering from COVID-19 commonly experience additional ailments, such as arrhythmia, depression, anxiety, and fatigue. Healthcare professionals on the frontlines face an elevated risk of mental illness. However, it is crucial to recognize that the general population also grapples with comparable levels of mental distress. Conclusion: The COVID-19 pandemic has underscored the significance of addressing mental health concerns. Various strategies can help mitigate the impact, including counselling, fostering open lines of communication, providing mental support, ensuring comprehensive patient care, and administering appropriate medications. In severe cases, treatment may involve the supplementation of essential vitamins and antidepressant therapy. By understanding the direct and indirect impacts of COVID-19 on mental health, healthcare providers and policymakers can develop targeted interventions to support individuals and communities affected by the pandemic. Continued research and collaborative efforts are essential to address this pervasive issue effectively.

Investigation of Pancreatic-beta cells Role in the Biological Process of Ageing.

BACKGROUND: Cellular senescence is associated with the formation and progression of a range of illnesses, including ageing and metabolic disorders such as diabetes mellitus and pancreatic beta cell dysfunction. Ageing and reduced glucose tolerance are interconnected. Often, Diabetes is becoming more common, which is concerning since it raises the risk of a variety of age-dependent disorders such as cardiovascular disease, cancer, Parkinson's disease, stroke, and Alzheimer's disease. OBJECTIVES: The objectives of this study are to find out the most recent research on how ageing affects the functions of pancreatic beta cells, beta cell mass, beta cell senescence, mitochondrial dysfunction, and hormonal imbalance. METHODS: Various research and review manuscripts are gathered from various records such as Google Scholar, PubMed, Mendeley, Scopus, Science Open, the Directory of Open Access Journals, and the Education Resources Information Centre, using different terms like "Diabetes, cellular senescence, beta cells, ageing, insulin, glucose". RESULTS: In this review, we research novel targets in order to discover new strategies to treat diabetes. Abnormal glucose homeostasis and type 2 diabetes mellitus in the elderly may aid in the development of novel medicines to delay or prevent diabetes onset, improve quality of life, and, finally, increase life duration. CONCLUSION: Aging accelerates beta cell senescence by generating premature cell senescence, which is mostly mediated by high glucose levels. Despite higher plasma glucose levels, hepatic gluconeogenesis accelerates and adipose tissue lipolysis rises, resulting in an increase in free fatty acid levels in the blood and worsening insulin resistance throughout the body.

Butein ameliorates chronic stress induced atherosclerosis via targeting anti-inflammatory, anti-fibrotic and BDNF pathways.

Chronic stress is a major risk factor for various diseases, including cardiovascular diseases (CVDs). Chronic stress enhances the release of pro-inflammatory cytokines like IL-1ß, IL-6, and TNF-α, making individuals susceptible to atherosclerosis which is dominant cause for CVDs. In present study, we validated a mouse model of chronic unpredictable stress (CUS), and assessed the characteristic features of atherosclerosis in thoracic aortas of CUS mice. The CUS procedure consisted of exposing groups of mice to random stressors daily for 10-weeks. The stress response was verified by presence of depressive-like behaviors and increased serum corticosterone in mice which was determined by battery of behavioural tests (SPT, EPMT, NSFT) and ELISA, respectively. Atherosclerosis parameters in CUS mice were evaluated by lipid indices estimation followed by histological assessment of plaque deposition and fibrosis in thoracic aorta. Further, we assessed the efficacy of a polyphenol, i.e. Butein in conferring protection against chronic stress-induced atherosclerosis and the possible mechanism of action. Butein (20 mg/kg x 28 days, alternatively, i.p.) was administered to CUS mice after 6-weeks of CUS exposure till the end of the protocol. Butein treatment decreased peripheral IL-1ß and enhanced peripheral as well as central BDNF levels. Histological assessment revealed decreased macrophage expression and reduced fibrosis in thoracic aorta of Butein treated mice. Further, treatment with Butein lowered lipid indices in CUS mice. Our findings thus, suggest that 10-weeks of CUS induce characteristic features of atherosclerosis in mice and Butein can offer protection in CUS-induced atherosclerosis through multiple mechanisms including anti-inflammatory, antifibrotic and anti-adipogenic actions.

Nano to rescue: repository of nanocarriers for targeted drug delivery to curb breast cancer.

Breast cancer is a heterogeneous disease with different intrinsic subtypes. The conventional treatment of surgical resection, chemotherapy, immunotherapy and radiotherapy has not shown significant improvement in the survival rate of breast cancer patients. The therapeutics used cause bystander toxicities deteriorating healthy tissues. The breakthroughs of nanotechnology have been a promising feat in selective targeting of tumor site thus increasing the therapeutic gain. By the application of nanoenabled carriers, nanomedicines ensure targeted delivery, stability, enhanced cellular uptake, biocompatibility and higher apoptotic efficacy. The present review focuses on breakthrough of nanoscale intervention in targeted drug delivery as novel class of therapeutics. Nanoenabled carriers like polymeric and metallic nanoparticles, dendrimers, quantum dots, liposomes, solid lipid nanoparticles, carbon nanotubes, drug-antibody conjugates and exosomes revolutionized the targeted therapeutic delivery approach. These nanoassemblies have shown additional effect of improving the solubility of drugs such as paclitaxel, reducing the dose and toxicity. The present review provides an insight on the different drug conjugates employed/investigated to curb breast cancer using nanocarrier mediated targeted drug delivery. However, identification of appropriate biomarkers to target, clearer insight of the biological processes, batch uniformity, reproducibility, nanomaterial toxicity and stabilities are the hurdles faced by nanodrugs. The potential of nano-therapeutics delivery necessitates the agglomerated efforts of research community to bridge the route of nanodrugs for scale-up, commercialization and clinical applications.

The multifactorial roles of microglia and macrophages in the maintenance and progression of glioblastoma.

The functional characteristics of glial cells, in particular microglia, have attained considerable importance in several diseases, including glioblastoma, the most hostile and malignant type of intracranial tumor. Microglia performs a highly significant role in the brain's inflammatory response mechanism. They exhibit anti-tumor properties via phagocytosis and the activation of a number of different cytotoxic substances. Some tumor-derived factors, however, transform these microglial cells into immunosuppressive and tumor-supportive, facilitating survival and progression of tumorigenic cells. Glioma-associated microglia and/or macrophages (GAMs) accounts for a large proportion of glioma infiltrating cells. Once within the tumor, GAMs exhibit a distinct phenotype of initiation that subsequently supports the growth and development of tumorigenic cells, angiogenesis and stimulates the infiltration of healthy brain regions. Interventions that suppress or prohibit the induction of GAMs at the tumor site or attenuate their immunological activities accommodating anti-tumor actions are likely to exert positive impact on glioblastoma treatment. In the present paper, we aim to summarize the most recent knowledge of microglia and its physiology, as well as include a very brief description of different molecular factors involved in microglia and glioblastoma interplay. We further address some of the major signaling pathways that regulate the baseline motility of glioblastoma progression. Finally, we discussed a number of therapeutic approaches regarding glioblastoma treatment.

Potential of long non-coding RNAs as a therapeutic target and molecular markers in glioblastoma pathogenesis.

Glioblastoma (GB) is by far the most hostile type of malignant tumor that primarily affects the brain and spine, derived from star-shaped glial cells that are astrocytes and oligodendrocytes. Despite of significant efforts in recent years in glioblastoma research, the clinical efficacy of existing medical intervention is still limited and very few potential diagnostic markers are available. Long non-coding RNAs (lncRNAs) that lacks protein-coding capabilities were previously thought to be "junk sequences" in mammalian genomes are quite indispensible epigenetic regulators that can positively or negatively regulate gene expression and nuclear architecture, with significant roles in the initiation and development of tumors. Nevertheless, the precise mechanism of these distortedly expressed lncRNAs in glioblastoma pathogenesis is not yet fully understood. Since the advent of high-throughput sequencing technologies, more and more research have elucidated that lncRNAs are one of the most promising prognostic biomarkers and therapeutic targets for glioblastoma. In this paper, I briefly outlined the existing findings of lncRNAs. And also summarizes the profiles of different lncRNAs that have been broadly classified in glioblastoma research, with emphasis on both their prognostic and therapeutic values.