Dysregulation of Gamma Delta T-Cells, CD8+ T Cells, CD4+ T Cells, and Natural Killer Cells in Brain Pathology: Understanding HIV-Induced Impairment and Exploring Targeted GSH Therapy.

This review comprehensively explores the dysregulation of Gamma Delta T-cells, CD8+ T Cells, and Natural Killer T Cells in the context of Human Immunodeficiency Virus (HIV) infection and its implications for brain pathology. It encompasses an overview of the HIV disease process, immune cell dysregulation, association with neurological diseases, and the critical role of Glutathione (GSH) in T-cell function. The alterations in Gamma Delta T-cells during chronic infection, the intricate dynamics of Vδ1 and Vδ2 subsets, and the potential of Vγ9Vδ2 T cells in inhibiting HIV replication are discussed. Additionally, the review addresses the exhaustion, impaired cytotoxicity, and premature senescence of CD8+ T cells, as well as the dysregulation of Natural Killer Cells (NKCs) and their impact on overall immune system activity. Furthermore, it examines the role of Gamma Delta (γδ) T-cells in brain injuries, infections, and tumors and highlights the therapeutic implications of elevated GSH levels in promoting a T helper 1 (Th1) immune response. However, HIV-infected patients with decreased GSH exhibit a T helper 2 (Th2) bias, compromising protection against intracellular pathogens. Finally, the review discusses studies in murine models demonstrating the impact of GSH levels on immune responses and underscores the therapeutic potential of targeting GSH to enhance immunity in HIV patients. Overall, this review provides valuable insights into the complex interplay between immune dysregulation, GSH levels, and HIV-associated brain pathology, offering insights into potential therapeutic avenues for mitigating immune compromise and neurological impairments in HIV patients.

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation.

Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

Ferroptosis in Cardiovascular Disease and Cardiomyopathies: Therapeutic Implications of Glutathione and Iron Chelating Agents.

This review explores ferroptosis, a form of regulated cell death reliant on iron-induced phospholipid peroxidation, in diverse physiological and pathological contexts, including neurodegenerative disorders, and ischemia-reperfusion. In the realm of cardiovascular diseases, it significantly contributes to cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and restrictive cardiomyopathy. Ferroptosis involves intricate interactions within cellular iron metabolism, lipid peroxidation, and the balance between polyunsaturated and monounsaturated fatty acids. Molecularly, factors like p53 and NRF2 impact cellular susceptibility to ferroptosis under oxidative stress. Understanding ferroptosis is vital in cardiomyopathies, where cardiac myocytes heavily depend on aerobic respiration, with iron playing a pivotal role. Dysregulation of the antioxidant enzyme GPX4 is linked to cardiomyopathies, emphasizing its significance. Ferroptosis's role in myocardial ischemia-reperfusion injury, exacerbated in diabetes, underscores its relevance in cardiovascular conditions. This review explores the connection between ferroptosis, the NRF2 pathway, and atherosclerosis, emphasizing their roles in protecting cells from oxidative stress and maintaining iron balance. It discusses the use of iron chelating agents in managing iron overload conditions, with associated benefits and challenges. Finally, it highlights the importance of exploring therapeutic strategies that enhance the glutathione (GSH) system and the potential of natural compounds like quercetin, terpenoids, and phenolic acids in reducing oxidative stress.

The Role of Oxidative Stress in TB Meningitis and Therapeutic Options.

Meningitis is an inflammatory condition affecting the meninges surrounding the brain and spinal cord. Meningitis can be triggered by various factors, including infectious agents like viruses and bacteria and non-infectious contributors such as cancer or head injuries. The impact of meningitis on the central nervous system involves disruptions in the blood-brain barrier, cellular infiltrations, and structural alterations. The clinical features that differentiate between tuberculous meningitis (TBM) and non-tuberculous meningitis (NTM) are discussed in this review and aid in accurate diagnosis. The intricate interplay of reactive oxygen species, ferroptosis, and reactive nitrogen species within the central nervous system reveals a promising field of research for innovative therapeutic strategies tailored to TBM. This review highlights the alternative treatments targeting oxidative stress-induced TBM and ferroptosis, providing potential avenues for intervention in the pathogenesis of this complex condition.

Mycobacterial Endocarditis, A Rare Form of Infective Endocarditis.

This research project delves into the multifaceted dynamics of Mycobacterium tuberculosis (M.tb) endocarditis, a significant yet uncommon manifestation of tuberculosis (TB). Beginning with an overview of M.tb and the global challenges posed by TB, we navigate through the bacterium's evolution, transmission modes, and the intricate host immune response. The pathology and pathophysiology of M.tb endocarditis are explored, emphasizing its complexities and the host's efforts to contain the pathogen. The study extends to atypical mycobacterial endocarditis, highlighting the emergence of species like M.chimaera, M.fortuitum, and M.chelonae, with a focus on their association with life-threatening mycobacterial endocarditis. Clinical presentations and complications of M.tb endocarditis are detailed, addressing challenges in diagnosis, drug-resistant, co-infections with Human Immunodeficiency Virus (HIV), and potential sepsis. The research underscores the need for a deeper understanding of M.tb endocarditis to enhance prevention, diagnosis, and treatment strategies. Examining the genetic and environmental factors influencing M.tb endocarditis, the study discusses the interplay of immune-related genes, environmental conditions, and predispositions contributing to infection susceptibility. Despite challenges in treatment due to its rarity, the research highlights current protocols, surgical interventions, and promising pharmaceutical developments. Lastly, unraveling these intricate factors is crucial for refining strategies and conducting large-scale trials to address this global health threat effectively.

The Interplay between Mycobacterium tuberculosis and Human Microbiome.

Tuberculosis (TB), a respiratory disease caused by Mycobacterium tuberculosis (Mtb), is a significant cause of mortality worldwide. The lung, a breeding ground for Mtb, was once thought to be a sterile environment, but has now been found to host its own profile of microbes. These microbes are critical in the development of the host immune system and can produce metabolites that aid in host defense against various pathogens. Mtb infection as well as antibiotics can shift the microbial profile, causing dysbiosis and dampening the host immune response. Additionally, increasing cases of drug resistant TB have impacted the success rates of the traditional therapies of isoniazid, rifampin, pyrazinamide, and ethambutol. Recent years have produced tremendous research into the human microbiome and its role in contributing to or attenuating disease processes. Potential treatments aimed at altering the gut-lung bacterial axis may offer promising results against drug resistant TB and help mitigate the effects of TB.