HIV-TB Coinfection: Current Therapeutic Approaches and Drug Interactions.

The co-occurrence of human immunodeficiency virus (HIV) and tuberculosis (TB) infection poses a significant global health challenge. Treatment of HIV and TB co-infection often necessitates combination therapy involving antiretroviral therapy (ART) for HIV and anti-TB medications, which introduces the potential for drug-drug interactions (DDIs). These interactions can significantly impact treatment outcomes, the efficacy of treatment, safety, and overall patient well-being. This review aims to provide a comprehensive analysis of the DDIs between anti-HIV and anti-TB drugs as well as potential adverse effects resulting from the concomitant use of these medications. Furthermore, such findings may be used to develop personalized therapeutic strategies, dose adjustments, or alternative drug choices to minimize the risk of adverse outcomes and ensure the effective management of HIV and TB co-infection.

Role of Oxidative Stress in Tuberculosis Meningitis Infection in Diabetics.

Tuberculosis meningitis (TBM) is a result of the invasion of the meninges with the bacilli of Mycobacterium tuberculosis (Mtb), leading to inflammation of the meninges around the brain or spinal cord. Oxidative stress occurs when the body's cells become overwhelmed with free radicals, particularly reactive oxygen species (ROS). ROS plays a significant role in the pathogenesis of TBM due to their toxic nature, resulting in impairment of the body's ability to fight off infection. ROS damages the endothelial cells and impairs the defense mechanisms of the blood-brain barrier (BBB), which contributes to CNS susceptibility to the bacteria causing TBM. Diabetes mellitus (DM) is a common condition that is characterized by the impairment of the hormone insulin, which is responsible for modulating blood glucose levels. The increased availability of glucose in individuals with diabetes results in increased cellular activity and metabolism, leading to heightened ROS production and, in turn, increased susceptibility to TBM. In this review, we summarize our current understanding of oxidative stress and its role in both TBM and DM. We further discuss how increased oxidative stress in DM can contribute to the likelihood of developing TBM and potential therapeutic approaches that may be of therapeutic value.

Potential Role of Glutathione Antioxidant Pathways in the Pathophysiology and Adjunct Treatment of Psychiatric Disorders.

Oxidative stress is defined as the imbalance between the production of free radicals and their removal by antioxidants, leading to accumulation and subsequent organ and tissue damage. Antioxidant status and its role in the accumulation of free radicals has been observed in a number of psychological disorders. Glutathione is commonly referred to as the principal antioxidant of the brain and, therefore, plays a critical role in maintaining redox homeostasis. Reduced levels of glutathione in the brain increase its vulnerability to oxidative stress, and may be associated with the development and progression of several psychiatric disorders. Within this review, we focus on analyzing potential associations between the glutathione antioxidant pathway and psychiatric disorders: major depressive disorder, schizophrenia, bipolar disorder, and generalized anxiety disorder. Our research suggests that studies regarding these four disorders have shown decreased levels of GSH in association with diseased states; however, conflicting results note no significant variance in glutathione pathway enzymes and/or metabolites based on diseased state. In studying the potential of NAC administration as an adjunct therapy, various studies have shown NAC to augment therapy and/or aid in symptomatic management for psychiatric disorders, while contrasting results exist within the literature. Based on the conflicting findings throughout this review, there is room for study regarding the potential role of glutathione in the development and progression of psychiatric disorders. Our findings further suggest a need to study such pathways with consideration of the interactions with first-line pharmacotherapy, and the potential use of antioxidants as supplemental therapy.

Role of NF-κB during Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (M. tb) causes tuberculosis infection in humans worldwide, especially among immunocompromised populations and areas of the world with insufficient funding for tuberculosis treatment. Specifically, M. tb is predominantly exhibited as a latent infection, which poses a greater risk of reactivation for infected individuals. It has been previously shown that M. tb infection requires pro-inflammatory and anti-inflammatory mediators to manage its associated granuloma formation via tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), interferon-γ (IFN-γ), and caseum formation via IL-10, respectively. Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) has been found to play a unique mediator role in providing a pro-inflammatory response to chronic inflammatory disease processes by promoting the activation of macrophages and the release of various cytokines such as IL-1, IL-6, IL-12, and TNF-α. NF-κB's role is especially interesting in its mechanism of assisting the immune system's defense against M. tb, wherein NF-κB induces IL-2 receptors (IL-2R) to decrease the immune response, but has also been shown to crucially assist in keeping a granuloma and bacterial load contained. In order to understand NF-κB's role in reducing M. tb infection, within this literature review we will discuss the dynamic interaction between M. tb and NF-κB, with a focus on the intracellular signaling pathways and the possible side effects of NF-κB inactivation on M. tb infection. Through a thorough review of these interactions, this review aims to highlight the role of NF-κB in M. tb infection for the purpose of better understanding the complex immune response to M. tb infection and to uncover further potential therapeutic methods.

Regulation of T Cells in Cancer by Nitric Oxide.

The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.

Reversal of Resistance to Anti-CD20 Antibody Therapies: Targeting Intracellular Resistant Factors.

Rituximab, a chimeric mouse/human monoclonal antibody (mAb) targeting CD20, has proven to improve treatment outcomes in a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Rituximab in combination with standard chemotherapeutic regimens (R-CHOP) has proven to be the current standard treatment, with successful outcomes in a larger subset of patients compared to monotherapy. However, in addition to initially nonresponding patients, evidence suggests that many responding patients develop resistance to further treatments. The mechanisms by which monoclonal antibodies target CD20 in vivo are poorly understood, although the implicated mechanisms include the direct induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). The processes of other postulated mechanisms considered to be intracellular antitumor effects are also described in this review. Here we discuss methods for reversing resistance to anti-CD20 antibody therapies via targeting intracellular signaling pathways that regulate resistant factors. With an increased understanding of the underlying mechanisms of resistance, more effective new approaches may be developed for early diagnosis and therapeutic responses.

Identifying Crosstalk between Raf Kinase Inhibitor Protein and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which hyperactive autoantibodies attack and damage healthy tissues and organs. SLE can affect multiple organs, such as the skin, kidneys, joints, and brain. The pathogenesis of SLE is multifaceted and complex, making it difficult to develop targeted therapies to ameliorate symptoms and the onset of disease. A number of signaling pathways have been investigated and shown to be implicated in SLE; however, information regarding the specific pathways involved, at least in part, in the pathogenesis of SLE remains scarce. The role of Raf kinase inhibitor protein (RKIP) in key signaling pathways in cancer is well-studied. However, studies highlighting the role of RKIP in autoimmune diseases and the inflammatory response are emerging. Whereas the induction of RKIP in cancer is associated with improved responses and reduced resistance, the overexpression of RKIP in normal tissues inhibits inflammatory cytokines and chemokines and may also inhibit autoimmunity. In this review, we have analyzed the potential crosstalk between the signaling pathways that regulate SLE and RKIP and whether targeting the pathways that activate the expression of RKIP may prove to be a novel therapeutic tool against the pathogenesis of SLE.