Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.

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.

The Role of Obesity in Breast Cancer Pathogenesis.

Research has shown that obesity increases the risk for type 2 diabetes mellitus (Type 2 DM) by promoting insulin resistance, increases serum estrogen levels by the upregulation of aromatase, and promotes the release of reactive oxygen species (ROS) by macrophages. Increased circulating glucose has been shown to activate mammalian target of rapamycin (mTOR), a significant signaling pathway in breast cancer pathogenesis. Estrogen plays an instrumental role in estrogen-receptor-positive breast cancers. The role of ROS in breast cancer warrants continued investigation, in relation to both pathogenesis and treatment of breast cancer. We aim to review the role of obesity in breast cancer pathogenesis and novel therapies mediating obesity-associated breast cancer development. We explore the association between body mass index (BMI) and breast cancer incidence and the mechanisms by which oxidative stress modulates breast cancer pathogenesis. We discuss the role of glutathione, a ubiquitous antioxidant, in breast cancer therapy. Lastly, we review breast cancer therapies targeting mTOR signaling, leptin signaling, blood sugar reduction, and novel immunotherapy targets.

Cutaneous Manifestations of Mycobacterium tuberculosis: A Literature Review.

Tuberculosis is an ancient disease that humanity struggled with for centuries and continues to struggle with. The bacteria Mycobacterium tuberculosis often infects the lungs through respiratory transmission and manifests itself through various symptoms, including cutaneous infections. Cutaneous tuberculosis (CTB) comprises about 1% to 1.5% of all extrapulmonary manifestations and is often accompanied by polymorphous lesions, including papules, nodules, plaques, ulcers, gummas, and verrucous lesions. CTB is most commonly observed in low-income, HIV, and immunosuppressed populations, similar to intrapulmonary manifestations. The main pathogen for CTB is M. tuberculosis but less commonly with M. bovis and BCG vaccine, and the modes of transmission are largely classified into exogenous and endogenous CTB. Current treatment options for CTB include oral therapy of antibiotic medications such as rifampicin, streptomycin, ethambutol, isoniazid, and pyrazinamide, which is occasionally combined with surgical intervention.

The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review.

Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute- and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute- and long-COVID-19.

Atypical Staphylococcal Septic Arthritis in a Native Hip: A Case Report and Review.

Septic arthritis is a synovial fluid and joint tissue infection with significant morbidity and mortality risk if not diagnosed and treated promptly. The most common pathogen to cause septic arthritis is Staphylococcus aureus, a Gram-positive bacterium. Although diagnostic criteria are in place to guide the diagnosis of staphylococcal septic arthritis, there is a lack of adequate sensitivity and specificity. Some patients present with atypical findings which make it difficult to diagnose and treat in time. In this paper, we present the case of a patient with an atypical presentation of recalcitrant staphylococcal septic arthritis in a native hip complicated by uncontrolled diabetes mellitus and tobacco usage. We review current literature on diagnosing S. aureus septic arthritis, novel diagnostic technique performance to guide future research and assist clinical suspicion, and current S. aureus vaccine development for at-risk patients.

Neutrophils in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb) continues to be a leading cause of mortality within developing countries. The BCG vaccine to promote immunity against M. tb is widely used in developing countries and only in specific circumstances within the United States. However, current the literature reports equivocal data on the efficacy of the BCG vaccine. Critical within their role in the innate immune response, neutrophils serve as one of the first responders to infectious pathogens such as M. tb. Neutrophils promote effective clearance of M. tb through processes such as phagocytosis and the secretion of destructive granules. During the adaptative immune response, neutrophils modulate communication with lymphocytes to promote a strong pro-inflammatory response and to mediate the containment M. tb through the production of granulomas. In this review, we aim to highlight and summarize the role of neutrophils during an M. tb infection. Furthermore, the authors emphasize the need for more studies to be conducted on effective vaccination against M. tb.

Pathogenesis, Diagnostic Challenges, and Risk Factors of Pott's Disease.

Tuberculosis (TB) prevalence is increasing in developed nations and continuing to cause significant mortality in low- and middle-income countries. As a result of the uptick in cases, there also exists an increased prevalence of extrapulmonary TB. TB is caused by Mycobacterium tuberculosis (M. tb). When M. tb disseminates to the vertebral column, it is called Pott's disease or spinal TB. The frequency, symptoms, and severity of the disease range by the location of the spine and the region of the affected vertebrae. While the current literature shows that timely diagnosis is crucial to reduce the morbidity and mortality from Pott's disease, there is a lack of specific clinical diagnostic criteria for Pott's disease, and the symptoms may be very non-specific. Studies have shown that novel molecular diagnostic methods are effective and timely choices. Research has implicated the risk factors for the susceptibility and severity of Pott's disease, such as HIV and immunosuppression, poverty, and malnutrition. Based on the current literature available, our group aims to summarize the pathogenesis, clinical features, diagnostic challenges, as well as the known risk factors for Pott's disease within this literature review.