Periodontitis and diabetes mellitus co-morbidity: A molecular dialogue.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and periodontitis are two biologically linked diseases that often coexist in complex interaction. While periodontitis may lead to insulin receptor desensitization, diabetes may increase the expression of inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin 6 (IL-6), in the gingival crevicular fluid and activate osteoclasts via Receptor activator of nuclear factor kappa-Β ligand (RANK-L) production, leading to bone resorption. However, the association between the two diseases processes, where one may exacerbate the progression of the other, is unclear. In addition, both diseases have similar mechanistic themes, such as chronic inflammation and oxidative stress. This review aimed to investigate the pathophysiological and molecular mechanisms underlying T2DM and periodontitis. HIGHLIGHT: Uncontrolled diabetes is often associated with severe periodontitis, measured by clinical attachment loss. Alteration in the oral microbiome composition, which may activate the host inflammatory response and lead to irreversible oxidative stress, is a common finding in both diseases. An understanding of the molecular crosstalk between the two disease processes is crucial for developing therapeutic targets that inhibit bone resorption and halt the progression of periodontitis in patients with diabetes. CONCLUSION: The Oral microbiome composition in T2DM and periodontitis shifts toward dysbiosis, favoring bacterial pathogens, such as Fusobacteria and Porphyromonas species. Both conditions are marked by pro-inflammatory immune activity via the activation of Interleukin 17 (IL-17), Interleukin 1 (IL-1), TNF-α, and Nuclear Factor Kappa Beta (NF-κB). Common molecular crosstalk signaling appears to involve advanced glycation end products (AGEs) and oxidative stress. Thus, future drug targets are multifactorial, ranging from modulatory of host inflammatory response to preventing the accumulation of AGEs and oxidative free radicals.

The preclinical candidate indole-2-carboxamide improves immune responses to Mycobacterium tuberculosis infection in healthy subjects and individuals with type 2 diabetes.

A novel group of agents known as the indole-2-carboxamides (often referred to as indoleamides) have been shown to demonstrate high antimycobacterial activity. Studies have demonstrated that the best indoleamides possess desirable ADME/Tox properties, with less adverse effects and increased efficacy against both MDR-TB (multi-drug resistant TB) and XDR-TB (extensively drug-resistant TB). The primary mechanism of killing Mycobacterium tuberculosis (Mtb) by indoleamides is by disrupting the function of the essential mycolic acid transporter MmpL3 protein (Mycobacterial membrane protein Large 3). Therefore, targeting this essential mycobacterial transporter by small molecules opens new possibility for the development of novel and effective anti-TB agents. In the present study, we characterized the effects of indoleamides in altering the viability of Mtb in an in vitro granuloma model using immune cells derived from healthy subjects and those with type 2 diabetes mellitus (T2DM). Our results indicate that treatment with the best indoleamide 3 resulted in a significant reduction in the viability of Mtb in both THP-1 macrophages as well as in granulomas derived from healthy individuals and subjects with T2DM. Graphical Abstract.

Flavonoid Mixture Inhibits Mycobacterium tuberculosis Survival and Infectivity.

BACKGROUND: Flavonoids have been shown to exert anti-pathogenic potential, but few studies have investigated their effects on Mycobacterium tuberculosis (Mtb) infectivity. We hypothesized that a flavonoid mixture would have a favorable influence on cell death and the resolution of Mtb infection in THP-1 macrophages and in granulomas derived from both healthy participants and those with type 2 diabetes mellitus (T2DM). METHODS: THP-1 macrophages, and in vitro granulomas from healthy participants (N = 8) and individuals with T2DM (N = 5) were infected with Mtb. A mixed flavonoid supplement (MFS) at a concentration of 0.69 mg per ml was added as treatment to Mtb infected THP-1 macrophages and granulomas for 8 to 15 days. RESULTS: MFS treatment significantly reduced the intracellular Mtb survival, increased cell density, aggregation, and granuloma formation, and increased glutathione (GSH) levels. IL-12 and IFN-γ levels tended to be higher and IL-10 lower when Mtb infected THP-1 macrophages and granulomas obtained from healthy subjects were treated with MFS compared to control. CONCLUSIONS: MFS treatment exerted a strong influence against Mtb infectivity in THP-1 macrophages and in granulomas including antimycobacterial effects, GSH enrichment, cytokine regulation, and augmented granuloma formation. Our data support the strategy of increased flavonoid intake for managing tuberculosis.

Glutathione as a Marker for Human Disease.

Glutathione (GSH), often referred to as "the master antioxidant," participates not only in antioxidant defense systems, but many metabolic processes, and therefore its role cannot be overstated. GSH deficiency causes cellular risk for oxidative damage and thus as expected, GSH imbalance is observed in a wide range of pathological conditions including tuberculosis (TB), HIV, diabetes, cancer, and aging. Consequently, it is not surprising that GSH has attracted the attention of biological researchers and pharmacologists alike as a possible target for medical intervention. Here, we discuss the role GSH plays amongst these pathological conditions to illuminate how it can be used as a marker for human disease.

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.

Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis.

Mycobacterium tuberculosis is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, and the rate of resistance of M. tuberculosis to antibiotics is ever increasing. We tested the synergistic effects of N-acetyl cysteine (NAC; the precursor molecule for the synthesis of glutathione [GSH]) and individual first-line antibiotics typically given for the treatment of TB, such as isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), to improve the ability of macrophages to control intracellular M. tuberculosis infection. GSH, a pleiotropic antioxidant molecule, has previously been shown to display both antimycobacterial and immune-enhancing effects. Our results indicate that there was not only an increase in beneficial immunomodulatory effects but also a greater reduction in the intracellular viability of M. tuberculosis when macrophages were treated with the combination of antibiotics (INH, RIF, EMB, or PZA) and NAC.

Effects of ReadiSorb L-GSH in Altering Granulomatous Responses against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (M. tb), a rod-shaped acid-fast bacterium, is the causative agent of tuberculosis (TB). TB remains one of the leading causes of morbidity and mortality worldwide. Additionally, approximately one-third of the world's population has latent tuberculosis infection (LTBI) as a result of the body's primary mechanism of defense against M. tb infection, the formation of a granuloma. A granuloma is the aggregation of immune cells that encapsulate the bacteria to keep them localized to prevent further infection and thus the bacteria become quiescent. However, if an individual becomes immunocompromised, they become more susceptible to M. tb, which may lead to bacterial reactivation and an active infection, because the host is no longer able to generate adequate immune responses. In this study, we examined liposomal glutathione's (L-GSH) effectiveness in promoting the formation of solid, stable granulomas. We assessed this ability by generating in vitro human granulomas constructed from peripheral blood mononuclear cells (PBMCs) that were derived from healthy subjects and testing their granulomatous effector responses against both M. bovis bacille Calmette-Guérin (BCG) and the highly virulent Erdman strain of M. tb. Additionally, we measured the survival and immune characteristics of the Erdman strain of M. tb in THP-1 originated macrophages as well as in vitro granulomas generated from individuals from type 2 diabetes (T2DM). Our results demonstrate that L-GSH treatment can decrease the intracellular survival of both BCG and virulent M. tb, as well as downregulate the levels of overexpressed proinflammatory cytokines delegated from the granulomas derived from not only healthy subjects but also individuals with T2DM.

Restoring Cytokine Balance in HIV-Positive Individuals with Low CD4 T Cell Counts.

HIV infects and destroys CD4+ T cells leading to a compromised immune system. In a double-blinded study, a group of HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 were given either an empty liposomal supplement or a liposomal glutathione (L-GSH) supplement to take over a 3-month period. Baseline measurements in HIV-positive subjects show a significant decrease in levels of interleukin (IL)-12, IL-2, and interferon (IFN)-γ, along with a substantial increase in the levels of IL-6, IL-10, transforming growth factor (TGF)-ß, and free radicals, compared to healthy individuals. Supplementation of HIV-positive subjects with L-GSH for 3 months resulted in a notable increase in the levels of IL-12, IL-2, and IFN-γ, with a concomitant decrease in the levels of IL-6, IL-10, and free radicals, and stabilization in the levels of TGF-ß, IL-1, and IL-17, compared to their placebo counterparts. Levels of free radicals in CD4+ T cells stabilized, while GSH levels increased in the treatment group. Those in the placebo group showed no significant difference throughout the study. In summary, supplementation with L-GSH in HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 can help restore redox homeostasis and cytokine balance, therefore aiding the immune system to control opportunistic infections.