Uncovering the Roles of Mycobacterium tuberculosis melH in Redox and Bioenergetic Homeostasis: Implications for Antitubercular Therapy.

Mycobacterium tuberculosis ( Mtb ), the pathogenic bacterium that causes tuberculosis, has evolved sophisticated defense mechanisms to counteract the cytotoxicity of reactive oxygen species (ROS) generated within host macrophages during infection. The melH gene in Mtb and Mycobacterium marinum ( Mm ) plays a crucial role in defense mechanisms against ROS generated during infection. We demonstrate that melH encodes an epoxide hydrolase and contributes to ROS detoxification. Deletion of melH in Mm resulted in a mutant with increased sensitivity to oxidative stress, increased accumulation of aldehyde species, and decreased production of mycothiol and ergothioneine. This heightened vulnerability is attributed to the increased expression of whiB3 , a universal stress sensor. The absence of melH also resulted in reduced intracellular levels of NAD + , NADH, and ATP. Bacterial growth was impaired, even in the absence of external stressors, and the impairment was carbon-source-dependent. Initial MelH substrate specificity studies demonstrate a preference for epoxides with a single aromatic substituent. Taken together, these results highlight the role of melH in mycobacterial bioenergetic metabolism and provide new insights into the complex interplay between redox homeostasis and generation of reactive aldehyde species in mycobacteria. Importance: This study unveils the pivotal role played by the melH gene in Mycobacterium tuberculosis and Mycobacterium marinum in combatting the detrimental impact of oxidative conditions during infection. This investigation revealed notable alterations in the level of cytokinin-associated aldehyde, para -hydroxybenzaldehyde, as well as the redox buffer ergothioneine, upon deletion of melH . Moreover, changes in crucial cofactors responsible for electron transfer highlighted melH 's crucial function in maintaining a delicate equilibrium of redox and bioenergetic processes. MelH prefers epoxide small substrates with a phenyl substituted substrate. These findings collectively emphasize the potential of melH as an attractive target for the development of novel antitubercular therapies that sensitize mycobacteria to host stress, offering new avenues for combating tuberculosis.

Increased risk of coronary heart disease in patients with chronic osteomyelitis: a population-based study in a cohort of 23 million.

OBJECTIVES: Chronic inflammatory disease may trigger vascular atherosclerosis. This study aimed to determine whether chronic osteomyelitis (COM) is linked to an increased risk of coronary heart disease (CHD). METHODS: A national insurance claim dataset of more than 23 million enrolees was used to identify 15 054 patients with newly diagnosed COM and 60 216 randomly selected age-matched and gender-matched controls between 2001 and 2009 for comparing the risk and incidence of CHD. The study period was from the entry date to the first date of the following events: the diagnosis of CHD, death, withdrawal from the Taiwan National Health Insurance programme or the end of 2010. The analysis of the CHD risk was performed using Cox proportional hazards regression model. RESULTS: During a follow-up period of 67 927 person-years, the overall incidence rate of CHD in COM cohort was 1.95 times higher than non-COM cohort (16.66 vs 8.52 per 1000 person-years). After controlling age, gender and four comorbidities (hypertension, diabetes, hyperlipidaemia and stroke), the risk remained significantly higher in the COM cohort than the control group (adjusted HR=1.65, 95% CI 1.54 to 1.78, p<0.001). In age-stratified analysis, the younger population had a stronger association between COM and CHD risk than the elderly (from HR=3.42, 95% CI 1.60 to 7.32 in age <35 to HR 1.39, 95% CI 1.15 to 1.68 in age ≥80). CONCLUSIONS: This study demonstrates that COM is an independent risk factor for CHD, particularly in the younger population. Further studies are necessary to explore the underlying mechanisms linking COM and CHD.

Ovatodiolide inhibits the maturation of allergen-induced bone marrow-derived dendritic cells and induction of Th2 cell differentiation.

Ovatodiolide was a unique macrocyclic diterpenoid isolated from the traditional Chinese medicinal herb Anisomeles indica. The present study attempted to examine the ovatodiolide effects on dendritic cell (DC) maturation and immuno-stimulatory activities. The effects of ovatodiolide on DC surface molecule expression, cytokine production, and capacity to induce T-cell differentiation were examined in ovalbumin (OVA)/thymic stromal lymphopoietin (TSLP)-stimulated DCs. Ovatodiolide attenuated the expression of DC surface molecules CD80, CD86, histocompatibility complex (MHC) class II, and Th2 subset of CD4(+) T cells co-stimulatory molecule-OX40 ligand production. Additionally, ovatodiolide suppressed the CD4(+) T cells proliferation, and production of inflammatory cytokines interleukin (IL)-4, IL-5, and tumor necrosis factor (TNF)-α. This study may be useful to develop ovatodiolide as a therapeutic adjuvant.

Induction of apoptosis by ethanolic extract of Corchorus olitorius leaf in human hepatocellular carcinoma (HepG2) cells via a mitochondria-dependent pathway.

Corchorus olitorius L.,is a culinary and medicinal herb, widely used as a vegetable in several countries in Asia. Many studies have shown that C. olitorius contains several antioxidants and exhibits anti-inflammatory and anti-proliferative activities in various in vitro and in vivo settings. Recently, C. olitorius has been approved for its antitumor activity; however, the underlying molecular mechanisms remain unclear. The goal of this study was to investigate the effects of ethanol extract of C. olitorius (ECO) on the growth of human hepatocellular carcinoma (HepG2) cells and gain some insights into the underlying mechanisms of its action. We found that HepG2 cells, treated with ECO for 24 h at a concentration higher than 12.5 µg/mL, displayed a strong reduction in cell viability, whereas normal FL83B hepatocytes were not affected. DNA fragmentation and nuclear condensation were evidenced by the increased subG1 population of ECO-treated HepG2 cells. ECO triggered the activation of procaspases-3 and -9 and caused the cleavage of downstream substrate, poly ADP-ribose polymerase (PARP), followed by down-regulation of the inhibitor of caspase-activated DNase (ICAD) signaling. Moreover, the increased release of cytochrome c from mitochondria with decreased membrane potential demonstrated the apoptosis induced through the caspases cascade. Our findings indicated that ECO might be effective against hepatocellular carcinoma through induction of apoptosis via mitochondria-dependent pathway.

Electronic microscopy evidence for mitochondria as targets for Cd/Se/Te-based quantum dot 705 toxicity in vivo.

The safety of quantum dots (QDs) 705 was evaluated in this study. Mice were treated with QD705 (intravenous) at a single dose of (40 pmol) for 4, 12, 16, and 24 weeks. Effects of QD705 on kidneys were examined. While there was a lack of histopathology, reduction in renal functions was detected at 16 weeks. Electron microscopic examination revealed alterations in proximal convoluted tubule (PCT) cell mitochondria at even much earlier time, including disorientation and reduction of mitochondrial number (early change), mitochondrial swelling, and later compensatory mitochondrial hypertrophy (enlargement mitochondria: giant mitochondria with hyperplastic inner cristae) as well as mitochondrial hyperplasia (increase in mitochondrial biogenesis and numbers) were observed. Such changes probably represent compensatory attempts of the mitochondria for functional loss or reduction of mitochondria in QD705 treated animals. Moreover, degeneration of mitochondria (myelin-figure and cytoplasmic membranous body formation) and degradation of cytoplasmic materials (isolated cytoplasmic pockets of degenerated materials and focal cytoplasmic degradation) also occurred in later time points (16-24 weeks). Such mitochondrial changes were not identical with those induced by pure cadmium. Taken together, we suggest that mitochondria appeared to be the target of QD705 toxicity and specific mitochondrial markers may be useful parameters for toxicity assessments of QDs or other metal-based nanomaterials.