Multifaceted Actions of Succinate as a Signaling Transmitter Vary with Its Cellular Locations

Since the identification of succinate's receptor in 2004, studies supporting the involvement of succinate signaling through its receptor in various diseases have accumulated and most of these investigations have highlighted succinate's pro-inflammatory role. Taken with the fact that succinate is an intermediate metabolite in the center of mitochondrial activity, and considering its potential regulation of protein succinylation through succinyl-coenzyme A, a review on the overall multifaceted actions of succinate to discuss whether and how these actions relate to the cellular locations of succinate is much warranted. Mechanistically, it is important to consider the sources of succinate, which include somatic cellular released succinate and those produced by the microbiome, especially the gut microbiota, which is an equivalent, if not greater contributor of succinate levels in the body. Continue learning the critical roles of succinate signaling, known and unknown, in many pathophysiological conditions is important. Furthermore, studies to delineate the regulation of succinate levels and to determine how succinate elicits various types of signaling in a temporal and spatial manner are also required.

Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw / 国际口腔科学杂志·英文版

Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts (n=30); patients with periodontal disease without a history of BP therapy (Control, n=10), patients with periodontal disease having history of BP therapy but without ONJ (BP, n=5) and patients with BRONJ (BRONJ, n=15). Denaturing gradient gel electrophoresis of polymerase chain reaction (PCR)-amplified 16S rRNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ (71.6%), BP (70.3%) and Control (59.1%). Significant differences (P<0.05) in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix-loop-helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.

Antibiotics for the treatment of leptospirosis: systematic review and meta-analysis of controlled trials

Leptospirosis is a zoonotic disease prevalent mainly in developing countries and is associated with high case fatality. Antibiotics especially penicillin are the mainstay of treatment for a suspected or confirm case of leptospirosis but role of Penicillin has not been evaluated systematically in the light of current evidence. The present systematic review and meta-analysis is done to evaluate the role of antibiotics in the treatment of leptospirosis. Parallel group clinical trials involving use of penicillin in treatment of leptospirosis were searched from all available sources. Ten clinical trials were found suitable as per laid inclusion criteria eligible for present systematic review and five clinical trials were included in meta analysis. Clinical trials included for meta-analysis were compared on the basis of mortality, fever days, numbers of patients presenting with oliguria, and number of patients undergoing need based dialysis. Analysis was done by comprehensive meta analysis software 2. Qualitative outcomes are summarized as odds ratio and quantitative outcomes are summarized as standard mean difference with 95% confidence interval. Random and fixed models are used for analysis. There was no significant difference between penicillin group and controlled group for mortality [Odds ratio 1.59 [95% CI 0.59-4.29], P = 0.35], fever days [std difference in mean = -0.223 [95% CI 0.394-0.995], P = 0.358], number of patients presenting with oliguria [Odds ratio 1.795 [95% CI 0.325-9.929], P = 0.502], and number of patients who underwent need based dialysis [Odds ratio 1.587 [95% CI 0.919-2.731], P = 0.098]. Role of various antibiotics in treatment of leptospirosis is uncertain, and can be attributed to nonavailability of adequate clinical trials. Role of penicillin in the treatment of leptospirosis can be debated