PI3K/AKT pathway mediates the antidepressant- and anxiolytic-like roles of hydrogen sulfide in streptozotocin-induced diabetic rats via promoting hippocampal neurogenesis

We have previously demonstrated that hydrogen sulfide (H₂S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H₂S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H₂S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H₂S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H₂S in STZ-induced diabetic rats and enhance our understanding of the robustness of H₂S as a therapeutic strategy for treatment of depression in diabetes mellitus.     

Postranslational Modification of Ion Channels in Colonic Inflammation

Voltage-gated ion channels are key regulators of cell excitability. There is significant evidence that these channels are subject to modulation by redox status of the cells. Here we review the post-translational modifications of ion channels that occur in colonic inflammation. The redox mechanisms involve tyrosine nitration, covalent modification of cysteine residues and sulfhydration by hydrogen sulfide in experimental colitis. In the setting of colonic inflammation, modifications of cysteine and tyrosine are likely to occur at several sites within the same channel complex. In this review we describe alterations in channel function due to specific modifications of tyrosine and cysteine residues by reactive nitrogen, oxygen and hydrogen-sulfide resulting in altered motility.     

Identification of a functional dddD-Rh for dimethyl sulfide production in the Antarctic Rhodococcus sp. NJ-530

Dimethylsulfoniopropionate (DMSP) is widespread in the oceans, and its biological metabolite, dimethyl sulfide (DMS), plays an important role in the atmosphere. The Antarctic region has become a hotspot in DMS studies due to the high spatial and temporal variability in DMS(P) concentration, but the level of bacterial DMS production remains unclear. In this study, a bacterium isolated from Antarctic floating ice, Rhodococcus sp. NJ-530, was found to metabolize DMSP into DMS, and the rate of DMS production was measured as 3.96 pmol·mg protein⁻¹·h⁻¹. Rhodococcus sp. NJ-530 had a DddD-Rh enzyme containing two CaiB domains, which belonged to the CoA-transferase III superfamily. However, the DddD-Rh had a molecular weight of 73.21 kDa, which was very different from previously characterized DddD enzymes in sequence and evolution. In vitro assays showed that DddD-Rh was functional in the presence of acetyl-CoA. This was the first functional DddD from Gram-positive Actinobacteria. Moreover, a quantitative real-time polymerase chain reaction revealed that high temperature facilitated the expression of dddD-Rh, and changes of salinity had little effect on it. This study adds new evidence to the bacterial DMS production in the Southern Ocean and provides a basis for investigating the metabolic mechanism of DMSP in extreme environments.     

蛋氨酸限制提高内源性H2S活性延缓衰老的机制研究进展

蛋氨酸限制(Methionine restriction,MetR)作为饮食限制的方法之一,能够改善多种无脊椎动物、啮齿类动物及包括人类灵长类动物的衰老及其相关疾病。但MetR对衰老的具体调节作用机制尚未完全明确,目前除了与饮食限制的共有机制以外,越来越多的研究表明内源性硫化氢(Endogenous hydrogen sulfide,H2S)可能是其发挥效应的主要机制。硫化氢作为水溶性和脂溶性的小分子气体,在延缓衰老进程和改善衰老相关疾病中具有重要意义。本文阐述了MetR通过提高内源性H2S的活性延缓衰老的机制及相关研究。     

Diallyl sulfide alleviates cisplatin‐induced nephrotoxicity in rats via suppressing NF‐κB downstream inflammatory proteins and p53/Puma signalling pathway

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo‐sulfide, present in garlic, in cisplatin‐induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno‐protective effect of DAS in cisplatin‐induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis‐induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co‐treated with DAS. In addition, DAS significantly restored Cis‐depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis‐elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis‐increased renal expression of nuclear factor kappa B (NF‐κB) and subsequent pro‐inflammatory mediators; tumour necrosis factor alpha (TNF‐α), interleukin‐1β (IL‐1β), intercellular adhesion molecule‐1 (ICAM‐1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co‐treatment with DAS significantly inhibited Cis‐increased caspase‐8 and ‐9 levels. Additionally, DAS significantly mitigated Cis‐induced protein expression of p53, Puma, and Bax while, it significantly restored Cis‐reduced protein expression of Bcl‐xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin‐induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.     

纳米硫化镉呼吸道亚慢性暴露对雄性大鼠的生殖毒性

目的探讨纳米硫化镉(CdS)对大鼠睾丸的氧化损伤及对精子的影响。方法 32只雄性清洁级SD大鼠随机分为对照组(蒸馏水)、10 mg/kg、20 mg/kg和30 mg/kg的纳米CdS组,每组8只。采用肺灌注方法染毒,2次/周,持续染毒12周。计算睾丸脏器系数,测定睾丸组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活力和丙二醛(MDA)含量,观察精子数量、畸形率、活动度和睾丸的病理学变化。结果与对照组相比,30 mg/kg染毒组精子数量、精子活动度降低,10、20、30 mg/kg染毒组精子畸形率增高(P<0.05)。与对照组相比,30 mg/kg染毒组的大鼠睾丸SOD、GSH-Px活力降低(P<0.05),10、20、30 mg/kg染毒组的大鼠睾丸MDA含量增高(P<0.05)。染毒组生精小管内生精细胞脱落,层次减少,各级生精细胞排列紊乱,管内生精细胞疏松、排列紊乱、上皮变薄,管腔内可见脱落的精子细胞。结论纳米硫化镉经呼吸道染毒可致大鼠睾丸病理改变,氧化损伤,并且引起精子数量减少,活动度降低,畸形率增加。     

Assessment of newly developed tongue sulfide probe for detecting oral malodor

AIM: The present study examined the relationship between sulfide levels on tongue dorsum surfaces (pS levels) and oral malodor. METHOD: The pS levels of 20 systemically healthy volunteers were evaluated using an industrial device equipped with a newly-developed tongue sulfide probe. The pS levels on 3 parts of the tongue--anterior, middle and posterior along the median groove of the tongue dorsum--were determined for each subject. RESULTS: The device reported the pS level in a digital score ranging from 0.0 (< 10(-7) M of sulfide) to 5.0 (> or = 10(-2) M of sulfide) in increments of 0.5. Oral malodor was assessed by measuring the level of volatile sulfur compounds in mouth air, as well as by the organoleptic method. The pS levels were 0.03 +/- 0.11, 0.20 +/- 0.41 and 0.88 +/- 0.76 for the anterior, middle and posterior parts, respectively. This difference was significant (p<0.001). Both oral malodor measurements showed significant correlation (p<0.05) with the pS levels of middle and posterior parts of tongue. CONCLUSION: It was concluded that the tongue sulfide probe might be useful in management of subjects with oral malodor.     

Chemotaxis and degranulation of polymorphonuclear leukocytes in the presence of sulfide

In polymicrobial infections such as periodontal disease, the polymorphonuclear leukocytes (PMN) may have to work in the absence of oxygen and in the presence of significant levels of hydrogen sulfide. There are conflicting results reported on the chemotactic capacity of PMN under anaerobic conditions. It is not known whether PMN are able to migrate and release the contents of their granules in the presence of sulfide. PMN were exposed to various levels of sulfide and their chemotaxis and degranulation were studied when they were stimulated with N-formyl-inethionyl-leucyl-phenylalanine or zymosan-activated serum. Chemotaxis was evaluated with the agarose method. The release of granule markers, lactoferrin and myeloperoxidase, was evaluated with enzyme-linked immunosorbent assay. PMN had similar capacity for chemotaxis under aerobic and anaerobic conditions. The migration of PMN was only to a minor extent inhibited by 1–2 mM sulfide. The release of lactoferrin and myeloperoxidase was the same under aerobic and anaerobic conditions and was not significantly influenced by sulfide. PMN seem to be very well suited to defend the tissue against bacteria under the harsh conditions prevailing in the periodontal pocket.     

不同牙周状态下牙周袋内挥发性硫化物水平的比较

目的：检测牙周健康者、慢性龈炎和慢性牙周炎患牙牙周袋内挥发性硫化物水平,为牙周炎的早期诊断提供客观指标.方法：选择牙周健康者、慢性龈炎及慢性牙周炎患者3组,治疗前记录牙周各项临床指标,并用金刚牙科探针记录颊侧近远中牙周袋内挥发性硫化物（VSC）水平.结果：3组中慢性牙周炎组牙周袋内VSC水平与牙周健康组牙周袋内VSC水平及慢性龈炎组牙周袋内VSC水平比较均有显著差异（P＜0.05）,牙周健康组牙周袋内VSC水平与慢性龈炎组牙周袋内VSC水平比较无显著性差异（P＞0.05）.VSC与临床指标PLI（P＜0.01,r=0.593）、PD（P＜0.01,r=0.720）、BI（P＜0.01,r=0.662） 、AL（P＜0.01,r=0.746）均相关.结论：牙周袋内VSC可能是反映牙周组织状况的一项较为客观的指标.     

Hydrogen sulfide causes apoptosis in human pulp stem cells

Introduction

Untreated dental caries will eventually lead to pulpal inflammation. Although much is known regarding the interaction of microbial antigens and the immunologic defense systems of pulp, many aspects of the pathogenesis of pulpitis are not fully understood. The relationship between human pulp stem cells (HPSCs) and the pathogenesis of pulpitis remains among the poorly understood areas. Many of the invading bacteria are known to produce considerable amounts of hydrogen sulfide (H₂S), which causes apoptosis in some tissues. The aims of this study were to determine whether H₂S causes apoptosis in HPSCs and to examine its signaling pathway.

Methods

Stem cells were isolated from human dental pulp and incubated with 50 ng/mL H₂S for 48 hours. To detect apoptosis, the cells were analyzed by using flow cytometry. The mitochondrial signaling pathway was examined by determining mitochondrial membrane depolarization. Activation of the key apoptotic enzymes caspase-9, caspase-8, and caspase-3 was assessed by using enzyme-linked immunosorbent assay. Release of cytochrome C from mitochondria was also determined.

Results

The number of apoptotic cells increased significantly with H₂S treatment from 1.6% to 16.3% (P < .01). Significant increases were also measured in the amounts of caspase-9 and caspase-3 and in cytochrome C release (all P < .01) and in mitochondrial membrane depolarization (P < .05), whereas caspase-8 activity was not found.

Conclusions

H₂S causes apoptosis in HPSCs by activating the mitochondrial pathway. It is suggested that H₂S might be one of the factors modifying the pathogenesis of pulpitis by causing loss of viability of HPSCs through apoptosis.