Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis.

Hydrogen sulfide (H2S) is involved in numerous pathophysiological processes and shares overlapping functions with CO and •NO. However, the importance of host-derived H2S in microbial pathogenesis is unknown. Here we show that Mtb-infected mice deficient in the H2S-producing enzyme cystathionine ß-synthase (CBS) survive longer with reduced organ burden, and that pharmacological inhibition of CBS reduces Mtb bacillary load in mice. High-resolution respirometry, transcriptomics and mass spectrometry establish that H2S stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that H2S reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to H2S regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived H2S to promote growth and disease, and suggest that host-directed therapies targeting H2S production may be potentially useful for the management of tuberculosis and other microbial infections.

Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn's Disease, a Randomized Controlled Trial.

BACKGROUND: Cannabidiol (CBD) is an anti-inflammatory cannabinoid shown to be beneficial in a mouse model of IBD. Lacking any central effect, cannabidiol is an attractive option for treating inflammatory diseases. AIM: To assess the effects of cannabidiol on Crohn's disease in a randomized placebo-controlled trial. PATIENTS AND METHODS: Twenty patients aged 18-75 years with a Crohn's disease activity index (CDAI) >200 were randomized to receive oral (10 mg) CBD or placebo twice daily. Patients did not respond to standard treatment with steroids (11 patients), thiopurines (14), or TNF antagonists (11). Disease activity and laboratory parameters were assessed during 8 weeks of treatment and 2 weeks thereafter. Other medical treatment remained unchanged. RESULTS: Of 20 patients recruited 19 completed the study. Their mean age was 39 ± 15, and 11 were males. The average CDAI before cannabidiol consumption was 337 ± 108 and 308 ± 96 (p = NS) in the CBD and placebo groups, respectively. After 8 weeks of treatment, the index was 220 ± 122 and 216 ± 121 in the CBD and placebo groups, respectively (p = NS). Hemoglobin, albumin, and kidney and liver function tests remained unchanged. No side effects were observed. CONCLUSION: In this study of moderately active Crohn's disease, CBD was safe but had no beneficial effects. This could be due to lack of effect of CBD on Crohn's disease, but could also be due to the small dose of CBD, the small number of patients in the study, or the lack of the necessary synergism with other cannabinoids. Further investigation is warranted. CLINICALTRIALS.GOV: NCT01037322.

Inhalation exposure model of hydrogen sulfide (H2S)-induced hypometabolism in the male Sprague-Dawley rat.

Hydrogen sulfide (H2S) has been accepted as a physiologically relevant cell-signaling molecule with both toxic and beneficial effects depending on its concentration in mammalian tissues. Notably, exposure to H2S in breathable air has been shown to decrease aerobic metabolism and induce a reversible hypometabolic-like state in laboratory rodent models. Herein, we describe an experimental exposure setup that can be used to define the reversible cardiovascular and metabolic physiology of rodents (rats) during H2S-induced hypometabolism and following recovery.

Redox Biology of Hydrogen Sulfide: Implications for Physiology, Pathophysiology, and Pharmacology.

Hydrogen sulfide (H2S) has emerged as a critical mediator of multiple physiological processes in mammalian systems. The pathways involved in the production, consumption, and mechanism of action of H2S appear to be sensitive to alterations in the cellular redox state and O2 tension. Indeed, the catabolism of H2S through a putative oxidation pathway, the sulfide quinone oxido-reductase system, is highly dependent on O2 tension. Dysregulation of H2S homeostasis has also been implicated in numerous pathological conditions and diseases. In this review, the chemistry and the main physiological actions of H2S are presented. Some examples highlighting the cytoprotective actions of H2S within the context of cardiovascular disease are also reported. Elucidation of the redox biology of H2S will enable the development of new pharmacological agents based on this intriguing new redox cellular signal.

Metabolic and cardiac signaling effects of inhaled hydrogen sulfide and low oxygen in male rats.

Low concentrations of inhaled hydrogen sulfide (H(2)S) induce hypometabolism in mice. Biological effects of H(2)S in in vitro systems are augmented by lowering O(2) tension. Based on this, we hypothesized that reduced O(2) tension would increase H(2)S-mediated hypometabolism in vivo. To test this, male Sprague-Dawley rats were exposed to 80 ppm H(2)S at 21% O(2) or 10.5% O(2) for 6 h followed by 1 h recovery at room air. Rats exposed to H(2)S in 10.5% O(2) had significantly decreased body temperature and respiration compared with preexposure levels. Heart rate was decreased by H(2)S administered under both O(2) levels and did not return to preexposure levels after 1 h recovery. Inhaled H(2)S caused epithelial exfoliation in the lungs and increased plasma creatine kinase-MB activity. The effect of inhaled H(2)S on prosurvival signaling was also measured in heart and liver. H(2)S in 21% O(2) increased Akt-P(Ser473) and GSK-3ß-P(Ser9) in the heart whereas phosphorylation was decreased by H(2)S in 10.5% O(2), indicating O(2) dependence in regulating cardiac signaling pathways. Inhaled H(2)S and low O(2) had no effect on liver Akt. In summary, we found that lower O(2) was needed for H(2)S-dependent hypometabolism in rats compared with previous findings in mice. This highlights the possibility of species differences in physiological responses to H(2)S. Inhaled H(2)S exposure also caused tissue injury to the lung and heart, which raises concerns about the therapeutic safety of inhaled H(2)S. In conclusion, these findings demonstrate the importance of O(2) in influencing physiological and signaling effects of H(2)S in mammalian systems.