Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization

BackgroundIntimal hyperplasia (IH) remains a major limitation in the long-term success of any type of revascularization. IH is due to vascular smooth muscle cell (VSMC) dedifferentiation, proliferation and migration. The gasotransmitter Hydrogen Sulfide (H2S) inhibits IH in pre-clinical models. However, there is currently no clinically approved H2S donor. Here we used sodium thiosulfate (STS), a clinically-approved source of sulfur, to limit IH.MethodsHypercholesterolemic LDLR deleted (LDLR-/-), WT or CSE-/- male mice randomly treated with 4g/L STS in the water bottle were submitted to focal carotid artery stenosis to induce IH. Human vein segments were maintained in culture for 7 days to induce IH. Further in vitro studies were conducted in primary human vascular smooth muscle cell (VSMC).FindingsSTS inhibited IH in mice and in human vein segments. STS inhibited cell proliferation in the carotid artery wall and in human vein segments. STS increased polysulfides in vivo and protein persulfidation in vitro, which correlated with microtubule depolymerization, cell cycle arrest and reduced VSMC migration and proliferation.InterpretationSTS, a drug used for the treatment of cyanide poisoning and calciphylaxis, protects against IH in a mouse model of arterial restenosis and in human vein segments. STS acts as an H2S donor to limit VSMC migration and proliferation via microtubule depolymerization.FundingThis work was supported by the Swiss National Science Foundation (grant FN-310030_176158 to FA and SD and PZ00P3-185927 to AL); the Novartis Foundation to FA; and the Union des Sociétés Suisses des Maladies Vasculaires to SD.Graphical AbstractResearch in contextEvidence before this studyIntimal hyperplasia (IH) is a complex process leading to vessel restenosis, a major complication following cardiovascular surgeries and angioplasties. Therapies to limit IH are currently limited. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. However, despite these potent cardiovascular benefits in pre-clinical studies, H2S-based therapeutics are not available yet. Sodium thiosulfate (Na2S2O3) is an FDA-approved drug used for the treatment of cyanide poisoning and calciphylaxis, a rare condition of vascular calcification affecting patients with end-stage renal disease. Evidence suggest that thiosulfate may generate H2S in vivo in pre-clinical studies.Added value of this studyHere, we demonstrate that STS inhibit IH in a surgical mouse model of IH and in an ex vivo model of IH in human vein culture. We further found that STS increases circulating polysulfide levels in vivo and inhibits IH via decreased cell proliferation via disruption of the normal cell’s cytoskeleton. Finally, using CSE knockout mice, the main enzyme responsible for H2S production in the vasculature, we found that STS rescue these mice from accelerated IF formation.Implications of all the available evidenceThese findings suggest that STS holds strong translational potentials to limit IH following vascular surgeries and should be investigated further.

Revisiting Konzo Risk Factors in Three Areas Differently Affected by Spastic Paraparesis in Eastern Democratic Republic of the Congo Discloses a Prominent Role of the Nutritional Status—A Comparative Cross-Sectional Study

This comparative cross-sectional study aimed to better understand the respective contributions of protein malnutrition and cassava-derived cyanide poisoning in the development of konzo. We compared data on nutritional status and cyanide exposure of school-age adolescent konzo-diseased patients to those of non-konzo subjects of similar age from three areas in the Eastern Democratic Republic of the Congo. Our results show that konzo patients had a high prevalence of both wasting (54.5%) and stunting (72.7%), as well as of cyanide poisoning (81.8%). Controls from Burhinyi and those from Idjwi showed a similar profile with a low prevalence of wasting (3.3% and 6.5%, respectively) and intermediate prevalence of stunting (26.7% and 23.9%, respectively). They both had a high prevalence of cyanide poisoning (50.0% and 63.0%, respectively), similar to konzo-patients. On the other hand, controls from Bukavu showed the lowest prevalence of both risk factors, namely chronic malnutrition (12.1%) and cyanide poisoning (27.6%). In conclusion, cassava-derived cyanide poisoning does not necessarily coexist with konzo outbreaks. The only factor differentiating konzo patients from healthy individuals exposed to cyanide poisoning appeared to be their worse nutritional status. This further suggests that, besides the known role of cyanide poisoning in the pathogenesis of konzo, malnutrition may be a key factor for the disease occurrence.

A Retrospective Descriptive Study on Death Due to Cyanide Poisoning Over a Period of 20 Years in Government Medical College, Thiruvananthapuram

BACKGROUND Cyanide is a rapidly acting poison which has been the suicidal agent of choice since time unknown. Its notoriety also extends to homicide, and it has often been used by serial killers. It is found in nature and is used in various industries, but is difficult to obtain nowadays as a result of strict policy implementation. METHODS All cases of cyanide poisoning over a period of 20 years from 2000 to 2019 were studied. Samples were sent for identification and quantification by GC-MS to the chemical examiner’s laboratory. Data was collected in pro forma and entered into Microsoft Excel and analysed using statistical package for social sciences (SPSS). RESULTS A total of 84 cases were studied over a period of 20 years. The majority of cases were recorded in the first decade of the study period. Most common age group involved was 31 to 40 years. Males comprised 84.9 % of the total. Majority were suicidal in nature, and 22.6 % were suicide pacts. The reason for committing suicide could not be found in 59.3 %. 67.9 % were found dead or brought dead to the hospital. In 24 % cases, the typical smell of bitter almonds was identified. Police were able to make out the presence of poison in 83.3 % during the preliminary investigation. CONCLUSIONS Males were the commonly affected. Ingestion of poison was the method of administration in all cases. Majority were suicides, and occurred in the residence of the victims. In majority of cases, police could identify the cause of death as poisoning. The characteristic smell could be identified only in a few cases. KEYWORDS Cyanide, Corrosion, Poisoning, Suicide