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Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM.Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods.Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001).Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H 2 S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H 2 S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H 2 S as a potential COVID-19 therapy.

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Background Diabetes-induced liver injury is a complication of diabetes mellitus of which there are no approved drugs for effective treatment or prevention. This study investigates possible hepatoprotective effect of alpha-lipoic acid (ALA), and sulfane sulfur/hydrogen sulfide pathway as a novel protective mechanism in a rat model of type 2 diabetes-induced liver injury. Methods Thirty Sprague–Dawley rats underwent fasting for 12 h after which fasting blood glucose was measured and rats were randomly assigned to diabetic and non-diabetic groups. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). Diabetic rats were treated daily with ALA (60 mg/kg/day p.o.) or 40 mg/kg/day DL-propargylglycine (PPG, an inhibitor of endogenous hydrogen sulfide production) for 6 weeks and then sacrificed. Liver, pancreas and blood samples were collected for analysis. Untreated T2DM rats received distilled water. Results Hypoinsulinemia, hyperglycemia, hepatomegaly and reduced hepatic glycogen content were observed in untreated T2DM rats compared to healthy control group (p < 0.001). Also, the pancreas of untreated T2DM rats showed severely damaged pancreatic islets while liver damage was characterized by markedly increased hepatocellular vacuolation, sinusoidal enlargement, abnormal intrahepatic lipid accumulation, severe transaminitis, hyperbilirubinemia, and impaired hepatic antioxidant status and inflammation compared to healthy control rats (p < 0.01). While pharmacological inhibition of hepatic sulfane sulfur/hydrogen sulfide with PPG administration aggravated these pathological changes (p < 0.05), ALA strongly prevented these changes. ALA also significantly increased hepatic expression of hydrogen sulfide-producing enzymes (cystathionine γ-lyase and 3-mecaptopyruvate sulfurtransferase) as well as hepatic sulfane sulfur and hydrogen sulfide levels compared to all groups (p < 0.01). Conclusions To the best of our knowledge, this is the first experimental evidence showing that ALA prevents diabetes-induced liver injury by activating hepatic sulfane sulfur/hydrogen sulfide pathway via upregulation of hepatic cystathionine γ-lyase and 3-mecaptopyruvate sulfurtransferase expressions. Therefore, ALA could serve as a novel pharmacological agent for the treatment and prevention of diabetes-induced liver injury, with hepatic sulfane sulfur/hydrogen sulfide as a novel therapeutic target.

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Diabetic kidney disease (DKD) is a common global health challenge characterized by a decline in renal function among the diabetic population, which progresses to end-stage renal disease (ESRD). Evidence in the literature suggests a strong association between DKD and the development of diabetic foot ulceration (DFU). DFU is a serious health issue that complicates both type 1 and type 2 diabetes mellitus, and negatively impacts the quality of life of diabetic patients. Patients with advanced DKD or ESRD have a five-fold increased risk of developing DFU, with 6.5–10 times higher rate of amputation than their non-nephropathic counterparts. Multiple and inter-related pathways of DFU in DKD have been identified in which ischemia, neuropathy and infection are major contributing pathologies. However, extensive research to comprehensively assess the progression of DFU in DKD is lacking. In this chapter, we discuss the causal pathways in DFU development and progression, the relationship between DKD and DFU as well as treatment options and measures to achieve both primary and secondary prevention.