Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Efficacy and tolerability of oral iron protein succinylate: a systematic review of three decades of research.

Objective: Oral supplementation with iron is a standard intervention for treating or preventing iron deficiency with or without anemia. Over the last few decades, various forms of oral iron have been developed to improve treatment tolerability and iron bioavailability. In this review, we gathered research data regarding the use of iron protein succinylate since it was first marketed in the 1980s.Methods: Electronic databases - PubMed and the Cochrane Library - were searched for studies published up to March 2019. Clinical or observational studies reporting data on the tolerability of oral iron protein succinylate were included. Results were statistically described to evaluate and compare the efficacy and safety of iron protein succinylate with the comparators under study.Results: Iron protein succinylate was investigated in 54 studies: 38 randomized clinical trials and 16 observational studies, with a total of 8454 subjects. Of them, 8142 were included in the efficacy analysis: patients were divided into three population subtypes: general (n = 1899), gynecological/obstetric (n = 5283), and pediatric (n = 960). In total, 6450 patients received iron protein succinylate, experiencing a significant change in hemoglobin and ferritin in all populations. The change in all parameters was similar or higher with iron protein succinylate compared to other iron treatments evaluated. Overall, study groups receiving iron protein succinylate reported the lowest rate of adverse events.Conclusions: Although all iron treatments analyzed are effective and safe, our results suggest that iron protein succinylate may be an excellent choice to treat iron deficiency and anemia due to its superior effectiveness and tolerability.

Tolerability of different oral iron supplements: a systematic review.

OBJECTIVE: A systematic review was conducted to analyze the tolerability of several oral iron supplements based on data obtained in available publications and to report the incidence of adverse effects (AEs) for each supplement both overall and gastrointestinal. METHODS: Electronic databases - Medline, the Cochrane Library, and Embase were searched for studies published up to January 2009. Clinical or observational studies reporting data on the tolerability of oral iron supplements were included. Results were described statistically and a quasi-binomial logistic regression model was developed to evaluate and compare the tolerability of the supplements studied. RESULTS: For this review 111 studies were included, with data on 10,695 patients. Ferrous sulfate with mucoproteose had the lowest incidence of AEs (4.1% for overall AEs, 3.7% for gastrointestinal AEs [GAEs]) and was used as the reference supplement in the regression model. Incidence rates of overall AEs for the other supplements were 7.3% for iron protein succinylate [GAEs: 7%; OR for AE compared to the reference supplement, 1.96], 23.5% for ferrous glycine sulfate [GAEs: 18.5%; OR: 5.90], 30.9% for ferrous gluconate [GAEs: 29.9%; OR: 11.06], 32.3% for ferrous sulfate without mucoproteose [GAEs: 30.2%; OR: 11.21], and 47.0% for ferrous fumarate [GAEs: 43.4%; OR: 19.87]. The differences in incidence of AEs between extended-release ferrous sulfate with mucoproteose and all other supplements except iron protein succinylate were statistically significant at p < 0.001. These findings are subject to some limitations as the designs and methodologies of the studies included show heterogeneity among them that has partially been counteracted by the large sample size provided by the substantial number of trials, which is considered a strength in tolerability studies. CONCLUSION: Extended-release ferrous sulfate with mucoproteose appears to be the best tolerated of the different oral iron supplements evaluated.

Mechanism of sarpogrelate action in improving cardiac function in diabetes.

Although sarpogrelate, a 5-HT(2A) receptor antagonist, has been reported to exert beneficial effects in diabetes, the mechanisms of its action are not understood. In this study, diabetes was induced in rats by an injection of streptozotocin (65 mg/kg) and the animals were assessed 7 weeks later. Decreased serum insulin as well as increased serum glucose, cholesterol, and triglyceride levels in diabetic animals were associated with increased blood pressure and heart/body weight ratio. Impaired cardiac performance in diabetic animals was evident by decreased heart rate, left ventricular developed pressure, rate of pressure development, and rate of pressure decay. Treatment of diabetic animals with sarpogrelate (5 mg/kg) or insulin (10 units/kg) daily for 6 weeks attenuated the observed changes in serum insulin, glucose, and lipid levels as well as blood pressure and cardiac function by varying degrees. Protein content for membrane glucose transporters (GLUT-1 and GLUT-4) was depressed in diabetic heart; the observed alteration in GLUT-4 was partially prevented by both sarpogrelate and insulin, whereas that in GLUT-1 was attenuated by sarpogrelate only. Incubation of myoblast cells with sarpogrelate and insulin stimulated glucose uptake; these effects were additive. 5-hydroxytryptamine was found to inhibit glucose-induced insulin release from the pancreas; this effect was prevented by sarpogrelate. These results suggest that sarpogrelate may improve cardiac function in chronic diabetes by promoting the expression of membrane glucose transporters as well as by releasing insulin from the pancreas.

[Preclinical study of Reamberin and Remaxol safety].

Preclinical safety of reamberin, a preparation of succinic acid intended for the treatment of patients with shock conditions of different etiology, and remaxol a drug intended for the treatment of patients with liver dysfunction caused by acute intoxication was performed. Both medicines belong to the 5th class of practically non-toxic drugs. Their administration to experimental animals for 30 days did not cause toxic effects on the functional and morphological state of main systems and organs. Both medicines do not affect specific (humoral and cellular) and non-specific immune response and do not cause sensibilization, mutagenic, embryotoxic and teratogenic effects, and also do no alter parameters of reproductive functions of rats.

Drug evaluation: bevirimat--HIV Gag protein and viral maturation inhibitor.

Panacos Pharmaceuticals Inc is developing the HIV Gag protein and viral maturation inhibitor bevirimat for the potential oral treatment of HIV infection. Phase II clinical trials are underway and phase III trials expected to commence in 2007.

Effect of neuronol on lifespan and development of spontaneous tumors in SAMP-1 mice with genetically accelerated aging.

Treatment of female SAMP-1 mice with Neuronol (drug containing succinic acid) given with drinking water starting from the age of 2 months during the whole life prolonged the lifespan and markedly reduced mortality of animals aged 1.5-2 years. Neuronol inhibited the development of spontaneous tumors, primarily lymphomas, and significantly prolonged lifespan in mice with tumors. Long-term treatment with Neuronol had no pathological side effects. Our experiments demonstrated geroprotective and anticarcinogenic activity of Neuronol and safety of its long-term use.

[The corrective action of limontar in metabolic disorders in the mother-fetus system caused by ethanol exposure during pregnancy]. / Issledovanie korrigiruiushchego deistviia limontara pri obmennykh narusheniiakh v sisteme mat'--plod, vyzvannykh vozdeistviem étanola vo vremia beremennosti.

It was established in experiments on nonbred albino rats that injection of limontar (1 mg/kg) in the fetal period of pregnancy in alcoholic intoxication (6 g/kg) leads to weight loss by the female, normalization of the character of behavior and metabolic shifts in the organism, and removal of the symptoms of excitation of the sympathetic link of cardiovascular system regulation. No harmful effect of limontar on the mother-fetus biosystem was detected.

Iron protein succinylate: preclinical safety assessment.

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.

Complications of carbenoxolone therapy.

Side effects from carbenoxolone are common and are due to electrolyte disturbance, such as sodium retention and hypokalaemia. They occur particularly in the elderly, who may already be being treated for other illnesses. Eight patients are described with serious side effects from carbenoxolone therapy, some of which were unrecognized for some time because of inadequate follow-up or because clinicians were unfamiliar with them.