Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein.

Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.

Exogenous succinate impacts mouse brown adipose tissue mitochondrial proteome and potentiates body mass reduction induced by liraglutide.

Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction.NEW & NOTEWORTHY Exogenous succinate induces major changes in brown adipose tissue protein expression affecting particularly mitochondrial respiration and structural proteins. When given exogenously in drinking water, succinate mitigates body mass gain in a rodent model of diet-induced obesity; in addition, when given in association with the glucagon-like peptide-1 receptor agonist, liraglutide, succinate increases body mass reduction promoted by liraglutide alone.

Receptor GPR91 contributes to voiding function and detrusor relaxation mediated by succinate.

AIM: Succinate activates the receptor GPR91 identified in the bladder. The present study aims to unravel the mechanisms of bladder relaxation by succinate and how the receptor is involved in structural and functional changes of the bladder. METHODS: Physiological recordings of bladder function were carried out by cystometry and organ bath from C57BL/6 mice, homozygous GPR91-/- mice, and Sprague-Dawley (SD) rats. GPR91 expression was confirmed by polymerase chain reaction and tissue morphology was examined by light (Masson trichrome) and fluorescence microscopy. Nitric oxide (NO) and ATP secretion were measured. RESULTS: Bladders of GPR91 KO mice had a greater mass to body weight ratio with a thicker bladder wall compared to C57BL/6 mice. They also displayed increased basal and maximal bladder pressures, and decreased intercontraction intervals, bladder capacity, micturition volume, and compliance. During cystometry, bladders of SD rats and C57BL/6 mice instilled with succinate (10 mM) showed signs of relaxation while bladders of GPR91 KO mice were unresponsive. Similarly, in organ bath, succinate relaxed bladder strips preincubated with carbachol, except GPR91 KO ones. Relaxation was stronger in the presence of urothelium and independent of NO synthesis. Bladder strips from all mice groups showed similar responses to KCl, carbachol, and electrical stimulation. In vitro, succinate increased NO secretion in urothelial cell culture of both C57BL6 and GPR91 KO mice while ATP secretion was potently decreased by succinate in C57BL6 culture only. CONCLUSION: Succinate through GPR91 is essential to bladder structure and contraction. GPR91 relaxes the detrusor partially by decreasing urothelial ATP secretion.

[The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases].

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.

Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker.

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.

A new target for the treatment of endometrium cancer by succinic acid.

Endometrium cancer is the most common invasive gynecologic malignancy in developed countries. Succinic acid (CO2HCH2-CH2CO2H) is a type of dibasic acid that has uncolored crystal. Succinic acid is used in bakery products and aromatized products. It is naturally found in some vegetables. Succinic acid has no adverse effects because it is metabolized by body cells and has a role in the tricarboxylic acid cycle (TCA) as a cycle media component. The TCA cycle and its enzyme components have some crucial roles for basal cell metabolism. Any mistakes, concentration differences in product, or enzyme deficiencies are important within the cell this cycle. In this proposal project, we aimed to investigate the effect of succinic acid at different doses and at different times in an endometrial cancer cell line. The study was performed using methods that determine for apoptosis (for cytotoxicity, WST-1, for caspase enzyme activity, Caspase 3/BCA; apoptotic determination using flow cytometry; Annexin V; to understand mitochondrial membrane potential; JC-1). The results showed that 5 and 10 µM concentration of succinic acid resulted in apoptosis in endometrium cancer; no such effect was seen in the control cell line, which comprised healthy lung cells.  According to our results, it is thought that succinic acid would be effective for the treatment of endometrial cancer cell lines, thus providing new data for other areas of cancer research.

Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives.

Threefold administration of 3-hydroxypyridine derivatives emoxipine and mexidol in optimal doses corresponding to the therapeutic dose range for humans produced an anxiolytic effect and stimulated risk behavior in the elevated plus maze test in rats. These effects were most pronounced after injection of 3-hydroxypyridine derivative emoxipine. Combination of 3-hydroxypyridine cation and succinate anion in the mexidol structure led to attenuation of the anxiolytic effect and less pronounced stimulation of the risk behavior. By the anxiolytic effect and induction of risk behavior, emoxipine and mexidol were close to the reference substance amitriptyline. Reamberin, a succinic acid derivative, had no pronounced tranquilizing properties, but risk behavior induction was similar to that produced by mexidol. In contrast to other test agents, the reference substance α-lipoic acid produced anxiogenic effects and suppressed risk behavior. The obtained results suggest that Russian-made 3-hydroxypyridine derivatives emoxipine and mexidol are promising preparations for the treatment of anxiety disorders.

[DIFFERENTIATED APPROACH TO CLOSING OF WOUND SURFACES TRUNK AND EXTREMITIES AFTER ITS MECHANICAL DAMAGE].

The results of examination and treatment of 231 patients on defects covering tissues of the trunk and limbs were presented. The severity of the injury determined by classification A. V. Kaplan, O. M. Markova. In 10 patients wound treatment method used, developed in the clinic, using the combined preparation of hyaluronic acid with sodium succinate (Latsert), ensuring efficiency of treatment. Differentiated approach to the selection of closing wound surfaces method caused by mechanical damage, allowed to achieve satisfactory results in 97.84% of cases.

Effects of 3-hydroxypyridine derivatives and succinic acid on endometrial leukocyte infiltration, cytokinemia and related affective symptoms during exacerbation of the chronic inflammation of the uterus and adnexa.

We studied the effects of original Russian derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) on the time course of endometrial leukocyte infiltration, blood levels of inflammatory cytokines (IL-1ß and TNF-α), and indicators of affective status in women with exacerbation of the chronic inflammation of the uterus and adnexa. It was found that emoxipine, reamberin, and mexidol included in the complex therapy corrects anxiety and depressive disorders depending on the degree of reduction of endometrial leukocyte infiltration and blood levels of inflammatory cytokines. Derivatives of 3-hydroxypyridine (emoxipine and mexidol) exhibited efficiency, which were superior to derivative of succinic acid (reamberin) in the degree of reduction in endometrial leukocyte and neutrophyl infiltration and in severity of anxiety and depressive disorders. Mexidol, a 3-hydroxypyridine and succinic acid derivative, was most effective and surpassed emoxipine by the degree of reduction of inflammatory cytokine level in the blood and the severity of affective anxiety symptoms in women with exacerbation of the chronic inflammation of the uterus and adnexa.

[Quality of life and cognitive functions in patients with end-stage renal failure on hemodialysis using a succinate-containing dialyzing solution].

AIM: To assess changes in quality of life (QL) and cognitive functions in patients with end-stage renal failure (ESRF) treated with hemodialysis using a succinate-containing dialyzing solution (SCDS). SUBJECTS AND METHODS: Sixty-seven patients with ESRF on hemodialysis using SCDS were examined. The investigators determined QL indicators using a Russianized variant of the Kidney Disease Quality of Life Short Form (KDQOL-SF) and the indicators of cognitive functions by the Benton visual retention test intended to evaluate visual short-term memory. The 6-minute walk test was used to evaluate exercise tolerance. The patients were examined before and 6 months after initiation of SCDS use. RESULTS: Following 6 months of SCDS treatment, the patients showed positive changes in a number of QL indicators. Their exercise capacity (p = 0.03) and the quality of sleep (p = 0.03), and social interaction (p = 0.02) were improved. The magnitude of the complaints related to disease and treatment decreased (p = 0.001). The level of patient frustration was reduced (p < 0.001). Different limitations associated with chronic kidney disease and dialysis therapy came to disturb the patients to a lesser degree (p = 0.02). The Bentoin visual retention test exhibited fewer errors (p = 0.04). CONCLUSION: Hemodialysis treatment with SCDS improved a number of QL indicators and cognitive functions in the patients.

[Experience of treatment of diabetic foot syndrome].

In The Clinic of Cathedra of The Catastrophes Medicine, Military Medicine, Anesthesiology and Reanimatology in 2010 - 2013 yrs 53 patients, ageing 23-65 yrs, were treated for diabetic foot syndrome (DFS) of neuropathic and mixed forms. Diagnostic-treatment algorithm was proposed for determination of level and degree of a circulation and neuropathic disorders, introduction of which have promoted optimization of surgical and local treatment, improvement of the complex treatment results in patients, suffering DFS. A new method of treatment application, using combined preparation of hyaluronic acid with the sodium succinic, have permitted to achieve a complete healing of the ulcer defect.

[Correction of neurotrophic disorders in patients, suffering consequences of a spinal cord and peripheral nerves trauma].

On clinical base of cathedra of the disasters medicine, military medicine, anesthesiology and reanimatology in 2010 - 2013 yrs 62 patients were treated for neurotrophic disorders, in 12 of them the method was applied, elaborated in the clinic. For neurotrophic ulcers in 5 patients autodermoplasty was performed, using splitted cutaneous flap, in 1 for the wound defect on a forearm--plasty, using rotational cutaneo-adipose flap, based on axial blood supply. In 44 patients after a spinal cord trauma a neurotrophic defects degree III - IV have formed. The kind of operative intervention was selected depending on size of the defect, the wound depth and functional peculiarities of the injured area. Introduction of a new method of treatment of neurotrophic ulcers of the lower extremities, using preparation of hyaluronic acid with sodium succinate, expands the perspectives of treatment in patients, suffering defects of cover tissues. Differentiated approach to choice of the wound closure method, caused by damage of central and peripheral neural system, have permitted to achieve positive results in 98.1% of patients.

[Possibilities of «therapeutic retargeting¼ of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action]. / Vozmozhnosti «terapevticheskogo perenatselivaniya¼ proizvodnykh 3-oksipiridina i yantarnoi kisloty, obuslovlennye ikh dofaminergicheskim deistviem.

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting¼ of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.

[Serum metabolome by gas chromatography-mass spectrometry (GC-MS) in patients with ulcerative colitis and celiac disease].

Metabolomics is the emerging science of measurement and analysis of metabolome--the complete set of low molecular weight compounds in a cell, tissue, organ or whole organism. One of the aims of metabolomics is to research the response of an organism to a pathophysiological insult by measuring the concentrations of small molecule metabolites in biofluids and tissues and its dynamics. Intestinal microbiota is most probably involved in the development and maintenance of autoimmune inflammation in ulcerative colitis and celiac disease. Gas chromatography-mass spectrometry (GC - MS) of serum generates comprehensive metabolic profiles, reflecting integrated human (systemic) and gut microbial metabolism which may be altered in disease states. The aim of this study was to investigate GC - MS-based serum metabolomic profiles in UC and CD patients. Serum metabolic profiles were collected from 75 individuals: 20 patients with mild-moderate active UC, 35 CD patients, and 20 healthy controls (HC). We characterized 84 serum metabolites by use GC-MS. 18 metabolites at least have a combined (human + microbial) origin. In serum of UC patients, phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (4-HPAA), 3-indolylacetic acid (IAA), succinic acid (SA) and fumaric acid (FA) were the metabolites most prominently increased, whereas 3-phenylpropionic acid (PPA) was significantly decreased. Serum of CD patients showed significant increases in IAA, 3-indolepropionic acid (IPA), SA and FA. Increased serum levels of succinic acid suggest its possible damaging effect on intestinal mucosa especially in ulcerative colitis. Orally administered butyrate + inulin as supplement to mesalazine in UC or gluten free diet in CD was effective in reducing disease activity with a marked improvement of serum metabolomic profiles (including SA reduction) and gut microbiota in both diseases. There were no any adverse events.

Puerarin-Tanshinone IIA Suppresses atherosclerosis inflammatory plaque via targeting succinate/HIF-1α/IL-1ß axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory injury is an important pathological factor for the formation of atherosclerotic plaque. It is well known that Puerarin and Tanshinone IIA (Pue-Tan) can significantly reduce interleukin-1ß (IL-1ß) levels and delay the atherosclerosis (AS) process clinically in China. Previous evidence has shown that the Succinate/HIF-1α/IL-1ß inflammatory signaling axis (Succinate axis) promotes the progression of atherosclerotic inflammatory plaques. It is not clear whether Pue-Tan inhibits inflammatory plaques by reducing the level of IL-1ß through the succinate signaling axis. AIM OF STUDY: Find out the interaction between Pue-Tan targets and the succinate axis by means of network pharmacology and bioinformatics analysis and to further confirm whether Pue-Tan can inhibit vascular inflammation and delay the formation of atherosclerotic inflammatory plaques by targeting the succinate signaling axis. MATERIALS AND METHODS: Firstly, animal experiments were conducted to verify the changing relationship between Succinate and IL-1ß under Pue-Tan intervention. Secondly, network pharmacology approach was employed to uncover the specific targets of Pue-Tan in the intervention of AS from multiple levels of components, proteins, and pathways, and at the same time, the target must be a key factor of the succinate signaling axis. Autodock vina1.5.6 was applied to molecular docking for Pue-Tan and target protein. Subsequently, cells experiment and animal experiment were performed to verify Pue-Tan inhibiting the inflammatory progression of atherosclerosis by targeting succinate signaling axis. RESULTS: Firstly, we first found that the reduction of IL-1ß was positively correlated with succinate in the serum of Pue-Tan-treated mice. Secondly, network pharmacology compared with molecular docking showed that hypoxia-induced factor-1α (HIF-1α) was the key target of Pue-Tan and the key node of succinate singling axis. Finally, in vitro study, Pue-Tan significantly reduced the factors of succinate axis just as HIF-1α siRNA; in vivo study, we confirmed a decreased expression of succinate axis and ICAM-1 in the aorta of ApoE-/- mice under Pue-Tan intervention, which was consistent with the in vitro results. CONCLUSION: This study confirmed that Pue-Tan blocked the succinate axis by targeting HIF-1α to prevent the formation of atherosclerotic inflammatory plaques and delay the pathological process of AS. Network Pharmacology, Bioinformatics of Molecular Docking, and Molecular Biology Validation can be used as a effective way to discover and verify the pharmacological mechanism of TCM.

Application of metabolomics in urolithiasis: the discovery and usage of succinate.

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.

Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells.

BACKGRUOUND: Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study. METHODS: In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver. RESULTS: Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis. CONCLUSION: Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.

Xianglian pill modulates gut microbial production of succinate and induces regulatory T cells to alleviate ulcerative colitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Xianglian pill (XLP), a traditional Chinese formula, is widely used as treatment for ulcerative colitis (UC) in China. However, the mechanism of its therapeutic effect is still unclear. AIM OF THE STUDY: Our previous studies showed a low oral bioavailability and a predominant distribution of major XLP ingredients in the gut. In the present study, we aimed to explore the mechanism of action of XLP on UC with respect to the regulation of gut microecology. MATERIALS AND METHODS: UC model rats established using 5% dextran sulfate sodium were treated with XLP. After the treatment period, bodyweight, colon length, histopathology, and inflammatory changes were evaluated. Further, changes in gut microbiota structure were detected via 16S rRNA sequencing, and microbial metabolites in feces were analyzed via a metabolomic assay. Antibiotic intervention and fecal microbiota transplantation were also employed to explore the involvement of gut microbiota, while the level of regulatory T cells (Tregs) in mesenteric lymph nodes was determined via flow cytometry. Transcriptome sequencing was also performed to determine colonic gene changes. RESULTS: XLP alleviated colonic injury, inflammation, and gut microbial dysbiosis in UC model rats and also changed microbial metabolite levels. Particularly, it significantly decreased succinate level in the tyrosine pathway. We also observed that fecal microbiota derived from XLP-treated rats conferred resilience to UC model rats. However, this therapeutic effect of XLP on UC was inhibited by succinate. Moreover, XLP increased the level of anti-inflammatory cellular Tregs via gut microbiota. However, this beneficial effect was counteracted by succinate supplementation. Further, XLP induced the differentiation of Treg possibly by the regulation of the PHD2/HIF-1α pathway via decreasing microbial succinate production. CONCLUSIONS: Our findings indicated that XLP exerts its therapeutic effects on UC mainly via the gut microbiota-succinate-Treg differentiation axis.

Antihypoxic and antioxidant effects of exogenous succinic acid and aminothiol succinate-containing antihypoxants.

Pronounced antihypoxic and antioxidant effects of preventive injection of succinic acid, aminothiol antihypoxants gutimine and amtizol, and succinate-containing aminothiol antihypoxants gutimine succinate and amtizol succinate to Wistar rats with acute hypoxic hypoxia have been demonstrated. Exogenous succinic acid was inferior to aminothiol compounds by antihypoxic effect, but superior to them by its effect on the level of LPO products. Succinate in the aminothiol molecule modulated the intensity of their antihypoxic and antioxidant effects. It did not modulate the antihypoxic activity of amtizol, but reduced the antihypoxic effect of gutimine, presumably because of the physicochemical characteristics of aminothiols. Comparison of the intensities of antihypoxic and antioxidant effects of the studied drugs showed no direct relationship between these effects.

[Metabolic correction of structural changes in adrenal glands during experimental widespread purulent peritonitis].

Experiments on 55 male chinchilla rabbits with model widespread purulent peritonitis have been performed for determinig structural changes in adrenal glands with the aid of optical microscopy. The introduction of aerobic-anaerobic culture of E. Coli and B. Fragilis into the abdominal cavity causes expressed structural changes in parenchyma of adrenal glands within 6 hours. It is established for the first time that the administration of metabolic drugs citoflavin (containing succinic acid) and neoton (containing creatine phosphate) prevents the development of pathological structural changes in adrenal glands under conditions of experimental widespread purulent peritonitis.