Sodium acetate prevents testicular damage in Wistar rats subjected to testicular ischaemia/reperfusion injury.

AIMS: The aim of this study was to investigate the potential antioxidant, anti-inflammatory, and sperm function-preserving properties of sodium acetate (ACE), a histone deacetylase (HDAC) inhibitor, in a rat model of testicular torsion/detorsion (T/D). MAIN METHODS: Littermate Wistar rats of identical weight were subjected to sham surgery or testicular T/D by rotating the left testis at 720° around its axis along the spermatic cord clockwise and fixing it in this position for two and a half hours. 1 h before detorsion, T/D + ACE-treated rats were treated with ACE (200 mg/kg/day, per os) while T/D rats were vehicle-treated by administering 0.5 mL of distilled water. After 72 h, animals were euthanized, and the left testes were harvested for bio-molecular and histological analysis. KEY FINDINGS: Acetate administration attenuated T/D-induced rises in serum and testicular HDAC and testicular xanthine oxidase, uric acid, MDA, GSSG, MPO, TNF-α, IL-1ß, IL-6, NFkB, HIF-1α, and VCAM-1. In addition, acetate treatment alleviated T/D-induced decline in sperm quality (count, motility, viability, and normal morphology) and testicular 3ß-HSD, 17ß-HSD, testosterone, GSH, GSH/GSSG, SOD, catalase, GPx, GST, Nrf2, and HO-1. Furthermore, acetate prevented T/D-distorted testicular histoarchitecture and spermatogenic germ cell loss. SIGNIFICANCE: Sodium acetate during the post-ischaemic phase of testicular T/D may be beneficial in preventing I/R injury and maintaining fertility.

Sodium acetate abates lead-induced sexual dysfunction by upregulating testosterone-dependent eNOS/NO/cGMP signaling and activating Nrf2/HO-1 in male Wistar rat.

Oxidative stress has been linked with lead toxicity, including lead-induced sexual dysfunction. On the contrary, sodium acetate has been proven to exert antioxidant activity. However, the effect of sodium acetate on lead-induced sexual dysfunction has not been fully explored. This study investigated the effect of sodium acetate on lead-induced sexual dysfunction, exploring the involvement of testosterone, eNOS/NO/cGMP, and Nrf2/HO-1 signaling. Twenty male Wistar rats with similar weights were randomly assigned into four groups (n = 5 rats/group) after two weeks of acclimatization. Animals were vehicle-treated (0.5 ml/day of distilled water, per os), acetate-treated (200 mg/kg/day, per os), lead-treated (20 mg/kg/day, per os), or lead + acetate-treated. The results revealed that sodium acetate treatment attenuated lead-induced rise in penile lead, malondialdehyde and oxidized glutathione concentrations, and acetylcholinesterase activity. In addition, lead exposure prolonged mount, intromission, and ejaculation latency and reduced mount, intromission, and ejaculation frequency, as well as the motivation to mate and penile reflex, which were improved by acetate treatment. More so, acetate treatment ameliorated lead-induced reductions in absolute and relative penile weight, eNOS, NO, cGMP, luteinizing hormone, follicle-stimulating hormone, testosterone, dopamine, Nrf2, HO-1, and reduced glutathione concentrations, as well as glutathione reductase, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, and catalase activities. In conclusion, this study demonstrates that sodium acetate attenuated lead-induced sexual dysfunction by upregulating testosterone-dependent eNOS/NO/cGMP and Nrf2/HO-1 signaling. Despite the compelling data presented in this study, other possible associated mechanisms in the protective role of acetate should be explored.

Sodium acetate ameliorates doxorubicin-induced cardiac injury via upregulation of Nrf2/HO-1 signaling and downregulation of NFkB-mediated apoptotic signaling in Wistar rats.

Despite the effectiveness of doxorubicin (DOX) in the management of a wide range of cancers, a major challenge is its cardio-toxic effect. Oxidative stress, inflammation, and apoptosis are major pathways for the cardiotoxic effect of DOX. On the other hand, acetate reportedly exerts antioxidant, anti-inflammatory, and anti-apoptotic activities. This particular research assessed the impact of acetate on cardiotoxicity induced by DOX. Mechanistically, acetate dramatically inhibited DOX-induced upregulation of xanthine oxidase and uric acid pathway as well as downregulation of Nrf2/HO-1 signaling and its upstream proteins (reduced glutathione peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione, and catalase, glutathione reductase). In addition, acetate markedly attenuated DOX-driven rise inTNF-α, NFkB IL-6 and IL-1ß expression, and myeloperoxidase activity. Furthermore, acetate significantly ameliorated DOX-led suppression of Bcl-2 and Ca2+-ATPase activity and upregulation of Bax, caspase 3, and caspase 9 actions. Improved body weight, heart structural integrity, and cardiac function as depicted by cardiac injury markers convoyed these cascades of events. Summarily, the present study demonstrated that acetate protects against DOX-induced cardiotoxicity by upregulating Nrf2/HO-1 signaling and downregulating NFkB-mediated activation of Bax/Bcl-2 and caspase signaling.

Acetate attenuates cyclophosphamide-induced cardiac injury via inhibition of NF-kB signaling and suppression of caspase 3-dependent apoptosis in Wistar rats.

AIM: The goal of the current study was to examine the potential therapeutic effects of sodium acetate on cardiac toxicities caused by cyclophosphamide in Wistar rats. The possible involvement of NF-kB/caspase 3 signaling was also explored. MAIN METHODS: Thirty-two male Wistar rats were divided into four groups at random. (n = 8). The control animals received 0.5 mL of distilled water orally for 14 days, the acetate-treated group received 200 mg/kg/day of sodium acetate orally for 14 consecutive days, and cyclophosphamide-treated rats received 150 mg/kg /day of cyclophosphamide i.p. on day 8, while cyclophosphamide + acetate group received sodium acetate and cyclophosphamide as earlier stated. KEY FINDINGS: Results showed that cyclophosphamide-induced cardiotoxicity, which manifested as a marked drop in body and cardiac weights as well as cardiac weight/tibial length, increased levels of troponin, C-reactive protein, lactate, and creatinine kinase, and lactate dehydrogenase activities in the plasma and cardiac tissue. Histopathological examination also revealed toxic cardiac histopathological changes. These alterations were associated with a significant increase in xanthine oxidase and myeloperoxidase activities, uric acid, malondialdehyde, TNF-α, IL-1ß, NFkB, DNA fragmentation, and caspase 3 and caspase 9 activities in addition to a marked decline in Nrf2 and GSH levels, and SOD and catalase activities in the cardiac tissue. Acetate co-administration significantly attenuated cyclophosphamide cardiotoxicity by its antioxidant effect, preventing NFkB activation and caspase 9/caspase 3 signalings. SIGNIFICANCE: This study shows that acetate co-administration may have cardio-protective effects against cyclophosphamide-induced cardiotoxicity by inhibiting NF-kB signaling and suppressing caspase-3-dependent apoptosis.

Bidirectional Regulation of Sodium Acetate on Macrophage Activity and Its Role in Lipid Metabolism of Hepatocytes.

Short-chain fatty acids (SCFAs) are important metabolites of the intestinal flora that are closely related to the development of non-alcoholic fatty liver disease (NAFLD). Moreover, studies have shown that macrophages have an important role in the progression of NAFLD and that a dose effect of sodium acetate (NaA) on the regulation of macrophage activity alleviates NAFLD; however, the exact mechanism of action remains unclear. This study aimed to assess the effect and mechanism of NaA on regulating the activity of macrophages. RAW264.7 and Kupffer cells cell lines were treated with LPS and different concentrations of NaA (0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, and 5 mM). Low doses of NaA (0.1 mM, NaA-L) significantly increased the expression of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin 1 beta (IL-1ß); it also increased the phosphorylation of inflammatory proteins nuclear factor-κB p65 (NF-κB p65) and c-Jun (p < 0.05), and the M1 polarization ratio of RAW264.7 or Kupffer cells. Contrary, a high concentration of NaA (2 mM, NaA-H) reduced the inflammatory responses of macrophages. Mechanistically, high doses of NaA increased intracellular acetate concentration in macrophages, while a low dose had the opposite effect, consisting of the trend of changes in regulated macrophage activity. Besides, GPR43 and/or HDACs were not involved in the regulation of macrophage activity by NaA. NaA significantly increased total intracellular cholesterol (TC), triglycerides (TG), and lipid synthesis gene expression levels in macrophages and hepatocytes at either high or low concentrations. Furthermore, NaA regulated the intracellular AMP/ATP ratio and AMPK activity, achieving a bidirectional regulation of macrophage activity, in which the PPARγ/UCP2/AMPK/iNOS/IκBα/NF-κB signaling pathway has an important role. In addition, NaA can regulate lipid accumulation in hepatocytes by NaA-driven macrophage factors through the above-mentioned mechanism. The results revealed that the mode of NaA bi-directionally regulating the macrophages further affects hepatocyte lipid accumulation.

Sodium acetate ameliorates cisplatin-induced kidney injury in vitro and in vivo.

Cisplatin is an effective chemotherapeutic drug against tumors. Studies often report on the improvement of kidney injury by probiotics or short-chain fatty acids (SCFAs); however, the effects of SCFAs on cisplatin-induced kidney injury are rarely studied. The aim of this study is to evaluate the function of sodium acetate on preventing cisplatin-induced kidney injury. Cell viability was detected by MTT assay. SA-ß-gal staining was performed to investigate premature senescence. Reactive oxygen species (ROS) production was analyzed by H2DCFDA staining. Propidium iodide (PI) staining was analyzed by cell cycle. Protein expression was determined by Western blot assay. Annexin Ⅴ/PI staining was used to investigate cisplatin-induced apoptosis. Tumor growth and kidney injury were evaluated in C57BL/6 mice. Sodium acetate ameliorated cisplatin-induced premature senescence and ROS production in SV40 MES-13 glomerular cells, NRK-52E renal tubular cells, and NRK-49F renal fibroblast cells. Cisplatin-induced cell cycle arrest was inhibited by sodium acetate in SV40 MES-13 and NRK-49F cells. Sodium acetate alleviated cisplatin-induced apoptosis in vivo and in vitro but not cisplatin-induced fibrosis. Our study demonstrated that sodium acetate inhibited cisplatin-induced premature senescence, cell cycle arrest, and apoptosis by attenuating ROS production. This strategy may be useful in the treatment of cisplatin-induced kidney injury.

Effects of different temperatures of carbohydrate-protein-containing drinks on gastric emptying rate after exercise in healthy young men: randomized crossover trial.

BACKGROUND: The present study examined the effects of different temperatures of carbohydrate-protein-containing drinks after exercise on the subsequent gastric emptying rate in healthy young men. METHODS: Twelve healthy young men completed two, 1-day trials in random order. In both trials, the participants completed intermittent cycling exercise for 20 min, consisting of a 120% heart rate peak for 20 s, followed by 25 W for 40 s. Participants consumed 400 mL of carbohydrate-protein-containing drink (0.85 MJ) at 4 °C (EX + 4 °C) or 60 °C (EX + 60 °C) over a 5-min period after exercise. The participants sat on a chair for 2.5 h to measure their gastric emptying rate using the 13C-sodium acetate breath test. Subjective feelings of gastrointestinal discomfort and appetite were measured using a visual analog scale. Interstitial fluid glucose levels after drinking were measured using a continuous glucose-monitoring device. RESULTS: The percentage excretion of 13CO2 tended to be higher at EX + 60 °C than at EX + 4 °C from the start of the test until 30 min after drink ingestion (5.7 ± 0.5 vs. 6.5 ± 0.4%dose/h for the EX + 4 °C and EX + 60 °C trials, respectively; effect sizes [ES] = 0.277, p = 0.065). The time of maximum 13CO2 emissions per hour (Tmax-calc) and the time of half 13CO2 emissions per hour (T1/2) did not differ between trials. Subjective gastrointestinal discomfort was lower at EX + 60 °C compared to EX + 4 °C (ES = 0.328, p = 0.041). There were no significant differences in interstitial fluid glucose levels between the different temperatures of carbohydrate-protein-containing drinks after exercise (p = 0.698). CONCLUSIONS: Consumption of warm carbohydrate-protein-containing drinks after exercise may accelerate gastric emptying in the very early phase and may reduce gastric discomfort. TRIAL REGISTRATION: University Hospital Medical Information Network, UMIN000045626. Registered on June 10, 2021.

Sodium Acetate and Sodium Butyrate Differentially Upregulate Antimicrobial Component Production in Mammary Glands of Lactating Goats.

Short-chain fatty acids activate antimicrobial component production in the intestine. However, their effects on mammary glands remain unclear. We investigated the effects of acetate and butyrate on antimicrobial component production in mammary epithelial cells (MECs) or leukocytes cultured in vitro and in mammary glands of lactating Tokara goats in vivo. Our results showed that butyrate enhanced the production of ß-defensin-1 and S100A7 in MECs. Additionally, the infusion of butyrate into mammary glands through the teats enhanced ß-defensin-1 and S100A7 concentrations in milk. The infusion of acetate also increased ß-defensin-1 and S100A7 concentrations along with those of cathelicidin-2 and interleukin-8, which are produced by leukocytes. Furthermore, acetate promoted cathelicidin-2 and interleukin-8 secretion in leukocytes in vitro. These findings suggest that acetate and butyrate differentially upregulate antimicrobial component production in mammary glands, which could help to develop appropriate treatment for mastitis, thereby reducing economic losses and improving animal welfare in farming environments.

Acetate ameliorates nephrotoxicity in streptozotocin-nicotinamide-induced diabetic rats: Involvement of xanthine oxidase activity.

Impaired renal function is a common complication of diabetes mellitus (DM) that often degenerates to cardiovascular disease, contributing to high morbidity and reduced survival worldwide. Short chain fatty acids (SCFAs), including acetate has shown potential benefits in glycemic or metabolic regulation but its effect on diabetes-associated renal toxicity/impairment is not clear. Herein, we investigated the hypothesis that acetate would ameliorate renal toxicity, accompanying DM, possibly by suppression of xanthine oxidase (XO) activity. Adult male Wistar rats (230-260 g) were allotted into groups (n = 6/group) namely: control (vehicle; po), sodium acetate (NaAc)-treated (200 mg/kg), diabetic with or without NaAc groups. DM was induced by intraperitoneal injection of streptozotocin 65 mg/kg after a dose of nicotinamide (110 mg/kg). Diabetic animals showed increased fasting glucose and insulin, renal triglyceride, total cholesterol, atherogenic lipid, malondialdehyde, XO, tissue necrosis factor-α, uric acid, interleukin-6, aspartate transaminase/alanine aminotransferase ratio, gamma-glutamyl transferase and decreased glutathione and nitric oxide concentration. The renal tissue was characterized with disrupted tissue architecture, enlarged Bowman's space, congested glomeruli and adherence of abnormal segments of tuft to Bowman's capsule with consequent elevated serum creatinine and urea concentration. However, these alterations were attenuated by NaAc. The study demonstrates that acetate ameliorates diabetes-induced nephrotoxicity, which is associated with suppressed XO and its accompanied pro-inflammatory mediators. Therefore, SCFAs, acetate would be a promising dietary-derived therapeutic agent for the prevention and management of diabetes-associated renal disturbances.

Sodium acetate ameliorated systemic and renal oxidative stress in high-fructose insulin-resistant pregnant Wistar rats.

Pregnancy is an insulin-resistant condition especially at near term predisposing maternal kidneys to hyperinsulinemia-induced oxidative stress. The impact of fructose on renal metabolic dysregulation and oxidative stress in pregnancy requires elucidation. Short-chain fatty acids (SCFAs) are known for protective roles in oxidative stress conditions. Therefore, the study aimed at investigating fructose-induced glucose dysregulation and renal oxidative stress in pregnant and non-pregnant rats and the possible preventive role of SCFA, acetate. Thirty female Wistar rats were grouped (n = 5/group). Three groups were made pregnant (P); the other three remained non-pregnant (NP). Both pregnant and non-pregnant rats received drinking water (control), 10% fructose (w/v) (NP+F or P+F), and 10% (w/v) fructose plus sodium acetate (200 mg/kg) (NP+F+A or P+F+A) for 3 weeks. Renal and plasma glutathione antioxidant index (GSH/GSSG), G6PDH, and adenosine were significantly lower in NP+F and P+F groups compared with control while renal and plasma adenosine deaminase (ADA), xanthine oxidase (XO), uric acid (UA), lactate dehydrogenase (LDH), and malonaldehyde (MDA) were significantly elevated in NP+F and P+F groups compared with controls. HOMA-IR showed marked impairment in both NP+F and P+F groups. The P+F group revealed greater suppression in plasma and renal G6PDH-dependent antioxidant index, adenosine, and aggravation of LDH, MDA compared with the NP+F group (p < 0.05). Sodium acetate reduces plasma and renal surrogate oxidative stress markers, improved G6PD-dependent antioxidant index, and HOMA-IR in NP+F and P+F groups. Pregnancy exacerbates fructose-induced insulin resistance and renal oxidative stress whereas acetate ameliorated fructose-induced redox and glucose dysregulation in pregnant and non-pregnant rats.

Alcohol metabolite acetic acid activates BK channels in a pH-dependent manner and decreases calcium oscillations and exocytosis of secretory granules in rat pituitary GH3 cells.

Acetaldehyde and acetic acid/acetate, the active metabolites of alcohol (ethanol, EtOH), generate actions of their own ranging from behavioral, physiological, to pathological/cancerogenic effects. EtOH and acetaldehyde have been studied to some depth, whereas the effects of acetic acid have been less well explored. In this study, we investigated the effect of acetic acid on big conductance calcium-activated potassium (BK) channels present in GH3 rat pituitary tumor cells in more detail. In whole cell voltage clamp recordings, extracellular application of acetic acid increased total outward currents in a dose-dependent manner. This effect was prevented after the application of the specific BK channel blocker paxilline. Acetic acid action was pH-dependent-in whole cell current and single BK channel recordings, open probability (Po) was significantly increased by extracellular pH reduction and decreased by neutral or base pH. Acetic acid hyperpolarized the membrane potential, whereas acidic physiological solution had a depolarizing effect. Moreover, acetic acid reduced calcium (Ca2+) oscillations and exocytosis of growth hormone contained secretory granules from GH3 cells. These effects were partially prevented by BK inhibitors-tetraethylammonium or paxillin. In conclusion, our experiments indicate that acetic acid activates BK channels in GH3 cells which eventually contribute to acetic acid-induced membrane hyperpolarization, cessation of Ca2+ oscillations, and decrease of growth hormone release.

Suppression of uric acid and lactate production by sodium acetate ameliorates hepatic triglyceride accumulation in fructose-insulin resistant pregnant rats.

High fructose intake has been associated with perturbed lipid, uric acid and lactate homeostasis. However, consumption of fructose-sweetened beverages is not usually regulated during pregnancy. The effect of short-chain fatty acid (acetate) on the metabolic effects of high fructose intake during pregnancy is not known. We hypothesized that acetate prevents gestational fructose-induced hepatic triglyceride (TG) accumulation by suppressing uric acid and lactate production. Pregnant Wistar rats were randomly separated into three groups (n = 6/group) receiving drinking water (CON), 10 % (w/v) fructose drink (FRU) and 10 % (w/v) fructose with 200 mg/kg (w/w; p.o.) sodium acetate (FRU + ACE) daily for nineteen days. Fructose intake resulted in increased body weight gain, liver weight, fluid intake, visceral fat, insulin resistance, fasting blood glucose, insulin, plasma and hepatic TG, total cholesterol, free fatty acid, lipid peroxidation, adenosine deaminase, xanthine oxidase, uric acid, lactate, lactate dehydrogenase, and liver injury marker enzymes. However, gestational high fructose intake led to depressed plasma and hepatic glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant barrier, adenosine and food intake. All these effects except water intake and food intake were abated by sodium acetate. These results demonstrate that maternal fructose-enriched drink would cause hepatic TG accumulation that is associated with perturbed glucose, uric acid, lactate homeostasis, and G6PD-dependent antioxidant barrier. These results also demonstrate that acetate protects the liver against gestational fructose-induced TG accumulation by inhibiting uric acid and lactate production. Thus, acetate may be useful in the treatment of hyperuricemia- and hyperlactatemia-related disorders.

Sodium acetate prevents nicotine-induced cardiorenal dysmetabolism through uric acid/creatine kinase-dependent pathway.

BACKGROUND: Cigarette smoking or nicotine replacement therapy has been associated with cardiometabolic disorders (CMD). Hyperuricemia has been implicated in the pathogenesis of CMD and cardiorenal dysfunction. Gut microbiota-derived short chain fatty acids (SCFAs) have been reported to have beneficial glucoregulatory and cardiorenal protective effects. This study aimed at investigating the effect of acetate, a gut-derived SCFA, on nicotine-induced CMD and associated cardiorenal dysmetabolism. MATERIALS AND METHOD: Twenty-four male Wistar rats (n = 6/group) were grouped as: vehicle (p.o.), nicotine-exposed (1.0 mg/kg; p.o.), and sodium acetate-treated (200 mg/kg; p.o.) with or without nicotine exposure daily for 6 weeks. Glucose regulation was evaluated by oral glucose tolerance test and homeostatic model assessment of insulin resistance. Cardiac and renal triacylglycerol (TG), lactate, nitric oxide (NO), uric acid (UA) levels, lactate dehydrogenase (LDH), creatine kinase (CK), adenosine deaminase (ADA), and xanthine oxidase (XO) activities were measured. RESULTS: The CMD were confirmed in the nicotine-exposed rats that exhibited lower body weight, insulin resistance, endothelial dysfunction, glucose intolerance, increased cardiac and renal TG, TG/HDL-cholesterol, UA, lactate, lipid peroxidation, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, LDH, CK, ADA and XO activities. Concurrent treatment with acetate prevented nicotine-induced glucometabolic and cardiorenal alterations. CONCLUSION: In summary, these results implied that nicotine exposure caused glucometabolic dysregulation and surplus lipid deposit in the heart and kidney through increased UA production and CK activity. Therefore, oral acetate administration prevents cardiorenal lipotoxicity and glucometabolic dysregulation via suppression of UA production and CK activity in nicotine-exposed rats.

Short-Chain Fatty Acids Promote Intracellular Bactericidal Activity in Head Kidney Macrophages From Turbot (Scophthalmus maximus L.) via Hypoxia Inducible Factor-1α.

Short-chain fatty acids (SCFAs) are mainly produced by microbiota through the fermentation of carbohydrates in the intestine. Acetate, propionate, and butyrate are the most abundant SCFA metabolites and have been shown to be important in the maintenance of host health. In this study, head kidney macrophages (HKMs) were isolated and cultured from turbots. We found that the antibacterial activity of HKMs was increased after these cells were incubated with sodium butyrate, sodium propionate or sodium acetate. Interestingly, our results showed that all three SCFAs enhanced the expression of hypoxia inducible factor-1 α (HIF-1α) in HKMs, and further study confirmed that butyrate augmented the oxygen consumption of these cells. Moreover, HIF-1α inhibition diminished the butyrate-promoted intracellular bacterial killing activity of macrophages, and SCFAs also raised the gene expression and activity of lysozymes in HKMs via HIF-1α signaling. In addition, our results suggested that butyrate induced HIF-1α expression and the bactericidal activity of HKMs through histone deacetylase inhibition, while G protein-coupled receptors did not contribute to this effect. Finally, we demonstrated that butyrate induced a similar response in the murine macrophage cell line RAW264.7. In conclusion, our results demonstrated that SCFAs promoted HIF-1α expression via histone deacetylase inhibition, leading to the enhanced production of antibacterial effectors and increased bacterial killing of macrophages.

Sodium acetate protects against nicotine-induced excess hepatic lipid in male rats by suppressing xanthine oxidase activity.

Fatty liver is the hepatic consequence of chronic insulin resistance (IR) and related syndromes. It is mostly accompanied by inflammatory and oxidative molecules. Increased activity of xanthine oxidase (XO) exerts both inflammatory and oxidative effects and has been implicated in metabolic derangements including non-alcoholic fatty liver disease. Short chain fatty acids (SCFAs) elicit beneficial metabolic alterations in IR and related syndromes. In the present study, we evaluated the preventive effects of a SCFA, acetate, on nicotine-induced dysmetabolism and fatty liver. Twenty-four male Wistar rats (n = 6/group): vehicle-treatment (p.o.), nicotine-treated (1.0 mg/kg; p.o.), sodium acetate-treated (200 mg/kg; p.o.) and nicotine + sodium acetate-treated groups. The treatments lasted for 8 weeks. IR was estimated by oral glucose tolerance test and homeostatic model assessment of IR. Plasma and hepatic free fatty acid, triglyceride (TG), glutathione peroxidase, adenosine deaminase (ADA), XO and uric acid (UA) were measured. Nicotine exposure resulted in reduced body weight, liver weight, visceral adiposity, glycogen content and glycogen synthase activity. Conversely, exposure to nicotine increased fasting plasma glucose, lactate, IR, plasma and hepatic TG, free fatty acid, TG/HDL-cholesterol ratio, lipid peroxidation, liver function enzymes, plasma and hepatic UA, XO and ADA activities. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defense was not affected by nicotine. Concomitant treatment with acetate ameliorated nicotine-induced effects. Taken together, these results indicate that nicotine exposure leads to excess deposition of lipid in the liver by enhancing XO activity. The results also imply that acetate confers hepatoprotection and is accompanied by decreased XO activity.

Biochar enhanced microbial degradation of 17ß-estradiol.

Steroid estrogens (SEs), especially 17ß-estradiol (E2), can be a serious threat to the health of organisms. The removal of E2 from the natural environment is mainly carried out by microbial degradation partly mediated by biochar, which contains quinone structures. In this study, reed straw biochar samples made at four different heat treatment temperatures (HTTs) were used to mediate E2 microbial degradation by Shewanella oneidensis MR-1. The removal efficiency of E2 (95%) was highest in the presence of HTT - 500 °C biochar under anaerobic conditions after 120 h of microbial degradation. The effect of biochar on promoting microbial degradation was far more superior under anaerobic conditions than under aerobic conditions. The redox-activity and types of surface functional groups of biochar reveal that biochar can accept electrons generated by microorganisms in a timely manner. This mechanism promotes the metabolic process of cells and microbial degradation of E2 (exponential increase). Biochar particles rather than biochar-derived water-soluble organic compounds are responsible for this stimulating effect. These results highlight the impact that biochar has on microbial degradation of trace pollutants in a natural environment.

Sodium acetate improves disrupted glucoregulation and hepatic triglyceride content in insulin-resistant female rats: involvement of adenosine deaminase and dipeptidyl peptidase-4 activities.

Combined oral contraceptive (COC) treatment has been shown to be associated with glucose deregulation and increased triglyceride levels, but the mechanisms are elusive. Soluble dipeptidyl peptidase-4 (sDPP-4) and adenosine deaminase (ADA) are involved in the initiation and/or progression of cardiometabolic disorders. We therefore, hypothesized that increased DPP-4 and ADA activities are involved in glucose deregulation and hepatic triglyceride accumulation induced by COC treatment. This study also investigated whether short-chain fatty acid, acetate, would protect against COC-induced dysmetabolic effects. Female Wistar rats received (p.o.) vehicle and COC (1.0 µg ethinylestradiol plus 5.0 µg levonorgestrel) with or without sodium acetate (ACE; 200 mg) for 8 weeks. Treatment with COC led to increased plasma triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, insulin resistance, and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic triglycerides (TG), TG/HDL-cholesterol ratio, malondialdehyde, uric acid, lactate dehydrogenase, DPP-4, ADA, and xanthine oxidase (XO) activities. On the other hand, COC led to reduction in nitric oxide level. However, ACE significantly ameliorated the alterations induced by COC treatment, but XO activity remains elevated during COC treatment. This result also demonstrates that increased DPP-4 and ADA activities are at least in part involved in glucose deregulation and hepatic TG accumulation induced by COC treatment. Therefore, sodium acetate would impact positively on cardiometabolic disorders, at least in part, by inhibition of DPP-4 and ADA activities.

Acetate Mediates Alcohol Excitotoxicity in Dopaminergic-like PC12 Cells.

Neuronal excitotoxicity is the major cause of alcohol-related brain damage, yet the underlying mechanism remains poorly understood. Using dopaminergic-like PC12 cells, we evaluated the effect of N-methyl-d-aspartate receptors (NMDAR) on acetate-induced changes in PC12 cells: cell death, cytosolic calcium, and expression levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Treatment of PC12 cells with increasing concentrations of acetate for 4 h caused a dose-dependent increase in the percentage of cells staining positive for cell death using propidium iodide (PI) exclusion and cytosolic reactive oxygen species (ROS) using cell ROX detection analyzed via flow cytometry. The EC50 value for acetate was calculated and found to be 4.40 mM for PI and 1.81 mM for ROS. Ethanol up to 100 mM had no apparent changes in the percent of cells staining positive for PI or ROS. Acetate (6 mM) treatment caused an increase in cytosolic calcium measured in real-time with Fluo-4AM, which was abolished by coapplication with the NMDAR blocker memantine (10 µM). Furthermore, cells treated with acetate (6 mM) for 4 h had increased expression levels of TNFα relative to control, which was abolished by coapplication of memantine (10 µM). Co-application of acetate (6 mM) and memantine had no apparent reduction in acetate-induced cell death. These findings suggest that acetate is capable of increasing cytosolic calcium concentrations and expression levels of the pro-inflammatory cytokine TNFα through an NMDAR-dependent mechanism. Cell death from acetate was not reduced through NMDAR blockade, suggesting alternative pathways independent of NMDAR activation for excitotoxicity.

Endoglin inhibition by sodium acetate and flutamide ameliorates cardiac defective G6PD-dependent antioxidant defense in gestational testosterone-exposed rats.

Gestational androgen excess has been implicated in the development of cardiac dysfunction with poor mechanistic delineation. The role of sodium acetate on cardiac uric acid (UA) production and glucose-6-phosphate dehydrogenase (G6PD)-dependent antioxidant defense in pregnancy is not known. The study therefore sought to test the hypothesis that rats exposed to elevated testosterone in late pregnancy would have increased cardiac UA production and defective G6PD-dependent antioxidant defense. We also hypothesized that sodium acetate (SAc) or androgen receptor blocker, flutamide (Flu) would ameliorate these effects through endoglin inhibition. Twenty-four pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; po) or Flu (7.5 mg/kg; po) in the late gestation between gestational day 14 and 19. The results showed that in the late gestation, testosterone exposure led to increased plasma and cardiac endoglin. In the heart of rats exposed to gestational testosterone there were elevated lactate dehydrogenase, adenosine deaminase, xanthine oxidase, uric acid (UA), cardiac injury markers and decreased G6PD-dependent antioxidant defense. However, either SAc or Flu comparably ameliorated these testosterone-induced effects. The data from the present study revealed that testosterone exposure in the late gestation causes elevated cardiac Eng that is accompanied by increased UA production and defective G6PD-dependent anti-oxidant defenses. Besides, the findings also suggest that the inhibitory effect of SAc or Flu on endoglin attenuates UA production and enhances the G6PD-dependent anti-oxidant barrier, thereby implying that endoglin may be a potentially novel therapeutic intervention for cardiac dysfunction particularly in pregnancy.

Sodium acetate and androgen receptor blockade improve gestational androgen excess-induced deteriorated glucose homeostasis and antioxidant defenses in rats: roles of adenosine deaminase and xanthine oxidase activities.

Nutritional challenges and androgen excess have been implicated in the development of gestational diabetes and poor fetal outcome, but the mechanisms are not well delineated. The effects of short chain fatty acid (SCFA) on glucose dysmetabolism and poor fetal outcome induced by gestational androgen excess is also not known. We tested the hypothesis that blockade of androgen receptor (AR) and suppression of late gestational androgen excess prevents glucose dysmetabolism and poor fetal outcome through suppression of adenosine deaminase (ADA)/xanthine oxidase (XO) pathway. Twenty-four pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SCFA (sodium acetate; 200 mg/kg; p.o.) or AR blocker (flutamide; 7.5 mg/kg; p.o.) between gestational days 14 and 19. The results showed that late gestational androgen excess led to glucose deregulation, poor fetal outcome, increased plasma and hepatic free fatty acid and lactate dehydrogenase, liver function marker enzymes, malondialdehyde, uric acid, ADA and XO activities. Conversely, gestational androgen excess resulted in reduced body weight gain, visceral adiposity, plasma and hepatic anti-oxidant defenses (glutathione peroxidase, reduced glutathione/glutathione disulphide ratio, glucose-6-phosphate dehydrogenase, adenosine and nitric oxide). However, all these effects were ameliorated by either sodium acetate or flutamide treatment. The study demonstrates that suppression of testosterone by SCFA or AR blockade protects against glucose deregulation and poor fetal outcome by improvement of anti-oxidant defenses and replenishment of hepatic oxidative capacity through suppression of ADA/XO pathway. Hence, utility of SCFA should be encouraged for prevention of glucose dysmetabolism and poor fetal outcome.