Activation of Sirtuin 3 and Maintenance of Mitochondrial Integrity by N-Acetylcysteine Protects Against Bisphenol A-Induced Kidney and Liver Toxicity in Rats

Mitochondrial impairment ensuing from oxidative imbalance is related to adverse consequences of bisphenol A (BPA), a globally utilized industrial chemical. Recent evidence reveals sirtuin 3 (SIRT3) as a key regulator of mitochondrial homeostasis; however, its role in BPA toxicity remains unidentified. This study explored the potential benefits of N-acetylcysteine (NAC), an effective antioxidant, against BPA toxicity in the kidney and liver, and examined whether SIRT3 was involved in this condition. Male Wistar rats were fed with vehicle, BPA (5, 50 mg/kg), BPA (50 mg/kg) plus NAC (100 mg/kg) and were evaluated after 5 weeks. NAC treatment significantly diminished BPA-induced kidney and liver functional disorders, histopathological alterations, oxidative stress, and apoptosis. The increased mitochondrial reactive oxygen species, the disrupted membrane potential, the swelling, and the impaired mitochondrial fission caused by BPA were also mitigated upon concurrent treatment with NAC. The benefits of NAC were associated with enhanced AMPK-PGC-1α-SIRT3 signaling protein expressions, which led to decreased acetylation of superoxide dismutase 2 (SOD2) and increased expression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD). The findings demonstrate the efficacy of NAC in protecting BPA-induced kidney and liver injury, which, in part, is mediated by activating SIRT3 and improving mitochondrial function, dynamics, and oxidative imbalance

Acetylcholine Attenuates Hydrogen Peroxide-Induced Intracellular Calcium Dyshomeostasis Through Both Muscarinic and Nicotinic Receptors in Cardiomyocytes

Background/Aims: Oxidative stress induced intracellular Ca2+ overload plays an important role in the pathophysiology of several heart diseases. Acetylcholine (ACh) has been shown to suppress reactive oxygen species generation during oxidative stress. However, there is little information regarding the effects of ACh on the intracellular Ca2+ regulation in the presence of oxidative stress. Therefore, we investigated the effects of ACh applied before or after hydrogen peroxide (H2O2) treatment on the intracellular Ca2+ regulation in isolated cardiomyocytes. Methods: Single ventricular myocytes were isolated from the male Wistar rats for the intracellular Ca2+ transient study by a fluorimetric ratio technique. Results: H2O2 significantly decreased both of intracellular Ca2+ transient amplitude and decay rate. ACh applied before, but not after, H2O2 treatment attenuated the reduction of intracellular Ca2+ transient amplitude and decay rate. Both atropine (a muscarinic acetylcholine receptor blocker) and mecamylamine (a nicotinic acetylcholine receptor blocker) significantly decreased the protective effects of acetylcholine on the intracellular Ca2+ regulation. Moreover, the combination of atropine and mecamylamine completely abolished the protective effects of acetylcholine on intracellular Ca2+ transient amplitude and decay rate. Conclusion: ACh pretreatment attenuates H2O2-induced intracellular Ca2+ dyshomeostasis through both muscarinic and nicotinic receptors

N-Acetylcysteine Attenuates the Increasing Severity of Distant Organ Liver Dysfunction after Acute Kidney Injury in Rats Exposed to Bisphenol A

Distant organ liver damage after acute kidney injury (AKI) remains a serious clinical setting with high mortality. This undesirable outcome may be due to some hidden factors that can intensify the consequences of AKI. Exposure to bisphenol A (BPA), a universal chemical used in plastics industry, is currently unavoidable and can be harmful to the liver. This study explored whether BPA exposure could be a causative factor that increase severity of remote liver injury after AKI and examined the preventive benefit by N-acetylcysteine (NAC) in this complex condition. Male Wistar rats were given vehicle, BPA, or BPA + NAC for 5 weeks then underwent 45 min renal ischemia followed by 24 h reperfusion (RIR), a group of vehicle-sham-control was also included. RIR not only induced AKI but produced liver injury, triggered systemic oxidative stress as well as inflammation, which increasing severity upon exposure to BPA. Given NAC to BPA-exposed rats diminished the added-on effects of BPA on liver functional impairment, oxidative stress, inflammation, and apoptosis caused by AKI. NAC also mitigated the abnormalities in mitochondrial functions, dynamics, mitophagy, and ultrastructure of the liver by improving the mitochondrial homeostasis regulatory signaling AMPK-PGC-1α-SIRT3. The study demonstrates that NAC is an effective adjunct for preserving mitochondrial homeostasis and reducing remote effects of AKI in environments where BPA exposure is vulnerable

Effects of metformin, vildagliptin, and combination of vildagliptin and metformin on cardiac function before I/R injury (n = 11/group).

<p>*<i>P</i><0.05 vs. NDV, ^†<i>P</i><0.05 vs. HFDV.</p

Effects of vildagliptin, metformin, and combination of vildagliptin and metformin on metabolic parameters (n = 11/group).

<p>*<i>P</i><0.05 vs. NDV, ^†<i>P</i><0.05 vs. HFDV.</p

Effects of HFD consumption, vildagliptin, metformin, and combined drugs on HRV and echocardiographic parameters.

<p>(A) The LF/HF ratio was increased at week 8^th and week 12^thof HFD consumption.*p<0.05 vs. baseline, n = 11/group. (B) Vildagliptin, metformin, and combined drugs reduced the LF/HF ratio in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 11/group, (C) %FS was decreased after 12 weeks of HFD consumption.*p<0.05 vs. ND, n = 11/group. (D) LVEF was decreased after 12 weeks of HFD consumption.*p<0.05 vs. ND, n = 11/group. (E) Vildagliptin, metformin, and combined drugs increased %FS in HFD rats. *p<0.05 vs. HFDV, n = 11/group. (F) Vildagliptin, metformin, and combined drugs increased LVEF in HFD rats. *p<0.05 vs. HFDV, n = 11/group.</p

Effects of vildagliptin, metformin, combined drugs on arrhythmia, mortality rate, and phosphorylation of Cx43 level.

<p>(A) Combined drugs reduced arrhythmia score in HFD rats.*p<0.05 vs. HFDV, n = 11/group. (B) Combined drugs delayed time to the 1^st VT/VF onset in HFD rats. *p<0.05 vs. HFDV, n = 11/group. (C) Mortality rate was higher in HFDV, and combined drugs reduced mortality rate in both ND and HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 11/group. (D) Combined drugs increased p-Cx43 in HFD rats. *p<0.05 vs. HFDV, n = 5/group.</p

Effects of vildagliptin, metformin, and combined drugs on infarct size, Bax, and Bcl-2 expression.

<p>(A) Infarct size was increased in HFDV, and all treatments reduced infarct size in both ND and HFD rats. *p<0.05 vs. NDV, ^†p<0.01 vs. HFDV, n = 6/group. (B) Representative images showing TTC staining for infarct size determination. (C) Bax expression was increased in HFDV, and all treatments reduced Bax expression in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 5/group. (D) Bcl-2 expression was decreased in HFDV, and all treatments increased Bcl-2 expression in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 5/group.</p

Effects of vildagliptin, metformin, and combination of vildagliptin and metformin on cardiac function at the end of Reperfusion (n = 11/group).

<p>*<i>P</i><0.05 vs. NDV, ^†<i>P</i><0.05 vs. HFDV.</p