Tetrahydrocurcumin ameliorates postinfarction cardiac dysfunction and remodeling by inhibiting oxidative stress and preserving mitochondrial function via SIRT3 signaling pathway.

BACKGROUND: Myocardial infarction (MI) often leads to sudden cardiac death. Persistent myocardial ischemia increases oxidative stress and impairs mitochondrial function, contributing significantly to postinfarction cardiac dysfunction and remodeling, and the subsequent progression to heart failure (HF). Tetrahydrocurcumin (THC), isolated from the rhizome of turmeric, has antioxidant properties and has been shown to protect against cardiovascular diseases. However, its effects on HF after MI are poorly understood. PURPOSE: The objective was the investigation of the pharmacological effects of THC and its associated mechanisms in the pathogenesis of HF after MI. METHODS: A total of 120 mice (C57BL/6, male) were used for the in vivo experiments. An MI mouse model was created by permanent ligation of the left anterior descending coronary artery. The mice received oral dose of THC at 120 mg/kg/d and the effects on MI-induced myocardial injury were evaluated by assessment of cardiac function, histopathology, myocardial oxidative levels, and mitochondrial function. Molecular mechanisms were investigated by intraperitoneal injection of 50 mg/kg of the SIRT3 selective inhibitor 3-TYP. Meanwhile, mouse neonatal cardiomyocytes were isolated and cultured in a hypoxic incubator to verify the effects of THC in vitro. Lastly, SIRT3 and Nrf2 were silenced using siRNAs to further explore the regulatory mechanism of key molecules in this process. RESULTS: The mouse hearts showed significant impairment in systolic function after MI, together with enlarged infarct size, increased myocardial fibrosis, cardiac hypertrophy, and apoptosis of cardiomyocytes. A significant reversal of these changes was seen after treatment with THC. Moreover, THC markedly reduced reactive oxygen species generation and protected mitochondrial function, thus mitigating oxidative stress in the post-MI myocardium. Mechanistically, THC counteracted reduced Nrf2 nuclear accumulation and SIRT3 signaling in the MI mice while inhibition of Nrf2 or SIRT3 reversed the effects of THC. Cell experiments showed that Nrf2 silencing markedly reduced SIRT3 levels and deacetylation activity while inhibition of SIRT3 signaling had little impact on Nrf2 expression. CONCLUSION: This is the first demonstration that THC protects against the effects of MI. THC reduced both oxidative stress and mitochondrial damage by regulating Nrf2-SIRT3 signaling. The results suggest the potential of THC in treating myocardial ischemic diseases.

Dietary citrus flavonoid extract improves lactational performance through modulating rumen microbiome and metabolites in dairy cows.

The effects of dietary supplementation with citrus flavonoid extract (CFE) on milk performance, rumen fermentation, rumen microbiome, rumen metabolome, and serum antioxidant indexes were evaluated. Eight multiparous lactating cows were allocated to a replicated 4 × 4 Latin square with 25-d periods consisting of 20 d of adaptation and 5 d of sampling. Experimental treatments included a control diet (CON) and CON supplemented with 50 g d-1 (CFE50), 100 g d-1 (CFE100), and 150 g d-1 (CFE150). Feeding CFE to dairy cows increased milk production and milk lactose. Milk somatic cell count linearly reduced with increasing CFE amount. Supplementing CFE linearly increased the ruminal concentrations of total volatile fatty acids, acetate, propionate, butyrate, and microbial crude protein. Ruminal lipopolysaccharide linearly decreased with increasing CFE amount. Compared with CON, CFE150 cows exhibited a greater abundance of Firmicutes and a low abundance of Bacteroidetes. Cellulolytic bacteria (genera Ruminococcus, Clostridium, and Butyrivibrio) and carbohydrate metabolism were enriched in the CFE150 cows. For archaea and viruses, major methanogens (genera Methanobacterium and Methanosarcina) and phylum Uroviricota were inhibited in the CFE150 cows. Compared with CON, the ruminal concentrations of tyrosine, proline, pyruvate, glucose, and glucose-6-phosphate were higher in the CFE150 cows. The metabolites of citrus flavonoids, such as hippuric acid, hesperetin, and naringenin, were increased in the CFE150 cows. Supplementing CFE significantly improved the antioxidant capacity of the dairy cows. This study highlighted that dietary supplementation with CFE led to significant changes in the rumen microbial composition and metabolites, and consequently resulted in an improved lactational performance of dairy cows.

Lipidomic profiling using GC and LC-MS/MS revealed the improved milk quality and lipid composition in dairy cows supplemented with citrus peel extract.

Eight lactating cows were used to determine the effects of citrus peel extract (CPE) on milk performance, antioxidant properties, and milk lipids composition. CPE supplementation up to 150 g/d (CPE150) increased milk yield and the proportions of unsaturated fatty acids of conjugated linoleic acid. CPE with abundant polyphenol and flavonoids can transfer these bioactive substances to mammary gland and improve the antioxidant properties of milk obtained from cows. Lipidomics revealed that 56 lipid species were altered between CON vs CPE150, and there were five key differential metabolic pathways. In particular, milk phosphatidylethanolamine and phosphatidylcholine were significantly increased with dietary CPE supplementation. In summary, our results provide insights into the modifications in the milk components and milk quality of dairy cows received CPE. The inclusion of CPE in the diet of dairy cows may be an effective and natural way to increase the antioxidant amounts and beneficial lipids in milk.

Mulberry Leaf Extract Improves Metabolic Syndrome by Alleviating Lipid Accumulation In Vitro and In Vivo.

Metabolic syndrome (MS) is a metabolic disease with multiple complications. Mulberry leaf extract (MLE) is rich in flavonoids and has great potential in alleviating glucose and lipid metabolism disorders. This study evaluated the effect and mechanism of MLE on the alleviation of MS. The components of the MLE were analyzed, and then the regulation of lipid metabolism by MLE in vitro and in vivo was determined. In a hepatocyte model of oleic acid-induced lipid accumulation, it was found that MLE alleviated lipid accumulation and decreased the expression of genes involved in lipogenesis. Furthermore, MLE improved obesity, insulin resistance, plasma lipid profile, and liver function in MS mice after a 15-week intervention. MLE decreased the expression of SREBP1, ACC, and FAS through the AMPK signaling pathway to inhibit lipid synthesis and increase the level of CPT1A to promote lipid decomposition to achieve its hypolipidemic effect. Meanwhile, MLE was also shown to affect the composition of the gut microbiota and the production of short-chain fatty acids, which contributed to the alleviation of lipid accumulation. Our results suggest that MLE can improve MS by improving lipid metabolism through multiple mechanisms and can be developed into dietary supplements for the improvement of MS.

Tetrahydrocurcumin improves lipopolysaccharide-induced myocardial dysfunction by inhibiting oxidative stress and inflammation via JNK/ERK signaling pathway regulation.

BACKGROUND: Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven to contribute to the prevention of various cardiovascular diseases by decreasing oxidative stress and inflammation. This study was performed to investigate the functions and mechanism of action of THC in septic cardiomyopathy. METHODS: After the oral administration of THC (120 mg/kg) for 5 consecutive days, a mouse model of sepsis was established via intraperitoneal lipopolysaccharide (LPS, 10 mg/kg) injection. Following this, cardiac function was assessed, pathological section staining was performed, and inflammatory markers were detected. RESULTS: Myocardial systolic function was severely compromised in parallel with the accumulation of reactive oxygen species and enhanced cardiomyocyte apoptosis in mice with sepsis. These adverse changes were markedly reversed in response to THC treatment in septic mice as well as in LPS-treated H9c2 cells. Mechanistically, THC inhibited the release of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-6, by upregulating mitogen-activated protein kinase phosphatase 1, to block the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK). Additionally, THC enhanced the levels of antioxidant proteins, including nuclear factor-erythroid 2-related factor 2, superoxide dismutase 2, and NAD(P)H quinone oxidoreductase 1, while decreasing gp91phox expression. Furthermore, upon THC treatment, Bcl-2 expression was significantly increased, along with a decline in Bax and cleaved caspase-3 expression, which reduced cardiomyocyte loss. CONCLUSION: Our findings indicate that THC exhibited protective potential against septic cardiomyopathy by reducing oxidative stress and inflammation through the regulation of JNK/ERK signaling. The findings of this study provide a basis for the further evaluation of THC as a therapeutic agent against septic cardiomyopathy.

Myricetin ameliorated ischemia/reperfusion-induced brain endothelial permeability by improvement of eNOS uncoupling and activation eNOS/NO.

Disruption of the blood-brain barrier (BBB) has been considered as a major pathological change in stroke. eNOS/NO play a key role in maintain BBB function. Myricetin is one of the common flavones widely exists in food and fruit, show certain protective effect on the brain function. This experiment establishes oxygeneglucose deprivation and reoxygenation (OGD/R) brain cell model. The regulated effects of Myricetin on BBB function, eNOS/NO and eNOS uncoupling were evaluated. To investigate the molecular mechanism, Akt and Nrf2 inhibitor were also used. The result showed that Myricetin could significantly decreased the enhancement of endothelial permeability and inflammation in OGD/R model, in addition regulated eNOS/NO pathway. The regulate effect in endothelial permeability and eNOS activity by Myricetin were both decreased when combined with Akt inhibitor or Nrf2 inhibitor, and was abrogated when combined with Akt and Nrf2 inhibitor simultaneously. The regulated effect on eNOS uncoupling by Myricetin were abrogated when combined with Nrf2 inhibitor, but not with Akt inhibitor. In conclusion, Myricetin showed significant protect effect on ischemia/reperfusion-induced brain endothelial permeability, and related to simultaneously regulated Akt pathway and improvement of eNOS uncoupling through Nrf2 pathway.

Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1ß: In vivo and in vitro studies.

Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of α-myosin heavy chain, downregulated the expression level of ß-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1ß) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1ß using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1ß.

Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1.

Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress.

AIM: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. METHODS: Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. RESULTS: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 µmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. CONCLUSION: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.

HIF-1α signaling activation by post-ischemia treatment with astragaloside IV attenuates myocardial ischemia-reperfusion injury.

In this study, we evaluated the effect of astragaloside IV (Ast IV) post-ischemia treatment on myocardial ischemia-reperfusion (IR) injury (IRI). We also examined whether hypoxia inducible factor-1α (HIF-1α) and its downstream gene-inducible nitric oxide (NO) synthase (iNOS) play roles in the cardioprotective effect of Ast IV. Cultured cardiomyocytes and perfused isolated rat hearts were exposed to Ast IV during reperfusion in the presence or absence of the HIF-1α inhibitor 2-methoxyestradiol (2-MeOE2). The post-ischemia treatment with Ast IV protected cardiomyocytes from the apoptosis and death induced by simulated IRI (SIRI). Additionally, in cardiomyocytes, 2-MeOE2 and HIF-1α siRNA treatment each not only abolished the anti-apoptotic effect of post-ischemia treatment with Ast IV but also reversed the upregulation of HIF-1α and iNOS expression. Furthermore, after treatment with Ast IV, post-ischemic cardiac functional recovery and lactate dehydrogenase (LDH) release in the coronary flow (CF) were improved, and the myocardial infarct size was decreased. Moreover, the number of apoptotic cells was reduced, and the upregulation of the anti-apoptotic protein Bcl2 and downregulation of the pro-apoptotic protein Caspase3 were reversed. 2-MeOE2 reversed these effects of Ast IV on IR-injured hearts. These results suggest that post-ischemia treatment with Ast IV can attenuate IRI by upregulating HIF-1α expression, which transmits a survival signal to the myocardium.

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway.

In this study, we evaluated the effect of curcumin (Cur) post-treatment on isolated perfused rat hearts that had been subjected to a protocol of ischemia and reperfusion injury. We also examined whether the Janus kinase 2 and signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway plays a role in the cardioprotective effects of Cur post-treatment. Isolated perfused rat hearts were subjected to 60 min of ischemia, followed by 60 min of reperfusion. The hearts were exposed to 1-µM Cur during the first 10 min of reperfusion in the absence or presence of the JAK kinase-specific inhibitor AG490 (AG, 1 µM). The Cur treatment conferred a cardioprotective effect, and the treated hearts demonstrated an improved post-ischemic cardiac functional recovery, a decreased myocardial infarct size and decreased lactate dehydrogenase release in the coronary flow, a reduced number of apoptotic cardiomyocytes, up-regulation of the anti-apoptotic protein Bcl2 and down-regulation of the pro-apoptotic protein Caspase3. AG blocked the Cur-mediated cardioprotection by inhibiting the JAK2/STAT3 signaling pathway, as reflected by the abrogation of the Cur-induced up-regulation of Bcl2 and down-regulation of Caspase3. The results suggest that Cur post-treatment can attenuate IR injury through the activation of the JAK2/STAT3 signaling pathway, which transmits a survival signal to the myocardium.

α-Linolenic acid intake attenuates myocardial ischemia/reperfusion injury through anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats.

BACKGROUND AND AIMS: Patients with diabetes show enhanced susceptibility to myocardial ischemia/reperfusion (MI/R) injury. Epidemiological studies indicated that consumption of α-linolenic acid (ALA) significantly reduces the risk of cardiac events in post-acute myocardial infarction patients. The present study attempted to investigate the effects of ALA intake on MI/R injury in normal and diabetic rats and its mechanisms. METHODS: The high-fat diet-fed streptozotocin (HFD-STZ) rat model was developed. Age-matched normal and HFD-STZ rats were randomly assigned to receive normal diet or ALA (oral gavage, 500 µg/kg per day). After 4 weeks of feeding, animals were subjected to 30 min of myocardial ischemia and 4 or 6 h of reperfusion. RESULTS: Compared with the normal control, HFD-STZ rats showed more severe myocardial functional impairment and injury. Although ALA intake for 4 weeks did not change myocardial function and injury in normal rats, it significantly improved the instantaneous first derivation of left ventricle pressure, reduced infarct size, plasma creatine kinase and lactate dehydrogenase activities, and apotosis at the end of reperfusion in HFD-STZ diabetic rats. Moreover, ALA intake not only significantly reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations but reduced the increase in superoxide production and malonaldialdehyde formation and simultaneously enhanced the antioxidant capacity in the diabetic hearts. Myocardial PI3K expression and Akt phosphorylation were increased by ALA intake in diabetic but not normal rats. CONCLUSIONS: Chronic ALA intake confers cardioprotection in MI/R by exerting anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats, which is possibly through PI3K-Akt-dependent mechanism.