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Objective To explore the effect and mechanism of luteolin (LTN) in sepsis-induced cardiac injury. Methods Caecal ligation perforation (CLP) was used to establish a septic model in mice, and 42 mice were randomly divided into Sham group, CLP group and CLP+LTN group, with 14 mice in each group. The 48-hour survival rate was observed. Ultrasonography was used to detect cardiac function, Western blotting was employed to detect the expression of SIRT1, p-p65 and p65, and PCR was applied to measure the mRNA levels of inflammatory cytokines. In in vitro study, LPS of 1 μg/mL was used to treat mouse macrophagocyte RAW 264.7, and then the medium was used to treat mouse cardiomyocytes HL-1. LPS-treated RAW 264.7 cells and RAW 264.7+LPS medium-treated HL-1 cells were co-cultured with different concentrations of LTN, and the optimal LTN concentration was determined by TNF-α ELISA kit and CCK-8 assay. Then after SIRT1 expression of RAW 264.7 cells and HL-1 cells was knocked down by siRNA, the expression of above proteins was detected by Western blotting, and mRNA expression levels of inflammatory cytokines were measured by PCR, ATP content was detected by reagent kit, and cell viability was detected by CCK-8 assay. Results The mice of the CLP group had significantly lower 48-hour survival rate, cardiac function and SIRT1 expression (P < 0.05), and increased protein level of p-p65/p65 and mRNA levels of IL-1, TNF-α and IL-6 (P < 0.05) when compared with the Sham group. However, these effects were reversed by LTN treatment (P < 0.05). In RAW 264.7 cells, LTN treatment significantly reversed LPS-induced decrease of SIRT1 expression, and increases in protein level of p-p65 and mRNA levels of IL-1, TNF-α and IL-6 (P < 0.05). Nevertheless, SIRT1 knockdown abolished the effect of LTN (P < 0.05). In HL-1 cells, LTN treatment significantly reversed the decrease of SIRT1 expression, ATP content and cell viability induced by RAW 264.7+LPS medium (P < 0.05), but this effect could be partially eliminated by SIRT1 knockdown (P < 0.05). Conclusion LTN can inhibit inflammatory response and enhance the anti-inflammatory effect of cardiomyocytes by activating SIRT1, and thus reduce sepsis-induced cardiac dysfunction.

Objective To investigate the role and underlying mechanism of Sestrin2 in hypoxia/reoxygenation injury of rat cardiomyocytes. Methods H9C2 cardiomyocytes were cultured in vitro and inflicted to establish hypoxia/reoxygenation injury (H/R) model. Thus, the cells were divided into control group, hypoxia 4-hour group (H4h group), and hypoxia 4-hour + reoxygenation 2- and 4-hour groups (H4hR2h and H4hR4h groups). Cell survival rate was measured by cell counting kit-8 (CCK8) assay; Annexin V/7AAD staining with flow cytometry was used to detect cell apoptosis. Micro-enzymatic method was used to detect the content of myocardial injury marker, lactate dehydrogenase (LDH). Then H9C2 cardiomyocytes were divided into normal control group, hypoxia 4-hour+si-NC group (negative control), hypoxia 4-hour+Sestrin2 siRNA group, hypoxia/reoxygenation 4 hour+si-NC group and hypoxia/reoxygenation 4 h+Sestrin2 siRNA group. Recombinant siRNA for Sestrin2 silencing and negative control (si-NC) were constructed and transfected into H9C2 cardiomyocytes with liposomes. The expression of Sestrin2, Nrf2 and HO-1 proteins was detected by Western blotting. Flow cytometry was used to measure the cell apoptosis. Results The cell viability of cardiomyocytes was significantly lower (P < 0.05), and the apoptosis (P < 0.05) as well as LDH level (P < 0.01) was obviously increased in the H4hR4h group than the control group. The expression of Sestrin2 protein was increased in both hypoxia and reoxygenation groups when compared with the control group (P < 0.01), with the level in the H/R groups higher than that in the H groups (P < 0.01). Transfected of Sestrin2 siRNA significantly knocked down the protein expression (P < 0.05), enhanced the cell apoptosis (P < 0.05), and decreased the expression levels of Nrf2 (P < 0.01) and HO-1 (P < 0.05). Conclusion Sestrin2 exerts protective effect on oxidative damage in H9C2 cardiomyocytes induced by H/R injury, which might be due to its activating Nrf2/HO-1 related signaling pathway.

Epidemiological studies show an association between low body selenium and the risk of hypertension. However, whether selenium deficiency causes hypertension remains unknown. Here, we report that Sprague-Dawley rats fed a selenium-deficient diet for 16 weeks developed hypertension, accompanied with decreased sodium excretion. The hypertension of selenium-deficient rats was associated with increased renal angiotensin II type 1 receptor (AT 1 R) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the AT 1 R antagonist candesartan. Selenium-deficient rats had increased systemic and renal oxidative stress; treatment with the antioxidant tempol for 4 weeks decreased the elevated blood pressure, increased sodium excretion, and normalized renal AT 1 R expression. Among the altered selenoproteins in selenium-deficient rats, the decrease in renal glutathione peroxidase 1 (GPx1) expression was most prominent. GPx1, via regulation of NF-κB p65 expression and activity, was involved in the regulation of renal AT 1 R expression because treatment with dithiocarbamate (PDTC), an NF-κB inhibitor, reversed the up-regulation of AT 1 R expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of AT 1 R expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal AT 1 R expression, Na + -K + -ATPase activity, hydrogen peroxide (H 2 O 2 ) generation, and the nuclear translocation of NF-κB p65 protein in selenium-deficient RPT cells. Our results demonstrated that long-term selenium deficiency causes hypertension, which is due, at least in part, to decreased urine sodium excretion. Selenium deficiency increases H 2 O 2 production by reducing GPx1 expression, which enhances NF-κB activity, increases renal AT 1 R expression, causes sodium retention and consequently increases blood pressure., Competing Interests: Declaration of competing interest The authors declared there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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Advanced glycosylation end products (AGE) and its receptor (RAGE) axis is involved in the regulation of lipid homeostasis and is critical in the pathogenesis of diabetic atherosclerosis. We investigated the protective role of resveratrol against the AGE-induced impairment on macrophage lipid homeostasis. In THP-1-derived macrophages, RAGE was dose-dependently induced by AGE and played a key role in the AGE-induced cholesterol accumulation. Resveratrol markedly reduced RAGE expression via peroxisome proliferator-activated receptor (PPAR) gamma but not PPARalpha or AMP-activated protein kinase. Importantly, pretreatment with resveratrol significantly ameliorated AGE-induced up-regulation of scavenger receptor-A (SR-A) and down-regulation of ATP-binding cassette (ABC) A1 and ABCG1 and thus effectively prevented the cholesterol accumulation in macrophages as shown by cellular cholesterol analysis and oil red O staining. Moreover, blockade of PPARgamma abolished all these effects of resveratrol. Collectively, our results indicate that resveratrol prevents the impairment of AGE on macrophage lipid homeostasis partially by suppressing RAGE via PPARgamma activation, which might provide new insight into the protective role of resveratrol against diabetic atherosclerosis.