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Atherosclerosis (AS), a chronic sterile inflammatory disorder, is one of the leading causes of mortality worldwide. The dysfunction and unnatural death of plaque cells, including vascular endothelial cells (VEC), macrophages, and vascular smooth muscle cells (VSMC), are crucial factors in the progression of AS. Pyroptosis was described as a form of cell death at least two decades ago. It is featured by plasma membrane swelling and rupture, cell lysis, and consequent robust release of cytosolic contents and pro-inflammatory mediators, including interleukin-1β (IL-1β), IL-18, and high mobility group box 1 (HMGB1). Pyroptosis of plaque cells is commonly observed in the initiation and development of AS, and the levels of pyroptosis-related proteins are positively correlated with plaque instability, indicating the crucial contribution of pyroptosis to atherogenesis. Furthermore, studies have also identified some candidate anti-atherogenic agents targeting plaque cell pyroptosis. Herein, we summarize the research progress in understating (1) the discovery and definition of pyroptosis; (2) the characterization and molecular mechanisms of pyroptosis; (3) the regulatory mechanisms of pyroptosis in VEC, macrophage, and VSMC, as well as their potential role in AS progression, aimed at providing therapeutic targets for the prevention and treatment of AS. [ABSTRACT FROM AUTHOR]

In the article titled "Adipose-Derived Stromal Cells Attenuate Adipose Inflammation in Obesity through Adipocyte Browning and Polarization of M2 Macrophages" [[1]], the authors identified error in Figure 5(a) which was introduced during the preparation of the manuscript. REFERENCES 1 Zhang W.-C., Qin F., Wang X.-J., Liu Z.-F., Lin Z., Zeng A., Zhang M.-Z., Yu N.-Z., Long X. Adipose-Derived Stromal Cells Attenuate Adipose Inflammation in Obesity through Adipocyte Browning and Polarization of M2 Macrophages. [Extracted from the article]

• 7-O-(2-(Propylamino)-2-oxoethyl) hesperetin (HD-4d), a new synthesized compound in our laboratory. • HD-4d has obvious anti-inflammatory effect in vivo and in vitro. • HD-4d promoted NLRP12 expression in EtOH and lipopolysaccharide (LPS)-induced RAW264.7 cells and alcohol-induced mouse liver. • HD-4d can suppress p -P65 expression through activating NLRP12 expression. Alcoholic liver disease (ALD) is a liver disease caused by long-term heavy drinking. Alcoholic liver injury is a part of alcoholic liver disease. A large number of studies have shown that alcohol metabolism and endotoxin / lipopolysaccharide (LPS) and cycles can cause massive activation of macrophages, leading alcoholic liver injury. Hesperetin is a dihydro-flavonoid extracted from the fruits of Citrus in Rutaceae. It has a variety of pharmacological activities, including antibacterial, anti-inflammatory, antioxidant and so on, but recent studies have shown that hesperetin derivatives have stronger anti-inflammatory effects than hesperetin. In order to improve the anti-inflammatory activity of hesperetin, our group used ethyl-bromoacetate to replace the hydroxyl group at the 7 position of hesperetin to obtain the hesperetin derivative 7-O-(2-(Propylamino)-2-oxoethyl) hesperetin (HD-4d). In this study, we found that HD-4d had hepatoprotective and anti-inflammatory effects on alcoholic liver injury in C57BL/6J mice, and it also had noticeable anti-inflammatory effects in EtOH and LPS-induced RAW264.7 cells. Besides, we found that HD-4d can reduce the expression of inflammatory factors by up-regulating NLRP12 in vivo and in vitro. We found that the expression of NLRP12 was significantly increased in EtOH and LPS-induced RAW264.7 cells compared with the control group. Moreover, the inhibitory effect of HD-4d on inflammation weakened considerably after silencing NLRP12 in RAW264.7 cells. However, when NLRP12 was overexpressed with plasmid pEX-3-NLRP12, the effect of HD-4d on alcohol and LPS induced inflammation was remarkably increased. In addition, further studies indicated that HD-4d inhibited the activation and phosphorylation of the p65 protein by up-regulating NLRP12. In conclusion, HD-4d activated NLRP12 to reduce liver injury and inflammatory response through the NF-кB pathway. [ABSTRACT FROM AUTHOR]

A schematic model of O-alkyl and o-benzyl hesperitin derivative-1L ameliorates alcoholic liver injury by inhibiting BRD2-NF-κB signaling pathway. Therefore, HD-1L is a potential treatment option for inhibiting liver inflammation and the progression of Alcoholic liver diseases. [Display omitted] • HD-1L, a new compound synthesized in our laboratory. • HD-1L alleviates liver injury in alcohol-induced liver injury mice. • HD-1L attenuates the inflammatory response in vivo and in vitro. • Potential pharmacological mechanism of HD-1L administration in ALI. • HD-1L may be a valid candidate for ALI. Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl 4 -induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6–8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Liver fibrosis, a chronic inflammatory healing reaction, progresses to hepatocirrhosis without effective intervention. Hesperetin derivative (HD-16), a monomer compound derived from hesperitin, exerts anti-inflammatory and hepatoprotective effects against a spectrum of liver diseases. However, the anti-fibrotic potential of HD-16 in liver fibrosis and its underlying mechanism have not yet been elucidated. In this study, we investigated the anti-fibrotic effect of HD-16 on mouse liver fibrosis induced by CCl 4 and on LX-2 cells (human immortalized HSCs) stimulated by TGF-β1, in vivo and in vitro. HD-16 exerted an anti-fibrotic effect via regulation of the AMPK/SIRT3 pathway. Pharmacodynamic results showed that HD-16 alleviated the degree of injury and inflammation in CCl 4 -induced mouse liver fibrosis. Consistently, HD-16 also effectively inhibited the expression of α-SMA, Col1α1, Col3α1, and TIMP-1 in TGF-β1-activated LX-2 cells. Mechanistically, HD-16 promoted SIRT3 expression and activity in fibrotic liver and activated LX-2 cells. Furthermore, SIRT3 depletion attenuated the anti-fibrotic effects of HD-16. Intriguingly, HD-16 increased AMPK phosphorylation, whereas inhibition of SIRT3 expression did not affect AMPK phosphorylation. In contrast, AMPK silencing suppressed SIRT3 expression, suggesting that SIRT3 is a downstream target of AMPK in liver fibrosis. Overall, HD-16 attenuated CCl 4 -induced liver inflammation and fibrosis by activating the AMPK/SIRT3 pathway, and HD-16 may be a potential anti-fibrotic compound in the treatment of liver fibrosis. A schematic model of hesperetin derivative-16 attenuates CCl 4 -induced inflammation and liver fibrosis by activating the AMPK/SIRT3 pathway. Hesperetin derivative-16 alleviates liver injury, inflammation, and fibrogenesis in CCl 4 -induced mouse liver fibrosis and in LX-2 cells (human immortalized HSCs) stimulated by TGF-β1. HD-16 activates the AMPK/SIRT3 pathway in liver fibrosis, and activation of the AMPK/SIRT3 pathway facilitates the anti-fibrotic effect of HD-16. [Display omitted] [ABSTRACT FROM AUTHOR]