Abstract Cachexia is one of the serious complications in patients with end-stage cancer.Progressive depletion of skeletal muscle is an important feature of cachexia.Previous studies have found that excessive activation of autophagy accelerates skeletal muscle wasting in cachexia,and glutamine released from excessive catabolism of muscle tissue can trigger the autophagy.Mammalian target of rapamycin complex 1(mTORC1) and AMP-activated protein kinase(AMPK) signaling regulate autophagy genesis;moreover,glutamine regulates the mTORC1 and AMPK signaling pathways.Therefore,it is deduced that higher level of glutamine may result in abnormal autophagy by regulating mTORC1 and AMPK in cancer cachexia,which contributes to the development of skeletal muscle wasting.Here,this review discusses the following three perspectives:firstly,autophagy hyperactivation is involved in skeletal muscle wasting in cancer cachexia.Secondly,how mTORC1 and AMPK signaling pathways regulate autophagy.Finally,glutamine is involved in skeletal muscle wasting in cancer cachexia by induced autophagy hyperactivation via regulating mTORC1/AMPK signaling.Our study will provide a scientific basis for the development of potential therapeutic strategies.

Systemic inflammation of cachexia is an important cause of high mortality of degenerative diseases such as ad-vanced cancer,and also the most important factor to aggravate the cachexia process.Systemic inflammation of cachexia has a profound impact on the proliferation and invasion of tumors and the catabolism of muscle and adipose tissue in patients with cachexia.In recent years,studies have shown that the dysfunction of gut microbiota during cachexia is an important cause of cachexia systemic inflamma-tion and a key therapeutic target.The dysfunctions of intestinal barrier mediated by gut microbiota and the translocation of bacterial tox-ins during the cachexia period are important causes of cachexia systemic inflammation.This article mainly summarized the relationship between gut microbiota and cachexia systemic inflammation,and summarized the mechanism of intestinal flora inducing cachexia sys-temic inflammation by regulating short chain fatty acids,lipopolysaccharide,flagellin,peptidoglycan and other substances,with a view to providing new ideas for the prevention and treatment of cachexia systemic inflammation from the perspective of intestinal flora.

Objective Exploring the mechanism of mitophagy-mediated efferocytosis in myocardial fibrosis progression based on transcriptomics and bioinformatics,with potential chinese herbal medicine prediction and experimental validation.Methods A rat model of myocardial fibrosis was constructed by injecting angiotensin Ⅱ subcutaneously.RNA extraction and high-throughput sequencing were performed on myocardial tissue of rats,and differentially expressed genes(DEGs)were detected.Efferocytosis-related genes(ERGs)were obtained from the GeneCards database,and the intersection of DEGs and ERGs was mapped using the"venneuler"package in R 4.2.0 software.Differentially expressed efferocytosis-related genes(DEERGs)were obtained,and KEGG and GO enrichment analyses were performed for DEERGs.The network analysis of protein-to-protein interactions(PPI)and identification of key genes of DEERGs and mitochondrial autophagy(PINK1,P62)were conducted.The key genes were imported into Coremine database for chinese herbal medicine prediction.Combined with the Traditional Chinese Medicine pathogenesis of myocardial fibrosis and the previous research progress,the highest frequency of Astragali Radix,Carthami Flos and Lepidii Semen was selected for animal experiments.Masson staining was used to analyze the degree of fibrosis.Mitochondrial swelling assay and mitochondrial membrane potential detection were performed to evaluate the extent of mitochondrial dysfunction.RT-PCR and Western blot were employed to measure the mRNA and protein expression of mitophagy-related genes to assess mitophagy levels.Cardiac-resident macrophages were isolated,treated with AngⅡ,and subsequently assessed for their efferocytosis of apoptotic endothelial cells.Results There were 428 DEGs between in the control group and model group,including 165 up-regulated and 263 down-regulated DEGs.250 ERGs were identified from GeneCards database,and 12 DEERGs were obtained by drawing the intersection of DEGs and ERGs.KEGG and GO enrichment analysis of DEERGs showed that the process involved cellular burial,mitochondrial autophagy and endothelial cell regulation.PPI network analysis and identification of key genes of DEERGs and mitochondrial autophagy(PINK1,P62)were performed.The top 10 key genes were HIF1A,PINK1,GABARAP,ARG1,PPARG,UCP2,SQSTM1,CD36,SIRT1 and RAB7A.The key genes were imported into Coremine database to search for corresponding chinese herbal medicine.The most frequent ones were Astragali Radix,Carthami Flos and Lepidii Semen.Experimental validation demonstrated that the Astragali Radix,Carthami Flos and Lepidii Semen formulation inhibited AngⅡ-induced myocardial fibrosis and improved cardiac function in rats.Notably,it significantly enhanced the efferocytosis of apoptotic endothelial cells by AngⅡ-treated resident macrophages,with the high-dose group showing the most pronounced effect(P<0.05).Mechanistic studies using the high-dose Astragali Radix,Carthami Flos and Lepidii Semen formulation group revealed that,compared to control and model groups,the treatment group exhibited reduced mitophagy and ameliorated mitochondrial dysfunction(P<0.05).Conclusion The Astragali Radix,Carthami Flos and Lepidii Semen formulation may inhibit excessive mitophagy by regulating the expression of PINK1 and P62,promote macrophage efferocytosis,and thereby suppress the formation of myocardial fibrosis.

Objective Exploring the mechanism of mitophagy-mediated efferocytosis in myocardial fibrosis progression based on transcriptomics and bioinformatics,with potential chinese herbal medicine prediction and experimental validation.Methods A rat model of myocardial fibrosis was constructed by injecting angiotensin Ⅱ subcutaneously.RNA extraction and high-throughput sequencing were performed on myocardial tissue of rats,and differentially expressed genes(DEGs)were detected.Efferocytosis-related genes(ERGs)were obtained from the GeneCards database,and the intersection of DEGs and ERGs was mapped using the"venneuler"package in R 4.2.0 software.Differentially expressed efferocytosis-related genes(DEERGs)were obtained,and KEGG and GO enrichment analyses were performed for DEERGs.The network analysis of protein-to-protein interactions(PPI)and identification of key genes of DEERGs and mitochondrial autophagy(PINK1,P62)were conducted.The key genes were imported into Coremine database for chinese herbal medicine prediction.Combined with the Traditional Chinese Medicine pathogenesis of myocardial fibrosis and the previous research progress,the highest frequency of Astragali Radix,Carthami Flos and Lepidii Semen was selected for animal experiments.Masson staining was used to analyze the degree of fibrosis.Mitochondrial swelling assay and mitochondrial membrane potential detection were performed to evaluate the extent of mitochondrial dysfunction.RT-PCR and Western blot were employed to measure the mRNA and protein expression of mitophagy-related genes to assess mitophagy levels.Cardiac-resident macrophages were isolated,treated with AngⅡ,and subsequently assessed for their efferocytosis of apoptotic endothelial cells.Results There were 428 DEGs between in the control group and model group,including 165 up-regulated and 263 down-regulated DEGs.250 ERGs were identified from GeneCards database,and 12 DEERGs were obtained by drawing the intersection of DEGs and ERGs.KEGG and GO enrichment analysis of DEERGs showed that the process involved cellular burial,mitochondrial autophagy and endothelial cell regulation.PPI network analysis and identification of key genes of DEERGs and mitochondrial autophagy(PINK1,P62)were performed.The top 10 key genes were HIF1A,PINK1,GABARAP,ARG1,PPARG,UCP2,SQSTM1,CD36,SIRT1 and RAB7A.The key genes were imported into Coremine database to search for corresponding chinese herbal medicine.The most frequent ones were Astragali Radix,Carthami Flos and Lepidii Semen.Experimental validation demonstrated that the Astragali Radix,Carthami Flos and Lepidii Semen formulation inhibited AngⅡ-induced myocardial fibrosis and improved cardiac function in rats.Notably,it significantly enhanced the efferocytosis of apoptotic endothelial cells by AngⅡ-treated resident macrophages,with the high-dose group showing the most pronounced effect(P<0.05).Mechanistic studies using the high-dose Astragali Radix,Carthami Flos and Lepidii Semen formulation group revealed that,compared to control and model groups,the treatment group exhibited reduced mitophagy and ameliorated mitochondrial dysfunction(P<0.05).Conclusion The Astragali Radix,Carthami Flos and Lepidii Semen formulation may inhibit excessive mitophagy by regulating the expression of PINK1 and P62,promote macrophage efferocytosis,and thereby suppress the formation of myocardial fibrosis.

Systemic inflammation of cachexia is an important cause of high mortality of degenerative diseases such as ad-vanced cancer,and also the most important factor to aggravate the cachexia process.Systemic inflammation of cachexia has a profound impact on the proliferation and invasion of tumors and the catabolism of muscle and adipose tissue in patients with cachexia.In recent years,studies have shown that the dysfunction of gut microbiota during cachexia is an important cause of cachexia systemic inflamma-tion and a key therapeutic target.The dysfunctions of intestinal barrier mediated by gut microbiota and the translocation of bacterial tox-ins during the cachexia period are important causes of cachexia systemic inflammation.This article mainly summarized the relationship between gut microbiota and cachexia systemic inflammation,and summarized the mechanism of intestinal flora inducing cachexia sys-temic inflammation by regulating short chain fatty acids,lipopolysaccharide,flagellin,peptidoglycan and other substances,with a view to providing new ideas for the prevention and treatment of cachexia systemic inflammation from the perspective of intestinal flora.

Studies on promoting thermogenesis of brown and beige adipose tissue have become a hot topic in various metabolic conditions, which based on the conclusions that brown and beige adipose tissue are able to facilitate weight loss and improve metabolic health.However, recent studies showed that there were several problems for the anti-obesity application via promoting brown/beige adipose tissue thermogenesis.In obese individuals, classical brown adipose tissue presents thermogenesis dysfunction.Moreover, the beige adipose tissue has significantly lower thermogenesis capability compared with brown adipose tissue.On such conditions, excessively excited sympathetic innervation is essential to increase energy consumption in obesity via increasing classic brown adipose thermogenesis and inducing white adipose tissue browning.However, excessive excited sympathetic nerve results in cardiovascular side effects.Additionally, excessive induction of white adipose tissue browning might disrupt the white adipose tissue homeostasis and aggravate the intrinsic metabolic disorders.Therefore, solving these practical application problems of brown/beige adipose tissue is a new research area for improving metabolic disorders.

Adipocytes are classified into three types, including white, brown, and “beige/brite” adipocytes. There exist differences in origin of adipocytes, gene expressions, morphology, and functions among three kinds of adipocytes. Multiple factors such as physical and chemical factors, neurohormonal and immunological factors, transcriptional factors have been shown to regulate and control the browning process and lipolysis of white adipose tissue. Thus, they may become new targets for anti-obesity intervention. In the process of obesity, chronic inflammation reaction, adipose tissue remodeling and abnormal angiogenesis occurring in the adipose tissue cause pathological fat expansion and reduce lipid storage in adipocytes. Understanding adipocytes biology is important to decipher how the aberrant adipose tissue contributes to obesity and metabolic disorders, and provides guidance for treating obesity.

[ ABSTRACT] AIM:To investigate the preventive effect of Guizhi decoction on myocardial injury after chemical sympathectomy induced by 6-hydroxydopamine (6-OHDA).METHODS:Wistar rats (n=54) were randomly divided in-to 6 groups.Methycobal and Guizhi decoction ( with different proportions between Ramulus Cinnamomi and Radix paeoniae Alba at 2∶1, 1∶2 or 1∶1) were pre-administered to the rats.Immunohistochemical method was used to observe the cardiac sympathetic nerve distribution.The contents of tyrosine hydroxylase (TH), choline acetylaminotransferase (ChAT) and growth-associated protein 43 (GAP-43) in the left ventricle were measured by ELISA.The serum levels of myocardial en-zymes and morphology of myocardial tissues were also observed.RESULTS:6-OHDA successfully induced cardiac sympa-thetic denervation as the contents of TH and GAP-43 in the left ventricle declined significantly.Compared with model group, the content of TH was elevated in both methycobal group and Guizhi decoction groups, while the content of GAP-43 was elevated only in Guizhi decoction groups.The serum levels of myocardial enzymes and the histopathological changes of the cardiac tissues were deteriorated after injection of 6-OHDA, indicating that the myocardial injury was established. Methycobal and Guizhi decoction normalized the abnormal change.Guizhi decoctions at 2∶1 and 1∶1 showed the best effi-cacy.CONCLUSION:6-OHDA-induced sympathetic denervation causes myocardial injury.Guizhi decoction with the proportions between Ranulus Cinnamomi and Radix paeoniae Alba at 2∶1 and 1∶1 effectively alleviate the myocardial injury after cardiac sympathetic denervation induced by 6-OHDA.

The role of chronic inflammation and autonomic neuropathy in the crucial underlying process con -tributing to the initiation and the progression of various cardiovascular diseases is well established .It is well known that the immune system is innervated by the autonomic nervous system , and the inflammatory reaction and immune reaction are re-gulated by the autonomic nerve system .Vagus nerve depresses inflammatory reaction via cholinergic anti-inflammatory path-way (CAP), while sympathetic nervous system has bidirectional regulation of pro-inflammation and anti-inflammation, which are affected by several factors such as the concentration of neurotransmitters or types of receptors .In this paper , we reviewed different effects of CAP and sympathetic nervous system on cardiovascular inflammatory reaction .Activation of CAP and regaining normal sympathetic function will improve the chronic inflammation in the process of cardiovascular disea -ses.Low-toxic and selective α7nAchR agonist is expected to be applied in cardiovascular diseases to alleviate chronic in -flammation .

Aim To investigate the preventive effect of Guizhi decoction on cardiac sympathetic sprouting induced by 4-Methylcatechol (4-MC) . Methods The rat models of cardiac sympathetic sprouting were in-duced by 10 mg · L-1 4-MC ( 10μg · kg-1 body weight, i. p. ) . Guizhi decoctions ( with different pro-portion between Ramulus Cinnamomi and Radix Paeon-iae Alba, 1 : 1, 1 : 2 and 2 : 1) and metoprolol were administered to the rats. Heart rate and electrocardio-gram ( ECG ) were observed, the content of norepi-nephrine (NE), growth associated protein (GAP-43), tyrosine hydroxylase ( TH ) and acetylcholine transfer-ase enzyme ( CHAT) in myocardial homogenate of left ventricular and right atrial were determined by ELISA method, and immunofluorescence assay was used to observe cardiac nerve sprouting and sympathetic distri-bution. Results 4-MC caused cardiac sympathetic sprouting and parasympathetic was not influenced. Heart rate of the model group was improved significant-ly and higher than that of the other groups . Compared with the model group, the content of NE, GAP-43 and TH in left ventricle and right atrium of the metoprolol group and Guizhi decoction group were decreased( P<0.05 ) , and the immunofluorescence result showed that the distribution of TH positive nerve was reduced sig-nificantly(P<0.05). It was demonstrated that Guizhi decoction of the proportion between Ramulus Cinnamo-mi and Radix Paeoniae Alba 1 : 1 and 1 : 2 had the best efficacy, which was similar to the efficacy of meto-prolol. Conclusion Guizhi decoction ( with the pro-portion between Ramulus Cinnamomi and Radix Paeon-iae Alba 1 : 1 and 1 : 2 ) effectively inhibits the cardi-ac sympathetic sprouting induced by 4-MC.