Insomnia is a sleep disorder characterized by difficulty in falling asleep， sleep maintenance disorder and impaired daytime function. Its pathological mechanism involves multiple factors such as nerve excitability， circadian rhythm， cell apoptosis， oxidative stress injury. As a classical tyrosine kinase signaling pathway， phosphatidylinositol 3-kinase/protein kinase B（PI3K/Akt） triggers Akt phosphorylation cascade， inducing inflammatory response， apoptosis， autophagy， oxidative damage， nerve excitability， and circadian rhythm imbalance. Traditional Chinese medicine（TCM） can improve sleep by targeting the PI3K/Akt pathway. Based on this， this paper systematically reviews the research progress on the regulation of PI3K/Akt pathway by traditional Chinese medicine（TCM） for insomnia at home and abroad. These drugs can regulate neuronal excitability by regulating the PI3K/Akt pathway， affect the circadian rhythm， alleviate inflammation， apoptosis， autophagy and oxidative stress， and thus regulate sleep-wake. Furthermore， literature review indicates that the PI3K/Akt signaling pathway may represent a specific pathway underlying phlegm-turbidity disturbing the upper Jiao-type insomnia.

Insomnia is a sleep disorder characterized by difficulty in falling asleep， sleep maintenance disorder and impaired daytime function. Its pathological mechanism involves multiple factors such as nerve excitability， circadian rhythm， cell apoptosis， oxidative stress injury. As a classical tyrosine kinase signaling pathway， phosphatidylinositol 3-kinase/protein kinase B（PI3K/Akt） triggers Akt phosphorylation cascade， inducing inflammatory response， apoptosis， autophagy， oxidative damage， nerve excitability， and circadian rhythm imbalance. Traditional Chinese medicine（TCM） can improve sleep by targeting the PI3K/Akt pathway. Based on this， this paper systematically reviews the research progress on the regulation of PI3K/Akt pathway by traditional Chinese medicine（TCM） for insomnia at home and abroad. These drugs can regulate neuronal excitability by regulating the PI3K/Akt pathway， affect the circadian rhythm， alleviate inflammation， apoptosis， autophagy and oxidative stress， and thus regulate sleep-wake. Furthermore， literature review indicates that the PI3K/Akt signaling pathway may represent a specific pathway underlying phlegm-turbidity disturbing the upper Jiao-type insomnia.

BACKGROUND:Ferroptosis is an iron-dependent regulatory form of cell death characterized by iron-dependent lipid peroxidation.Long-chain acyl-coenzyme A synthase 4(ACSL4)is involved in the formation of lipid peroxidation substrates,thereby resulting in ferroptosis.Recent studies have shown that ACSL4-mediated ferroptosis plays a key role in atherosclerotic cardiovascular disease. OBJECTIVE:To summarize the structural function and regulatory mechanism of ACSL4 and its potential molecular mechanism mediating ferroptosis,and to elaborate the application of ACSL4 driving ferroptosis in atherosclerosis,ischemic stroke and myocardial infarction,in order to provide a new therapeutic strategy for the treatment of atherosclerotic cardiovascular diseases. METHODS:Relevant literature was searched in PubMed database from database inception to August 2023 using the keywords of"atherosclerosis,ferroptosis,long-chain acyl-coenzyme A synthase 4,ACSL4,glutathione peroxidase 4,ischemic stroke,myocardial infarction,endothelial cell,smooth muscle cells,foam cell."Finally,76 documents were included for review and analysis. RESULTS AND CONCLUSION:ACSL4 participates in the formation of coenzyme derivatives of polyunsaturated fatty acids and inserts them into phospholipids to provide substrates for lipid peroxidation,the core mechanism of iron death.Among the regulatory factors of ACSL4 expression,integrin α6β4,intracellular vesicular transport factor p115,and zinc lipoprotein A20 negatively regulate its expression.Meanwhile,multiple miRs down-regulate its expression by binding to 3'-UTR.On the contrary,up-regulation of ACSL4 is mostly regulated by transcription factors.ACSL4-dependent production of phospholipids containing polyunsaturated fatty acids is an essential prerequisite for lipid peroxidation and ferroptosis.Moreover,ACSL4 and glutathione peroxidase 4 are mutually dependent as positive and negative regulators of ferroptosis,and their specific mechanisms remain to be further studied.ACSL4-mediated ferroptosis is involved in the pathological mechanism of atherosclerosis,ischemic stroke,and myocardial infarction.Endothelial cell injury in atherosclerosis is closely related to ACSL4-mediated ferroptosis,but there are no reports on the involvement of ACSL4 in foam cell formation,smooth muscle cell phenotype transformation,and calcification.ACSL4 has become a research hotspot as a biomarker and potential target of ferroptosis.Targeting ACSL4 to inhibit ferroptosis may become a new direction for the treatment of atherosclerotic cardiovascular diseases.However,there are few studies on drugs inhibiting ACSL4,and further studies are needed in the future.

Ischemic heart disease (IHD) is associated with high morbidity and mortality rates. Reperfusion therapy is the best treatment option for this condition. However, reperfusion can aggravate myocardial damage through a phenomenon known as myocardial ischemia/reperfusion (I/R) injury, which has recently gained the attention of researchers. Several studies have shown that Chinese herbal medicines and their natural monomeric components exert therapeutic effects against I/R injury. This review outlines the current knowledge on the pathological mechanisms through which mitochondria participate in I/R injury, focusing on the issues related to energy metabolism, mitochondrial quality control disorders, oxidative stress, and calcium. The mechanisms by which mitochondria mediate cell death have also been discussed. To develop a resource for the prevention and management of clinical myocardial I/R damage, we compiled the most recent research on the effects of Chinese herbal remedies and their monomer components.

This study investigated the regulatory potential of salidroside (SAL), a primary active compound in Rhodiola rosea L., on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha (HIF-1a) pathway in osteoblasts. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to validate whether the receptor activator of nuclear factor-?B ligand (RANKL) is the downstream target gene of HIF-1a in osteoblasts. The study also utilized lipopolysaccharide (LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo. Furthermore, conditioned medium (CM) from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1a pathway. Hypoxic condition-induced overexpression of HIF-1a upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells. In vivo, SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1a by downregulating the expression of RANKL, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and angiopoietin-like 4 (ANGPTL4). In the paracrine experiment, conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. RANKL emerges as the downstream target gene regulated by HIF-1a in osteoblasts. SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.
Animals ; Osteoblasts/cytology* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Glucosides/administration & dosage* ; Cell Differentiation/drug effects* ; Phenols/administration & dosage* ; Mice ; Osteoclasts/metabolism* ; RANK Ligand/genetics* ; Rhodiola/chemistry* ; Osteogenesis/drug effects* ; Signal Transduction/drug effects* ; Interleukin-6/genetics* ; Male ; RAW 264.7 Cells ; Osteolysis/genetics* ; Humans ; Mice, Inbred C57BL

Objective This study aimed to observe the effect of Jiang Tang San Hao Formula(JTSHF)on systemic and intestinal inflammation,as well as on the NLRP3 inflammasome in type 2 diabetic mice(T2DM),and to elucidate its anti-diabetic molecular mechanisms.Methods Four-week-old male C57BL/6 N mice were used to establish the T2DM model using a high-fat diet combined with streptozotocin injection.The diabetic mice were randomly divided into the model,metformin,and JTSHF groups.A control group was also set to provide baseline comparisons.Each group of mice was orally administered with the corresponding medication daily.The metformin group was orally administered with 0.20 g/kg metformin,the JTSHF group was orally administered with 4.26 g/kg JTSHF,and the control group and model group were orally administered with an equal amount of sterile water continuously for 8 weeks.After an 8-week drug intervention via gavage,the lipopolysaccharide(LPS),tumor necrosis factor-alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6)serum and colon levels were quantified using an enzyme-linked immunosorbent assay(ELISA).The pathological morphology of the colon was observed using hematoxylin and eosin staining.NOD-like receptor protein 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),caspase-1,zonula occludens-1(ZO-1),occludin,and G-protein coupled receptor 43(GPR43)protein expression in the colon were assessed using immunohistochemistry.The mRNA expression levels of NLRP3,ASC,caspase-1,ZO-1,Occludin,and GPR43 in the colon were detected using Real-time PCR.Results The ELISA data revealed significant differences in inflammatory markers among the groups.Compared with the model group,the JTSHF group exhibited notably reduced LPS,TNF-α,IL-1β,and IL-6 levels(P<0.05).Moreover,compared with the model group,JTSHF treatment upregulated ZO-1,occludin,and GPR43 protein and mRNA expression in the colon and downregulated NLRP3,ASC,and Caspase-1 protein and mRNA expression(P<0.05).Conclusion The inflammatory reaction of T2DM mice is apparent.JTSHF effectively alleviates the systemic and intestinal inflammatory response of T2DM mice by inhibiting the NLRP3 inflammasome and repairing the intestinal mucosal barrier,highlighting the potential molecular mechanisms of the anti-diabetes effects of JTSHF.

Objective We investigated the effects of Xueguan Ruanhua Pills(XGRHW) on ferroptosis in ApoE-/- atherosclerotic mice through the nuclear factor E2 related factor 2 (Nrf2)/xCT/glutathione peroxidase 4 (GPX4) signaling pathway.Methods Ten male C57BL/6J mice in the normal group were fed normal chow. Additionally, 50 ApoE-/- mice were fed high-fat chow for 12 weeks, and were divided into the following five groups (10 mice per group): the model group, the XGRHW low-dose (2.34g/kg) group, the XGRHW high-dose (4.68 g/kg) group, the XGRHW high-dose combined with the Nrf2 inhibitor ML385 (0.03 g/kg) group, and the ferrostatin-1 (1 mg/kg) group. Drugs were administered for 6 weeks. The blood levels of four types of lipids were detected by an automatic lipid analyzer, lipid deposition in the aorta was observed by Oil Red O staining, histomorphological changes in the aortic sinus were observed by HE staining, the serum levels of Fe2+, MDA, GSH, and SOD were determined by colorimetric assays, and the expression levels of FTH1 and FTL in the aortic sinus were observed by immunofluorescence. The protein levels of Nrf2, xCT, and GPX4 in mouse aortic tissues were detected by Western blotting. The ultrastructural changes of aortic mitochondria were observed by transmission electron microscopy.Results Compared with the normal group, mice in the model group showed obvious lipid plaque deposition in the aorta, severely calcified lesions in the aortic sinus, elevated serum levels of TC, TG, LDL-C, Fe2+, and MDA, decreased levels of HDL-C, SOD, and GSH (P<0.01), and decreased protein expressions of aortic Nrf2, xCT, and GPX4 as well as the iron storage proteins FTH1 and FTL (P<0.01), and serve damage to mitochondrial structure and morphology. Compared with the model group, the relative aortic plaque area was decreased, calcified lesions in the aortic sinus were decreased, serum levels of TC, TG, LDL-C, Fe2+, and MDA were decreased, and HDL-C, SOD, and GSH levels were increased in the XGRHW low-dose and high-dose and ferrostatin-1 groups (P<0.05 or P<0.01), and Nrf2, xCT, GPX4, and the iron storage proteins FTH1 and FTL were upregulated in aortic tissues (P<0.05 or P<0.01), and mitochondrial structure approaching normal. In the XGRHW high-dose+ML385 group, compared with the XGRHW high-dose group, the levels of blood lipids and lipid peroxidation were increased and the protein levels of Nrf2, xCT, and GPX4 in aortic tissue and the iron storage proteins FTH1 and FTL were decreased (P<0.01), and mitochondrial structure was damaged indicating that ML385 could inhibit the therapeutic effect of the XGRHW in atherosclerotic mice.Conclusion The XGRHW can improve blood lipid levels and reduce the degree of arterial plaque lesions in atherosclerotic mice, and its mechanism of action may be related to activation of the Nrf2/xCT/GPX4 pathway to inhibit ferroptosis.

Objective This study aimed to observe the effect of Jiang Tang San Hao Formula(JTSHF)on systemic and intestinal inflammation,as well as on the NLRP3 inflammasome in type 2 diabetic mice(T2DM),and to elucidate its anti-diabetic molecular mechanisms.Methods Four-week-old male C57BL/6 N mice were used to establish the T2DM model using a high-fat diet combined with streptozotocin injection.The diabetic mice were randomly divided into the model,metformin,and JTSHF groups.A control group was also set to provide baseline comparisons.Each group of mice was orally administered with the corresponding medication daily.The metformin group was orally administered with 0.20 g/kg metformin,the JTSHF group was orally administered with 4.26 g/kg JTSHF,and the control group and model group were orally administered with an equal amount of sterile water continuously for 8 weeks.After an 8-week drug intervention via gavage,the lipopolysaccharide(LPS),tumor necrosis factor-alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6)serum and colon levels were quantified using an enzyme-linked immunosorbent assay(ELISA).The pathological morphology of the colon was observed using hematoxylin and eosin staining.NOD-like receptor protein 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),caspase-1,zonula occludens-1(ZO-1),occludin,and G-protein coupled receptor 43(GPR43)protein expression in the colon were assessed using immunohistochemistry.The mRNA expression levels of NLRP3,ASC,caspase-1,ZO-1,Occludin,and GPR43 in the colon were detected using Real-time PCR.Results The ELISA data revealed significant differences in inflammatory markers among the groups.Compared with the model group,the JTSHF group exhibited notably reduced LPS,TNF-α,IL-1β,and IL-6 levels(P<0.05).Moreover,compared with the model group,JTSHF treatment upregulated ZO-1,occludin,and GPR43 protein and mRNA expression in the colon and downregulated NLRP3,ASC,and Caspase-1 protein and mRNA expression(P<0.05).Conclusion The inflammatory reaction of T2DM mice is apparent.JTSHF effectively alleviates the systemic and intestinal inflammatory response of T2DM mice by inhibiting the NLRP3 inflammasome and repairing the intestinal mucosal barrier,highlighting the potential molecular mechanisms of the anti-diabetes effects of JTSHF.

Objective This study aimed to observe the effect of Jiang Tang San Hao Formula(JTSHF)on systemic and intestinal inflammation,as well as on the NLRP3 inflammasome in type 2 diabetic mice(T2DM),and to elucidate its anti-diabetic molecular mechanisms.Methods Four-week-old male C57BL/6 N mice were used to establish the T2DM model using a high-fat diet combined with streptozotocin injection.The diabetic mice were randomly divided into the model,metformin,and JTSHF groups.A control group was also set to provide baseline comparisons.Each group of mice was orally administered with the corresponding medication daily.The metformin group was orally administered with 0.20 g/kg metformin,the JTSHF group was orally administered with 4.26 g/kg JTSHF,and the control group and model group were orally administered with an equal amount of sterile water continuously for 8 weeks.After an 8-week drug intervention via gavage,the lipopolysaccharide(LPS),tumor necrosis factor-alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6)serum and colon levels were quantified using an enzyme-linked immunosorbent assay(ELISA).The pathological morphology of the colon was observed using hematoxylin and eosin staining.NOD-like receptor protein 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),caspase-1,zonula occludens-1(ZO-1),occludin,and G-protein coupled receptor 43(GPR43)protein expression in the colon were assessed using immunohistochemistry.The mRNA expression levels of NLRP3,ASC,caspase-1,ZO-1,Occludin,and GPR43 in the colon were detected using Real-time PCR.Results The ELISA data revealed significant differences in inflammatory markers among the groups.Compared with the model group,the JTSHF group exhibited notably reduced LPS,TNF-α,IL-1β,and IL-6 levels(P<0.05).Moreover,compared with the model group,JTSHF treatment upregulated ZO-1,occludin,and GPR43 protein and mRNA expression in the colon and downregulated NLRP3,ASC,and Caspase-1 protein and mRNA expression(P<0.05).Conclusion The inflammatory reaction of T2DM mice is apparent.JTSHF effectively alleviates the systemic and intestinal inflammatory response of T2DM mice by inhibiting the NLRP3 inflammasome and repairing the intestinal mucosal barrier,highlighting the potential molecular mechanisms of the anti-diabetes effects of JTSHF.

Objective To explore the factors for 30-day prognosis of patients with paraquat(PQ)or diquat(DQ)poisoning so as to establish a binary Logistic equation to judge the prognosis and provide effective treatment.Methods We recruited 109 patients with PQ(n=82)or DQ(n=27)poisoning who met the inclusion and exclusion criteria in The First and The Second Affiliated Hospital of Xi'an Jiaotong University from January 2010 to October 2021,and obtained their prognosis of 30 days by medical records and telephone.The death group(n=46)and the survival group(n=63)were divided.The clinical data,biochemical data at 1 h after admission,administration of hemoperfusion(HP)and whether HP combined with continuous renal replacement treatment(CRRT)were compared between the two groups.The independent risk factors in the two groups were analyzed,and the binary Logistic regression equation model was established and verified.Results Age,dosage,lactic acid(Lac),and administration of HP were independent risk factors for 30 days mortality(P＜0.05).Regression equation:Y=Logit(P)=-3.588+0.05 × age+0.031 × dosage+0.467 × Lac-1.915 × presence of HP(no HP assigned as 0,with HP assigned as 1).The model was tested by Hosmer-Lemeshow goodness of fit:x2=7.645,freedom=8,P=0.469,which indicated that the model had a good fit.The sensitivity of the model was 86.96％,the specificity was 88.89％,area under the curve(AUC)was 0.93,the 95％confidence interval(CI)was 0.88-0.98,and the P value was＜0.001.The calibration degree of the model was good,and the C-index was 0.931.The clinical decision curve analysis(DCA)showed that the model had a good standardized net benefit.Conclusion The model can scientifically and effectively predict the 30-day prognosis of patients with PQ or DQ poisoning and guide clinicians.