Objective To investigate the association between the TyG index,its modified variants,and the risk of developing colorectal cancer(CRC).Methods This study included a total of 93,177 participants from the 2006 Kailuan Group health examination cohort.Participants were categorized into four quartiles(Q1-Q4)according to their TyG and modified TyG indices.Follow-up began at the baseline examination,with incident CRC as the primary outcome.Participants were censored at the time of CRC diagnosis,death,or the end of the study,whichever occurred first.The dose-response relationship between TyG and its modified indices and the risk of CRC was evalu-ated using restricted cubic splines(RCS)in conjunction with Cox proportional hazards regression models,yielding hazard ratios(HRs)and 95%confidence intervals(CIs).To compare the strength of associations between TyG and its modified versions(TyG-BMI,TyG-WC,TyG-WHR,TyG-WHtR,TyG-WWI)and CRC risk,HRs for CRC per one standard deviation increase in each index were calculated and compared.Results Both the TyG index and its modified variants demonstrated a significant dose-response relationship with the risk of CRC incidence.Specifically,for the TyG index,each 1-standard deviation(SD)increase was associated with a 1.17-fold(95%CI:1.09～1.27)higher risk of CRC.Compared with the first quartile(Q1),the third quartile(Q3)and fourth quartile(Q4)exhibited a 1.25-fold(95%CI:1.01～1.55)and 1.26-fold(95%CI:1.01～1.57)increased risk,respectively.For TyG-BMI,each 1-SD increase was linked to a 1.20-fold(95%CI:1.07～1.35)elevated CRC risk.Compared with Q1,Q3 and Q4 showed a 1.32-fold(95%CI:1.06～1.64)and 1.51-fold(95%CI:1.21～1.88)increase,respectively.Regarding TyG-WC,each 1-SD increment was associated with a 1.22-fold(95%CI:1.13～1.32)higher CRC risk,with Q3 and Q4 showing a 1.35-fold(95%CI:1.08～1.70)and 1.56-fold(95%CI:1.24～1.96)increased risk compared to Q1.For TyG-WHtR,each 1-SD increase was associated with a 1.24-fold(95%CI:1.08-1.42)higher CRC risk.Compared with Q1,Q2,Q3,and Q4 demonstrated a 1.31-fold(95%CI:1.03～1.66),1.55-fold(95%CI:1.23～1.95),and 1.60-fold(95%CI:1.27～2.02)increase,respectively.In the case of TyG-WHR,each 1-SD increase was associated with a 1.19-fold(95%CI:1.10～1.29)higher CRC risk,with Q4 showing a 1.42-fold(95%CI:1.14～1.77)increased risk compared to Q1.Finally,for TyG-WWI,each 1-SD increase was associated with a 1.22-fold(95%CI:1.13～1.32)elevated CRC risk,with both Q3 and Q4 showing a 1.58-fold increase(Q3:95%CI:1.26～1.98;Q4:95%CI:1.25～1.99).Stratified analyses by sex and age consistently revealed significant associations between the TyG index and its modified variants and CRC risk.Furthermore,these indices were independently associated with the incidence of both colon cancer and rectal cancer.Conclusions(1)Elevated levels of the TyG index and its modified variants are independent risk factors for CRC.(2)Both the TyG index and its modified forms demonstrate a significant dose-response association with the incidence of CRC.(3)Among the modified TyG indices,TyG-WWI,TyG-WHtR,TyG-BMI,TyG-WC,and TyG-WHR showed stronger correlations with CRC risk compared to the original TyG index.

Objective To investigate the association between the TyG index,its modified variants,and the risk of developing colorectal cancer(CRC).Methods This study included a total of 93,177 participants from the 2006 Kailuan Group health examination cohort.Participants were categorized into four quartiles(Q1-Q4)according to their TyG and modified TyG indices.Follow-up began at the baseline examination,with incident CRC as the primary outcome.Participants were censored at the time of CRC diagnosis,death,or the end of the study,whichever occurred first.The dose-response relationship between TyG and its modified indices and the risk of CRC was evalu-ated using restricted cubic splines(RCS)in conjunction with Cox proportional hazards regression models,yielding hazard ratios(HRs)and 95%confidence intervals(CIs).To compare the strength of associations between TyG and its modified versions(TyG-BMI,TyG-WC,TyG-WHR,TyG-WHtR,TyG-WWI)and CRC risk,HRs for CRC per one standard deviation increase in each index were calculated and compared.Results Both the TyG index and its modified variants demonstrated a significant dose-response relationship with the risk of CRC incidence.Specifically,for the TyG index,each 1-standard deviation(SD)increase was associated with a 1.17-fold(95%CI:1.09～1.27)higher risk of CRC.Compared with the first quartile(Q1),the third quartile(Q3)and fourth quartile(Q4)exhibited a 1.25-fold(95%CI:1.01～1.55)and 1.26-fold(95%CI:1.01～1.57)increased risk,respectively.For TyG-BMI,each 1-SD increase was linked to a 1.20-fold(95%CI:1.07～1.35)elevated CRC risk.Compared with Q1,Q3 and Q4 showed a 1.32-fold(95%CI:1.06～1.64)and 1.51-fold(95%CI:1.21～1.88)increase,respectively.Regarding TyG-WC,each 1-SD increment was associated with a 1.22-fold(95%CI:1.13～1.32)higher CRC risk,with Q3 and Q4 showing a 1.35-fold(95%CI:1.08～1.70)and 1.56-fold(95%CI:1.24～1.96)increased risk compared to Q1.For TyG-WHtR,each 1-SD increase was associated with a 1.24-fold(95%CI:1.08-1.42)higher CRC risk.Compared with Q1,Q2,Q3,and Q4 demonstrated a 1.31-fold(95%CI:1.03～1.66),1.55-fold(95%CI:1.23～1.95),and 1.60-fold(95%CI:1.27～2.02)increase,respectively.In the case of TyG-WHR,each 1-SD increase was associated with a 1.19-fold(95%CI:1.10～1.29)higher CRC risk,with Q4 showing a 1.42-fold(95%CI:1.14～1.77)increased risk compared to Q1.Finally,for TyG-WWI,each 1-SD increase was associated with a 1.22-fold(95%CI:1.13～1.32)elevated CRC risk,with both Q3 and Q4 showing a 1.58-fold increase(Q3:95%CI:1.26～1.98;Q4:95%CI:1.25～1.99).Stratified analyses by sex and age consistently revealed significant associations between the TyG index and its modified variants and CRC risk.Furthermore,these indices were independently associated with the incidence of both colon cancer and rectal cancer.Conclusions(1)Elevated levels of the TyG index and its modified variants are independent risk factors for CRC.(2)Both the TyG index and its modified forms demonstrate a significant dose-response association with the incidence of CRC.(3)Among the modified TyG indices,TyG-WWI,TyG-WHtR,TyG-BMI,TyG-WC,and TyG-WHR showed stronger correlations with CRC risk compared to the original TyG index.

Objective To clarify the anti-inflammatory effect of chlorogenic acid on lipopolysaccharide(LPS)-induced inflamma-tion in macrophage RAW264.7,and to reveal its possible molecular mechanism.Methods The cellular activity of RAW264.7 after the intervention of different concentrations of chlorogenic acid was detected by CCK-8 method;the macrophage RAW264.7 was stimulated by LPS to preset cellular inflammatory state.The blank control group(K group,n=3),the model control group(L group,n=3),and the experimental group(S group,n=3)were administered separately,and the cell morphology was dynamically observed;cell precipita-tion and supernatants were obtained at 24 h and 48h,respectively.The concentrations of inflammatory cytokine interleukin(IL)-1β,monocyte chemoattractant protein-1(MCP-1),and arginase-1(Arg-1)in the cell supernatants were detected by enzyme-linked immunosorbent assay(ELISA);the mRNA expression of prostaglandin endoperoxide synthase 2(PTGS2),transforming growth factor-β1(TGF-β1),high mobility histone 1(HMGB1),and nuclear transcription factor-κB(NF-κB)were detected by quantitative real-time PCR(RT-qPCR).Results RAW264.7 cellular inflammatory state was successfully preset with 1 μg/ml LPS;12.5～200.0μg/ml chlorogenic acid had no distinct toxicity on RAW264.7.Chlorogenic acid at 50μg/ml and 200μg/ml had obvious proliferation effects on RAW264.7 cells(P＜0.05).Compared with the model control group,the content of IL-1 β protein in the supernatant of the experimental group was significantly decreased,while the content of Arg-1 was significantly increased(P＜0.05).Compared with the model control group,50μg/ml of chlorogenic acid significantly decreased the mRNA expressions of NF-κB,TGF-β1,PTGS2,and HMGB1 in LPS-induced inflammatory cells(P＜0.05).Conclusion Chlorogenic acid has a distinct inhibitory effect on LPS-induced RAW264.7 inflammatory response,which may be achieved by regulating molecular expression of the HMGB1-mediated NF-κB pathway.

Based on network pharmacology and in vitro experiments,this study was performed to explore the possible mechanism of astragaloside Ⅳ(AS-Ⅳ)in the prevention and treatment of pneumonia by regulating immune function in RAW264.7 macrophages.Pharm Mapper,SwissTargetPrediction and STITCH databases were used to predict the target sites of AS-Ⅳ,while Genecard and DisGeNET databases were used to retrieve the pneumonia targets,and the intersection with AS-Ⅳ targets was obtained.Then STRING platform and Cytoscape software were used to construct the protein interaction network of the intersection targets,and the core targets were selected according to the degree value.The DAVID database was used for GO functional annotation and KEGG pathway enrichment analysis,and the KEGG database was further used to predict the possible pathways of AS-Ⅳ intervention in pneumonia.For in vitro experiment,macrophage RAW264.7 of logarithmic phase were randomly divided into 3 groups:control group(C),model group(M)and the AS-Ⅳ group(AS-Ⅳ).Except for group C,the other two groups were stimulated with LPS,and the AS-Ⅳ group was further intervened by AS-Ⅳ.CCK8 method was used to determine the effect of AS-Ⅳ on the proliferation of RAW264.7 cells;ELISA was used to determine the secretion levels of NF-κB,IL-1β,MCP-1 and Arg-1;qPCR was used to detect the gene expression of TLR4 and its downstream pathway molecules HMGB1 and TLR4 in each group.Network pharmacological analysis predicted that AS-Ⅳ had 158 targets and 112 intersection targets with pneumonia,while the enrichment analysis of KEGG pathway obtained 126 pathways.In consider with literature,HMGB1,TLR4,TRIF,Myd88 and NF-κB were identified as the target of pathway to be verified.Further in vitro experiments confirmed that NF-κB,IL-1β and MCP-1 in AS-Ⅳ group were significantly decreased as compared with M group,while Arg-1 was significantly increased,the expression of HMGB1,TLR4,TRIF and Myd88 genes were significantly decreased as compared with M group.Taken together,AS-Ⅳ can regulate the inflammatory immune responses of RAW264.7 through HMGB1/TLR4 related signaling pathways,which provides experimental basis and data support for clinical pneumonia treatment.

Background: Heart failure (HF) is the leading cause of death worldwide. Myocardial infarction (MI) is a major contributor to HF. Shengmai injection (SMI) has exhibited protective efficacy in preventing HF. However, the advantages of SMI in the progression of MI-induced HF remain unclear. Objective: To reveal the advantages of SMI in the progression of MI-induced HF. Methods: The differently expressed proteins in rat models with ischemia at the 7th, 14th, 21st, and 28th days were obtained from PubMed. The “compound-target” network of SMI was constructed via the Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine database. The protein-protein interaction relationship was constructed, and biological function was applied to evaluate the advantage effect of SMI in the progression of MI-induced HF. In addition, the prediction results were validated in rats with left anterior descending coronary artery ligation. The cardiac function and heart performance were observed via echocardiography, hematoxylin-eosin staining, and Masson staining, and the levels of procollagen type I carboxy-terminal propeptide, recombinant versican (VCAN), and collagen 1A1 (COL1A1) weremeasured via enzyme-linked immunosorbent assay in rat plasma. In vitro, H9c2 cells were treated with Angiotensin II (Ang II), and the cell viability, the level of reactive oxygen species (ROS) and Ca , and the expression of ANP and connective tissue growth factor were evaluated. Furthermore, the schizandrin A was identified as one of the possible key compounds. After schizandrin A treatment, the level of ROS and Ca and the expression of COL1A1 and VCAN were evaluated. Results: There were 189 compounds and 1612 targets involved in the “compound-target” network, and an interaction relationship was constructed. According to the top subnetwork, the Gene Ontology annotation revealed that SMI may have an antifibrotic and cardiac protective effect against MI-induced HF. In rats, SMI increased ejection fraction, left ventricular fractional shortening, and cardiac output and decreased fibrosis injury; moreover, SMI decreased the levels of procollagen type I carboxy-terminal propeptide, VCAN, and COL1A1 within 35 days. When compared with the Ang II treatment group, SMI increased cell viability and decreased cellular calcium concentration, ROS generation, and the expression of ANP and connective tissue growth factor in vitro. Furthermore, schizandrin A was discovered to be a possible compound in myocardial protection. Schizandrin A increased cell viability after Ang II treatment while decreasing COL1A1 and VCAN levels. Conclusions: This method demonstrates that SMI has an antifibrotic effect. This study provides a promising perspective on translating omics data to clinical applications, as well as an appealing approach to investigating the precise intervention of a multicomponent drug.

Based on network pharmacology and in vitro experiments,this study was performed to explore the possible mechanism of astragaloside Ⅳ(AS-Ⅳ)in the prevention and treatment of pneumonia by regulating immune function in RAW264.7 macrophages.Pharm Mapper,SwissTargetPrediction and STITCH databases were used to predict the target sites of AS-Ⅳ,while Genecard and DisGeNET databases were used to retrieve the pneumonia targets,and the intersection with AS-Ⅳ targets was obtained.Then STRING platform and Cytoscape software were used to construct the protein interaction network of the intersection targets,and the core targets were selected according to the degree value.The DAVID database was used for GO functional annotation and KEGG pathway enrichment analysis,and the KEGG database was further used to predict the possible pathways of AS-Ⅳ intervention in pneumonia.For in vitro experiment,macrophage RAW264.7 of logarithmic phase were randomly divided into 3 groups:control group(C),model group(M)and the AS-Ⅳ group(AS-Ⅳ).Except for group C,the other two groups were stimulated with LPS,and the AS-Ⅳ group was further intervened by AS-Ⅳ.CCK8 method was used to determine the effect of AS-Ⅳ on the proliferation of RAW264.7 cells;ELISA was used to determine the secretion levels of NF-κB,IL-1β,MCP-1 and Arg-1;qPCR was used to detect the gene expression of TLR4 and its downstream pathway molecules HMGB1 and TLR4 in each group.Network pharmacological analysis predicted that AS-Ⅳ had 158 targets and 112 intersection targets with pneumonia,while the enrichment analysis of KEGG pathway obtained 126 pathways.In consider with literature,HMGB1,TLR4,TRIF,Myd88 and NF-κB were identified as the target of pathway to be verified.Further in vitro experiments confirmed that NF-κB,IL-1β and MCP-1 in AS-Ⅳ group were significantly decreased as compared with M group,while Arg-1 was significantly increased,the expression of HMGB1,TLR4,TRIF and Myd88 genes were significantly decreased as compared with M group.Taken together,AS-Ⅳ can regulate the inflammatory immune responses of RAW264.7 through HMGB1/TLR4 related signaling pathways,which provides experimental basis and data support for clinical pneumonia treatment.

As far the current severe coronavirus disease 2019 (COVID-19), respiratory disease is still the biggest threat to human health. In addition, infectious respiratory diseases are particularly prominent. In addition to killing and clearing the infection pathogen directly, regulating the immune responses against the pathogens is also an important therapeutic modality. Sirtuins belong to NAD+-dependent class III histone deacetylases. Among 7 types of sirtuins, silent information regulator type-1 (SIRT1) played a multitasking role in modulating a wide range of physiological processes, including oxidative stress, inflammation, cell apoptosis, autophagy, antibacterial and antiviral functions. It showed a critical effect in regulating immune responses by deacetylation modification, especially through high-mobility group box 1 (HMGB1), a core molecule regulating the immune system. SIRT1 was associated with many respiratory diseases, including COVID-19 infection, bacterial pneumonia, tuberculosis, and so on. Here, we reviewed the latest research progress regarding the effects of SIRT1 on immune system in respiratory diseases. First, the structure and catalytic characteristics of SIRT1 were introduced. Next, the roles of SIRT1, and the mechanisms underlying the immune regulatory effect through HMGB1, as well as the specific activators/inhibitors of SIRT1, were elaborated. Finally, the multitasking roles of SIRT1 in several respiratory diseases were discussed separately. Taken together, this review implied that SIRT1 could serve as a promising specific therapeutic target for the treatment of respiratory diseases.

ObjectiveTo investigate the effect of Liuwei Dihuangwan on memory function of senescence-accelerated mouse prone 8 （SAMP8） mice by regulating autophagy through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/forkhead box O3a （FoxO3a） pathway. MethodSix male senescence-accelerated mouse resistant 1 （SAMR1） mice of SPF grade aging 6 months were assigned to a normal group， and 24 male SAMP8 mice of SPF grade aging 6 months were randomly divided into a model group， a donepezil group （0.747 mg·kg^-1）， and high- and low-dose Liuwei Dihuangwan groups （2.700 and 1.350 g·kg^-1）， with 6 mice in each group. The mice were treated with drugs by gavage for 2 months. Morris water maze was used to detect the learning and memory abilities of mice in each group. Nissl staining was used to observe the neurons in the cortex and hippocampus. The positive expression of microtubule-associated protein 1 light chain 3B （LC3B） in the cortex and hippocampus was detected by immunohistochemistry （IHC）. Western blot was used to detect the protein expression of the mammalian ortholog of yeast ATG6 （Beclin-1）， B cell lymphoma-2 （Bcl-2）， autophagy-related gene 5 （ATG5）， cysteinyl aspartate-specific protease 3 （Caspase-3）， Caspase-9， Akt， p-Akt， FoxO3a， and p-FoxO3a. ResultCompared with the normal group， the model group showed prolonged escape latency （P<0.05，P<0.01）， reduced number of platform crossings and the residence time in the target quadrant （P<0.01）， decreased neurons with reduced volume and dispersed distribution in the cortex and hippocampus， increased positive expression of LC3B （P<0.01）， elevated expression of Beclin-1 and ATG5 in the cortex （P<0.01）， declined Bcl-2 expression （P<0.01）， up-regulated Caspase-3 and Caspase-9 expression （P<0.01）， and decreased expression levels of p-Akt/Akt and p-FoxO3a/FoxO3a （P<0.01）. Compared with the model group， the donepezil group and the Liuwei Dihuangwan groups showed shortened 3 d escape latency （P<0.05，P<0.01）， increased number of platform crossings （P<0.01）， and prolonged residence time in the target quadrant （P<0.01）. In the donepezil group， the number of neurons in the cortex and hippocampus was increased. In the Liuwei Dihuangwan groups， the number of neurons and Nissl bodies increased with denser distribution and lower degree of cell damage. The positive expression of LC3B in the cortex and hippocampus was decreased in the donepezil group and Liuwei Dihuangwan groups （P<0.01）. The expression of Beclin-1 was decreased in the Liuwei Dihuangwan groups （P<0.01）. The expression of ATG5 was decreased in the donepezil group and the low-dose Liuwei Dihuangwan group （P<0.01）. The donepezil group and the Liuwei Dihuangwan groups showed the increased expression level of Bcl-2 in the cortex （P<0.01）， decreased expression level of Caspase-3 （P<0.01）， reduced expression level of Caspase-9 （P<0.05，P<0.01）， and elevated expression levels of p-Akt/Akt and p-FoxO3a/FoxO3a （P<0.01）. ConclusionLiuwei Dihuangwan can effectively improve the learning and memory abilities of the SAMP8 mice and protect neurons. Its mechanism may be related to the regulation of the PI3K/Akt/FoxO3a signaling pathway， down-regulation of the expression of ATG5， Beclin-1， and LC3B， and the inhibition of apoptosis.

ObjectiveTo investigate the protective effect of Liuwei Dihuangwan on neurovascular injury in SAMP8 mice. MethodThe Alzheimer's disease （AD） model with insufficiency of kidney essence was induced in 75 SAMP8 mice aging 6 months. The model mice were divided into model group， positive control group （donepezil hydrochloride， 0.747 mg·kg^-1·d^-1）， and high-， medium-， and low-dose Liuwei Dihuangwan groups （2.700， 1.350， 0.675 g·kg^-1·d^-1）， with 15 mice in each group. Fifteen SAMR1 mice were assigned to a normal control group. All mice were administered continuously for 2 months. The spatial memory of mice was tested by the Morris water maze. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the hippocampus and cortex of brain tissues. The immunohistochemical method （IHC） was used to detect the deposition of amyloid β-protein （Aβ） and the expression of von Willebrand factor （vWF） and CD34 in the hippocampus and cortex of brain tissues. Electron microscopy was used to observe the ultrastructural changes in cerebral microvessels. Western blot was used to detect the protein expression levels of the receptor of advanced glycation endproduct （RAGE）， low-density lipoprotein receptor-related protein 1 （LRP1）， vascular endothelial growth factor A （VEGF-A）， and P-selection in the hippocampus and cortex of brain tissues. ResultCompared with the normal control group， the model group showed prolonged escape latency and swimming distance （P<0.01）， increased number of glial cells， decreased number of nerve cells， blurred tight junctions or enlarged gap of the brain microvascular endothelial cells， severely injured membrane structure， swollen mitochondria of endothelial cells， ruptured membrane， massive dissolution in cristae， increased protein expression of Aβ and vWF in the hippocampus and cortex （P<0.01）， reduced protein expression of CD34 （P<0.05）， elevated protein expression of RAGE and P-selection in the cortex （P<0.01）， and decreased protein expression level of LRP1 and VEGF-A （P<0.01）. Compared with the model group， the Liuwei Dihuangwan groups showed shortened escape latency and swimming distance （P<0.05）， reduced number of glial cells in the cortex and hippocampus， increased number of microvessels in the cortex， clear double-layer membrane structure in tight junctions between the microvascular endothelial cells， increased number of mitochondria with intact membrane and recovered mitochondrial cristae， decreased protein expression of Aβ， vWF， RAGE， and P-selection in the hippocampus and cortex （P<0.05）， and increased protein expression of CD34， LRP1， and VEGF-A （P<0.05）. ConclusionLiuwei Dihuangwan can regulate Aβ metabolism through the RAGE/LRP1 receptor system and promote cerebral microvascular angiogenesis by inhibiting vWF expression and increasing VEGF-A and CD34， thereby improving cerebral microvascular injury in SAMP8 mice.

The occurrence and development of the tumor are closely associated with the tumor microenvironment (TME) and host immune status. Traditional TNM staging has gradually been insufficient in the assessment of patients' outcomes, as the TNM system solely evaluated tumor cell characteristics and failed to predict clinical outcomes based on immune factors. Therefore, immunoscore (IS), derived from the concept of immune contexture, was proposed to establish a more comprehensive and accurate TNM-I staging above the TNM staging. Recently, increasing studies have shown that IS can predict the survival outcome and treatment efficacy more accurately than TNM staging. Moreover, IS possess characteristics such as feasibility, convenience, robustness and reproducibility, which make it possible for IS to be used as a biomarker for clinical application, to classify patients better and contribute to developing individualized treatment strategies, ultimately, to improve the overall survival of patients with cancer. This article reviews of the progress of immunoscore in predicting patients' prognosis and response to therapy among different tumors.