Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.

ObjectiveThis study aims to investigate the effects of Linggui Zhugantang （LGZGT） on ventricular remodeling （VR） in mice with myocardial infarction （MI） and its impact on the Ras homologgene A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） signaling pathway. MethodsThe MI model of mice was established by ligating the left anterior descending coronary artery （LAD）. They were divided into the sham-operated group， the model group， the low-dose， medium-dose， and high-dose groups of LGZGT （2.34， 4.68， 9.36 g·kg^-1）， and the captopril group （3.25 mg·kg^-1）， with 10 mice in each group. After four weeks of continuous drug administration by gavage， the level of cardiac function in each group of mice was examined using small animal Doppler ultrasound. Hematoxylin-eosin （HE） staining and Masson staining was used to assess the morphological changes of myocardial tissue and calculate the rate of collagen fiber deposition in mouse myocardial tissue. Wheat germ agglutinin （WGA） staining was employed to compare the cross-sectional area of cardiomyocytes in each group of mice. The expression levels of α-smooth muscle actin （α-SMA）， matrix metalloproteinase-2 （MMP-2）， type Ⅰcollagen （Col Ⅰ）， Col Ⅲ， tissue inhibitor of metalloproteinase 1（TIMP1）， B-cell lymphoma-2 （Bcl-2）-associated X protein （Bax）， Bcl-2， Caspase-3， and cleaved Caspase-3 were detected by Western blot. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to evaluate the mRNA levels of the pathway-related genes RhoA， ROCK1， and ROCK2. The protein expression levels of RhoA， ROCK1， and ROCK2 were tested by Western blot. ResultsThe level of cardiac function was markedly declined in the model group compared to the sham-operated group（P<0.01）. Myocardial tissue morphology changed significantly. The cross-sectional area of cardiomyocytes was significantly enlarged. The expression of α-SMA， MMP-2， Col Ⅰ， and Col Ⅲ was significantly upregulated（P<0.01）， and TIMP1 protein expression was significantly reduced（P<0.01）. The expressions of apoptosis-related proteins Bax were significantly up-regulated（P<0.01）， while the expression of Bcl-2 protein was significantly decreased（P<0.01）. The mRNA expression of RhoA， ROCK1， and ROCK2 were significantly upregulated （P<0.01）. Compared to the model group， the low-dose， medium-dose， and high-dose groups of LGZGT and the captopril group significantly reversed the experimental results of the model group in a dose-dependent manner （P<0.05， P<0.01）. ConclusionLGZGT significantly attenuated myocardial fibrosis， myocardial hypertrophy， and cardiomyocyte apoptosis after MI in mice and effectively reversed VR， the mechanism of which may be related to the modulation of the RhoA/ROCK signaling pathway.

ObjectiveThis study aims to investigate the effects of Linggui Zhugantang （LGZGT） on ventricular remodeling （VR） in mice with myocardial infarction （MI） and its impact on the Ras homologgene A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） signaling pathway. MethodsThe MI model of mice was established by ligating the left anterior descending coronary artery （LAD）. They were divided into the sham-operated group， the model group， the low-dose， medium-dose， and high-dose groups of LGZGT （2.34， 4.68， 9.36 g·kg^-1）， and the captopril group （3.25 mg·kg^-1）， with 10 mice in each group. After four weeks of continuous drug administration by gavage， the level of cardiac function in each group of mice was examined using small animal Doppler ultrasound. Hematoxylin-eosin （HE） staining and Masson staining was used to assess the morphological changes of myocardial tissue and calculate the rate of collagen fiber deposition in mouse myocardial tissue. Wheat germ agglutinin （WGA） staining was employed to compare the cross-sectional area of cardiomyocytes in each group of mice. The expression levels of α-smooth muscle actin （α-SMA）， matrix metalloproteinase-2 （MMP-2）， type Ⅰcollagen （Col Ⅰ）， Col Ⅲ， tissue inhibitor of metalloproteinase 1（TIMP1）， B-cell lymphoma-2 （Bcl-2）-associated X protein （Bax）， Bcl-2， Caspase-3， and cleaved Caspase-3 were detected by Western blot. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to evaluate the mRNA levels of the pathway-related genes RhoA， ROCK1， and ROCK2. The protein expression levels of RhoA， ROCK1， and ROCK2 were tested by Western blot. ResultsThe level of cardiac function was markedly declined in the model group compared to the sham-operated group（P<0.01）. Myocardial tissue morphology changed significantly. The cross-sectional area of cardiomyocytes was significantly enlarged. The expression of α-SMA， MMP-2， Col Ⅰ， and Col Ⅲ was significantly upregulated（P<0.01）， and TIMP1 protein expression was significantly reduced（P<0.01）. The expressions of apoptosis-related proteins Bax were significantly up-regulated（P<0.01）， while the expression of Bcl-2 protein was significantly decreased（P<0.01）. The mRNA expression of RhoA， ROCK1， and ROCK2 were significantly upregulated （P<0.01）. Compared to the model group， the low-dose， medium-dose， and high-dose groups of LGZGT and the captopril group significantly reversed the experimental results of the model group in a dose-dependent manner （P<0.05， P<0.01）. ConclusionLGZGT significantly attenuated myocardial fibrosis， myocardial hypertrophy， and cardiomyocyte apoptosis after MI in mice and effectively reversed VR， the mechanism of which may be related to the modulation of the RhoA/ROCK signaling pathway.

BACKGROUND:Osteoporosis is a significant contributor to the global burden of disease and disability.Plasma proteins are involved in complex biological processes and play a crucial role in uncovering disease mechanisms and identifying potential therapeutic targets.Although existing studies have suggested an association between plasma proteins and osteoporosis,the causal nature of these associations is not fully clarified.Therefore,it is imperative to identify the causal proteins associated with osteoporosis and potential therapeutic targets for the amelioration and management of this condition using large-scale plasma protein data.OBJECTIVE:To evaluate the causal relationship between plasma proteins and osteoporosis based on the UK Biobank database as source information using the two-sample Mendelian randomization.METHODS:A total of 1 001 plasma protein-related genome-wide significant quantitative trait loci(P<5×10-8)were obtained from the UK Biobank database and used as instrumental variables,with linkage disequilibrium excluded.Summary data on osteoporosis were collected from the FinnGen database,which included 438 872 individuals of European descent.The study was analyzed using inverse variance weighting,MR-Egger regression,weighted median,and several sensitivity analyses to ensure the robustness of the results.Further,a protein-protein interaction network was constructed,and Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to explore the functional relevance and potential mechanisms of plasma proteins.RESULTS AND CONCLUSION:(1)The Mendelian randomization analysis using the inverse variance weighted method identified 50 plasma proteins that have causal associations with osteoporosis(P<0.05).Among them,20 plasma proteins,including chromosome 19 open reading frame 12(odds ratio[OR]=0.610;95%confidence interval[CI]:0.483-0.769,P=2.967×10-5)and epidermal growth factor(EGF;OR=0.877;95%CI:0.770-0.999,P=0.049),might be associated with a reduced risk of osteoporosis.In contrast,30 plasma proteins,such as C-C motif chemokine ligand(CCL)18(OR=1.091;95%CI:1.037-1.147,P=0.001)and CD209(OR=1.036;95%CI:1.003-1.070,P=0.034),might be associated with an increased risk of osteoporosis.After Bonferroni correction,only chromosome 19 open reading frame 12 showed a significant causal association with osteoporosis.(2)Multiple sensitivity analyses revealed no evidence of pleiotropy or heterogeneity,indicating the robustness of the results.(3)The construction of the PPI network identified core proteins such as EGF,CCL5,C-X-C motif chemokine ligand(CXCL)13,CXCL5,vascular endothelial growth factor C,CCL17,CCL18,TEK receptor tyrosine kinase,tyrosine kinase with immunoglobulin like and EGF like domains 1,and CCL23.(4)Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that these plasma proteins play essential roles in the immune system,influencing osteoporosis through processes such as signal transduction,cell migration,and chemotaxis.(5)This study reveals the potential causal associations between 1 001 plasma proteins and osteoporosis,highlighting the utility of a large-scale,data-driven approach to identify new biomarkers and drug targets in diverse populations.Additionally,our findings suggest that processes such as immune signaling,cell migration,and chemotaxis play significant roles in the pathogenesis of osteoporosis,offering new directions for research under specific genetic backgrounds and environmental factors.Finally,the core proteins identified in this study(e.g.,EGF,CCL5,and CXCL13)may serve as novel biomarkers or therapeutic targets,providing a new basis for the precise prevention and treatment of osteoporosis.

BACKGROUND:Osteoporosis is a significant contributor to the global burden of disease and disability.Plasma proteins are involved in complex biological processes and play a crucial role in uncovering disease mechanisms and identifying potential therapeutic targets.Although existing studies have suggested an association between plasma proteins and osteoporosis,the causal nature of these associations is not fully clarified.Therefore,it is imperative to identify the causal proteins associated with osteoporosis and potential therapeutic targets for the amelioration and management of this condition using large-scale plasma protein data.OBJECTIVE:To evaluate the causal relationship between plasma proteins and osteoporosis based on the UK Biobank database as source information using the two-sample Mendelian randomization.METHODS:A total of 1 001 plasma protein-related genome-wide significant quantitative trait loci(P<5×10-8)were obtained from the UK Biobank database and used as instrumental variables,with linkage disequilibrium excluded.Summary data on osteoporosis were collected from the FinnGen database,which included 438 872 individuals of European descent.The study was analyzed using inverse variance weighting,MR-Egger regression,weighted median,and several sensitivity analyses to ensure the robustness of the results.Further,a protein-protein interaction network was constructed,and Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to explore the functional relevance and potential mechanisms of plasma proteins.RESULTS AND CONCLUSION:(1)The Mendelian randomization analysis using the inverse variance weighted method identified 50 plasma proteins that have causal associations with osteoporosis(P<0.05).Among them,20 plasma proteins,including chromosome 19 open reading frame 12(odds ratio[OR]=0.610;95%confidence interval[CI]:0.483-0.769,P=2.967×10-5)and epidermal growth factor(EGF;OR=0.877;95%CI:0.770-0.999,P=0.049),might be associated with a reduced risk of osteoporosis.In contrast,30 plasma proteins,such as C-C motif chemokine ligand(CCL)18(OR=1.091;95%CI:1.037-1.147,P=0.001)and CD209(OR=1.036;95%CI:1.003-1.070,P=0.034),might be associated with an increased risk of osteoporosis.After Bonferroni correction,only chromosome 19 open reading frame 12 showed a significant causal association with osteoporosis.(2)Multiple sensitivity analyses revealed no evidence of pleiotropy or heterogeneity,indicating the robustness of the results.(3)The construction of the PPI network identified core proteins such as EGF,CCL5,C-X-C motif chemokine ligand(CXCL)13,CXCL5,vascular endothelial growth factor C,CCL17,CCL18,TEK receptor tyrosine kinase,tyrosine kinase with immunoglobulin like and EGF like domains 1,and CCL23.(4)Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that these plasma proteins play essential roles in the immune system,influencing osteoporosis through processes such as signal transduction,cell migration,and chemotaxis.(5)This study reveals the potential causal associations between 1 001 plasma proteins and osteoporosis,highlighting the utility of a large-scale,data-driven approach to identify new biomarkers and drug targets in diverse populations.Additionally,our findings suggest that processes such as immune signaling,cell migration,and chemotaxis play significant roles in the pathogenesis of osteoporosis,offering new directions for research under specific genetic backgrounds and environmental factors.Finally,the core proteins identified in this study(e.g.,EGF,CCL5,and CXCL13)may serve as novel biomarkers or therapeutic targets,providing a new basis for the precise prevention and treatment of osteoporosis.

Suzi Jiangqitang is one of the classical formulas in the Catalogue of Ancient Classical Formulas （the second batch）—Han Medicine. The research method of philology was employed to systematically review the ancient documents and modern medical reports of Suzi Jiangqitang. The key information of this formula， including origin， composition， compatibility， original plants， processing method， dosage， preparation method， usage， and indications， was summarized to provide literature and data support for the development and clinical application of this formula. Suzi Jiangqitang is originally known as Zusuzi Tang， which is derived from Important Prescriptions Worth a Thousand Gold for Emergency. This formula is composed of Perillae Fructus， Pinelliae Rhizoma， Peucedani Radix， Magnoliae Officinalis Cortex， Glycyrrhizae Radix et Rhizoma， Angelicae Sinensis Radix， Citri Reticulatae Pericarpium， Perillae Folium， Jujubae Fructus， Zingiberis Rhizoma Recens， and Cinnamomi Cortex. The original plants of other herbal medicines except Peucedani Radix follow those in the 2020 edition of Pharmacopoeia of the People's Republic of China. Raw materials of Angelicae Sinensis Radix， Peucedani Radix， Cinnamomi Cortex， Citri Reticulatae Pericarpium， Perillae Folium， and Jujubae Fructus are used in this formula. Perillae Fructus， Pinelliae Rhizoma， Glycyrrhizae Radix et Rhizoma， and Magnoliae Officinalis Cortex in this formula are stir-fried， processed with alumen， stir-fried， and processed with ginger， respectively， and the fresh material of Zingiberis Rhizoma Recens is used in this formula. The recommended formula is composed of 15 g Perillae Fructus， 15 g Pinelliae Rhizoma， 6 g Angelicae Sinensis Radix， 6 g Glycyrrhizae Radix et Rhizoma， 6 g Peucedani Radix， 6 g Magnoliae Officinalis Cortex， 9 g Cinnamomi Cortex， and 9 g Citri Reticulatae Pericarpium. On the basis of the recommended dosage， other herbal medicines are crushed and mixed with five pieces of Perillae Folium， one jujube， and two ginger pieces. The mixture should be decocted in 450 mL water to reach a volume of 240 mL. After removal of the residue， the decoction should be taken warm with no time limitation. In ancient times， Suzi Jiangqitang was most commonly used to treat dermatophytosis， dyspnea with cough， red eyes， blood syndrome， globus hysteriocus， and headache. In modern times， it is commonly used for treating respiratory diseases， especially chronic obstructive pulmonary disease and dyspnea with cough. In addition， this formula is used to treat circulatory and digestive diseases， such as pulmonary heart disease， constipation， and vomiting. It is also used to treat globus hysteriocus and blood syndrome. Although the range of indications is wide， the diseases treated by Suzi Jiangqitang are generally caused by excess in the upper， deficiency in the lower， and failure of Qi to ascend or descend.

Objective To elucidate the influence of two procedures aortic root remodeling using a straight tubular artificial vessel while preserving the aortic valve and the Florida sleeve procedure on the biomechanics of the aortic root.Methods Five finite element models of the aortic root were reconstructed using computed tomography angiography images,including two cases of aortic root remodeling(A1 and A2),two cases of the Florida sleeve procedure(B1 and B2),and one control group without aortic root pathology(C).Numerical simulations were performed to obtain the blood flow and pressure distribution result to assess the differences in the hemodynamics of the aortic root.Results There were no significant differences in the peak systolic velocity between the two procedures and the control.However,the flow velocity after aortic root remodeling was smoother,similar to the model of the control group,with a more stable average aortic pressure and wall shear stress.In the Florida sleeve procedure,high-speed blood flow affected the vessel wall,leading to various degrees of wall shear stress and pressure concentrations along the aortic wall.Conclusions After aortic root replacement with valve preservation,blood flow patterns in the reconstructed aortic root depended on postoperative changes in sinus geometry.Both surgical procedures showed favorable blood flow patterns;however,the flow pattern after aortic root remodeling was more stable than that after the Florida sleeve procedure.

Objective: To identify the associated factors of peripheral blood lymphocyte counts (PBLC) in gastric cancer patients Methods: In this cross⁃sectional study , data were collected from patients underwent gastric cancer surgery. Univariate analysis , multiple linear regression and variable importance metrics were used to assess factors associating PBLC in pre⁃operative patients. The findings were further investigated by fitting locally weighted regression(loess) and robust linear model (rlm) . Results: Patients with pre⁃operative PBLC < 1 . 1 × 109/L( group A) were 138(20. 72% ) , whereas patients with PBLC ≥ 1. 1 × 109/L ( group B) were 528(79. 28% ) . Compared to group B , patients in group A were older[(64. 61 ± 10. 42 years) vs (62. 18 ± 10. 41 years) , P < 0. 05 ] and showed lower neutrophils [(3. 21 ± 1. 41) × 109/L vs (3. 59 ± 1. 31) × 109/L , P < 0. 01] . Lymphopenia was associated with later stage of gastric cancer, P < 0. 01 . A multiple linear regression model with randomly distributed residuals found that age ( β = - 0. 01 , t = - 3. 70 , P < 0. 01) and tumor stage [ β ( Ⅱ vs Ⅰ ) = - 0. 16 , t =- 2. 79 , P < 0. 01 ; β ( Ⅲ vs Ⅰ ) = - 0. 18 , t = - 3. 86 , P < 0. 01 ; β ( Ⅳ vs Ⅰ ) = - 0. 21 , t = - 2. 16 , P <0. 05] were to be statistically significant factors for lymphopenia. Neutrophil increase (β = 0. 05 , t = 3. 61 , P < 0. 01) was associated with a higher PBLC. The relative importance analysis for continuous independent variables showed that relative importance metric LMGs in variable age , neutrophil and CEA were 55. 55% , 44. 14% and 0. 31% respectively. Loess and rlm models showed that age was the negatively influencing factor of PBLC. Conclusion PBLC in gastric cancer patients were positively associated with neutrophils , and negatively associated with age and tumor stages.

Objective: To explore the factors associated with the distance from the anal verge to rectal cancer (DAVtRC) ． Methods: 102 patients with rectal cancer provided the clinicopathological data．Two groups of patients were created : low rectal cancer group ( LRC) for those with DAVtRCs less than 7cm and mid / high rectal cancer group ( M / HRC) for those with DAVtRCs greater than 7 cm． The two groups' clinical and pathological differences were compared．Quantile regression was used to analyze the associations between DAVtRC and the clinicopathological factors. Results : LRC had a lower median DAVtRC (5. 00 cm ［IQR : 4. 00，6. 00 cm］) than that in M / HRC ［10. 00 cm(IQR : 10. 00，11. 00 cm) ］(P＜0. 01) ，but had higher mean monocytes［(0. 41 ± 0. 16) vs (0. 34 ± 0. 11) ，P＜0. 05］．In the model with continuous and categorical variables at 95% quantile，DAVtRC was negatively associated with age ( β = －0. 204 ，P ＜0. 01 ) ，TNM stage ( Ⅲ + Ⅳ vs Ⅰ : β = －6. 623 ，P < 0. 01) ，platelet (PLT，β = －0. 024，P＜0. 01) ，vessel invasion(β = －1. 544，P＜0. 01) ，but positively associat- ed with BMI(β = 0. 278，P＜0. 01) ，tumor diameters(β = 0. 548，P＜0. 01) ，male(β = 1. 421，P＜0. 01) ，low and middle differentiations(β = 4. 727，P＜0. 01) ，T stage(T2 vs T1 : β = 4. 422，P＜0. 01) ，N stage(N1 vs N0 : β = 6. 670，P＜0. 01) ，nerve invasion(β = 1. 825，P ＜0. 01) ，carcinoembryonic antigen( CEA，β = 0. 068，P < 0. 01) ，lymphocyte(L，β = 3. 068，P＜0. 01) ，platelet lymphocyte ratio(PLR , β = 0. 045，P＜0. 01) ，lymphocyte monocyte ratio(LMR , β = 1. 088，P ＜0. 01) ．Quantile regression curves showed that the coefficients of age，body mass index(BMI) ，tumor diameter，PLT，PLR and LMR were different in different quantiles of DAVtRC． Conclusion DAVtRC is significantly associated with multiple clinicopathological factors in rectal cancer，but in different quantiles，the coefficients are different.

Objective To construct and appraise a new model for predicting the prognosis of rectal cancer patients using the Lasso-Cox strategy.Methods The clinical pathological data of 599 rectal cancer patients who underwent radical resection were analyzed.Comparison between groups,Lasso and Cox regression were used to select varia-bles and construct a model,and its discrimination,consistency,and clinical benefits were appraised by the receiv-er operating characteristic(ROC),calibration curve,and decision curve analysis.Results Comparison between groups showed that age,body mass index(BMI),preoperational nutrition status,carbohydrate antigen199(CA199),preoperative chemotherapy,intraoperative blood transfusion,vascular or nerve invasion,cancer nod-ules,pathologic T,N,and TNM stages,tumor recurrence or metastasis,radiotherapy and postoperative survival time were associated with grouping of death or survival in rectal cancer patients.Among them,8 variables were se-lected by lasso and contained into the Cox regression model.Age(HR=1.04,P＜0.05),BMI(HR=0.89,P＜0.05),blood transfusion(HR=2.29,P＜0.05),postoperative chemotherapy(HR=0.16,P＜0.01),recur-rence(HR=43.67,P＜0.01),and metastasis(HR=2.75,P＜0.05)were identified as independent prognostic factors,which were used to construct a nomogram model.The area under the curve(AUC)and the 95％confi-dence interval of the receiver operating characteristic(ROC)curve of the predictive model was 0.95(0.91-0.99),P＜0.01.The predicted probability of 1-year and 3-year survival was close to the actual probability.The DCA curve of the model was far away from a decision line parallel to the X-axis and another line with a negative slope.Conclusion The newly established nomogram has good discrimination,consistency and clinical benefits,which help predict the prognosis of rectal cancer after surgery.