The onset and progression of chronic heart failure （CHF） are closely associated with myocardial energy metabolism disorders， and this pathological process significantly affects patient prognosis. Traditional Chinese medicine （TCM）， grounded in time-based medical theories such as the correspondence between humans and nature and the theory of circadian flow of meridians （Ziwu Liuzhu）， exhibits intrinsic consistency with modern circadian rhythm theory， providing a unique theoretical framework for understanding and intervening in CHF from a temporal perspective. This article systematically explores the impact of circadian rhythms on energy metabolism and the potential mechanisms by which TCM active ingredients intervene in CHF through a review of relevant literature. It is found that various TCM active ingredients， including flavonoids （such as nobiletin）， alkaloids （such as berberine）， and polyphenols （such as resveratrol）， can improve mitochondrial function， promote fatty acid oxidation， enhance glucose uptake and utilization efficiency， maintain metabolic balance， and alleviate oxidative stress and inflammatory responses in myocardial cells by regulating the expression and rhythms of core circadian clock genes such as CLOCK， BMAL1， PER， and CRY. These actions thereby correct energy metabolism disorders and improve cardiac function. Further exploration of the interaction mechanisms between these components and the circadian rhythms holds promise for providing novel theoretical foundations and potential intervention strategies for the prevention and treatment of CHF.

Nonalcoholic fatty liver disease（NAFLD） is the most common chronic liver disease in the world. Because of its complex pathogenesis， high clinical prevalence and large population， it poses a great threat and challenge to public health in the world. Therefore， active intervention measures are needed. Currently， western medicine is effective in reducing weight， reducing liver fat content， improving glucose-lipid metabolism and insulin resistance. However， for patients with NAFLD-related fibrosis and cirrhosis， there is still a lack of sufficient histological evidence to support its benefits， and randomized controlled trials are still needed to clarify. Lifestyle intervention is an important cornerstone for the treatment of NAFLD， but there are many problems such as poor implementation and low compliance of patients， and the clinical efficacy is not ideal. Traditional Chinese medicine（TCM） has the significant advantages of multiple pathways and multiple targets. Berberine， the active ingredient of TCM， can interfere with the production of NAFLD from multiple pathways， including increasing energy consumption， weight loss， improving glucose-lipid metabolism， improving insulin resistance， anti-inflammatory， anti-oxidation， regulating intestinal flora， restoring bile acid homeostasis， anti-fibrosis and so on， which can play a positive role in the treatment of NAFLD. At the same time， it was found that the combination of BBR with Chinese and western medicines had significant advantages in promoting drug absorption， improving oral bioavailability， increasing the highest biological distribution in the liver， enhancing the overall therapeutic effect of NAFLD， and reducing adverse drug reactions， which could provide reference for clinical medication.

AIM:To explore the mechanism by which activation of α7 nicotinic acetylcholine receptor(nAChR)in combination with cold stimulation promotes the beiging of white adipose tissues in obese mice.METHODS:Male C57BL/6J mice,aged 8 weeks,were acclimated for 1 week before fed with high-fat diet(HFD)for 12 weeks to estab-lish an obese model.Fifty mice were randomly divided into 5 groups:control group(low-fat diet),HFD group,model group(HFD+cold stimulation),agonist group(HFD+cold stimulation+α7 nAChR agonist GTS-21),and inhibitor group(HFD+cold stimulation+α7 nAChR inhibitor α-bungarotoxin).Interventions lasted for 4 weeks.Serum levels of total cho-lesterol(TG),triglyceride(TC)and free fatty acid(FFA),and the levels of tumor necrosis factor-α(TNF-α),interleu-kin-1β(IL-1β),IL-10,Toll-like receptor 4(TLR4),nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),transforming growth factor-β(TGF-β),cyclic adenosine monophosphate(cAMP)and norepinephrine(NE)in while adipose tissues were measured using ELISA.Hematoxylin-eosin(HE)staining was performed to observe morpho-logical changes in white adipose tissues.The mRNA levels of nitric oxide synthase 2(NOS2),arginase 1(Arg1),uncou-pling protein 1(UCP1),peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α)and PR domain-containing 16(PRDM16)in white adipose tissues were determine by RT-qPCR.Immunohistochemistry was employed to examine the expression levels of CD86,CD206,C/EBP homologous protein(CHOP),immunoglobulin heavy-chain binding protein(BiP)and UCP1.Western blot analysis was conducted to detect the protein levels of CHOP,BiP,UCP1,α7 nAChR,nu-clear factor-κB(NF-κB)p65,phosphorylated Janus kinase 2(p-JAK2)and phosphorylated signal transducer and activa-tor of transcription 3(p-STAT3)in white adipose tissues.RESULTS:Activation of α7 nAChR with GTS-21,combined with cold-induced thermogenesis,led to decreased levels of TC,TG and FFA in peripheral blood and reduced lipid droplet area in white adipose tissues.Additionally,α7 nAChR activation resulted in decreased expression of TLR4 and NLRP3.In white adipose tissue,there was an increase in Arg1 mRNA level and CD206 expression,while NOS2 mRNA level and CD86 expression decreased.Phosphorylation of the JAK2/STAT3 pathway was up-regulated,and NF-κB p65 level de-creased.The levels of pro-inflammatory cytokines TNF-α and IL-1β were reduced,whereas the levels of anti-inflammatory factors TGF-β and IL-10 increased.Expression of CHOP and BiP also declined.Furthermore,α7 nAChR activation in-creased the mRNA levels of PRDM16 and PGC-1α,as well as UCP1 expression in white adipose tissues.CONCLUSION:Activation of α7 nAChR combined with cold stimulation not only promotes the beiging of white adipose tissue in obese mice,but also alliviates metabolic disorders,thereby enhancing the thermogenic efficiency of white adipose tissue beiging.

Objective To investigate the correlation between myocardial fibrosis(MF)and left ventricular ejection fraction(LVEF)and myocardial injury markers in heart failure patients via cardiac magnetic resonance(CMR).Methods Seventy-six patients with heart failure were selected,including 32 cases of heart failure with preserved ejection fraction(HFpEF)(HFpEF group),15 cases of heart failure with mid-range ejection fraction(HFmEF)(HFmEF group),and 29 patients of heart failure with reduced ejection fraction(HFrEF)(HFrEF group).Additionally,7 healthy individuals undergoing physical examinations were included(control group).CMR parameters and biological markers for the heart failure groups were collected for all subjects.The differences in native T1 value and extracellular volume fraction(ECV)between the heart failure group and the control group were compared,respectively.The differences in native T1 value,ECV,late gadolinium enhancement(LGE)score,serum creatine kinase-MB(CK-MB),cardiac troponin Ⅰ knockdown(cTnI-KD),and N-terminal pro-brain natriuretic peptide(NT-proBNP)among heart failure subgroups were also compared,respectively.Spearman correlation analysis was used to examine the relationships between MF imaging indicators and LVEF,as well as NT-proBNP levels.Results The differences in native T1 value,ECV,LGE score,and NT-proBNP between the heart failure group and the control group,as well as between the heart failure subgroups were statistically significant(P＜0.05).The native T1 value,ECV,and LGE score in the heart failure group were positively correlated with NT-proBNP,and negatively correlated with LVEF.Conclusion The native T1 value,ECV value and LGE score are correlated with heart failure severity.CMR can detect myocardial injury early in patients with HFpEF and provide valuable information for risk stratification of MF.

AIM:To explore the mechanism by which activation of α7 nicotinic acetylcholine receptor(nAChR)in combination with cold stimulation promotes the beiging of white adipose tissues in obese mice.METHODS:Male C57BL/6J mice,aged 8 weeks,were acclimated for 1 week before fed with high-fat diet(HFD)for 12 weeks to estab-lish an obese model.Fifty mice were randomly divided into 5 groups:control group(low-fat diet),HFD group,model group(HFD+cold stimulation),agonist group(HFD+cold stimulation+α7 nAChR agonist GTS-21),and inhibitor group(HFD+cold stimulation+α7 nAChR inhibitor α-bungarotoxin).Interventions lasted for 4 weeks.Serum levels of total cho-lesterol(TG),triglyceride(TC)and free fatty acid(FFA),and the levels of tumor necrosis factor-α(TNF-α),interleu-kin-1β(IL-1β),IL-10,Toll-like receptor 4(TLR4),nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),transforming growth factor-β(TGF-β),cyclic adenosine monophosphate(cAMP)and norepinephrine(NE)in while adipose tissues were measured using ELISA.Hematoxylin-eosin(HE)staining was performed to observe morpho-logical changes in white adipose tissues.The mRNA levels of nitric oxide synthase 2(NOS2),arginase 1(Arg1),uncou-pling protein 1(UCP1),peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α)and PR domain-containing 16(PRDM16)in white adipose tissues were determine by RT-qPCR.Immunohistochemistry was employed to examine the expression levels of CD86,CD206,C/EBP homologous protein(CHOP),immunoglobulin heavy-chain binding protein(BiP)and UCP1.Western blot analysis was conducted to detect the protein levels of CHOP,BiP,UCP1,α7 nAChR,nu-clear factor-κB(NF-κB)p65,phosphorylated Janus kinase 2(p-JAK2)and phosphorylated signal transducer and activa-tor of transcription 3(p-STAT3)in white adipose tissues.RESULTS:Activation of α7 nAChR with GTS-21,combined with cold-induced thermogenesis,led to decreased levels of TC,TG and FFA in peripheral blood and reduced lipid droplet area in white adipose tissues.Additionally,α7 nAChR activation resulted in decreased expression of TLR4 and NLRP3.In white adipose tissue,there was an increase in Arg1 mRNA level and CD206 expression,while NOS2 mRNA level and CD86 expression decreased.Phosphorylation of the JAK2/STAT3 pathway was up-regulated,and NF-κB p65 level de-creased.The levels of pro-inflammatory cytokines TNF-α and IL-1β were reduced,whereas the levels of anti-inflammatory factors TGF-β and IL-10 increased.Expression of CHOP and BiP also declined.Furthermore,α7 nAChR activation in-creased the mRNA levels of PRDM16 and PGC-1α,as well as UCP1 expression in white adipose tissues.CONCLUSION:Activation of α7 nAChR combined with cold stimulation not only promotes the beiging of white adipose tissue in obese mice,but also alliviates metabolic disorders,thereby enhancing the thermogenic efficiency of white adipose tissue beiging.

Objective To investigate the correlation between myocardial fibrosis(MF)and left ventricular ejection fraction(LVEF)and myocardial injury markers in heart failure patients via cardiac magnetic resonance(CMR).Methods Seventy-six patients with heart failure were selected,including 32 cases of heart failure with preserved ejection fraction(HFpEF)(HFpEF group),15 cases of heart failure with mid-range ejection fraction(HFmEF)(HFmEF group),and 29 patients of heart failure with reduced ejection fraction(HFrEF)(HFrEF group).Additionally,7 healthy individuals undergoing physical examinations were included(control group).CMR parameters and biological markers for the heart failure groups were collected for all subjects.The differences in native T1 value and extracellular volume fraction(ECV)between the heart failure group and the control group were compared,respectively.The differences in native T1 value,ECV,late gadolinium enhancement(LGE)score,serum creatine kinase-MB(CK-MB),cardiac troponin Ⅰ knockdown(cTnI-KD),and N-terminal pro-brain natriuretic peptide(NT-proBNP)among heart failure subgroups were also compared,respectively.Spearman correlation analysis was used to examine the relationships between MF imaging indicators and LVEF,as well as NT-proBNP levels.Results The differences in native T1 value,ECV,LGE score,and NT-proBNP between the heart failure group and the control group,as well as between the heart failure subgroups were statistically significant(P＜0.05).The native T1 value,ECV,and LGE score in the heart failure group were positively correlated with NT-proBNP,and negatively correlated with LVEF.Conclusion The native T1 value,ECV value and LGE score are correlated with heart failure severity.CMR can detect myocardial injury early in patients with HFpEF and provide valuable information for risk stratification of MF.

BACKGROUND:Bone mineral density is the clinical gold standard for determining bone strength,but bone mineral density is less sensitive to changes in bone mass,with large changes in bone mineral density only occurring when bone mass is significantly reduced,so bone mineral density has limited ability to predict changes in bone strength and fracture risk. OBJECTIVE:A model of the normal and osteoporotic hip joint was developed to analyze the stresses and deformation in the hip of normal and osteoporotic patients under single-leg standing conditions. METHODS:A healthy adult female volunteer at the age of 36 years was selected as the study subject.The CT data of the hip joint of this volunteer were obtained and saved in DICOM format.The hip joint model was reconstructed in three dimensions,and the material properties were assigned by the gray value assignment method to obtain the normal and osteoporotic hip joint models according to the empirical formula.The same boundary conditions and loads were set to simulate the stresses and deformation in the normal and osteoporotic hip joints in the single-leg standing position. RESULTS AND CONCLUSION:(1)In the finite element model of the normal and osteoporotic hip,the stress distribution was more concentrated in the medial region of the femoral neck.(2)In the hip bone,the stress distribution was mainly concentrated in the upper part of the acetabulum.(3)The stress peaks in the medial femoral neck and upper acetabulum were larger in the normal hip model than in the osteoporotic hip model,probably due to the reduced bone strength of the osteoporotic bone.(4)The peak Von Mises of both normal and osteoporotic hip models were concentrated on the medial femoral neck,and the peak Von Mises of the hip bone was smaller,indicating that the overall effect of osteoporosis on hip bone stresses was relatively small.(5)In terms of deformation in the single-leg standing position,the maximum deformation in the normal hip model was located at the acetabulum and femoral head,and the maximum deformation was located at the upper part of the greater trochanter of the femur.(6)It is suggested that the finite element analysis method to model the values of parameters related to bone tissue in osteoporosis may improve clinical prediction of bone strength changes and fracture risk.It is explained from the biomechanical view that the intertrochanteric femur and femoral neck are good sites for osteoporotic hip fractures.

Objective To investigate the effects of α7 nicotinic acetylcholine receptor(nAChR)agonist on β3-adrenoceptor agonist-induced impairment of white fat homeostasis and beige adipose formation and heat production in obese mice.Methods Forty obese C57BL/6J mice were randomized into high-fat feeding group,β3-adrenoceptor agonist-treated model group,α7 nAChR agonist group,and α7 nAChR inhibitor group(n=10),with another 10 mice with normal feeding as the blank control group.White adipose tissue from the epididymis of the mice were sampled for HE staining of the adipocytes.The expression levels of TNF-α,IL-1β,IL-10 and TGF-β in the white adipose tissue were determined by ELISA,and the mRNA levels of iNOS,Arg1,UCP-1,PRDM-16 and PGC-1α were detected using RT-qPCR.Western blotting was performed to detect the expression levels of NF-κB P65,p-JAK2,p-STAT3 in the white adipose tissue.Results Compared with those in the blank control group,the mice with high-fat feeding showed significantly increased body weight,more fat vacuoles in the white adipose tissue,increased volume of lipid droplets in the adipocytes,upregulated iNOS mRNA expression and protein expression of TNF-α and IL-1β,and lowered expression of Arg-1 mRNA and IL-10 and TGF-β proteins(P<0.01).Treatment with α7 nAChR significantly reduced mRNA levels of PRDM-16,PGC-1α and UCP-1,lowered TNF-α and IL-1β expressions,increased IL-10 and TGF-β expressions,and reduced M1/M2 macrophage ratio in the white adipose tissues(P<0.05 or 0.01).Conclusion Activation of α7 nAchR improves white adipose tissue homeostasis impairment induced by β3 agonist,promotes transformation of M1 to M2 macrophages,reduces inflammatory response in white adipose tissue,and promote beige adipogenesis and thermogenesis in obese mice.

Objective To investigate the effects of α7 nicotinic acetylcholine receptor(nAChR)agonist on β3-adrenoceptor agonist-induced impairment of white fat homeostasis and beige adipose formation and heat production in obese mice.Methods Forty obese C57BL/6J mice were randomized into high-fat feeding group,β3-adrenoceptor agonist-treated model group,α7 nAChR agonist group,and α7 nAChR inhibitor group(n=10),with another 10 mice with normal feeding as the blank control group.White adipose tissue from the epididymis of the mice were sampled for HE staining of the adipocytes.The expression levels of TNF-α,IL-1β,IL-10 and TGF-β in the white adipose tissue were determined by ELISA,and the mRNA levels of iNOS,Arg1,UCP-1,PRDM-16 and PGC-1α were detected using RT-qPCR.Western blotting was performed to detect the expression levels of NF-κB P65,p-JAK2,p-STAT3 in the white adipose tissue.Results Compared with those in the blank control group,the mice with high-fat feeding showed significantly increased body weight,more fat vacuoles in the white adipose tissue,increased volume of lipid droplets in the adipocytes,upregulated iNOS mRNA expression and protein expression of TNF-α and IL-1β,and lowered expression of Arg-1 mRNA and IL-10 and TGF-β proteins(P<0.01).Treatment with α7 nAChR significantly reduced mRNA levels of PRDM-16,PGC-1α and UCP-1,lowered TNF-α and IL-1β expressions,increased IL-10 and TGF-β expressions,and reduced M1/M2 macrophage ratio in the white adipose tissues(P<0.05 or 0.01).Conclusion Activation of α7 nAchR improves white adipose tissue homeostasis impairment induced by β3 agonist,promotes transformation of M1 to M2 macrophages,reduces inflammatory response in white adipose tissue,and promote beige adipogenesis and thermogenesis in obese mice.

In the past decade, high-throughput sequencing technologies have generated a massive amount of genomic mutation data. The interpretation of mutation data from tumor samples has revealed mutational features highly associated with carcinogenic factors, which are referred to as mutational signatures. These mutational signatures enable the assessment of the contribution rates of various carcinogenic factors during the multi-stage development of tumors. Ionizing radiation-induced gene mutations constitute the molecular basis for its carcinogenic effects. Clarifying the patterns of mutational signatures induced by ionizing radiation is of great importance for a profound understanding of stochastic effects. This review presents the research history and analytical method of mutational signatures as well as a comprehensive summary of the current status of research on mutational signatures induced by ionizing radiation. The future development of this field is also discussed.