ObjectiveTo observe the effect of Yangxin Tongmai Formula （养心通脉方） by midnight-noon ebb-flow administration method for rat models of premature coronary heart disease （PCHD） with blood stasis syndrome， and to explore the possible mechanism of action from the perspective of DNA methylation differential gene expression. MethodsThere were 3 SD rats in each of the blank group， model group and Yangxin Tongmai Formula group， and the rats in the model group and Yangxin Tongmai Formula group were fed with high-fat chow plus vitamin D3 by gavage plus isoproterenol hydrochloride by subcutaneous injection to construct rat models of PCHD with blood stasis syndrome. After successful modelling， rats in Yangxin Tongmai Formula group were gavaged with 18 g/（kg‧d） of Yangxin Tongmai Formula， and rats in blank group and the model group were gavaged with 4 ml/（kg‧d） of 0.9% NaCl solution， and serum samples of rats in each group were collected for DNA methylation sequencing after 3 weeks to screen for the relevant DNA methylation differentiation genes. In addition， rats with successful modelling of PCHD with blood stasis were randomly divided into model group， Yangxin Tongmai Formula with midnight-noon ebb-flow administration method group ［18 g/（kg‧d） of Yangxin Tongmai Formula was gavaged twice in the heart channel period （12：00） and pericardium channel period （20：00）］， the Yangxin Tongmai Formula control group ［18 g/（kg‧d） of Yangxin Tongmai Formula was gavaged twice at 8：00 and 18：00］ and the Atorvastatin Calcium group ［atorvastatin calcium tablets solution 1.8 mg/（kg‧d） at the same intervention time as that in Yangxin Tongmai Formula control group］， and set up a blank group of 8 rats in each group. The model group and blank group were gavaged with 0.9% NaCl solution 4 ml/（kg‧d） for the same time as the Yangxin Tongmai Formula control group. After 3 weeks of gavage， the blood lipids ［including total cholesterol （TC）， low-density lipoprotein （LDL）， high-density lipoprotein （HDL）］ levels of rats in each group were detected； the HE staining of myocardial tissues and thoracic aorta was used to observe the pathomorphological changes； the levels of serum inflammation indexes ［tumour necrosis factor alpha （TNF-alpha）， lipopolysaccharide （LPS）， and interleukin 10 （IL-10）］ were detected； immunoprecipitation-realtime fluorescence quantitative PCR was used to detect the relative expression of cardiac tissue screening differential genes. ResultsThe genes screened for differentially methylated regions were calmodulin 2 （Calm2）， calcium voltage-gated channel subunit α1s （Cacna1s）， and phospholipase Cβ1 （Plcb1）. Compared with the blank group， rats in the model group showed elevated levels of TC， LDL， TNF-α and LPS， and decreased levels of HDL and IL-10 （P＜0.05 or P＜0.01）； HE staining showed obvious swelling of myocardial fibres， accompanied by a large number of inflammatory cell infiltration， and thickening of the inner wall of the aortic vessels with internal wall damage， which was visible as a large number of lipid cholesterol crystals and obvious inflammatory cell infiltration. Compared with the model group， the TC， LDL， TNF-α and LPS contents of rats in the Yangxin Tongmai Formula with midnight-noon ebb-flow administration method group， the Yangxin Tongmai Formula control group， and the atorvastatin calcium group all reduced， and the contents of HDL and IL-10 all elevated （P＜0.05）， with the improvement of myocardial tissue damage and the reduction of inflammatory infiltration， and the improvement of the damage of the inner lining of the thoracic aorta and the reduction of lipid infiltration. Compared with Yangxin Tongmai Formula control group， LDL， TNF-α and LPS contents reduced， and IL-10 contents increased in the midnight-noon ebb-flow administration method group （P＜0.05）. Compared with the model group， the relative expression of Calm2 and Plcb1 genes decreased and the relative expression of Cacna1s gene increased in Yangxin Tongmai Formula control group and the midnight-noon ebb-flow administration method group （P＜0.05）； compared with the Yangxin Tongmai Formula control group， the relative expression of Calm2 gene decreased and the relative expression of Cacna1s gene increased in the midnight-noon ebb-flow administration method group （P＜0.05）. ConclusionThe intervention of Yangxin Tongmai Formula in the heart channel period （12：00） and pericardium channel period （20：00） was more effective in improving the blood lipid level， inhibiting inflammation， and improving myocardial tissue damage in rats of PCHD with blood stasis syndrome， and Calm2 and Cacna1s genes may be the key targets of Yangxin Tongmai Formula in intervening the blood stasis syndrome of PCHD.

OBJECTIVE:The quality of systematic reviews/meta-analyses directly affects the reliability of clinical decision-making basis.Currently,there is no literature quality research on the systematic reviews/meta-analyses of platelet rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis both domestically and internationally.This article will comprehensively evaluate the methodological quality,reporting quality,and evidence quality of the systematic reviews/meta-analyses of platelet rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis.METHODS:Computer searches were conducted on CNKI,WanFang Data,VIP,CBM,PubMed,Embase,and The Cochrane Library.From the establishment of the database until January 24,2024,all systematic reviews/meta-analyses treated with platelet rich plasma versus hyaluronic acid for knee osteoarthritis were collected.Two evaluators independently conducted literature screening and data extraction,and used the AMSTAR 2,PRISMA 2020,and GRADE systems to evaluate and summarize the methodological,reporting,and evidence quality of the included systematic reviews/meta-analyses.RESULTS:A total of 18 qualified systematic reviews/meta-analyses were included,and the results showed that the efficacy and safety of platelet rich plasma might be better than that of hyaluronic acid.The methodological quality of all 18 studies was extremely low;4 reports had poor quality and relatively serious information defects,while 14 reports had moderate quality and some information defects.Among the 275 outcome measures of 16 systematic reviews/meta-analyses,there were 9 medium quality evidence,90 low-quality evidence,and 176 extremely low-quality evidence,with no high-quality evidence.CONCLUSION:At present,the quality of systematic reviews/meta-analyses literature on the treatment of knee osteoarthritis with platelet rich plasma versus hyaluronic acid is relatively low.In the future,the authors of the systematic reviews need to strictly follow the entries of quality evaluation tools such as AMSTAR 2 and PRISMA 2020 in terms of plan registration,research type explanation,retrieval strategy,exclusion list,research site and funding source,bias risk analysis,publication bias evaluation,and public information acquisition,and conduct evidence quality evaluation on the combined results of the systematic reviews/meta-analyses to provide more reliable and rigorous evidence-based basis for clinical practice.

BACKGROUND:Carnosic acid,a bioactive compound found in rosemary,has been shown to reduce inflammation and reactive oxygen species(ROS).However,its mechanism of action in osteoclast differentiation remains unclear. OBJECTIVE:To investigate the effects of carnosic acid on osteoclast activation,ROS production,and mitochondrial function. METHODS:Primary bone marrow-derived macrophages from mice were extracted and cultured in vitro.Different concentrations of carnosic acid(0,10,15,20,25 and 30 μmol/L)were tested for their effects on bone marrow-derived macrophage proliferation and toxicity using the cell counting kit-8 cell viability assay to determine a safe concentration.Bone marrow-derived macrophages were cultured in graded concentrations and induced by receptor activator of nuclear factor-κB ligand for osteoclast differentiation for 5-7 days.The effects of carnosic acid on osteoclast differentiation and function were then observed through tartrate-resistant acid phosphatase staining,F-actin staining,H2DCFDA probe and mitochondrial ROS,and Mito-Tracker fluorescence detection.Western blot and RT-PCR assays were subsequently conducted to examine the effects of carnosic acid on the upstream and downstream proteins of the receptor activator of nuclear factor-κB ligand-induced MAPK signaling pathway. RESULTS AND CONCLUSION:Tartrate-resistant acid phosphatase staining and F-actin staining showed that carnosic acid dose-dependently inhibited in vitro osteoclast differentiation and actin ring formation in the cell cytoskeleton,with the highest inhibitory effect observed in the high concentration group(30 μmol/L).Carnosic acid exhibited the most significant inhibitory effect during the early stages(days 1-3)of osteoclast differentiation compared to other intervention periods.Fluorescence imaging using the H2DCFDA probe,mitochondrial ROS,and Mito-Tracker demonstrated that carnosic acid inhibited cellular and mitochondrial ROS production while reducing mitochondrial membrane potential,thereby influencing mitochondrial function.The results of western blot and RT-PCR revealed that carnosic acid could suppress the expression of NFATc1,CTSK,MMP9,and C-fos proteins associated with osteoclast differentiation,and downregulate the expression of NFATc1,Atp6vod2,ACP5,CTSK,and C-fos genes related to osteoclast differentiation.Furthermore,carnosic acid enhanced the expression of antioxidant enzyme proteins and reduced the generation of ROS during the process of osteoclast differentiation.Overall,carnosic acid exerts its inhibitory effects on osteoclast differentiation by inhibiting the phosphorylation modification of the P38/ERK/JNK protein and activating the MAPK signaling pathway in bone marrow-derived macrophages.

ObjectiveTo investigate the association and translational mechanism between the hepatotoxicity of Xianling Gubao （XLGB） and its treatment of osteoporosis based on a zebrafish model. MethodsZebrafish were randomly selected four days after fertilization （4 dpf） and exposed to different concentrations of XLGB （0.7，0.35 mg·L^-1） for 96 h. At the endpoint of the exposure， the mortality rates of zebrafish in the treatment groups of different concentrations were counted， and the "dose-toxicity" curves were plotted. The 10% sublethal concentration （LC₁₀） was calculated. The liver area， acridine orange staining， and pathological tissue sections of transgenic zebrafish ［CZ16 （gz15Tg.Tg （fabp 10a： ds Red； ela31： EGFP）］ were used as indicators to confirm the hepatic damage caused by the sublethal concentration of XLGB. By using the prednisolone （PNSL）-induced osteoporosis model of zebrafish， the anti-osteoporosis activity of XLGB was evaluated by using the area of skull stained by alizarin red and the cumulative optical density value as indicators. Then， the toxicity difference of XLGB on the liver of zebrafish in healthy and osteoporotic states was compared， and the mechanism of the translational action of the toxicity of XLGB was predicted based on network pharmacology and real-time polymerase chain reaction（Real-time PCR）. ResultsThe LC₁₀ of XLGB on zebrafish （8 dpf） was 0.7 mg·L^-1. Compared with the blank group， the sublethal concentration （LC₁₀=0.7 mg·L^-1， 1/2 LC₁₀=0.35 mg·L^-1） of XLGB induced an increase in the number of apoptosis of hepatocytes in a dose-dependent manner， and the tissue arrangement of the liver was disordered and loose. The vacuoles were obvious， and the fluorescence area of the liver was significantly reduced （P<0.01）. Compared with the blank group， the mineralized area and cumulative optical density value of zebrafish skull in the PNSL model group were significantly reduced （P<0.01）， and those in the 0.7，0.35 mg·L^-1 XLGB treatment group were significantly increased compared with the model group （P<0.01）. Most importantly， 0.7 mg·L^-1 XLGB had no significant effect on the liver of zebrafish in the osteoporosis disease model compared with the blank group. The results of network pharmacology and real-time PCR experiments showed that the toxic transformation of XLGB might be related to the differences in the expression levels of key targets， such as tumor protein 53 （TP53）， cysteine aspartic acid specific protease-3（Caspase-3）， interleukin（IL）-6， and alkaline phosphatase（ALP） in different organismal states. ConclusionUnder certain conditions， XLGB has hepatotoxicity in normal zebrafish， but under osteoporotic conditions， XLGB not only exerts significant anti-osteoporosis activity but also alleviates hepatotoxicity significantly， which provides a reference for the safe clinical use of XLGB and real evidence for the theories of traditional Chinese medicine of attacking poison with poison and of treating disease with corresponding drugs without damage to the body.

Aging is a complex process triggered by multiple factors,characterized by the gradual decline of physiological and behavioral capabilities.Among various organs,the brain is particularly susceptible to aging effects.Brain aging not only leads to cognitive decline in the elderly but also increases the risk of neurodegen-erative diseases,resulting in reduced quality of life and increased social aging burdens.Therefore,it is essential to thoroughly investigate the mechanisms and biomarkers of both physiological and pathological brain aging to enable early prevention,monitoring,and intervention.Mitochondria play a crucial role in both physiological and pathological brain aging processes,making mitochondrial-related mechanisms and biomarkers key research directions in this field.This article reviews the main manifestations and mechanistic differences between physi-ological and pathological brain aging,summarizes mitochondrial mechanisms in brain aging,identifies mito-chondrial-associated biomarkers,and proposes health-promoting,mitochondria-targeting interventions.

Chaihu Guizhi Ganjiangtang （CGG）is a classic prescription in the Treatise on Cold Damage，which has the effects of clearing and relieving stagnation heat in Shaoyang，warming and dissolving water drink，and relieving the pivot mechanism. It is a classic prescription for treating spleen deficiency and liver depression and stopping internal stagnation caused by water drink. The formula is exquisite and well-matched and is often modified and used by ancient and modern medical practitioners to treat various miscellaneous diseases of internal and external medicine，with significant therapeutic effects. In recent years，with the rapid development of modern pharmacology，research on the micro mechanism of CGG has been continuously developed and deepened，providing new ideas for the treatment of diseases with CGG. Therefore，the authors systematically searched databases such as China National Knowledge Infrastructure，Wanfang Data Knowledge Service Platform，VIP Database， and PubMed for literature on the clinical application and pharmacological mechanism of CGG published by Chinese and foreign scholars in recent years. This article summarized the literature from two aspects：the modern clinical application and mechanism of action of CGG and elaborated on the diseases treated by CGG in modern literature，involving digestive system，respiratory system，nervous system，endocrine system，circulatory system，urinary system，gynecology，as well as its application in reducing the side effects of radiotherapy and chemotherapy， gynecology， dermatology， ophthalmology， and orthopedics. At the same time，the mechanism of CGG in treating diseases may be related to anti-inflammatory，anti-oxidative stress， regulation of immunity， anti-fibrosis， anti-tumor， improvement of gastrointestinal flora and motility， protection of liver tissue， reduction of blood lipids and blood sugar， and regulation of hormone levels.

Chronic hepatitis B（CHB）is one of the major challenges in the global public health field. As of 2022，approximately 254 million people worldwide were infected with the hepatitis B virus（HBV）. CHB is one of the main causes of liver cirrhosis and hepatocellular carcinoma（HCC）. Nucleos（t）ide analogs（NAs）and interferon therapy can delay the progression of liver fibrosis by inhibiting viral replication，but they cannot completely avoid the problem of heterogeneous treatment responses. Some patients are in a state of low-level viremia（LLV）during treatment. The persistent LLV state can induce chronic inflammation and the progression of liver fibrosis，ultimately increase the risk of HCC. In patients with poor treatment responses，the continuous active viral replication can induce immune disorders，accelerate the evolution of fibrosis to the decompensated stage of liver cirrhosis，and increase the risk of patient death. This article aims to review the definition，mechanisms，and impact on treatment outcomes of LLV and suboptimal response based on the latest research，provide a basis for optimizing antiviral therapy for CHB.

OBJECTIVE:The quality of systematic reviews/meta-analyses directly affects the reliability of clinical decision-making basis.Currently,there is no literature quality research on the systematic reviews/meta-analyses of platelet rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis both domestically and internationally.This article will comprehensively evaluate the methodological quality,reporting quality,and evidence quality of the systematic reviews/meta-analyses of platelet rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis.METHODS:Computer searches were conducted on CNKI,WanFang Data,VIP,CBM,PubMed,Embase,and The Cochrane Library.From the establishment of the database until January 24,2024,all systematic reviews/meta-analyses treated with platelet rich plasma versus hyaluronic acid for knee osteoarthritis were collected.Two evaluators independently conducted literature screening and data extraction,and used the AMSTAR 2,PRISMA 2020,and GRADE systems to evaluate and summarize the methodological,reporting,and evidence quality of the included systematic reviews/meta-analyses.RESULTS:A total of 18 qualified systematic reviews/meta-analyses were included,and the results showed that the efficacy and safety of platelet rich plasma might be better than that of hyaluronic acid.The methodological quality of all 18 studies was extremely low;4 reports had poor quality and relatively serious information defects,while 14 reports had moderate quality and some information defects.Among the 275 outcome measures of 16 systematic reviews/meta-analyses,there were 9 medium quality evidence,90 low-quality evidence,and 176 extremely low-quality evidence,with no high-quality evidence.CONCLUSION:At present,the quality of systematic reviews/meta-analyses literature on the treatment of knee osteoarthritis with platelet rich plasma versus hyaluronic acid is relatively low.In the future,the authors of the systematic reviews need to strictly follow the entries of quality evaluation tools such as AMSTAR 2 and PRISMA 2020 in terms of plan registration,research type explanation,retrieval strategy,exclusion list,research site and funding source,bias risk analysis,publication bias evaluation,and public information acquisition,and conduct evidence quality evaluation on the combined results of the systematic reviews/meta-analyses to provide more reliable and rigorous evidence-based basis for clinical practice.

Chronic hepatitis B（CHB）is one of the major challenges in the global public health field. As of 2022，approximately 254 million people worldwide were infected with the hepatitis B virus（HBV）. CHB is one of the main causes of liver cirrhosis and hepatocellular carcinoma（HCC）. Nucleos（t）ide analogs（NAs）and interferon therapy can delay the progression of liver fibrosis by inhibiting viral replication，but they cannot completely avoid the problem of heterogeneous treatment responses. Some patients are in a state of low-level viremia（LLV）during treatment. The persistent LLV state can induce chronic inflammation and the progression of liver fibrosis，ultimately increase the risk of HCC. In patients with poor treatment responses，the continuous active viral replication can induce immune disorders，accelerate the evolution of fibrosis to the decompensated stage of liver cirrhosis，and increase the risk of patient death. This article aims to review the definition，mechanisms，and impact on treatment outcomes of LLV and suboptimal response based on the latest research，provide a basis for optimizing antiviral therapy for CHB.

Objective:To explore the value of a radiomics nomogram based on T 1WI for prediction of the relapse of osteosarcoma after surgery within 1 year from multicenter data. Methods:The imaging and clinical data of 107 patients with pathologica1ly confirmed osteosarcoma who received neoadjuvant chemotherapy before surgery from 6 hospitals from January 2009 to October 2017 were retrospectively analyzed. A training cohort consisted of 75 patients from firstly enrolled 4 hospitals and an independent validation cohort of 32 patients from other 2 hospitals. Pretreatment T 1WI was used to extract radiomics features. Least absolute shrinkage and selection operator (LASSO) regression was applied to reduce the dimension and then the radiomics signature was constructed to predict the relapse of osteosarcoma after surgery within 1 year in training cohort. Independent clinical risk factors were screened using one-way logistic regression, and then a radiomics nomogram incorporated the radiomics signature and MRI characteristics was developed by multivariate logistic regression. The predictive nomogram was evaluated using receiver operating characteristic (ROC) curve in the training cohort, and validated in the independent validation cohort. The calibration curve was used to evaluate the agreement between prediction and actual observation and the decision curve was used to demonstrate the clinical usefulness. Results:Based on T 1WI from multicenter institutions, the radiomics signature was built using 2 valuable selected features that were significantly associated with relapse within 1 year. Two selected features included 1 gray-level co-occurrence matrices (GLCM) feature (L_G_1.0_GLCM_homogeneity1, LASSO coefficient 3.122) and 1 gray-level run length matrix (GLRLM) feature (GLRLM_RP, LASSO coefficient -2.474). The prediction nomogram including radiomics signature and MRI characteristics (joint invasion and perivascular involvement) showed good discrimination with the area under the ROC curve of 0.884 and 0.821 in the training and validation cohorts, respectively. The calibration curve showed that the nomogram achieved good agreement between prediction and actual observation. Decision curve analysis demonstrated that the radiomics nomogram was clinically useful when the threshold probability was greater than 21%. Conclusion:The radiomics nomogram based on T 1WI can be used as a non-invasive quantitative tool to predict relapse of osteosarcoma within 1 year before treatment, which provides support for clinical decision-making in osteosarcoma.