The prescription Mahuang Shengmatang in the Treatise on Cold Damage （《伤寒论》） has sparked considerable debate among medical practitioners throughout history， with varying opinions on its indications， pathogenesis described in the text， principle of compatibility， and clinical applications. Both ancient and modern interpreters of Mahuang Shengmatang often focus on herbal compatibility as a primary approach to deduce the pathogenesis and treatment methods. Building upon this foundation， this paper utilizes herbal dosage as a clue to discern the primary and secondary herbs in the prescription. It further analyzes the principle of compatibility based on herbal indications， summarizing the indications and therapeutic principles of this prescription. Ultimately， it reveals the underlying pathogenesis reflected in the text. The internal closure of heat and toxin leads to the stagnation of Qi， preventing Yang Qi from reaching the extremities and causing cold hands and feet. When the pathogenic Qi finds no outlet， it floods both the upper and lower regions of the body， attacking the throat and causing cough with expectoration of pus and blood， and descending to the large intestine to consume Yin fluids， resulting in persistent diarrhea. Based on this pathogenesis， the paper expands the scope of symptoms and signs associated with the prescription， providing a more detailed portrayal of the applicable patient population and enhancing the basis for clinical prescription references. Additionally， the paper presents considerations on several controversial topics， suggesting that the "lower pulse" described in the text refers to the lower limb arterial pulsation， and the symptoms and signs resemble those of septic shock in modern medicine. Therefore， Mahuang Shengmatang should be categorized as a prescription for treating warm diseases and it is not developed by ZHANG Zhongjing. By employing a detailed discussion on the syndrome， pathogenesis， and clinical application in the texts of Mahuang Shengmatang from the dosage， principle of compatibility， and herbal indications， this paper not only enriches the theoretical foundation of Mahuang Shengmatang but also provides a comprehensive perspective and fresh ideas for understanding its clinical application.

Pituitary adenylate cyclase activating polypeptide（PACAP）， as an important neuropeptide， plays a key role in the pathophysiological process of migraine. Although current anti-（calcitonin gene-related peptide，CGRP） targeted therapy has become a major breakthrough in migraine treatment， some patients show suboptimal responses to anti-CGRP therapy. In recent years， PACAP-38 has attracted significant attention as a potential novel therapeutic target. This article systematically reviews the molecular characteristics of PACAP-38， its pathological association with migraine， and the latest research advances in related targeted drugs， in order to provide new ideas for the precise treatment of migraine.
Neuropeptides

Objective To investigate the effect and mechanisms of celecoxib on right heart function in mice with acute high-altitude hypoxia exposure.Methods Male C57BL/6J mice(7 weeks old)were housed in a hypobaric chamber simulating an altitude of 5 800 m for 2 d to establish an animal model of acute hypobaric hypoxia.①Eighteen mice were randomly assigned to plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S),and high-altitude hypoxia exposure+celecoxib(H+Cel).Body weight and routine blood indicators were measured,and cardiac ultrasound examination were performed for heart rate(HR),pulmonary artery acceleration time to ejection time ratio(AT/ET),tricuspid annular plane systolic excursion(TAPSE),tricuspid annular systolic velocity(S'),and left ventricular ejection fraction(LVEF)and fractional shortening(FS).Targeted metabolomic profiling was applied to detect the cardiac arachidonic acid(AA)metabolite levels.The contents of 12,13-dihydroxy-9Z-octadecenoic acid(12,13-diHOME)in the heart,liver,brown adipose tissue,and plasma were quantified by ELISA.② Eighteen mice were randomly assigned into plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S)and high-altitude hypoxia exposure+12,13-diHOME(H+di)groups.Body weight,routine blood tests,and echocardiography were performed as above.③ Thirty-two mice were randomly divided into high-altitude hypoxia exposure+saline(H+S),high-altitude hypoxia exposure+celecoxib(H+Cel),high-altitude hypoxia exposure+soluble epoxide hydrolase inhibitor(sEHI)(H+sEHI),and high-altitude hypoxia exposure+sEHI+celecoxib(H+sEHI+Cel)groups.Body weight,routine blood tests,and echocardiography were performed as above.Cardiac and plasma contents of 12,13-diHOME and epoxyeicosatrienoic acids(EETs)were measured by ELISA.Results ① Compared to the P+S group,the H+S group exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.001),increased counts of white blood cells(WBC)and neutrophils(P<0.01)and decreased TAPSE,S'and AT/ET both at resting state and under stress(P<0.01,P<0.001).Compared to the H+S group,the H+Cel group exhibited significantly increase of cardiac 12,13-diHOME level(P<0.05),reduced WBC and lymphocyte counts(P<0.01,P<0.05)and improved TAPSE and S'levels at resting state and under stress(P<0.01,P<0.001).② Compared to the H+S group,the H+di group demonstrated significantly improvement of TAPSE at basal and under stress(P<0.001)and a trend towards improved TAPSE at resting state(P=0.0532),but no obvious differences was observed in WBC and neutrophil counts between the H+di group and the H+S group.③ Compared to the H+Cel group,both the H+sEHI and H+sEHI+Cel groups exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.01,P<0.05)though no statistical changes in cardiac function indicators.Compared to the H+S group,WBC counts and lymphocyte were decreased,and serum EETs level was incrased in the H+Cel group,H+sEHI group and H+sEHI+Cel group(P<0.01,P<0.001).Conclusion Celecoxib can elevate cardiac level of 12,13-diHOME and improves right heart function in mice after acute high-altitude hypoxia exposure through the CYP450-sEH metabolic pathway.

Objective:To analyze the clinical features and prognosis of acute B lymphoblastic leukemia (B-ALL) children carrying a TCF3: : PBX1 fusion gene and to evaluate the prognostic value of this gene.Methods:Retrospective cohort study.A total of 2 164 B-ALL children aged 0-18 years diagnosed and treated at 19 pediatric centers from October 2016 to June 2022 were enrolled.They were divided into the positive group and the negative group according to whether they carried a TCF3: : PBX1 fusion gene.The clinical characteristics, treatment response, adverse reactions, and prognosis of the 2 groups of patients were analyzed.The rank sum and Kruskal-Wallis tests were used to compare two and more than two groups of numerical variables, respectively.Fisher′s exact test was used to compare categorical variables.Results:Among the 2 164 patients, 116 (5.4%) were TCF3: : PBX1 positive, of which 70 patients were female, accounting for 60.3%.There were 840 female patients in the TCF3: : PBX1-negative group, accounting for 41.0%.There was a significant difference in the ratio of females between the TCF3: : PBX1-positive and TCF3: : PBX1-negative groups ( P<0.001).No significant difference was observed in age of onset between the two groups( P>0.05).The proportion of bone marrow naive cells [54.00 (14.00, 76.50)% vs.29.00 (3.00, 68.00)%], white blood cell counts [25.30 (10.46, 60.94)×10 9/L vs.9.03 (4.38, 30.73)×10 9/L] and hemoglobin counts [82.00(63.00, 101.00) g/L vs.74.00(60.00, 90.00) g/L] in the TCF3: : PBX1-positive group were significantly higher than those in the negative group at the onset (all P<0.05).In terms of treatment response, the proportion of peripheral blood naive cells on Day 8 in the TCF3: : PBX1-positive group was significantly higher than that in the negative group [2.00 (0, 9.00)% vs.0 (0, 2.00)%, P<0.001].The proportion of minimal residual disease <0.1% on Day 15 in the TCF3: : PBX1-positive group was significantly higher than that in the negative group ( P=0.038).There were no significant differences in cumulative recurrence rate, treatment-related mortality (TRM), and overall survival (OS) between the TCF3: : PBX1-positive group and TCF3: : PBX1-negative group (all P>0.05).The cumulative recurrence risk of TCF3: : PBX1-positive patients was 9.646 times higher than that of ETV6: : RUNX1-positive patients with better prognosis( HR=9.646, 95% CI: 1.026-90.700, P=0.047).There were no significant differences in TRM and OS between TCF3: : PBX1-positive and ETV6: : RUNX1-positive patients (all P>0.05).A significant enrichment of PAX5 mutations was detected in TCF3: : PBX1-positive patients.Among the 7 high-risk TCF3: : PBX1-positive patients in a single center, 4 patients had PAX5 mutations, and this proportion was significantly higher than that in other patients ( P<0.001). Conclusions:B-ALL children carrying a TCF3: : PBX1 fusion gene have a high remission rate and good long-term prognosis after intensive chemotherapy.It is suggesting that TCF3: : PBX1-positive B-ALL patients should be rated at intermediate risk to receive intensive chemotherapy.

Myocardial hypertrophy is characterized by the deleterious response of the heart to various stressors,leading to an increase in cardiomyocyte size and subsequent cardiac dysfunction.Autophagy,as a catabolic degradation process necessary for maintaining cellular homeostasis,has recently become an important mechanism in relation to the development of myocardial hypertrophy.Drawing on insights from recent molecular,cellular,and pharmacological studies,this review comprehensively explores the dual roles of autophagy compounds in myocardial hypertrophy.We investigated the contribution of autophagy flux in cardiomyocytes under physiological and pathological conditions,highlighting the complex interactions among autophagy and cardiomyocyte growth,survival,and function.In addition,we discuss the potential of modulating autophagic activity using drugs for the treatment of myocardial hypertrophy and heart failure.A critical examination of established models and the exploration of new autophagy regulators will further our understanding of the complex mechanisms that control myocardial hypertrophy and facilitate the development of targeted therapies.Ongoing research is expected to elucidate the definitive role of autophagy regulators,providing insights into their therapeutic potential and implications for clinical interventions in patients with myocardial hypertrophy and related pathologies.

Myocardial hypertrophy is characterized by the deleterious response of the heart to various stressors,leading to an increase in cardiomyocyte size and subsequent cardiac dysfunction.Autophagy,as a catabolic degradation process necessary for maintaining cellular homeostasis,has recently become an important mechanism in relation to the development of myocardial hypertrophy.Drawing on insights from recent molecular,cellular,and pharmacological studies,this review comprehensively explores the dual roles of autophagy compounds in myocardial hypertrophy.We investigated the contribution of autophagy flux in cardiomyocytes under physiological and pathological conditions,highlighting the complex interactions among autophagy and cardiomyocyte growth,survival,and function.In addition,we discuss the potential of modulating autophagic activity using drugs for the treatment of myocardial hypertrophy and heart failure.A critical examination of established models and the exploration of new autophagy regulators will further our understanding of the complex mechanisms that control myocardial hypertrophy and facilitate the development of targeted therapies.Ongoing research is expected to elucidate the definitive role of autophagy regulators,providing insights into their therapeutic potential and implications for clinical interventions in patients with myocardial hypertrophy and related pathologies.

Objective:To analyze the clinical features and prognosis of acute B lymphoblastic leukemia (B-ALL) children carrying a TCF3: : PBX1 fusion gene and to evaluate the prognostic value of this gene.Methods:Retrospective cohort study.A total of 2 164 B-ALL children aged 0-18 years diagnosed and treated at 19 pediatric centers from October 2016 to June 2022 were enrolled.They were divided into the positive group and the negative group according to whether they carried a TCF3: : PBX1 fusion gene.The clinical characteristics, treatment response, adverse reactions, and prognosis of the 2 groups of patients were analyzed.The rank sum and Kruskal-Wallis tests were used to compare two and more than two groups of numerical variables, respectively.Fisher′s exact test was used to compare categorical variables.Results:Among the 2 164 patients, 116 (5.4%) were TCF3: : PBX1 positive, of which 70 patients were female, accounting for 60.3%.There were 840 female patients in the TCF3: : PBX1-negative group, accounting for 41.0%.There was a significant difference in the ratio of females between the TCF3: : PBX1-positive and TCF3: : PBX1-negative groups ( P<0.001).No significant difference was observed in age of onset between the two groups( P>0.05).The proportion of bone marrow naive cells [54.00 (14.00, 76.50)% vs.29.00 (3.00, 68.00)%], white blood cell counts [25.30 (10.46, 60.94)×10 9/L vs.9.03 (4.38, 30.73)×10 9/L] and hemoglobin counts [82.00(63.00, 101.00) g/L vs.74.00(60.00, 90.00) g/L] in the TCF3: : PBX1-positive group were significantly higher than those in the negative group at the onset (all P<0.05).In terms of treatment response, the proportion of peripheral blood naive cells on Day 8 in the TCF3: : PBX1-positive group was significantly higher than that in the negative group [2.00 (0, 9.00)% vs.0 (0, 2.00)%, P<0.001].The proportion of minimal residual disease <0.1% on Day 15 in the TCF3: : PBX1-positive group was significantly higher than that in the negative group ( P=0.038).There were no significant differences in cumulative recurrence rate, treatment-related mortality (TRM), and overall survival (OS) between the TCF3: : PBX1-positive group and TCF3: : PBX1-negative group (all P>0.05).The cumulative recurrence risk of TCF3: : PBX1-positive patients was 9.646 times higher than that of ETV6: : RUNX1-positive patients with better prognosis( HR=9.646, 95% CI: 1.026-90.700, P=0.047).There were no significant differences in TRM and OS between TCF3: : PBX1-positive and ETV6: : RUNX1-positive patients (all P>0.05).A significant enrichment of PAX5 mutations was detected in TCF3: : PBX1-positive patients.Among the 7 high-risk TCF3: : PBX1-positive patients in a single center, 4 patients had PAX5 mutations, and this proportion was significantly higher than that in other patients ( P<0.001). Conclusions:B-ALL children carrying a TCF3: : PBX1 fusion gene have a high remission rate and good long-term prognosis after intensive chemotherapy.It is suggesting that TCF3: : PBX1-positive B-ALL patients should be rated at intermediate risk to receive intensive chemotherapy.

Objective: To describe the prevalence and association of dietary rhythm and depressive symptoms among adolescents, so as to provide a basis for improving unhealthy behavioral habits,and to promote adolescent physical and mental health. Methods: From October to December 2021, a total of 22 868 students were selected from one middle school and high school in urban and rural areas of eight cities, namely, Shenyang, Xuzhou, Shenzhen, Taiyuan, Nanchang, Zhengzhou, Chongqing, and Kunming cities, China, using a combination of purposive sampling and stratified cluster random sampling. A self administered questionnaire was used to assess adolescents dietary rhythm, and the Patient Health Questionnaire-9 (PHQ-9) was used to assess depressive symptoms. Binary Logistic regression model was employed to analyze the associations between adolescent dietary rhythm and depressive symptoms, while the associations between adolescent dietary rhythm and depressive symptoms across gender and physical activity levels were stratified by gender and physical activity levels. Results: The detection rate of depressive symptoms in adolescents was 44.4%. The respective differences in the detection rates of depressive symptoms among adolescents of different genders, physical activity levels, and dietary rhythm disorders were statistically significant ( χ 2=157.51, 105.02, 3 282.50, P <0.01). Taking the low disordered dietary rhythm group as the reference, binary Logistic regression analyses showed that after adjusting for confounding factors such as age, gender，family location, family economic situation, whether only child, parental education level, and learning burden, physical activity levels, depressive symptoms were positively correlated with adolescents in the moderate disordered dietary rhythm group ( OR=2.63, 95%CI =2.45-2.83) and the high disordered dietary rhythm group ( OR=6.38, 95%CI = 5.93- 6.86). In addition, after stratifying by gender, dietary rhythm were positively correlated with depressive symptoms. The moderate disordered group (male: OR=2.62, 95%CI =2.37-2.89, female: OR=2.67, 95%CI =2.40-2.97) and the highly disordered group (male: OR=5.74, 95%CI =5.19-6.35, female: OR=7.11, 95%CI =6.40-7.89) were positively correlated with depressive symptoms. After stratification by physical activity levels, low, moderate and above physical activity levels among adolescents in the disordered dietary rhythm group (low physical activity: OR=2.91, 95%CI =2.58-3.29, moderate and above physical activity: OR= 2.50, 95%CI =2.28-2.74), high disordered group (low physical activity: OR=6.51, 95%CI =5.94- 7.13 , moderate and higher physical activity: OR=6.18, 95%CI =5.47-6.97) were positively associated with depressive symptoms ( P <0.01). There was an interaction between dietary rhythm and physical activity levels in regard to the development of depressive symptoms in adolescents, taking the group with moderate and above physical activity levels and low disordered dietary rhythm as the reference,the detection rate of which was higher in adolescents with low levels of physical activity and those in the moderate or high disordered dietary rhythm group ( OR=1.50, 3.90, 95%CI=1.39-1.61, 3.63-4.19, P <0.01). Conclusions Dietary rhythm disorders were found to be positively associated with depressive symptoms in adolescents. Regular dietary behaviors and increased physical activity play an important positive role in promoting adolescent mental health.

Objective To explore whether hepatocyte Perilipin-2(Plin2)is involved in the development of fatty liver related to comparative gene identification-58(CGI-58)deficiency mice and compare the effects of Plin2 and Plin3 on lipid droplet formation and lipid accumulation.Methods Based on CGI-58Flox/Flox mice as animal model,the adeno-associated viruses targeting mouse liver,CGI-58 knockout and Plini2 knockdown were achieved by co-expression Cre protein and micro-RNA targeting Plin2(Mi-KD).Then CGI-58 deficiency mice were used as control(NC)to detect the differences in metabolic phenotype and liver pathology.AML-12 mouse hepatocytes were used as cellular model and interfered with siRNA to achieve Plin2/Plin3 knockdown in AML-12 cells.Lipid droplet formation and lipid accumulation were compared with Bodipy staining and enzyme colorimetry in basal condition or lipid-overloaded condition(OA inducement)after Plin2/Plin3 knockdown.Results Plin2 knockdown(Mi-KD)reduced PLIN2 protein level by＞99％in mouse livers.Mi-KD decreased hepatomegaly(P=0.019 5)and liver injury(P=0.000 4),while reduced the histological NAS score(P=0.000 2)and hepatic triglyceride content(P=0.016 6)in the CGI-58 deficiency female mice.Mi-KD prevented microvesicular hepatic steatosis in the CGI-58 deficient female mice.Plin3 knockdown significantly reduced the triglyceride content in basal condition of hepatocytes(P=0.001 4),and Plin2 knockdown just showed a decreased trend.Plin2 or Plin3 knockdown significantly reduced the triglyceride content separately in lipid-overloaded hepatocytes(P＜0.05).Conclusion Hepatocyte Plin2 is essential in the development of microvesicular hepatic steatosis caused by CGI-58 deficiency.Both Plin2 and Plin3 are involved in lipid droplet formation and lipid accumulation in hepatocytes,and Plin3 shows a stronger effect.

Objective To investigate the effect and potential mechanism of early exercise intervention on cerebral myelin in cerebral ischemia rats.Methods A total of 18 SD rats were randomly divided into the sham group,the middle cerebral artery occlusion resting group(MCAO-SED)and the middle cerebral artery occlusion exercise group(MCAO-EX),with 6 rats in each group.Except the sham group,the middle cerebral artery occlusion model was prepared by modified Longa line embolization method in other groups.After modeling,rats in the MCAO-EX group were placed on a treadmill for exercise intervention for 28 days.Neurological function was assessed by modified neural function deficit score(mNSS).Infarct volume was detected by MRI scanning(T2),myelin basic protein(MBP)expression was detected by immunofluorescence.Myelin sheath structure was detected by transmission electron microscopy.Western blot assay was used to detect endoplasmic reticulum stress-related protein expression.Apoptosis was detected by TUNEL staining.Results After 28 days of intervention,compared with the MCAO-SED group,the nerve function recovered well in the MCAO-EX group,infarct volume decreased,myelin integrity increased,MBP fluorescence intensity expression increased and MBP expression level increased.The expression levels of ATF6,p-IRE1,p-PERK and cleaved caspase 3 were significantly decreased,and apoptosis was reduced.Conclusion Early exercise can inhibit endoplasmic reticulum stress-induced apoptosis,promote cerebral myelin repair,reduce infarct size and improve nerve function.