Objective:To establish a mouse model of liver cancer resistant to PD-1 monoclonal antibody and analyze the changes in its metabolomics to explore the potential mechanism of drug resistance.Methods:BALB/c mice were randomly divided into control and treatment groups after being loaded with tumor,and a normal group was additionally set up.The normal and control groups were injected with saline,and the treatment group was injected with PD-1 monoclonal antibody,after which the mice in the treatment group were screened for drug resistant and response groups.Observed the drug-resistant situation,body mass,tumor growth and survival rate of mice in each group,calculate the spleen index.The pathological features of tumor tissues were observed by HE staining method.Serum metabolites were detected by non-targeted metabolomics.Finally,a bivariate Pearson correlation analysis was conducted between the differential serum metabolites and tumor size.Results:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established,and the drug resistance rate of the mice was 50％.Compared with the normal and response groups,mice in the resistant group showed an increase in body weight,a significant increase in tumor volume,a decrease in survival rate,and a significant increase in splenic index.There was less lymphocyte infiltration in the tumor tissue.Metabolomics analysis showed that the serum levels of glutamic acid and aspartic acid increased and malic acid decreased in the resistant mice compared with the response group,and these changes were closely related to the arginine biosynthesis pathway.Conclusions:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established.The changes in its peripheral serum metabolomics mainly involve arginine metabolism and the related changes of aspartate,malate and glutamate.

Aim Mouse model of myocardial hypertro-phy was established via intraperitoneal injection of iso-proterenol(ISO)in mice.This approach allows for an in-depth investigation into the pharmacological effects and mechanisms of action of emodin,offering novel in-sights and directions for the improvement of myocardial hypertrophy.Methods The mice were randomly di-vided into the following groups:control group(CON),emodin group(EMO),MAPK activator control group(EMO+Ani),model group(ISO),treatment group(ISO+EMO),and activator intervention group(ISO+EMO+Ani).After treatment with emodin and inter-vention with MAPK activator,the heart weight ratio and cardiac size of each group were observed.Hematoxy-lin-eosin(HE)staining was used to observe the patho-logical changes in cardiac tissue,and kits were utilized to measure the levels of GSH,LDH,and MDA in the serum.Western blot was employed to detect the protein expression levels of inflammatory and oxidative factors,as well as p-p38,p-ERK,p38,and ERK in cardiac tis-sue.Results Emodin can significantly inhibit the production of myocardial inflammatory and oxidative factors induced by ISO,thereby effectively alleviating the degree of myocardial hypertrophy and fibrosis.Af-ter the p38/ERK signaling pathway was specifically ac-tivated by farnesol,the improvement effect of emodin on myocardial hypertrophy was weakened.Further comparison revealed that,compared with the myocardi-al hypertrophy pathological model group,the pathologi-cal protein expression levels in the farnesol-treated group showed no significant difference,and were even higher in some indicators.Conclusion Emodin can effectively inhibit the release of inflammatory factors and improve the state of oxidative stress by modulating the p38/ERK signaling pathway,thereby exerting an ameliorative effect on myocardial hypertrophy.

Aim To explore the mechanism by which the compound Chaijin Jieyu formula(CCJJY)regulates the TLR4/NLRP3 signaling pathway to inhibit central oxidative stress and improve hippocampal synaptic plasticity damage in depression.Methods SD rats were randomly divided into the control group,chronic unpredictable mild stress group,sleep deprivation group,chronic unpredictable mild stress combined with sleep deprivation group,positive drug group(venlafax-ine+melatonin),low-dose group of CCJJY,medium dose group of CCJJY,and high-dose group of CCJJY,with nine rats in each group.Except for the control group,a rat model of depression complicated with in-somnia was established using chronic unpredictable mild stress combined with sleep deprivation.Depres-sion-like and sleep behaviors in rats were evaluated through weight,food intake,water maze,and pento-barbital sodium tests.ELisa was used to detect ROS,AANAT,and HPLC-EC was used to detect 5-HT con-tent,while Western blot/RT-PCR was used to detect the expression of IL-1β,TLR4,NLRP3,PSD-95,and SYN related proteins and mRNA.HE and Golgic stai-ning were used to observe the pathological changes in the third ventricle,hippocampus,and neuronal synap-ses.Results Compared with the control group,the depression-like behaviors of the model group rats were significant.The expression of IL-1β,TLR4,and NL-RP3 in the hippocampus increased,while the expres-sion of PSD-95 and SYN decreased.Activation of NL-RP3 inflammasomes led to "sleeve like" pathological changes in the third ventricle,with hippocampal neu-rons undergoing apoptosis and significant damage to neuronal synaptic plasticity.Compared with the model group,after intervention with CCJJY,the expression of ROS,IL-1β,TLR4,and NLRP3 decreased,while the expression of AANAT,5-HT,PSD-95,and SYN in-creased.Pathological damage to the third ventricle and hippocampal neurons was repaired.Conclusion The CCJJY improves hippocampal synaptic plasticity dam-age in depression by regulating the TLR4/NLRP3 sig-naling pathway to inhibit central oxidative stress.

Objective:To analyze the effects of lumbar sacral plexus block combined with low-dose ketamine on intraoperative blood pressure fluctuations and heart rate variability in elderly hypertensive hip replacement patients.Methods:88 elderly patients with hypertension who underwent hip replacement in our hospital from December 2022 to June 2024 were collected and divided into two groups using the drawing method:the conventional group(44 cases)and the experimental group(44 cases).The conventional group of patients received lumbar sacral plexus block after entering the room,followed by laryngeal mask anesthesia.The experimental group received intravenous injection of 0.2 mg/kg ketamine before laryngeal mask anesthesia on the basis of the control group.Compare the changes in systolic pressure(SBP)and diastolic pressure(DBP)levels between two groups of patients at the time of entry(T1),immediately after anesthesia(T2),during skin incision(T3),30 minutes after surgery(T4),during incision closure(T5),and immediately after surgery(T6);Standard deviation of R-R interval for all normal sinus beats(SDNN)and mean standard deviation of 5-minute heart beat interval(SDANN)before and 3 days after surgery;Intraoperative dosage of sufentanil,propofol,and usage rate of phenylephrine;And compare the levels of C-reactive protein(CRP),tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6)before and 3 days after surgery,and finally compare the incidence of adverse reactions between the two groups after surgery.Results:There was a certain degree of fluctuation in SBP and DBP during surgery in both groups of patients,but the fluctuation level in the experimental group was relatively small.There was no significant difference in SBP and DBP levels between the two groups of patients at T1,T2,and T6 times(P＞0.05).The experimental group had lower levels of SBP and DBP at T3,T4,and T5 times compared to the control group(P＜0.05);There was no significant difference in preoperative SDNN and SDANN between the two groups of patients(P＞0.05).After 3 days of surgery,there was no significant change in SDNN and SDANN in the experimental group,while SDNN and SDANN in the conventional group decreased,and the experimental group was higher than the conventional group(P＜0.05);By comparing the dosage of anesthetics,it was found that the experimental group had lower intraoperative doses of sufentanil and propofol compared to the control group,and the usage rate of phenylephrine was lower than that of the control group(P＜0.05);There was no significant difference in preoperative CRP,TNF-α,and IL-6 between the two groups of patients(P＞0.05).On postoperative day 3,CRP,TNF-α,and IL-6 increased in both the experimental group and the control group,with the experimental group being lower than the control group(P＜0.05);There was no significant difference in the incidence of postoperative adverse reactions between the two groups of patients(P＞0.05).Conclusion:Lumbar sacral plexus block combined with low-dose ketamine can stabilize intraoperative blood pressure levels,improve postoperative heart rate variability,reduce the use of anesthetics and vasoactive drugs,alleviate postoperative inflammatory reactions,and have high safety in elderly hypertensive hip replacement patients undergoing anesthesia.

Objective:To establish a mouse model of liver cancer resistant to PD-1 monoclonal antibody and analyze the changes in its metabolomics to explore the potential mechanism of drug resistance.Methods:BALB/c mice were randomly divided into control and treatment groups after being loaded with tumor,and a normal group was additionally set up.The normal and control groups were injected with saline,and the treatment group was injected with PD-1 monoclonal antibody,after which the mice in the treatment group were screened for drug resistant and response groups.Observed the drug-resistant situation,body mass,tumor growth and survival rate of mice in each group,calculate the spleen index.The pathological features of tumor tissues were observed by HE staining method.Serum metabolites were detected by non-targeted metabolomics.Finally,a bivariate Pearson correlation analysis was conducted between the differential serum metabolites and tumor size.Results:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established,and the drug resistance rate of the mice was 50％.Compared with the normal and response groups,mice in the resistant group showed an increase in body weight,a significant increase in tumor volume,a decrease in survival rate,and a significant increase in splenic index.There was less lymphocyte infiltration in the tumor tissue.Metabolomics analysis showed that the serum levels of glutamic acid and aspartic acid increased and malic acid decreased in the resistant mice compared with the response group,and these changes were closely related to the arginine biosynthesis pathway.Conclusions:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established.The changes in its peripheral serum metabolomics mainly involve arginine metabolism and the related changes of aspartate,malate and glutamate.

Aim Mouse model of myocardial hypertro-phy was established via intraperitoneal injection of iso-proterenol(ISO)in mice.This approach allows for an in-depth investigation into the pharmacological effects and mechanisms of action of emodin,offering novel in-sights and directions for the improvement of myocardial hypertrophy.Methods The mice were randomly di-vided into the following groups:control group(CON),emodin group(EMO),MAPK activator control group(EMO+Ani),model group(ISO),treatment group(ISO+EMO),and activator intervention group(ISO+EMO+Ani).After treatment with emodin and inter-vention with MAPK activator,the heart weight ratio and cardiac size of each group were observed.Hematoxy-lin-eosin(HE)staining was used to observe the patho-logical changes in cardiac tissue,and kits were utilized to measure the levels of GSH,LDH,and MDA in the serum.Western blot was employed to detect the protein expression levels of inflammatory and oxidative factors,as well as p-p38,p-ERK,p38,and ERK in cardiac tis-sue.Results Emodin can significantly inhibit the production of myocardial inflammatory and oxidative factors induced by ISO,thereby effectively alleviating the degree of myocardial hypertrophy and fibrosis.Af-ter the p38/ERK signaling pathway was specifically ac-tivated by farnesol,the improvement effect of emodin on myocardial hypertrophy was weakened.Further comparison revealed that,compared with the myocardi-al hypertrophy pathological model group,the pathologi-cal protein expression levels in the farnesol-treated group showed no significant difference,and were even higher in some indicators.Conclusion Emodin can effectively inhibit the release of inflammatory factors and improve the state of oxidative stress by modulating the p38/ERK signaling pathway,thereby exerting an ameliorative effect on myocardial hypertrophy.

Objective:To analyze the effects of lumbar sacral plexus block combined with low-dose ketamine on intraoperative blood pressure fluctuations and heart rate variability in elderly hypertensive hip replacement patients.Methods:88 elderly patients with hypertension who underwent hip replacement in our hospital from December 2022 to June 2024 were collected and divided into two groups using the drawing method:the conventional group(44 cases)and the experimental group(44 cases).The conventional group of patients received lumbar sacral plexus block after entering the room,followed by laryngeal mask anesthesia.The experimental group received intravenous injection of 0.2 mg/kg ketamine before laryngeal mask anesthesia on the basis of the control group.Compare the changes in systolic pressure(SBP)and diastolic pressure(DBP)levels between two groups of patients at the time of entry(T1),immediately after anesthesia(T2),during skin incision(T3),30 minutes after surgery(T4),during incision closure(T5),and immediately after surgery(T6);Standard deviation of R-R interval for all normal sinus beats(SDNN)and mean standard deviation of 5-minute heart beat interval(SDANN)before and 3 days after surgery;Intraoperative dosage of sufentanil,propofol,and usage rate of phenylephrine;And compare the levels of C-reactive protein(CRP),tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6)before and 3 days after surgery,and finally compare the incidence of adverse reactions between the two groups after surgery.Results:There was a certain degree of fluctuation in SBP and DBP during surgery in both groups of patients,but the fluctuation level in the experimental group was relatively small.There was no significant difference in SBP and DBP levels between the two groups of patients at T1,T2,and T6 times(P＞0.05).The experimental group had lower levels of SBP and DBP at T3,T4,and T5 times compared to the control group(P＜0.05);There was no significant difference in preoperative SDNN and SDANN between the two groups of patients(P＞0.05).After 3 days of surgery,there was no significant change in SDNN and SDANN in the experimental group,while SDNN and SDANN in the conventional group decreased,and the experimental group was higher than the conventional group(P＜0.05);By comparing the dosage of anesthetics,it was found that the experimental group had lower intraoperative doses of sufentanil and propofol compared to the control group,and the usage rate of phenylephrine was lower than that of the control group(P＜0.05);There was no significant difference in preoperative CRP,TNF-α,and IL-6 between the two groups of patients(P＞0.05).On postoperative day 3,CRP,TNF-α,and IL-6 increased in both the experimental group and the control group,with the experimental group being lower than the control group(P＜0.05);There was no significant difference in the incidence of postoperative adverse reactions between the two groups of patients(P＞0.05).Conclusion:Lumbar sacral plexus block combined with low-dose ketamine can stabilize intraoperative blood pressure levels,improve postoperative heart rate variability,reduce the use of anesthetics and vasoactive drugs,alleviate postoperative inflammatory reactions,and have high safety in elderly hypertensive hip replacement patients undergoing anesthesia.

Aging is comprehensively influenced by multiple fac-tors such as internal genes,cellular metabolism,external envi-ronment,and lifestyle habits.Among them,epigenetic regula-tion plays a core role.Epigenetic modifications,including DNA methylation,histone modification,heterochromatin remodeling,and non-coding RNA regulation,act in concert with the three-di-mensional genome architecture to precisely regulate gene expres-sion.This review elaborates on the factors influencing epigenetic regulation,as well as the mechanisms of how epigenetics affects the occurrence of organismal aging and the corresponding inter-vention strategies,providing relevant insights for uncovering the mechanisms of aging and preventing/treating aging-related disea-ses.

Aim To establish an animal model of diabetic kidney disease(DKD)integrating blood stasis syndrome and syndrome evaluation indicators.Methods Twenty-five SD rats were ran-domly divided according to body weight into a control group(8 rats)and a modeling group(17 rats).The modeling group was fed a high-sugar and high-fat diet for four weeks and induced to form diabetic rats by intraperitoneal injection of 30 mg·kg-1 streptozocin.The modeling rats were randomly divided into the DKD group and blood stasis syndrome combination group accord-ing to 24-hour urinary protein(24-hUP).The blood stasis syn-drome combination group was induced to replicate the DKD blood stasis syndrome model by injecting 10％high molecular weight D-glucoside three times at a dose of 0.05 mg·kg-1 via tail vein.The model was evaluated based on random blood glu-cose level,24-hUP level,syndrome assessment,pathological staining etc,and differential metabolites were selected using metabolomics.Results The comprehensive evaluation of syn-drome manifestations and pathological staining in the combined model of blood stasis syndrome in rats demonstrated successful replication.Utilizing the technique of liquid chromatography-mass spectrometry,22 differential metabolites were identified,with associated pathways showing a certain relevance to blood stasis syndrome in DKD.Conclusions The successful replica-tion of an animal model combining the syndrome of blood stasis in DKD has been achieved in this study.Evaluation of indicators and results from metabolomics studies consistently demonstrate a correlation with the syndrome of blood stasis in DKD.

Objective:To examine the manifestations and causes of administrative burden among primary healthcare professionals,and to explore its impact on job burnout through the mediating role of role conflict,providing theoretical and empirical support for governance-level burden-reduction strategies.Methods:An exploratory sequential mixed-methods design was employed,focusing on primary healthcare professionals in Shandong Province.In the first phase,in-depth interviews were conducted with 175 participants;in the second phase,a questionnaire survey of 1,096 participants and follow-up interviews with 107 participants were carried out.Results:The proportions of respondents who reported"heavy"or"very heavy"burdens were 62.7%for inspection,54.8%for documentation,51.8%for reporting,and 24.4%for meetings.Structural equation modeling showed that administrative burden had a direct effect on job burnout(0.150)and an indirect effect through role conflict(0.093).Qualitative findings further indicated that administrative burden largely stemmed from public health traceability requirements and medical insurance policies,and operated through both resource-based and value-based conflicts.Conclusions:Primary healthcare professionals face considerable administrative burdens,which may heighten job burnout through role conflict.Governance reforms should optimize inspection and assessment,streamline data reporting,refine record-keeping,and promote collaborative governance to break the chain of institutional pressure leading to burnout.