OBJECTIVE To identify and analyze adverse drug event （ADE） signals associated with tirzepatide based on the FDA Adverse Event Reporting System （FAERS） database， providing a reference for clinical medication safety. METHODS ADE reports from January 1， 2022， to June 30， 2024， with tirzepatide as the primary suspected drug， were extracted from the FAERS database. Medical Dictionary for Regulatory Activities was used to systematically categorize the selected system organ class （SOC） and preferred term of ADE. Signal mining and analysis were performed using the reporting odds ratio method and the proportional reporting ratio method. RESULTS A total of 39 229 ADE reports related to tirzepatide were obtained， including 3 934 severe ADE reports （10.03%）. The majority of severe ADE reports were related to hospitalization or prolonged hospitalization （3.82%）， involving 131 positive ADE signals. Among the reports with documented patient gender and age， 26 195 were female （66.77%）， 7 869 were male （20.06%）， and the majority of patients were aged 18-64 years （54.26%）. The top three most frequently reported ADE were injection site pain， nausea， and injection site hemorrhage. Strong ADE signals not mentioned in the tirzepatide instruction included injection site coldness， starvation ketoacidosis， injection site hemorrhage， hunger， elevated adrenaline， injection site skin cracking， binge eating， skin laxity， intestinal sepsis， lack of satiety， and dysesthesia. Subgroup analysis for patient’s gender and age showed differences in the proportion of ADE reports across different SOC. Male patients or those aged≥65 years had a higher risk of gastrointestinal system disorders compared to female patients or those aged ＜65 years. CONCLUSIONS In clinical use of tirzepatide， in addition to monitoring ADE listed in the instruction， attention should also be paid to ADE not mentioned in the instruction， such as injection site coldness， starvation ketoacidosis， injection site hemorrhage， elevated adrenaline， and intestinal sepsis， to ensure patient safety.

OBJECTIVE To evaluate the efficacy， safety and cost-effectiveness of tirzepatide for diabetes mellitus type 2 （T2DM） and long-term weight management， and provide evidence-based basis for clinical drug treatment and health insurance policy formulation. METHODS Computer searches were conducted in Embase， PubMed， the Cochrane Library， CNKI and health technology assessment （HTA） official website from their inception to October 1st 2024 to collect HTA report， systematic review/ meta-analysis and pharmacoeconomic study on tirzepatide for the treatment of T2DM or for weight management. After data extraction and quality evaluation， descriptive analysis was performed on the research results. RESULTS Totally 18 papers were included， including 14 systematic reviews/meta-analyses and 4 pharmacoeconomics studies， and no HTA report was retrieved. In terms of efficacy， most results showed that the tirzepatide 10 mg and 15 mg were significantly better than other glucagon-like peptide-1 （GLP-1） receptor agonists in reducing glycosylated hemoglobin， body weight， and waist circumference （P＜0.05）. In terms of safety， compared with other GLP-1 receptor agonists， tirzepatide did not increase the incidence of gastrointestinal-related adverse events （AE）， the incidence of AE of grade ≥3， or the incidence of severe hypoglycemia （P＞0.05）. However， tirzepatide 15 mg may significantly increased the incidence of hypoglycemia and the rate of discontinuation due to adverse reactions （P＜ 0.05）. In terms of cost-effectiveness， based on the background of foreign pharmacoeconomic studies， tirzepatide was more cost- effective compared to semaglutide and liraglutide in the treatment of T2DM or for weight management. CONCLUSIONS Tirzepatide at doses of 10 mg and 15 mg has good efficacy and safety for the treatment of T2DM and for long-term weight management. However， when using the 15 mg dose of tirzepatide， close monitoring is required due to the risk of hypoglycemia and discontinuation due to adverse reactions it may pose. Based on pharmacoeconomic studies conducted abroad results， tirzepatide exhibits economic advantages.

The circadian clock is a highly conserved timekeeping system in organisms, which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression. Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies. Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues, primarily manifested as a dysfunction of core clock components (particularly circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1)) and the widespread dysregulation of their downstream target genes. Notably, CLOCK demonstrates non-canonical oncogenic functions, including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways. This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1, encompassing multidimensional effects such as cell cycle control, DNA damage response, metabolic reprogramming, and tumor microenvironment (TME) remodeling. Regarding the therapeutic strategies, we focus on cutting-edge approaches such as chrononutritional interventions, chronopharmacological modulation, and treatment regimen optimization, along with a discussion of future perspectives. The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology, particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.
Humans ; ARNTL Transcription Factors/physiology* ; Neoplasms/therapy* ; CLOCK Proteins/physiology* ; Circadian Clocks/genetics* ; Animals ; Circadian Rhythm/genetics* ; Tumor Microenvironment ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic

BACKGROUND:Establishing a stable and reliable animal model of acute pancreatitis is of great significance for understanding its pathogenesis,pathophysiological characteristics,and clinical medication.Domestic and foreign studies have shown that cerulein,L-arginine,and sodium taurocholate can induce acute pancreatitis,but their pathophysiological characteristics and model characteristics are still unclear. OBJECTIVE:To establish an acute pancreatitis rat model using cerulein,L-arginine,and sodium taurocholate and to observe the changing patterns of model features at different time points. METHODS:Ninety-six healthy male Sprague-Dawley rats were randomly divided into normal group,cerulein group,L-arginine group,and sodium taurocholate group,with 24 rats in each group.Within each group,there were three subgroups(n=8 per group):12-,24-,and 48-hour subgroups.Cerulein was administered via intraperitoneal injection six times with a 1-hour interval.L-arginine was administered through two intraperitoneal injections with a 1-hour interval.Sodium taurocholate was injected for inducing acute pancreatitis models through retrograde injection into the bile-pancreatic duct.By examining the rat survival rate,gross morphology of the pancreas,calculating the pancreatic organ index,and measuring levels of amylase,lipase,alanine transaminase,aspartate transaminase,blood urea nitrogen,and creatinine,as well as observing pancreatic tissue pathological features through hematoxylin-eosin staining and conducting a pancreatic injury scoring,we evaluated the changing patterns of model features at different time points. RESULTS AND CONCLUSION:Compared with the normal group,the overall survival rate of rats was 100%in the cerulein group,88%in the L-arginine group,and 96%in the sodium taurocholate group.The pancreatic organ index was increased in all groups.Gross observation indicated that,In the cerulein group,pancreatic edema,blurred lobes,and looseness were visible.In the L-arginine group,the pancreatic glands were enlarged and thickened with patchy bleeding.In the sodium taurocholate group,pancreatic tissue showed varying degrees of congestion and edema accompanied by scattered flakes of hemorrhage and necrosis.The levels of serum alanine transaminase,aspartate transaminase,blood urea nitrogen,creatinine,amylase,and lipase in rats exhibited consistent changes.In the cerulein group,these parameters possibly peaked at 12 hours(P<0.05)and then showed a declining trend.In the L-arginine group,they reached the highest levels at 24 hours(P<0.05)and significantly decreased at 48 hours.In the sodium taurocholate group,serum amylase and lipase remained at higher levels at 12 hours with a slow decline trend(P<0.05).Compared with the normal group,microscopic examination revealed mild acinar edema and widened interlobular spaces in the cerulein group,with a higher presence of inflammatory cells.In the L-arginine group,there was widening of interlobular spaces,extensive infiltration of inflammatory cells,and patchy necrotic areas.In the sodium taurocholate group,significant pancreatic edema,structural disarray,extensive necrotic foci,and inflammatory cell infiltration were observed.Compared with the normal group,the pathological scores of induced acute pancreatitis in all three models were significantly different at each time point(P<0.05).Moreover,the pathological scores in each group increased over time,indicating a gradual worsening of pancreatic tissue damage.When comparing different models at the same time,there were differences in pathological scores,with the sodium taurocholate group having the highest scores,followed by the L-arginine group,and the cerulein group having the lowest scores.Analyzing the three models at the same time point,the most severe condition was in the sodium taurocholate group,which was characterized by pancreatic hemorrhage and necrosis,followed by the L-arginine group,which was characterized by necrosis,and the least severe condition was in the cerulein group,mainly characterized by edema.The serum biochemical index levels of the cerulein and L-arginine groups decreased at 48 hours,indicating that these two models may have a tendency to self-heal and belong to a self-limiting disease course.The serum biochemical index levels of the sodium taurocholate group decreased slowly after 12 hours.Therefore,pancreatic injury in the sodium taurocholate group might not be relieved after 48 hours or longer.

Insulin autoimmune syndrome(IAS),also known as autoimmune hypoglycemia,is one of the rare causes of hypoglycemia.Here,we described a case of a 57-year-old patient with type 2 diabetes mellitus who experienced recurrent and irregular severe hypoglycemic events after using lipoic acid.His insulin autoantibodies changed from negative to positive,and no pathogenic variation or suspected pathogenic variation related to the clinical feature of the subject was detected by gene test.Eventually,the patient was diagnosed as IAS.

Objective:To investigate the protective effect of hyperbaric oxygen therapy(HBOT)on myocardial fibrosis and oxidative stress induced by D-galactose(D-gal)in senescent model mice and its possible mechanism.Methods:Three-month-old male Kunming mice(n=27)were randomized into control, D-gal, and D-gal + HBOT groups.The control group received subcutaneous sterilized saline(5 ml · kg -1· d -1)for 8 weeks; the remaining 2 groups received subcutaneous D-gal(200 mg · kg -1· d -1)for 8 weeks. The D-gal + HBOT group underwent HBOT intervention at week 7~8.At the end of the experiment, the histopathological changes were analyzed by hematoxylin-eosin(HE)staining, and the fibrosis changes were analyzed by Masson staining and Sirius red staining.Oxidative stress kit was used to detect catalase(CAT), total superoxide dismutase(T-SOD)activity and malon-di-aldehyde(MDA)content in serum of mice.Western blotting was used to detect the expression levels of the aging-related proteins p53 and p16 in mouse heart tissue, the heart-function-related proteins atrial natriuretic peptide(ANP)and brain natriuretic peptide(BNP), and the oxidative stress-related protein superoxide dismutase 1(SOD1), superoxide dismutase 2(SOD2)and catalase(CAT). Results:Cardiac morphologic staining indicated that as compared with the control group, mice of D-gal group exhibited features of senescence and the increased fibrosis area, and senescence and fibrosis were obviously improved after HBOT intervention as compared with the D-gal group.The findings of the oxidative stress kit measurement indicated that as compared with the control group, the D-gal group had markedly decreased activities of CAT and T-SOD, significantly increased MDA content in the serum.After HBOT treatment, as compared with d-gal group, serum CAT and T-SOD activities were increased, while MDA content was decreased( F=126.85, 32.89, 157.50, all P<0.05).Furthermore, as compared with the control group, the D-gal group had obviously increased contents of p53, p16, ANP and BNP, while the content of CAT, SOD1 and SOD2 were obviously decreased.After HBOT intervention, as compared with the D-gal group, the contents of p53, p16, ANP、BNP were reduced, while the content of CAT, SOD1 and SOD2 were increased( F=36.37, 14.81, 23.28, 58.41, 12.79, 80.08, 6.63, all P<0.05). Conclusions:HBOT intervention could protects against cardiac injury in aging mice, which may be related to attenuating myocardial fibrosis, inducing the expression of antioxidant enzymes, and reducing oxidative stress.

Objective:To explore the influencing factors by investigating the spiritual health status of patients with lung cancer during perioperative period.Methods:A total of 208 perioperative patients who underwent radical resection of lung cancer in Cancer Hospital Chinese Academy of Medical Sciences from September 2020 to September 2021 were selected as research objects by the convenient sampling method. The General Data Questionnaire, Chinese version of Functional Assessment of Chronic illness Therapy-Spiritual (FACIT-SP-12) and Family APGAR Index (APGAR) were used to investigate the patients. Pearson correlation analysis was used to explore the correlation between spiritual health and family caring. Pearson correlation analysis was used to explore the correlation between spiritual health and family caring. Multiple linear regression analysis was used to investigate the influencing factors of spiritual health in patients with lung cancer during perioperative period. A total of 208 questionnaires were sent out and 200 were effectively received, with the effective recovery of 96.15%.Results:The total score of FACIT-SP-12 of 200 patients with perioperative lung cancer was (35.59±8.16) , indicating a moderate spiritual health level. The main factors affecting spiritual health of perioperative lung cancer patients were the degree of family care, marital status and payment of medical expenses ( P<0.05) . Conclusions:The spiritual health of perioperative lung cancer patients is in the middle level, and the spiritual health of patients with different family caring degrees, marital status and medical payment method is different. Clinical medical workers can carry out targeted nursing intervention according to individual conditions of patients to improve their quality of life.

Objective:To detect the expression of fibroblast-specific protein 1 (FSP1/S100A4) , ɑ-smooth-muscle actin (ɑ-SMA) and fibroblast-activated protein (FAP-ɑ) in tumor-associated fibroblasts (TAFs) in papillary thyroid carcinoma (PTC) , and to investigate its relationship with the origination and development of PTC.Methods:The expression of FSP1/S100A4, ɑ-SMA and FAP-ɑ in normal thyroid and PTC was determined by SP method of immunohistochemistry, and the relationship between these indicators and important clinicopathological parameters were analyzed.Results:The positive expression of FSP1/S100A4, ɑ-SMA and FAP-ɑ was observed in PTC, but not detected in the follicular epithelium or stromal cells of normal thyroid. In addition, the expression of FAP-ɑ was significantly related to tumor size, lymph node metastasis and TNM classification ( χ2=6.833, P<0.05; χ2=10.296, P<0.05; χ2=4.910, P<0.05) . The expression of ɑ-SMA was positively related to the invasion of capsule and lymph node metastasis ( χ2=6.008, P<0.05; χ2=11.766, P<0.05) . The expression of FSP1/S100A4 was negatively related to the clinicopathological parameters above ( P>0.05) in PTC. Conclusion:TAFs in PTC may indicate the infiltration and metastasis, which provideds new thinking for the treatment strategies of papillary thyroid carcinoma.

Objective To observe the effects of Yuanzhi San (YZS) on the ethology and cerebral acetylcholinesterase(AchE) activity of mouse model of memory disorder induced by scopolamine. Methods Sixty mice were randomly divided into six groups, namely blank control group, model group, positive medicine group, and low-dose, middle-dose and high-dose YZS groups. Except for the blank control group and model group were given the normal saline, the mice in other groups were administered with the corresponding drugs for 10 days. And then, mice in the medication groups were given subcutaneous injection of scopolamine in the dose of 3mg/kg to induce memory disorder model. Morris water maze test and step-down test were adopted for the observation of the learning-memory ability of the mice, and at the end of the tests, the activity of AchE in mouse cerebral cortex was measured by a biochemical method. Results Compared with the model group, escape latency was decreased, and retention time and swimming distance in the effective area in Morris water maze test were prolonged in YZS groups (P<0.05); latency in step-down test was also prolonged (P<0.05). YZS had an effect on decreasing AchE activity in the cerebral cortex of model mice (P < 0.05 compared with the model group). However, the differences were insignificant among the medication groups(P>0.05). Conclusion YZS exerts certain effect on improving learning-memory ability of memory disorder mice induced by scopolamine , and the mechanism might be related with the inhibition of AchE activity in the cerebral cortex of model mice.

Objective To explore the association between the students’emotional quotient (EQ),personality trait and interpersonal trust, and to clarify the potential function of interpersonal trust of higher students. Methods Interpersonal Trust Scale, Emotional Quotient Table and Eysenck Personality Questionnaire (EPQ) were used to investigate 364 students from Guangxi University and Guangxi Teachers Education University.SPSS 18.0 software was used for one-way ANOVA variance analysis,Pearson product-moment correlation analysis and stepwise Multiple Linear regression analysis.Results The differences in interpersonal trust,EQ and personality trait of EPQ had statistical significance between males and females,and the males’scores were higher than those of females (P <0.05,P < 0.01);the differencs in Lie of EPQ between nations had statistical significance and the scores of Dong, Hui and Tujia ethnic minority were higher than those of other nationalities (P < 0.01 ); the difference in personality trait of EPQ between educational background had statistical significances, and the undergraduates’scores were higher than those of master students (P <0.05).EQ was positively correlated with EPQ-E and EPQ-L (r=0.274,P <0.01;r =0.145,P <0.01),and was negatively correlated with EPQ-N and EPQ-P (r=-0.422,P <0.01;r = -0.202,P <0.01);interpersonal trust was negatively correlated with EQ and EPQ-E (r=-0.273,P <0.01;r=-0.169,P <0.01);special trust was negatively correlated with EQ and EPQ-E (r=-0.252,P <0.01;r = - 0.151,P < 0.01);interpersonal trust and general trust were negatively correlated with EPQ-P (r =0.313,P <0.01;r =0.338,P <0.01),and they were positively correlated with EPQ-L (r=-0.201,P <0.01;r = -0.217,P <0.01).Conclusion The students’EQ,personality trait are related to interpersonal trust of the students in Guangxi universities,and they have important prediction effects. Improving students’ EQ and interpersonal trust plays a positive role, whereas, the possible negative effects accompanying should never be neglected.