The abnormal accumulation of neutrophil extracellular traps （NETs） can promote the initiation and progression of pancreatic cancer， which is considered a potential therapeutic target for this disease. The Miraculous Pivot·Inquiry About Statement （《灵枢·口问》） have recorded the concept of "defensive qi stagnation". Based on the recognition that the function of defensive qi is similar to the immune function of neutrophils， and combining traditional Chinese medicine theory with clinical practice， it is proposed that the abnormal accumulation of NETs may be a pathological product of "defensive qi stagnation"， with the spleen being the critical site of pathology. Further exploring the application strategy of cleaning spleen and restoring defensive qi method in pancreatic cancer treatment， it is proposed to employ three approaches such as dredging method to eliminate spleen stagnation and inhibit pancreatic cancer proliferation， cleaning method to remove spleen dampness and suppress the inflammatory micro-environment， and tonifying method to strengthen Weiqi and to improve the immune microenvironment， which aims to provide new insights for the clinical treatment of pancreatic cancer with traditional Chinese medicine.

ObjectiveTo investigate the regulatory effect of icariin （ICA） on transforming growth factor-β₁ （TGF-β₁）/Smad pathway in bone microvascular endothelial cells （BMECs） and the effect on autophagy in BMECs. MethodsBMECs were isolated and cultured， and the cell types were identified by immunofluorescence. Cells were divided into the control group， model group （0.1 g·L^-1 methyl prednisolone）， ICA group （0.1 g·L^-1 methyl prednisolone +1×10^-5 mol·L^-1 ICA）， and TGF-β inhibitor group （0.1 g·L^-1 methyl prednisolone +1×10^-5 mol·L^-1 ICA +1×10^-5 mol·L^-1 LY2157299）. Transmission electron microscopy was used to observe the ultrastructure and autophagosome number of BMECs. Autophagy double-standard adenovirus was used to monitor the confocal autophagy flow generation of each cell. Real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot were used to detect the gene and protein expression of autophagy in the TGF-β₁/ Smad pathway. ResultsAfter cell separation culture， platelet endothelial cell adhesion molecule （CD31） and von willebrand factor （vWF） immunofluorescence identified BMECs. Transmission electron microscopy showed that the cell membrane was damaged， and the nucleus was pyknotic and broken in the model group. Compared with the model group， the ICA group had complete cell membranes， clear structures， with autophagy-lysosome sparsely distributed. The confocal photo showed that BMECs had autophagosomes and autophagy-lysosomes， and the autophagy expression of the ICA group was similar to that of the blank group. Compared with the blank group， in the model group and the LY2157299 group， autophagosomes and autophagy-lysosomes were barely seen in the autophagy flow. Compared with the blank group， the mRNA and protein expressions of autophagy effector protein 1 （Beclin1） and microtubule-associated protein 1 light chain 3B （LC3B） in the model group were significantly decreased （P<0.01）， and those of ubiquitin-binding protein （p62） were significantly increased （P<0.01）. The mRNA expression of TGF-β₁， Smad homolog 2 （Smad2）， and Smad homolog 3 （Smad3） decreased （P<0.05， P<0.01）. The protein expressions of TGF-β₁， p-Smad2， and p-Smad3 were significantly decreased （P<0.01）. Compared with those of the model group， the mRNA and protein expression of Beclin1 and LC3B in BMECs of the ICA group increased （P<0.01）， and those of p62 significantly reduced （P<0.01）. The mRNA expression of TGF-β₁， Smad2， and Smad3 increased significantly （P<0.01）. The protein expression of TGF-β₁， p-Smad2， and p-Smad3 increased significantly （P<0.01）. Compared with those in the model group， the mRNA and protein expressions of Beclin1， LC3B， and p62 in the inhibitor group were not statistically significant. The expression of key genes and proteins of the TGF-β₁ pathway in the inhibitor group was not statistically significant. ConclusionICA can promote glucocorticoid-induced autophagy expression of BMECs， and its mechanism may be related to activating the TGF-β₁/Smad signaling pathway.

BACKGROUND:The regeneration and remodeling of Achilles tendon rupture after surgery are difficulties in clinical treatment.Tissue engineering hydrogels afford the possibility on the healing of postoperative Achilles tendon. OBJECTIVE:To investigate the effect of tannic acid modified interpenetrating network hydrogel on tissue regeneration and remodeling of ruptured Achilles tendon in rats. METHODS:(1)The interpenetrating network hydrogel was prepared under the blue light and the immersion of CaSO4 solution.The micromorphology,mechanical properties,adhesion properties,in vitro drug release properties,and biocompatibility of hydrogels were characterized.(2)Thirty Sprague-Dawley rats were randomly divided into sham operation group,operation group,and hydrogel group,with 10 rats in each group.The animal model of Achilles tendon rupture was established in the latter two groups.In the operation group,the ruptured Achilles tendon was sutured using the modified Kessler method.In the hydrogel group,the ruptured Achilles tendon was repaired by the same method,and the tannic acid modified interpenetrating network hydrogel patch was completely wrapped around the joint of the broken end.Four weeks after the operation,imaging examination,histological evaluation,biomechanical test,and the level test of inflammatory factors were performed. RESULTS AND CONCLUSION:(1)Scanning electron microscope showed that tannic acid modified interpenetrating network hydrogels had porous microstructure with pore size of 3-10 μm,and the hydrogels had good in vitro drug release properties,adhesion strength and tensile strength.CCK-8 assay and live/dead staining showed that the hydrogel had no significant effect on the proliferation activity of rat bone marrow mesenchymal stem cells,and had good biocompatibility.(2)MRI imaging showed that compared with the operation group,the Achilles tendon in the hydrogel group showed uniform low signal,the thickness of the anteroposterior diameter of the Achilles tendon was reduced,and the boundary between the Achilles tendon and the surrounding tissue was more clear,and the performance was more similar to that of the sham operation group.Hematoxylin-eosin staining and Masson staining showed that the tendon fibers in the operation group were arranged in a loose and chaotic manner,with increased cell density and disordered arrangement,accompanied by obvious inflammatory cell infiltration,and intratendinous ossification appeared in some areas.In the hydrogel group,the tendon fibers were arranged in an orderly manner;the cell density was reduced and arranged orderly;the inflammatory cell infiltration was significantly reduced.The tensile strength of Achilles tendon in the operation group was lower than that in the sham operation group(P<0.05).The tensile strength of Achilles tendon in the hydrogel group was higher than that in the operation group(P<0.05).Compared with sham operation group,the mass concentration and mRNA expression of interleukin-1β,interleukin-6,and tumor necrosis factor α in Achilles tendon of rats were increased in the operation group(P<0.05).Compared with the operation group,the level and mRNA expression of three inflammatory factors were decreased in the hydrogel group.(3)It is concluded that tannic acid modified interpenetrating network hydrogel can inhibit the local inflammatory response and promote the tendon remodeling.

BACKGROUND:Studies have shown that patients with premature ovarian failure have changes in the structure of intestinal flora and that imbalance of intestinal microbiota may be one of the important mechanisms in the development of premature ovarian failure. OBJECTIVE:To investigate the effect of Liuwei Dihuang Wan on oxidative stress and intestinal microbiota in premature ovarian failure mice induced by cyclophosphamide. METHODS:Forty-five female ICR mice were randomized into three groups:blank group(normal mice),model group(premature ovarian failure mice),and Liuwei Dihuang Wan group.A mouse model of premature ovarian failure was prepared by one-time intraperitoneal injection of cyclophosphamide(120 mg/kg)in the latter two groups.After successful modeling,the Liuwei Dihuang Wan group was intragastrically administered for 28 continuous days,and the other two groups were intragastrically administered with the same amount of normal saline for 28 days.Mouse body mass was recorded weekly and ovarian index was calculated.The development of mouse follicles was observed using hematoxylin-eosin staining.ELISA method was used to detect serum levels of anti-Mullerian hormone,estradiol,follicle stimulating hormone,superoxide dismutase,glutathione peroxidase,and malondialdehyde.Meanwhile,the gut microbiome of all mice was detected through 16S rDNA sequencing. RESULTS AND CONCLUSION:The mice in the model group had loose hair,decreased vigor and grip strength,almost no increase in body mass,and decreased ovarian index.Whereas,the mouse body mass and ovarian index were increased after treatment with Liuwei Dihuang Wan(P<0.05).The estrous cycle of mice in the model group was disorganized;Liuwei Dihuang Wan could restore the estrous cycle and reduce the number of atretic follicles in mice with premature ovarian failure.The serum levels of follicle stimulating hormone and malondialdehyde in the model group significantly increased(P<0.01),while the levels of estradiol,anti-Mullerian hormone,superoxide dismutase,and glutathione peroxidase significantly decreased(P<0.01).Liuwei Dihuang Wan could significantly decrease the serum levels of follicle stimulating hormone and malondialdehyde(P<0.01),and increase the levels of estradiol,anti-Mullerian hormone,superoxide dismutase,and glutathione peroxidase.According to the 16S rDNA sequencing results,Liuwei Dihuang Wan could regulate the abundance and diversity of intestinal microbiota,and increase the relative abundance of beneficial bacteria.KEGG pathway analysis showed that the intestinal microbiota and metabolic pathways,biosynthesis of secondary metabolites,microbial metabolism in different environments,and biosynthesis of amino acids were regulated by Liuwei Dihuang Wan.To conclude,the changes in the structure of intestinal microbiome may be one of the potential mechanisms of Liuwei Dihuang Wan in treating premature ovarian failure.Liuwei Dihuang Wan can regulate the structure of intestinal microbiome,increase the number of beneficial bacteria,reduce the number of harmful bacteria,and thus improve the balance of intestinal microbiota.This regulatory effect helps to reduce oxidative stress levels and further inhibit ovarian oxidative stress in mice with premature ovarian failure.

BackgroundSevere mental disorders represent a major public health concern due to the high disability rates and substantial disease burden， which has garnered significant national attention and prompted their inclusion in public health project management systems. However， credible evidence regarding the current status of disease management and factors influencing disease stabilization among patients with severe mental disorders in Luzhou City， Sichuan Province， remains limited. ObjectiveTo investigate the current management status of patients with severe mental disorders in Luzhou City， Sichuan Province， and to analyze influencing factors of disease stabilization among patients under standardized care， so as to provide evidence-based insights for developing targeted management strategies to optimize clinical interventions for this patient population. MethodsIn March 2023， data were extracted from the Sichuan Mental Health Service Comprehensive Management Platform for patients with severe mental disorders in Luzhou City who received management between December 2017 and December 2022. Information on mental health service utilization and clinical status changes was collected. Trend analysis was conducted to evaluate temporal changes in key management indicators for severe mental disorders in Luzhou City. Logistic regression analysis was employed to identify factors influencing the disease stabilization or fluctuation of these patients. ResultsThis study enrolled a total of 20 232 patients. In Luzhou City， the stabilization rate and standardized management rate of severe mental disorders were 94.89% and 79.36% in 2017， respectively， which increased to 95.33% and 96.92% by 2022. The regular medication adherence rate rose from 34.42% in 2018 to 86.81% in 2022. In 2022， the regular medication adherence rate was 71.80% for schizophrenia， 55.26% for paranoid psychosis， and 51.43% for schizoaffective disorder. Multivariate analysis identified the following protective factors for disease stabilization： age of 18~39 years （OR=0.613， 95% CI： 0.409~0.918）， age of 40~65 years （OR=0.615， 95% CI： 0.407~0.931）， urban residence （OR=0.587， 95% CI： 0.478~0.720）， and regular medication adherence （OR=0.826， 95% CI： 0.702~0.973）. Risk factors for disease fluctuation included poor （OR=1.712， 95% CI： 1.436~2.040）， non-inclusion in care-support programs （OR=1.928， 95% CI： 1.694~2.193）， non-participation in community rehabilitation （OR=2.255， 95% CI： 1.930~2.634）， and intermittent medication adherence （OR=3.893， 95% CI： 2.548~5.946）. ConclusionThe stability rate， standardized management rate， and regular medication adherence rate of patients with severe mental disorders in Luzhou City have shown a year-by-year increase. Age， household registration status， economic condition， medication compliance， and community-based rehabilitation were identified as influencing factors for disease fluctuation in these patients. ［Funded by Luzhou Science and Technology Plan Project （number， 2022-ZRK-186）］

The food effect(FE)on drug absorption is an important part of clinical pharmacological studies of new drugs.The caloric ratios for each component of a high-fat meal are specified in the"Technical Guidelines for Food Bioavailability and Postprandial Bioequivalence Studies"approved by the US Food and Drug Administration(FDA)and the"Technical Guidelines for Food Effect Studies in New Drug Development"approved by the National Medical Products Administration.However,the recipes for high-fat meals vary among clinical research centers,showing their advantages and disadvantages.Thus,we present a modified version of high-fat meal recipes with easy-to-quantify calories,which is a combination of Western and Chinese flavors,easy to prepare,and meets Chinese tastes.The center satisfaction surveys showed that our modified version of the high-fat meal recipe greatly improved subject satisfaction and compliance,thus better safeguarding the quality of the trial.

Objective To investigate the effect of Jichuan decoction on defecation in rats with slow transit constipation(STC).Methods A total of 36 SD rats were divided into model group,experimental group and control group.Except the control group,STC rat models were established in the other two groups by gavage of 2％rhein acid suspension.The experimental group was given 170％Jichuan decoction of 10 mL·kg-1 by gavage,while the control group and model group were given with 0.9％NaCl by gavage,once a day for 30 days.Fecal dry-wet weight ratio and colon transport time were observed by fecal weighing and recording of first fecal discharge time;substance P(SP)and vasoactive peptide(VIP)contents in plasma were detected by kit;changes in intestinal flora were detected by real-time fluorescent quantitative polymerase chain reaction(qRT-PCR).Results The dry-wet ratio of feces in control group,model group and experimental group were(44.86±4.40)％,(53.44±3.52)％and(44.28±4.33)％,respectively;the colon transport time were(340.17±34.91),(424.67±37.26)and(377.36±38.87)min,respectively;plasma SP were(79.86±7.56),(60.30±2.41)and(78.84±5.83)pg·mL-1,respectively;plasma VIP were(30.56±2.87),(23.38±6.62)and(28.39±2.37)pg·mL-1,respectively;the numbers of Bifidobacterium were 7.77±0.04,5.19±0.09 and 7.45±0.03,respectively;the numbers of Lactobacillus were 6.40±0.07,4.10±0.05 and 6.36±0.08,respectively.There were statistically significant differences in the above indexes between model group and control group,and between experimental group and model group(P＜0.01,P＜0.05).Conclusion Jichuan decoction can improve the defecation of rats with slow transit constipation.

Objective To compare the bioavailability and bioequivalence of pivastatin calcium dispersive tablets in healthy Chinese subjects.Methods A single dose of pitavastatin calcium(2 mg)was orally administered to the test preparation or reference preparation under fasting and postprandial conditions,respectively.The plasma concentrations of pitavastatin calcium were measured at different time points before and after administration by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).The bioequivalence of the two formulations was evaluated.Results Subjects received pitavastatin calcium test preparation and reference preparation in fasting condition,the Cmax were(47.79±23.99)and(46.03±21.82)ng·L-1;AUC0_,were(96.56±42.64)and(97.96±35.40)ng·h·L-1;AUC0_∞ were(102.09±43.01)and(103.46±35.62)ng·h·L-1,respectively.The 90％confidence intervals of the geometric mean ratios of Cmax,AUC0_t and AUC0-∞ of pitavastin-calcium test formulation and reference formulation were 96.28％-111.16％,94.46％-101.19％and 94.77％-101.31％,respectively.Subjects received pitavastatin calcium test preparation and reference preparation in fasting condition,the Cmax were(27.32±10.68)and(28.58±11.39)ng·L-1;AUC0_t were(82.76±27.58)and(84.06±29.12)ng·h·L-1;AUC0_∞ were(87.88±26.93)and(89.29±29.18)ng·h·L-1,respectively.The 90％confidence intervals of the geometric mean ratios of Cmax,AUC0_t and AUC0_∞ of the test formulation and the reference formulation of pitavastatin calcium were 87.39％-102.10％,94.62％-101.34％and 94.88％-101.47％,respectively.All of them were within the bioequivalence range of 80.00％to 125.00％.Conclusion Two pivastatin calcium dispersion tablets were bioequivalent and safe in healthy Chinese adult subjects.

BACKGROUND:Sarcopenia is a progressive,generalized skeletal muscle disease that is closely related to the occurrence of osteoarthritis,fractures,limb disability and death in the elderly.Establishing animal models of sarcopenia is essential to understand the pathophysiology of sarcopenia and to identify effective treatment strategies. OBJECTIVE:To review the evaluation criteria of mouse models of sarcopenia and the modeling methods of mouse models of sarcopenia,and to analyze and compare the advantages and disadvantages of various modeling methods,in order to provide reference for the research and diagnosis and treatment of sarcopenia. METHODS:"Sarcopenia,skeletal muscle aging,mouse model,animal model"in Chinese and English were used as Chinese and English search terms,respectively.The search formula was"(sarcopenia OR skeletal muscle aging)AND(mouse model OR animal model)."CNKI,WanFang and PubMed were searched for related articles published from January 2010 and October 2022.A total of 59 articles were finally included for analysis. RESULTS AND CONCLUSION:There is a faster modeling time in SAMP8 mice and the type of muscle atrophy is consistent with that of patients with sarcopenia.Therefore,it is an ideal model.Although the surgical method can successfully induce muscle atrophy,it requires precise surgical operation,which is difficult and time-consuming.Hindlimb suspension modeling in mice is similar to that of the elderly and can be regarded as an effective model of senile sarcopenia.Although reagent injection molding is simple to perform,both the dose and number of days of administration of reagents are not clear and need to be further investigated.Transgenic mouse models are less commonly used and their model stability needs further study.The search for a mouse model with low cost,short time consumption and high simulation of human sarcopenia is still a future research direction.

Objective:To evaluate direct and indirect costs for schizophrenia,major depressive disorder(MDD)and bipolar disorder,and to compare their differences of cost composition,and to explore the drivers of the total costs.Methods:A total of 3 175 inpatients with schizophrenia,MDD,and bipolar disorder were recruited.In-patient's self-report total direct of medical costs outpatient and inpatient,out-of-pocket costs,and direct non-medical costs were regarded as direct costs.Productivity loss and other loss caused by damaging properties were defined as indirect costs.The perspectives of this study included individual and societal levels.Multivariate regression analysis was applied for detecting the factors influencing disease costs.Results:The total cost of schizophrenia was higher than those of MDD and bipolar disorder at individual and societal levels.The indirect costs of three mental disorders were higher than the direct costs,and the indirect cost ratio of bipolar disorder was higher than those of schizophre-nia and MDD.Age,gender,working condition and marital status(P＜0.05)were the important drivers of total costs.Conclusion:The economic burden of the three mental disorders is relatively heavy.Schizophrenia has heaviest disease burden,and the productivity loss due to mental disorders is the driving force of the soaring disease cost