Objective To explore the effects of combined exposure to bisphenol A (BPA) and high-fat diet on liver lipid metabolism and hepatocyte senescence in mice, and to elucidate the potential mechanisms of the onset and development of non-alcoholic fatty liver disease (NAFLD). Methods Specific pathogen free C57BL/6J mice were randomly divided into six groups, with 10 mice with equal numbers of each sex in each group. The mice in the control group and the simple BPA group were fed with regular diet, while others four groups of mice were fed with high-fat diet. At the same time, the mice in the simple BPA group were intragastric administered with BPA at a dose of 50 μg/kg body weight, while the mice in the low-, medium- and high-dose BPA+high-fat groups were intragastric administered with BPA at doses of 5, 50 and 500 μg/kg body weight respectively. The mice in the control group and the high-fat group were intragastric administered with the same volume of corn oil once per day for 90 consecutive days. Liver tissues were subjected to hematoxylin-eosin (HE) and Oil Red O staining. Liver coefficients and lipid-stained area ratios were calculated. Serum level of total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined using an automatic biochemical analyzer. The hepatic tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 levels were quantified by enzyme-linked immunosorbent assay. The relative expression of cholesterol regulatory element binding protein 1 (SREBP1), CCAAT enhancer binding protein α, P16, and phosphorylated histone H2AX (γ-H2AX) in liver tissues was detected using Western blotting. The interaction effect of the combined exposure to BPA and high-fat diet was observed based on the result of mice in the control group, the simple high-fat group, the simple BPA group, and the medium-dose BPA group+high-fat group (the combined exposure group) using a 2×2 factorial design. The results of mice in the simple high-fat group and the low-, medium-, and high-dose BPA+high-fat groups were used to observe the effect of BPA exposure dose under high-fat diet conditions. Results i) The interactive effect of combined exposure to BPA and high fat. The HE and Oil Red O staining results indicated that the combined exposure to BPA and high-fat diet successfully established NAFLD in mice. The interactive effect of combined exposure to BPA and high-fat diet on serum ALT activity and the relative expression of P16 in the liver tissue of female mice, as well as the serum ALT and AST activities and the relative expression of SREBP1 in the liver tissue of male mice was significant (all P<0.05). Specifically, the serum ALT activity of male mice in the combined exposure group was higher than that in the simple high-fat group (P<0.05), while the ALT activity in the serum of female mice in the combined exposure group was lower than that in the simple BPA group (P<0.05). The relative expression of SREBP1 protein in the liver tissue of male mice in the combined exposure group was higher than that in the control group, the simple high-fat group, and the simple BPA group (all P<0.05). For the other indicators, there were no significant differences in the interactive effect of combined exposure to BPA and high-fat diet (all P>0.05). ii) Dose effects of BPA exposure. The HE and Oil Red O staining result showed that the degree of vacuolar steatosis in the liver of female and male mice of medium- and high-dose BPA + high-fat groups was aggravated, and the range of inflammatory cell infiltration was expanded when compared with same-sex mice in the simple high-fat group. The serum ALT activity and the fat stained area ratio, as well as the relative expression of P16 in liver tissue of female mice in high-dose BPA + high-fat group increased (all P<0.05), while the level of IL-10 in liver tissue decreased (P<0.05), compared with the female mice in simple high-fat group. The serum ALT activity, the TNF-α level in liver tissue, and the relative expression of SREBP1, P16 and γ-H2AX proteins in liver tissue of male mice in high-dose BPA + high-fat group increased (all P<0.05), while the IL-6 level in liver tissue decreased (P<0.05), compared with the male mice in simple high-fat group. For the female or male mice in the low- and medium-dose BPA + high-fat groups, only some of the above indicators showed significant changes (all P<0.05). Conclusion The combined exposure to BPA and high-fat diet has a synergistic effect on the onset and development of NAFLD. The mechanism may be related to inducing cellular senescence and modulation of lipid synthesis pathways, thereby affecting liver steatosis. The exposure dose of BPA may affect the synergistic effect.

ObjectiveBy analyzing the current situation of drug selection and evaluation in medical institutions in the world，we aim to understand the development of relevant selection methods and tools，provide reference basis for drug selection in traditional Chinese medicine （TCM） medical institutions，and promote the optimization of drug catalogs in TCM medical institutions. MethodBased on the method of scoping review，the eight databases were systematically searched，the included documents were screened，extracted and analyzed，and the research results were graphically displayed. ResultA total of 23 articles were included in this study，including 13 in Chinese and 10 in English，involving 23 methods or tools related to drug selection. Of the 14 methods or tools from Chinese medical institutions，the earliest one was published in 2012，and five were published in 2022. The published methods or tools involved different levels of hospitals，different drug varieties，different evaluation angles，etc.，such as the drug selection methods of one county hospital and one township hospital， methods and tools for different types of drugs such as antibacterial drugs，ibuprofen preparations，proton pump inhibitors and hypoglycemic drugs used in pediatric intensive care units， Chinese patent medicine selection tools， tools for evaluation from the perspective of pharmacoeconomics， and universal tools for selecting domestic medical institutions. The nine drug selection tools of foreign medical institutions were from the European，American，Asian and African countries. It was first published in 1955. The contents included the formulation standards that medical institutions should follow for drug prescription sets，the management formulation and update of hospital prescription sets，and drug evaluation tools. ConclusionOn the whole，the drug selection methods and institutional methods of foreign medical institutions developed earlier than those in China. In recent years，Chinese medical institutions have paid high attention to drug selection and released various types of drug selection tools. However，the standardization should be further improved in the future.

Objective To systematically review the present status of oral Chinese patent medicines(CPMs)for treating functional dyspepsia(FD),explore the formation rules of CPMs,and reveal the potential problems by referring to the methods and procedures of Scoping review.Methods First,we screened all CPMs from the domestic-related drug catalogs which are generally accepted and own the force of law,then we sorted the CPMs based on the drug instructions while carrying out Chinese and English database document retrieval to review the clinical studies.Descriptive analysis of the basic feature and clinical research evidence of CPMs was performed combined with visual charts.Results This study included 42 CPMs for treating FD.Among the formulas of CPMs,Tangerine peel,Radices saussureae,Poria cocos,Glycyrrhiza,Atractylodes macrocephala,and Six Divine Qu appeared frequently.In addition,96 studies involving 21 CPMs were included,among which Zhizhu Kuanzhong Capsule,Liuwei Anxiao capsule,and Dalitong granules had more clinical literature.By analyzing the included 96 clinical studies,we found that the combination of Chinese and Western medicine was the main intervention,and the effective rate,clinical symptom score,and adverse reactions were the main outcomes that were concerned.In addition,8 studies had off-label use of diseases,involving the Wuling capsule to treat the FD whether the disease was accompanied by depression and anxiety symptoms or not,and Zhizhu Kuanzhong Capsule to treat the FD with anxiety and depression.Although the Wuling capsule and Zhizhu Kuanzhong capsule were off-label used in clinical practice,there was no beyond the scope of the guideline.Conclusion The qi-regulating drug,spleen-strengthening drug and digestant drugs are the usual Chinese medicines used for treating adult FD.In recent years,research on CPMs for treating adult FD has increased rapidly.But there is insufficient reflection of CPMs treatment characteristics,ambiguous differences from the primary and secondary outcomes,multiple composite outcomes,and not explicit information on FD or its symptoms in drug package insert,which needs to be improved in the future.

This study systematically and comprehensively sorted out the application status of Chinese patent medicines for the treatment of constipation in the clinic， to provide scientific evidence for future research directions and clinical drug use in this field. Based on the method of scoping review， the Chinese patent medicines for the treatment of constipation were retrieved from three drug lists to obtain the medicines that needed to be evaluated. A comprehensive and systematic search was carried out on the included studies on the treatment of constipation by Chinese patent medicines through eight Chinese and English databases， and the included studies were integrated and analyzed. The results were displayed in combination with charts. Thirty-four Chinese patent medicines and 118 studies were included in this study. According to the efficacies， Chinese patent medicines were divided into 4 categories， namely eliminating accumulation， purging fire， promoting Qi， and moistening bowels， involving 125 Chinese medicines. The overall attention of constipation research is on the rise. Marenwan （granules or soft capsules） gained the highest attention， with 42 studies， followed by Qirong Runchang oral liquid， with 21 studies， and Biantong tablets （capsules）， with 19 studies. There are 10 studies on Congrong Tongbian oral liquid. Seventeen Chinese patent medicines had no corresponding clinical research. There were 8 study design types， and all drugs were mainly randomized controlled trials except Danggui Longhui pill. Among the intervention types， the comparison between Chinese patent medicines and western medicines was the most. The highest outcome indicators were efficacy， safety evaluation， and main symptoms or scores， and there was a lack of a unified core outcome indicator set. There were few studies on adverse reactions and the economy. Only 11.86% of the studies were funded. Clinically， Chinese patent medicines are widely used in the treatment of constipation， and the amount of related research shows an increasing trend. However， some Chinese patent medicines lack corresponding clinical evidence， and the published research has problems such as unrigorous design， ununified criteria for efficacy evaluation， lack of comprehensive evidence studies， and insufficient funds. It is hoped that more investment will be made in this field in the future， and more attention will be paid to drugs with relatively blank research and constipation syndromes with few treatments. Comprehensive evidence studies such as systematic reviews should be carried out actively. And the study design should be standardized to provide reliable evidence for the treatment of constipation with Chinese patent medicines.

ObjectiveTo evaluate the safety， efficacy， and economy of the four Chinese patent medicines （CPMs）， including Simotang oral liquid， Liuwei Anxiao capsule， Baohe pill， and Jianwei Xiaoshi oral liquid in the treatment of functional dyspepsia （FD） by a rapid health technology assessment （RHTA）， thus providing evidence support for clinical decision making. MethodChina National Knowledge Infrastructure （CNKI）， WanFang Database， VIP Chinese Technology Periodical Database （VIP）， China Biology Medicine disc （CBMdisc）， PubMed， EMBASE， Cochrane Library， and Web of Science were searched by computer from inception to March 2022. After literature screening， data extraction， and quality evaluation， the descriptive analysis of the results combined with visual charts was performed. Nineteen studies were included， involving 18 randomized controlled trials （RCTs） and 1 Meta-analysis. Neither economic studies nor health technology assessment （HTA） reports were retrieved. ResultThe four CPMs were safe and effective in the treatment of FD， but economic research was lacking. Among them， Simotang oral liquid could be used for children with FD and FD caused by qi and food stagnation， liver and spleen disharmony， and liver and spleen stagnation. Liuwei Anxiao capsule could be used for adult patients with FD caused by food stagnation. Baohe pill could be used for the elderly with FD. Jianwei Xiaoshi oral liquid could be used for children with FD caused by spleen and stomach weakness. ConclusionThe four CPMs have their advantages in the treatment of FD. Among them， the clinical universality of Simotang oral liquid is higher. However， the quality of clinical evidence is generally low， and comparative analysis among drug dosage forms is lacking. In the future， it is necessary to improve， apply， and promote RHTA for rapid evidence production while carrying out a more standardized and scientific evidence-based demonstration of the comprehensive clinical efficacy of CPMs.

To understand the development status and provide the basis for the construction and development of health technology assessment （HTA） institutions/organizations in China， this paper systematically reviewed the status of international HTA institutions/organizations and the HTA institutions/organizations in western developed countries and some Asian countries. This study was based on the results of the second round of global survey on HTA conducted by the World Health Organization （WHO） in 2020/2021. The websites of WHO， International HTA Database （INAHTA）， international HTA institutions/organizations， and the HTA institutions/organizations in different countries were searched. After data extraction and classification， we summarized the status of 9 international HTA institutions/organizations （including Decide： Health Decision Hub， Health Technology Assessment International， HTAsiaLink， International Network of Agencies for Health Technology Assessment， European Network for Health Technology Assessment， Health Technology Assessment Network of the Americas， International Society for Pharmacoeconomics and Outcomes Research， Southern African Health Technology Assessment Society， International Information Network on New and Emerging Health Technologies）， 11 HTA institutions/organizations in western developed countries and Asian countries （including Canada， France， Germany， the United Kingdom， Australia， the United States， Japan， Malaysia， South Korea， Singapore， and Thailand）， and 6 HTA organizations/teams in China. The use of HTA varies greatly because of different medical and health systems among different countries， and thus the role of HTA in health decision-making varies among different countries. The international HTA institutions/organizations have greatly strengthened the communication between HTA institutions/organizations and the pharmaceutical industry and facilitated the promotion and practice of evidence-based health decision-making.

Objective To explore the effect and mechanism of necroptosis related proteins in middle cerebral artery occlusion (MCAO) induced brain ischemia/reperfusion injury in mice.Methods C57BL/6 mice were used to establish the brain ischemia/reperfusion injury model induced by MCAO.MCAO mice were treated with z-VAD.fmk (zVAD,1.1 g/kg),GSK'872 (0.7 g/kg) and combined intervention of zVAD and GSK'872,and neurological defect was evaluated by mNSS while brain infarct volume was measured by TTC staining.Western blot and immunofluorescence assay were used to detect protein expression and location of RIP1,RIP3 and MLKL,respectively.Results Neurological defect and brain infarction were caused by MCAO.Compared with MCAO group,zVAD,GSK'872 and the combined intervention alleviated neurological defect and reduced brain infarct volume significantly (P＜0.05 or P＜0.01).The protein levels of RIP3 and RIP1 MLKL were increased in mice of MCAO group,while GSK'872 and the combined intervention obviously downregulated the aforementioned protein expression [RIP1 (GSK'872:0.64± 0.02 vs MCAO:1.28±0.02,P＜0.01);RIP3 (GSK'872:1.08±0.02 vs MCAO:1.45±0.02,P＜0.01);MLKL (GSK'872:0.54±0.01 vs MCAO:1.00±0.01,P＜0.01)].However,zVAD only slightly reduced protein expression of MLKL (P＜0.05) but didn't change the protein expression of RIP1 and RIP3 (P＞0.05).Conclusion RIP1,RIP3 and MLKL are involved in the execution of necroptosis and contribute to the pathological progress of brain ischemia/reperfusion injury.

Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.