ObjectiveThis paper aims to investigate and evaluate the staged efficacy and safety of the representative empirical prescription of the “Zhu Ke Jiao” theory， Qijia Rougan prescription， combined with entecavir in the treatment of hepatic fibrosis in chronic hepatitis B. MethodsA multicenter randomized controlled clinical study was conducted， and 101 patients diagnosed with chronic hepatitis B-related hepatic fibrosis （CHB-HF） who met the diagnosis and inclusion criteria were randomly assigned to an observation group （Qijia Rougan prescription + entecavir） and a control group （entecavir）. The treatment duration was 24 weeks. Liver stiffness measurement （LSM）， fibrosis-4 index （FIB-4）， portal vein diameter， hepatitis B serology， biochemical indicators， hepatic fibrosis markers in serum ［hyaluronic acid （HA）， laminin （LN）， procollagen Ⅲ peptide （PⅢP）， and type Ⅳ collagen （Ⅳ-C）］， and traditional Chinese medicine syndrome scores were used as efficacy evaluation indicators. Efficacy assessments and explorations of different staged subgroups of Qijia Rougan prescription were conducted according to LSM values based on the Metavir pathological staging standard. ResultsA total of 98 cases were included for statistical analysis， with 49 cases in the observation group and 49 in the control group. The general data of the patients in both groups were comparable. Compared with the same group before treatment， the observation group showed a significant reduction in LSM and FIB-4 （P<0.01）， as well as notable improvements in LN， Ⅳ-C， and various TCM syndrome scores （P<0.05， P<0.01）. When compared to the control group after treatment， the observation group demonstrated significant improvements in LSM， FIB-4， and various TCM syndrome score indicators （P<0.05， P<0.01）， indicating that the observation group performed better than the control group. Subgroup analysis of the regression of hepatic fibrosis stages showed that compared to the same group before treatment， the observation group had better improvement in regression of stages F2 and F3 （P<0.05）. When compared to the control group after treatment， the observation group exhibited superior improvement in regression of stage F3 （P<0.05）. No adverse events occurred in either group during the treatment period. ConclusionCompared with entecavir alone， the combination of Qijia Rougan prescription and entecavir significantly improves the degree of hepatic fibrosis and clinical TCM symptoms in patients. The optimal intervention period is primarily during stage F3， which is a potential “interception” point of the “Zhu Ke Jiao” theory.

BACKGROUND:Exercise is an effective way to improve microvascular function in patients with type 2 diabetes.In recent years,exercise has been used as an intervention therapy for microvascular dysfunction in patients with type 2 diabetes.However,few studies have systematically explored the influence of factors,such as"exercise type,exercise intensity and amount of exercise,"on microvascular function in patients.To some extent,this limits the formulation of precise exercise prescriptions to improve microvascular dysfunction in patients with type 2 diabetes and the comparison of study results.OBJECTIVE:To investigate the effects of exercise type,intensity,frequency and amount of exercise on microvascular function in patients with type 2 diabetes mellitus,and to make suggestions on exercise prescription.METHODS:The first author used computer to search the studies on the improvement of microvascular function in type 2 diabetes patients involving exercise in CNKI,WanFang,PubMed and other databases.The search terms were"diabetes mellitus,type 2 diabetes mellitus,microcirculation,microvascular reactivity,microvessels,capillaries,vasodilation,blood perfusion volume,endothelial cells,shear stress,exercise,aerobic exercise,resistance exercise,high-intensity exercise"in Chinese and English.The articles were screened by a quick glance at the article titles and abstracts to exclude those that were not closely related to the topic,and finally 60 articles were included for review.RESULTS AND CONCLUSION:(1)Exercise is an effective way to improve microvascular function in patients with type 2 diabetes.Aerobic exercise lasting 12-24 weeks,3-5 times/week,exercise time＞30 minutes and intensity between 40％and 59％reserve oxygen intake can significantly improve microvascular function in patients with type 2 diabetes.On the basis of aerobic exercise,systemic resistance exercise 2-3 times a week(50％-85％1RM,every other day)or pressure resistance exercise can obtain better intervention effects.(2)In addition,exercise can improve microvascular function in patients with type 2 diabetes in a"dose-effect"manner,and patients can get better results from the intervention by increasing the amount of exercise,while maintaining safety.(3)The mechanism of exercise improving microvascular function in patients with type 2 diabetes is mainly related to promoting the release of nitric oxide and vascular endothelial growth factor from endothelial cells and inhibiting the release of endothelin1.

BACKGROUND:Exercise is an effective way to improve microvascular function in patients with type 2 diabetes.In recent years,exercise has been used as an intervention therapy for microvascular dysfunction in patients with type 2 diabetes.However,few studies have systematically explored the influence of factors,such as"exercise type,exercise intensity and amount of exercise,"on microvascular function in patients.To some extent,this limits the formulation of precise exercise prescriptions to improve microvascular dysfunction in patients with type 2 diabetes and the comparison of study results.OBJECTIVE:To investigate the effects of exercise type,intensity,frequency and amount of exercise on microvascular function in patients with type 2 diabetes mellitus,and to make suggestions on exercise prescription.METHODS:The first author used computer to search the studies on the improvement of microvascular function in type 2 diabetes patients involving exercise in CNKI,WanFang,PubMed and other databases.The search terms were"diabetes mellitus,type 2 diabetes mellitus,microcirculation,microvascular reactivity,microvessels,capillaries,vasodilation,blood perfusion volume,endothelial cells,shear stress,exercise,aerobic exercise,resistance exercise,high-intensity exercise"in Chinese and English.The articles were screened by a quick glance at the article titles and abstracts to exclude those that were not closely related to the topic,and finally 60 articles were included for review.RESULTS AND CONCLUSION:(1)Exercise is an effective way to improve microvascular function in patients with type 2 diabetes.Aerobic exercise lasting 12-24 weeks,3-5 times/week,exercise time＞30 minutes and intensity between 40％and 59％reserve oxygen intake can significantly improve microvascular function in patients with type 2 diabetes.On the basis of aerobic exercise,systemic resistance exercise 2-3 times a week(50％-85％1RM,every other day)or pressure resistance exercise can obtain better intervention effects.(2)In addition,exercise can improve microvascular function in patients with type 2 diabetes in a"dose-effect"manner,and patients can get better results from the intervention by increasing the amount of exercise,while maintaining safety.(3)The mechanism of exercise improving microvascular function in patients with type 2 diabetes is mainly related to promoting the release of nitric oxide and vascular endothelial growth factor from endothelial cells and inhibiting the release of endothelin1.

ObjectiveThis paper aims to investigate the differential mechanisms underlying the staged therapeutic effects of Qijia Rougan formula on liver fibrosis using proteomic technology. MethodsThe staged rat model of liver fibrosis was established by subcutaneous injection of carbon tetrachloride （CCl₄） and olive oil. One hundred and four SD rats were randomized into thirteen groups：a normal group，a two-week model group，a four-week model group，a six-week model group，an eight-week model group，a two-week Qijia Rougan formula group，a four-week Qijia Rougan formula group，a six-week Qijia Rougan formula group，an eight-week Qijia Rougan formula group，a two-week compound Biejia Ruangan tablet group，a four-week Compound Biejia Ruangan Tablet group，a six-week Compound Biejia Ruangan Tablet group，and an eight-week compound Biejia Ruangan tablet group. After two weeks of drug intervention，liver tissue and abdominal aortic blood samples were collected from the rats for testing. Hematoxylin-eosin （HE） staining，Masson staining，and Picro Sirius red staining were used to observe pathological damage and collagen fiber deposition in liver tissues. Immunohistochemistry （IHC） was employed to detect the contents of fibrosis markers in liver tissues. The contents of liver function indicators in the serum were measured using a fully automated biochemical analyzer，and the levels of liver fibrosis indicators in the serum were assessed by enzyme-linked immunosorbent assay （ELISA）. Liver tissues from the normal group，each model group，and each Qijia Rougan formula group were subjected to label-free quantitative proteomic analysis to identify differential proteins among the groups，with key proteins validated by Western blot. Finally，bioinformatics analysis was performed on the differential proteins. Results（1） The staged rat model of liver fibrosis constructed with CCl₄ and olive oil showed pathological results at the 2^nd，4^th，6^th，and 8^th weeks of modeling that were consistent with the Metavir standards for the F1，F2，F3，and F4 stages. Compared with those in the normal control group，the protein expressions of α-smooth muscle actin （α-SMA） and Collagen Ⅰ were significantly increased in each stage （P<0.05）. The levels of liver function indicators in the serum，including alanine aminotransferase （ALT），aspartate aminotransferase （AST），alkaline phosphatase （ALP），direct bilirubin （DBIL），and total bilirubin （TBil） in each model group，were significantly elevated in each stage （P<0.01）. The levels of liver fibrosis indicators in the serum，including procollagen Ⅲ peptide （PⅢP），type Ⅳ collagen（Ⅳ-C），hyaluronic acid （HA），and laminin （LN） in each model group，were significantly increased in each stage （P<0.05，P<0.01）. This study successfully established a staged rat model of liver fibrosis. （2） Compared with the model groups at each stage，the administration groups showed a reduction in hepatocyte ballooning degeneration，a more orderly arrangement of hepatocytes，and a decrease of inflammatory cell infiltration. The blue-stained collagen fibers became significantly thinner and finer，with reduced and narrowed fibrous septa. The areas of collagen fibers and Picro Sirius red staining were reduced （P<0.05）. The positive areas of α-SMA and Collagen Ⅰ expression were significantly decreased （P<0.05）. The levels of ALT，AST，ALP，DBIL，and TBil in the rats of the model groups at each stage were significantly reduced （P<0.05，P<0.01）. The levels of PⅢP，Ⅳ-C，HA，and LN in the rats of the model groups at each stage were significantly decreased （P<0.05）. Among these，the improvements in all indicators were most significant in the F3 stage （P<0.01）.（3） The proteomic results show that a total of 165 differential proteins exhibit a callback trend when comparing the model groups at four stages with the normal group，and when comparing the Qijia Rougan formula group with the model group. Western blot analysis reveals that the levels of NAD（P）H：quinone oxidoreductase 1 （NQO1），mitogen-activated protein kinase 1 （MAPK1），arginase 1 （Arg1），and glutathione S-transferase α1 （GSTA1） were consistent with the proteomic results. Bioinformatics results reveal that 165 differentially expressed proteins are enriched in multiple signaling pathways. Notably，signaling pathways such as drug metabolism-cytochrome P450，arginine biosynthesis，and the peroxisome proliferator-activated receptor （PPAR） signaling pathway were found to be closely associated with liver fibrosis，suggesting that the Qijia Rougan formula may exert its staged regulatory effects on liver fibrosis by regulating these pathways. ConclusionThe Qijia Rougan formula may achieve staged regulation of liver fibrosis by regulating drug metabolism-cytochrome P450，arginine biosynthesis，and the PPAR signaling pathway.

ObjectiveBased on the regulation of macrophage M2 polarization， this study aims to explore the molecular mechanism and action targets of the Qijia Rougan prescription and its key effector ingredients in anti-fibrosis， thereby providing a basis and reference for the development of new drugs for hepatic fibrosis. MethodsA rat model of hepatic fibrosis was established by subcutaneous injection of 40%CCl₄， followed by oral administration of Qijia Rougan granules. The volume of collagen fibers was detected using Masson staining， the fibrosis markers Collagen Ⅰ and α-SMA were detected using immunohistochemistry， the proportion of M2 macrophages was detected by flow cytometry. The expression levels of M2 macrophage phenotype markers CD163 and CD206 were detected using immunofluorescence double staining. Western blot was used to detect the levels of the transforming growth factor-β （TGF-β）， platelet derived growth factor subunit B （PDGFB）， interleukin-10 （IL-10）， phosphorylated Janus kinase 1 （p-JAK1）， and phosphorylated signal transducer and activator of transcription 6 （p-STAT6）. Real-time fluorescent quantitative PCR was used to detect the relative expression levels of JAK1， STAT6， Arginase 1（Arg1）， and Fizz1. Based on the theory of serum pharmacology， liquid chromatography-mass spectrometry and WENN analysis were used to obtain the active ingredients of Qijia Rougan prescription. Molecular docking and molecular dynamics simulation were performed to analyze the effector ingredients and their targets. The identified effector ingredients were interfered with IL-4-induced M2 polarization of RAW264.7 macrophage in vitro to validate the targets. ResultsQijia Rougan prescription significantly reduced the content of fibrosis markers α-SMA and Collagen Ⅰ， as well as collagen fiber content （P<0.05）. It decreased the proportion of M2 macrophages and the levels of related cytokines IL-10， TGF-β and PDGFB， and up-regulated the levels of p-JAK1 and p-STAT6 （P<0.05）. A total of 1 214 compounds were identified from Qijia Rougan prescription， medicated serum and blank serum， and 29 ingredients were finalized by Venn analysis， including 15 blood-entry prototypes and 14 drug metabolites. Molecular docking showed that enoxolone and berberine bound more strongly to JAK1， with binding free energies of -9.6 kcal·mol^-1（1 cal≈4.184 J） and -9.1 kcal·mol^-1， respectively. Molecular dynamics simulations showed that JAK1-enoxolone and JAK1-berberine exhibited stable simulation trajectories within 100 ns， with essentially identical conformations and high protein overlap before and after simulation. Their binding free energies were -25.18 5.0.81 kcal·mol^-1 and -27.39 7.0.85 kcal·mol^-1， respectively. The number of hydrogen bonds formed between JAK1 and enoxolone ranges from 0 to 5， and most of the time can be maintained at 2-3. In vitro intervention with enoxolone or berberine significantly reduced p-JAK1 and p-STAT6 levels （P<0.05）. ConclusionQijia Rougan prescription inhibits M2 macrophage polarization in hepatic fibrosis. Enoxolone and berberine are the key effector ingredients of Qijia Rougan prescription to inhibit macrophage M2 polarization through targeting JAK1 and modulating the JAK1/STAT6 signaling pathway， thereby ameliorating hepatic fibrosis. This study provides a basis for prescription optimization， clinical application and new drug development， as well as a reference for monolithic anti-hepatic fibrosis research.

Objective: To analyze the trend in burden of rheumatoid arthritis (RA) in China from 1990 to 2021, so as to provide insights into reducing the RA burden in China. Methods: Data of Global Burden of Disease Study 2021 were collected, and the incidence, mortality and disability-adjusted life years (DALY) of RA in China from 1990 to 2021 were analyzed and compared with global and different Socio-demographic Index (SDI) regions. The trend in burden of RA was analyzed using average annual percent change (AAPC). Results: The crude incidence rates of RA in China increased from 10.87/105 in 1990 to 17.38/105 in 2021, the crude mortality rates increased from 0.41/105 to 0.72/105, and the crude DALY rates increased from 34.26/105 to 58.61/105, with the increases of 59.98%, 77.95% and 71.06%, respectively. From 1990 to 2021, the standardized incidence rates of RA in China showed an increasing trend (AAPC=0.545%, P<0.05), the standardized mortality rates showed a decreasing trend (AAPC=-0.783%, P<0.05), and the standardized DALY rates showed no significant trend (AAPC=-0.017%, P>0.05). In 2021, the standardized incidence rate, standardized mortality rate and standardized DALY rate of RA were higher in females than in males; from 1990 to 2021, the standardized DALY rates of RA showed a decreasing trend in females (AAPC=-0.200%, P<0.05) and an increasing trend in males (AAPC=0.316%, P<0.05). The crude incidence rates of RA first increased and then decreased with age in 2021, reaching the highest in the age group of 75-<80 years at 34.36/105. Both the crude mortality rates and the crude DALY rates increased with age, reaching the highest in the age group of 95 years and older at 26.72/105 and 285.67/105, respectively. The standardized incidence rates and standardized DALY rates of RA in China in 2021 were lower than those in high SDI regions, while the standardized mortality rate was lower than that in medium-low SDI regions. Conclusions The burden of RA in China from 1990 to 2021 showed an upward trend, and was at a high level compared to different SDI regions. Higher disease burden of RA was seen in females and the elderly.

Intraoperative cell salvage (IOCS) has been widely applied as an important blood conservation measure in surgical operations. However, there is currently a lack of clinical practice guidelines for the implementation of IOCS in patients with malignant tumors. This report aims to provide clinicians with recommendations on the use of IOCS in patients with malignant tumors based on the review and assessment of the existed evidence. Data were derived from databases such as PubMed, Embase, the Cochrane Library and Wanfang. The guideline development team formulated recommendations based on the quality of evidence, balance of benefits and harms, patient preferences, and health economic assessments. This study constructed seven major clinical questions. The main conclusions of this guideline are as follows: 1) Compared with no perioperative allogeneic blood transfusion (NPABT), perioperative allogeneic blood transfusion (PABT) leads to a more unfavorable prognosis in cancer patients (Recommended); 2) Compared with the transfusion of allogeneic blood or no transfusion, IOCS does not lead to a more unfavorable prognosis in cancer patients (Recommended); 3) The implementation of IOCS in cancer patients is economically feasible (Recommended); 4) Leukocyte depletion filters (LDF) should be used when implementing IOCS in cancer patients (Strongly Recommended); 5) Irradiation treatment of autologous blood to be reinfused can be used when implementing IOCS in cancer patients (Recommended); 6) A careful assessment of the condition of cancer patients (meeting indications and excluding contraindications) should be conducted before implementing IOCS (Strongly Recommended); 7) Informed consent from cancer patients should be obtained when implementing IOCS, with a thorough pre-assessment of the patient's condition and the likelihood of blood loss, adherence to standardized internally audited management procedures, meeting corresponding conditions, and obtaining corresponding qualifications (Recommended). In brief, current evidence indicates that IOCS can be implemented for some malignant tumor patients who need allogeneic blood transfusion after physician full evaluation, and LDF or irradiation should be used during the implementation process.

Objective: Para-aortic lymph node dissection (PALND) is a widely used treatment that causes many complications. This study is to evaluate the efficacy and safety of nerve-sparing para-aortic lymph node dissection (NSPALND) by comparing it with conventional PALND in gynecological malignancies and to prove whether locating the superior hypogastric plexus (SHP) can help reveal the para-aortic nerves. Methods: This is a retrospective study of the patients who underwent para-aortic lymphadenectomy from January 2020 to December 2022 at Zhejiang Cancer Hospital. All of them were divided into NSPALND and PALND groups according to whether or not nervesparing was performed. The surgical, functional and oncological outcomes were evaluated. Results: There were 43 patients enrolled, of which, 20 patients underwent NSPALND and 23 patients underwent PALND. The para-aortic nerves were successfully revealed by locating the SHP in all 20 cases of NSPALND. The post-operative anal exhaust time in the NSPALND group was significantly shorter than that in the PALND group (2.5 vs. 4 days, p=0.006), and the incidence of acute intestinal obstruction in the NSPALND group was significantly lower than that in the PALND group (10% vs. 39%, p=0.029). There was no difference between the two groups in terms of catheterization duration, urinary retention, dysuria, as well as the number of lymph nodes removed and the para-aortic recurrence rate. Conclusion NSPALND can significantly reduce the rate of acute intestinal obstruction and improve post-operative intestinal function. Locating the SHP and using it as an anatomical landmark to reveal the para-aortic nerves is feasible. Its exact clinical value needs to be further studied.

Alzheimer’s disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory loss. As the incidence of AD continues to rise annually, researchers have shown keen interest in the active components found in natural plants and their neuroprotective effects against AD. Quercetin, a flavonol widely present in fruits and vegetables, has multiple biological effects including anticancer, anti-inflammatory, and antioxidant. Oxidative stress plays a central role in the pathogenesis of AD, and the antioxidant properties of quercetin are essential for its neuroprotective function. Quercetin can modulate multiple signaling pathways related to AD, such as Nrf2-ARE, JNK, p38 MAPK, PON2, PI3K/Akt, and PKC, all of which are closely related to oxidative stress. Furthermore, quercetin is capable of inhibiting the aggregation of β‑amyloid protein (Aβ) and the phosphorylation of tau protein, as well as the activity of β‑secretase 1 and acetylcholinesterase, thus slowing down the progression of the disease.The review also provides insights into the pharmacokinetic properties of quercetin, including its absorption, metabolism, and excretion, as well as its bioavailability challenges and clinical applications. To improve the bioavailability and enhance the targeting of quercetin, the potential of quercetin nanomedicine delivery systems in the treatment of AD is also discussed. In summary, the multifaceted mechanisms of quercetin against AD provide a new perspective for drug development. However, translating these findings into clinical practice requires overcoming current limitations and ongoing research. In this way, its therapeutic potential in the treatment of AD can be fully utilized.

Hepatocellular carcinoma(HCC)expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming.Aldolase A(ALDOA)plays a prominent role in glycolysis;however,little is known about its role in HCC development.In the present study,we aim to explore how ALDOA is involved in HCC proliferation.HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout,which is consistent with ALDOA overexpression encouraging HCC prolifera-tion.Mechanistically,ALDOA knockout partially limits the glycolytic flux in HCC cells.Meanwhile,ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase;ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function.A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun,and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells.In HCC patients,the expression level of ALDOA was correlated with the phosphorylation level of c-Jun(Thr93)and poor prognosis.Remarkably,hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models,and the knockdown of Aldoa strikingly decreased HCC development in vivo.Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription,opening additional avenues for anti-cancer therapies.