ObjectiveTo explore the mechanism of Yinchenhao Tang regulating the tumor necrosis factor receptor superfamily member 6 （Fas）/cysteine protease-8 （Caspase-8）/cysteine protease-3 （Caspase-3） signaling pathway to inhibit hepatocyte apoptosis and improve cholestatic liver injury （CLI）. MethodsAmong 48 Wistar rats，12 rats were randomly selected as the blank group，and the other rats were administered alpha-naphthalene isothiocyanate （ANIT） by gavage to induce a CLI model. The modeling rats were randomly divided into the model group， the ursodeoxycholic acid group（0.1 g·kg^-1） and the Yinchenhao Tang group（9.23 g·kg^-1），with 12 rats in each group. The rats in each group were given corresponding drugs by gavage for three consecutive days. The levels of alanine aminotransferase （ALT），aspartate aminotransferase （AST），alkaline phosphatase （ALP），gamma-glutamyl transpeptidase （γ-GT），total bilirubin （TBil） and total bile acid （TBA） in serum were detected. The levels of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） in liver tissue were detected. The histopathological changes of the liver were observed by hematoxylin-eosin （HE） staining. The protein and mRNA expressions of Fas，Caspase-8，Caspase-3，B-cell lymphoma-2 （Bcl-2） associated X protein （Bax） and Bcl-2 in liver tissue were detected by Western blot and real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultsCompared with those in the blank group，the levels of ALT，AST，ALP，γ-GT，TBA and TBil in serum of the model group were significantly increased （P<0.01）. The levels and mRNA expressions of TNF-α and IL-1β in liver tissue were significantly increased （P<0.01）. The arrangement of hepatocytes was disordered，and inflammatory cell infiltration and bile duct epithelial cell proliferation were observed. The protein and mRNA expressions of Fas，Caspase-8，Caspase-3 and Bax in liver tissue were significantly increased（P<0.05，P<0.01），while the protein and mRNA expressions of Bcl-2 were significantly decreased （P<0.05，P<0.01）. Compared with those in the model group，the levels of ALP，γ-GT，TBA and TBil in the serum of rats in the ursodeoxycholic acid group were significantly decreased. The levels and mRNA expressions of TNF-α and IL-1β in liver tissue were significantly decreased（P<0.05，P<0.01）. The protein and mRNA expressions of Fas，Caspase-8，Caspase-3 and Bax in liver tissue were significantly decreased （P<0.05，P<0.01），while the mRNA expression of Bcl-2 was significantly increased （P<0.05，）. The levels of ALT，AST，γ-GT，TBA and TBil in the serum of rats in the Yinchenhao Tang group were significantly decreased （P<0.01）. The levels and mRNA expressions of TNF-α and IL-1β in liver tissue were significantly decreased （P<0.05，P<0.01）. The protein expression of Fas and Bax and the mRNA expression of Fas，Caspase-8，Caspase-3 and Bax in liver tissue were significantly decreased （P<0.05，P<0.01），while the protein and mRNA expression of Bcl-2 were significantly increased （P<0.05，P<0.01）. Hepatocyte injury，inflammatory cell infiltration and proliferation of bile duct epithelial cells were reduced. ConclusionYinchenhao Tang can ameliorate CLI，and its mechanism may be related to inhibiting hepatocyte apoptosis mediated by the Fas/Caspase-8/Caspase-3 signaling pathway.

ObjectiveTo study the mechanism of Yinchenhao Tang on the improvement of cholestatic liver injury （CLI） by inhibiting toll-like receptor 4 （TLR4）/myeloid differentiation factor 88 （MyD88）/nuclear transcription factor-κB （NF-κB） pathway via regulating farnesol X receptor （FXR）. MethodsA total of 40 Wistar male rats were randomly selected， with 10 as a blank group，and the remaining rats were subjected to the CLI model induced by alpha-naphthalene isothiocyanate （ANIT）. After modeling，they were randomly divided into the model group， the ursodeoxycholic acid （0.1 g·kg^-1） group and the Yinchenhao Tang （9.23 g·kg^-1） group，with 10 animals in each group. Each administration group was given the corresponding drug by intragastric administration for three consecutive days. Alanine aminotransferase （ALT），aspartate aminotransferase （AST），alkaline phosphatase （ALP），γ-glutamyl transpeptidase （γ-GT），total bile acid （TBA），total bilirubin （TBil） and direct bilirubin （DBil） levels in serum were detected. Tumor necrosis factor-α （TNF-α），interleukin-1β （IL-1β），and interleukin-6 （IL-6） levels in liver tissue were detected. Real-time PCR was used to detect the mRNA expression of FXR，TLR4，MyD88，NF-κB，F4/80，TNF-α，IL-1β and IL-6 in liver tissue. Western blot was used to detect protein expression of FXR，TLR4，MyD88 and NF-κB in liver tissue. The histopathological changes of the liver were observed by hematoxylin-eosin （HE） staining. ResultsCompared with those in the blank group，ALT，AST，ALP，γ-GT，TBA，TBil and DBil levels in serum of rats in the model group were significantly increased （P<0.01）. The levels and mRNA expression of TNF-α，IL-1β and IL-6 in liver tissue were significantly increased （P<0.01），and the mRNA and protein expressions of FXR in liver tissue were decreased （P<0.01）. The mRNA and protein expressions of TLR4，MyD88 and NF-κB and the mRNA expression of F4/80 were obviously increased （P<0.05，P<0.01）. Hepatic histopathology showed inflammatory cell infiltration and proliferative changes of bile duct epithelial cells. Compared with those in the model group，ALT，ALP，γ-GT，TBA，TBil and DBil levels in serum of rats in the ursodeoxycholic acid group were obviously decreased （P<0.05，P<0.01），and the levels and mRNA expression of TNF-α，IL-1β and IL-6 in liver tissue were obviously decreased （P<0.05，P<0.01）. The mRNA and protein expressions of TLR4，MyD88 and NF-κB and the mRNA expression of F4/80 in liver tissue were obviously decreased （P<0.05，P<0.01）. ALT，AST，ALP，γ-GT，TBA，TBil and DBil levels in the serum of rats in the Yinchenhao Tang group were obviously decreased （P<0.05，P<0.01），and the levels and mRNA expression of TNF-α，IL-1β and IL-6 in liver tissue were obviously decreased （P<0.01）. The mRNA and protein expressions of FXR in liver tissue were significantly increased，and the mRNA expressions of TLR4，MyD88，NF-κB，and F4/80， as well as the protein expressions of TLR4 and NF-κB were obviously decreased （P<0.05，P<0.01）. The inflammatory cell infiltration of liver tissue and the proliferation of bile duct epithelial cells decreased. ConclusionYinchenhao Tang has an obvious protective effect on CLI，and its mechanism may be related to regulating FXR to inhibit TLR4/MyD88/NF-κB pathway-mediated inflammatory response.

OBJECTIVES: To study the therapeutic mechanism of Tuihuang Mixture against cholestasis. METHODS: Forty-eight Wistar rats were randomized equally into blank group, model group, ursodeoxycholic acid group and Tuihuang Mixture group. Except for those in the blank group, all the rats were given α‑naphthylisothiocyanate (ANIT) to establish rat models of cholestasis, followed by treatments with indicated drugs or distilled water. Serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL of the rats were determined, and hepatic expressions IL-1β, IL-18, FXR, NLRP3, ASC, Caspase-1 and GSDMD were detected using q-PCR, ELISA or Western blotting. Histopathological changes of the liver tissues were observed using HE staining. RESULTS: The rat models of cholestasis had significantly increased serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL with increased mRNA and protein expressions of IL-1β and IL-18, decreased protein and mRNA expressions of FXR, and increased protein expressions of NLRP3 and Caspase-1 and mRNA expressions of NLRP3, ASC, Caspase-1 and GSDMD in the liver tissue, showing also irregular arrangement of liver cells, proliferation of bile duct epithelial cells and inflammatory cells infiltration. Treatment of the rat models with Tuihuang Mixture significantly decreased serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL, lowered IL-1β and IL-18 and increased FXR protein and mRNA expressions, and reduced NLRP3, ASC, Caspase-1 and GSDMD proteins and NLRP3, ASC and Caspase-1 mRNA expressions in the liver tissue. Tuihuang Mixture also significantly alleviated hepatocyte injury, bile duct epithelial cell proliferation and inflammatory cell infiltration in the liver of the rat models. CONCLUSIONS Tuihuang Mixture can effectively improve cholestasis in rats possibly by inhibiting NLRP3 inflammatosome-mediated pyroptosis via regulating FXR.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein ; Rats ; Receptors, Cytoplasmic and Nuclear/metabolism* ; Cholestasis/drug therapy* ; Rats, Wistar ; Inflammasomes/metabolism* ; 1-Naphthylisothiocyanate ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Interleukin-18/metabolism* ; Caspase 1/metabolism* ; Interleukin-1beta/metabolism* ; Liver/metabolism*

Abstract Cholestasis can be seen in many acute and chronic liver diseases. If not intervened in time, persistent cholestasis can further progress to liver fibrosis, liver cirrhosis, liver failure, and even death. The pathogenesis of cholestasis is complex, and there is currently a lack of effective therapeutic drugs. Bile acids(BAs), the main component of bile, are synthesized from cholesterol in the liver as primary bile acids. After entering the intestine through the enterohepatic circulation, they are reshaped into secondary bile acids by gut microbiota. BAs can directly or indirectly affect the composition and function of gut microbiota, which in turn can regulate the synthesis and metabolism of BAs. The interaction between BAs and gut microbiota plays an important role in the pathogenesis and treatment of cholestasis. This review elucidates the bidirectional regulatory mechanisms between BAs and gut microbiota and their roles in the pathogenesis and treatment of cholestasis, aiming to provide insights and references for basic research and clinical practice related to cholestasis-associated diseases.

Aneurysmal subarachnoid hemorrhage(aSAH)is a type of hemorrhagic stroke with high morbidity and mortality.After treatment,most aSAH patients can completely recover their neurological func-tion,about 50％of aSAH patients will have cognitive disorder,mainly manifested as executive function,lan-guage and memory dysfunction,more than half of aSAH patients can not recover cognitive function,which brings great pressure to individuals and their families.This article aims to discuss the characteristics,influen-cing factors,assessment tools,potential mechanisms and drug therapy of post-ASAH cognitive disorder,in or-der to provide prevention and treatment strategies for clinical post-ASAH cognitive disorder.

Background::Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.Methods::This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied.Results::At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs. placebo, 95% CI 31%–69%) and 45% (low vs. placebo, 95% CI 26%–64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator’s Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. Conclusion::CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.Trial Registration::ClinicalTrials.gov, NCT04805411.

Objective:To investigate the clinical effect of local perforator advancement flap in repairing mid-face soft tissue defects and its correlation between with the three dimensional configuration of the skin ligament.Methods:1) 12 fresh adult cadaver specimens (7 males, 5 females, aged 54-87 years) were selected. After dehydration and degreasing of the cadaver head with acetone, plasticized and sliced with a fully transparent ultra-thin layer of epoxy resin, using a Leica MZ8 stereo microscope and a Leica DFC295 digital camera to observe and analyze the prepared slices, and observe the differences in the three-dimensional structural characteristics of the cutaneous ligaments in different parts of the midface (cheek, nose, orbital eyelid) . (2) A retrospective analysis was made of the case data of midface soft tissue defects admitted to the Plastic Surgery Department of the First Affiliated Hospital of Anhui Medical University from January 2015 to October 2021. All patients were repaired with local perforator advancement flap. The Pearson bivariate correlation test was used to analyze the correlation among flap advancement distance, flap area, flap aspect ratio, and defect size. The Kruskal-Wallis test was used to analyze the differences of flap area and flap aspect ratio in different parts of the midface.Results:1) Anatomical studies have shown that the running direction of the facial skin ligaments is the same as that of the expressive muscles, and their three-dimensional structures at the upper eyelid and the nasal and facial corners of the upper nasal alar are different. The upper eyelid skin ligaments run along the eyelid, while the upper nasal The supracutaneous ligaments run down the alar of the nose. (2) The clinical study included 18 patients, 8 males and 10 females, aged (65.1±22.9) years. The flaps of 18 patients survived after operation, the flap area was (13.85±9.38) cm 2, and the advancing distance was (1.94±0.75) cm. Statistical analysis showed that there was a correlation between the flap advancement distance and the flap incision area ( r=-0.712, P=0.022) and the flap aspect ratio ( r=-0.580, P =0.012). There was no correlation with the defect area ( r=-0.227, P=0.365) ; the aspect ratios of the cheek, nose and orbital lid flaps were 2.06±0.42 , 2.50±1.18, 3.25±0.93, and the differences were statistically significant ( H= 6.59, P=0.037). Conclusions:The local perforator advancement flap is an ideal method for repairing midface soft tissue defects. The differences in the construction of the skin ligaments in different parts of the mid-face will affect the ease of advancement of the flaps and other characteristics in each part, which may be the reasons for affecting the aspect ratio of the flap design.

Objective:To investigate the clinical effect of local perforator advancement flap in repairing mid-face soft tissue defects and its correlation with the three-dimensional configuration of the skin ligament.Methods:(1) Tweleve fresh adult cadaver specimens, including seven males and five females, aged 54-87 years old, were selected. After dehydration and degreasing of the cadaver head with acetone, plasticized and sliced with a fully transparent ultra-thin layer of epoxy resin, using a Leica MZ8 stereo microscope and a Leica DFC295 digital camera to observe and analyze the prepared slices and observe the differences in the three-dimensional structural characteristics of the cutaneous ligaments in different parts of the mid-face (cheek, nose, orbital eyelid). (2) A retrospective study was conducted with the data of mid-face soft tissue defects admitted to the Department of Plastic Surgery of the First Affiliated Hospital of Anhui Medical University from January 2015 to October 2021. All patients were repaired with local perforator advancement flaps. The Pearson bivariate correlation test was used to analyze the correlation among flap advancement distance, flap area, flap aspect ratio, and defect size. The Kruskal-Wallis test was used to analyze the differences in flap size and aspect ratio in different parts of the mid-face. The measurement data were described by Mean±SD or M( Q1, Q3). Results:(1) Anatomical studies have shown that the running direction of the facial skin ligaments is the same as that of the expressive muscles, and their three-dimensional structures at the upper eyelid and the nasal and facial corners of the upper nasal alar are different. The upper eyelid skin ligaments run along the eyelid, while the upper nasal cutaneous ligaments run down the nose alar. (2) The clinical study included 18 patients, including eight males and ten females, aged (64.6±23.4) years old. All flaps survived uneventfully. The average flap size was 10.6(8.0, 18.0) cm 2, and the average advancing distance was 2.8(2.0, 4.0) cm. Statistical analysis showed a correlation between the flap advancement distance, the flap incision area ( r=-0.71, P=0.022), and the flap aspect ratio ( r=-0.58, P=0.012). There was no correlation with the defect area ( r=-0.23, P=0.365); the aspect ratios of the cheek, nose, and orbital lid flaps were 2.1(1.9, 2.3), 2.0(1.6, 3.5), 3.5(3.0, 4.0), and the differences were statistically significant ( H=6.59, P=0.037). Conclusions:The local perforator advancement flap is an ideal method for repairing mid-face soft tissue defects. The differences in the construction of the skin ligaments in different parts of the mid-face will affect the ease of advancement of the flaps and other characteristics in each part, which may be the reasons for affecting the aspect ratio of the flap design.

Objective:To investigate the clinical effect of local perforator advancement flap in repairing mid-face soft tissue defects and its correlation between with the three dimensional configuration of the skin ligament.Methods:1) 12 fresh adult cadaver specimens (7 males, 5 females, aged 54-87 years) were selected. After dehydration and degreasing of the cadaver head with acetone, plasticized and sliced with a fully transparent ultra-thin layer of epoxy resin, using a Leica MZ8 stereo microscope and a Leica DFC295 digital camera to observe and analyze the prepared slices, and observe the differences in the three-dimensional structural characteristics of the cutaneous ligaments in different parts of the midface (cheek, nose, orbital eyelid) . (2) A retrospective analysis was made of the case data of midface soft tissue defects admitted to the Plastic Surgery Department of the First Affiliated Hospital of Anhui Medical University from January 2015 to October 2021. All patients were repaired with local perforator advancement flap. The Pearson bivariate correlation test was used to analyze the correlation among flap advancement distance, flap area, flap aspect ratio, and defect size. The Kruskal-Wallis test was used to analyze the differences of flap area and flap aspect ratio in different parts of the midface.Results:1) Anatomical studies have shown that the running direction of the facial skin ligaments is the same as that of the expressive muscles, and their three-dimensional structures at the upper eyelid and the nasal and facial corners of the upper nasal alar are different. The upper eyelid skin ligaments run along the eyelid, while the upper nasal The supracutaneous ligaments run down the alar of the nose. (2) The clinical study included 18 patients, 8 males and 10 females, aged (65.1±22.9) years. The flaps of 18 patients survived after operation, the flap area was (13.85±9.38) cm 2, and the advancing distance was (1.94±0.75) cm. Statistical analysis showed that there was a correlation between the flap advancement distance and the flap incision area ( r=-0.712, P=0.022) and the flap aspect ratio ( r=-0.580, P =0.012). There was no correlation with the defect area ( r=-0.227, P=0.365) ; the aspect ratios of the cheek, nose and orbital lid flaps were 2.06±0.42 , 2.50±1.18, 3.25±0.93, and the differences were statistically significant ( H= 6.59, P=0.037). Conclusions:The local perforator advancement flap is an ideal method for repairing midface soft tissue defects. The differences in the construction of the skin ligaments in different parts of the mid-face will affect the ease of advancement of the flaps and other characteristics in each part, which may be the reasons for affecting the aspect ratio of the flap design.