OBJECTIVE To investigate the effects and mechanism of Wenpi tongluo kaiqiao formula （WPTL） against neuronal necroptosis in Alzheimer’s disease （AD） mice based on the Z-DNA binding protein 1 （ZBP1）/mixed lineage kinase domain-like protein （MLKL） signaling pathway. METHODS Forty APP/PS1 transgenic AD mice were randomly divided into model group， WPTL low-dose （WPTL-L） group （10.4 g/kg， calculated by the raw medicine）， WPTL high-dose （WPTL-H） group （20.8 g/kg， calculated by the raw medicine） and donepezil hydrochloride group （3 mg/kg）， with 10 mice in each group； another 10 C57BL/6J mice were selected as normal control group. Intragastric administration， once a day， for 30 consecutive days. Twenty-four hours after the last administration， Morris water maze test was performed to evaluate learning and memory abilities； the pathological morphology of hippocampal tissues was observed； the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-4 （IL-4） were determined； the expressions of amyloid precursor protein （APP）， Tau protein， and ZBP1/MLKL signaling pathway-related proteins in hippocampal tissues were detected； the positive expression of phosphorylated receptor-interacting protein kinase 3 （p-RIPK3） in the neurons of hippocampal tissues and mRNA expression of ZBP1 were measured in hippocampal tissues. RESULTS Compared with normal control group， the escape latency of mice in model group was prolonged significantly on day 3 to 5 （P＜0.05）， the times of crossing platform reduced significantly （P＜0.05）， and obvious pathological changes were observed in the hippocampal tissue. The level of TNF- α， the expressions of APP， p-Tau and ZBP1， the phosphorylation levels of RIPK1， RIPK3 and MLKL， the fluorescence intensity of p-RIPK3 as well as the mRNA expression of ZBP1 were significantly increased （P＜0.05）， while the serum level of IL-4 was decreased significantly （P＜0.05）. Compared with model group， above indexes were reversed significantly in administration groups （P＜0.05）， and pathological damage of hippocampal tissue was alleviated. CONCLUSIONS WPTL can inhibit the ZBP1/MLKL signaling pathway， reduce neuronal necroptosis in AD mice， and inhibit inflammatory responses， thereby improving learning and spatial memory abilities in AD mice.

OBJECTIVE To investigate the intervention effect and its potential mechanism of Yifei xuanfei jiangzhuo formula by inhibiting mitochondrial fission in a vascular dementia （VaD） model rats. METHODS VaD rat model was established by bilateral common carotid artery ligation. The experimental animals were randomly divided into sham operation group （SHAM）， model group （MOD），Yifei xuanfei jiangzhuo formula low-dose group （YFXF-L）， Yifei xuanfei jiangzhuo formula high-dose group （YFXF-H）， and Donepezil hydrochloride group （positive control）， with 9 animals in each group. After 30 days of intervention， the spatial learning memory ability was assessed by Morris water maze experiment； HE staining was used to observe histopathological changes in CA1 area of hippocampus； ELISA was used to detect the levels of serum inflammatory factors [interleukin-1β （IL-1β） and IL-4]； Western blot was used to detect the expressions of heat shock protein 90 （HSP90）/mixed lineage kinase domain-like protein （MLKL）/dynamin-related protein 1 （Drp1） pathway-related proteins， mitochondrial fusion proteins （MFN1， MFN2）， and adenosine triphosphate synthase 5A （ATP5A） in hippocampal tissues. The immunohistochemistry was used to detect the level of phosphorylated MLKL （p-MLKL）； real-time fluorescence quantitative PCR was adopted to detect mRNA expressions ofHSP90， MFN1， MFN2 and ATP5A. RESULTS Compared with SHAM group， the escape latency of rats in the MOD group was significantly prolonged， the number of crossing the platform was significantly reduced， and the hippocampal tissues showed typical neuronal damage characteristics， the positive expression level of p-MLKL and the serum level of IL-1β significantly increased， while the serum level of IL-4 significantly decreased， the protein and mRNA expression of HSP90， as well as the protein expressions of p-MLKL/MLKL and p-Drp1（Ser616）/Drp1 were all significantly increased in hippocampal tissue， the protein and mRNA expressions of MFN1， MFN2 and ATP5A， and protein expression of p-Drp1（Ser637）/Drp1 were all significantly decreased （P＜0.05）. After the intervention of Yifei xuanfei jiangzhuo formula， above indicators in each treatment group were all significantly reversed （P＜0.05）. CONCLUSIONS Yifei xuanfei jiangzhuo formula may alleviate neuronal damage and neuroinflammatory responses in VaD rats by regulating the HSP90/MLKL/Drp1 signaling pathway， inhibiting mitochondrial fission， thereby maintaining mitochondrial dynamic balance and improving mitochondrial function.

With the rapid development of implant dentistry, increasing attention has been paid to the long-term stability and aesthetic outcomes of dental implants, among which sufficient volume and quality of soft and hard tissues are considered crucial contributing factors for successful treatment outcomes. Among the various available tissue regeneration strategies, plasmatrix, an autologous biomaterial derived from the patient ' s own peripheral blood, has demonstrated unique and significant clinical value in the regeneration and augmentation of both soft and hard tissues associated with dental implant therapy in recent years. This notable potential is primarily attributed to its rich content of multiple growth factors, viable cells, and a supportive fibrin scaffold, along with its excellent biocompatibility, tunable biodegradation profile, and a relatively simple and rapid preparation process that does not require complex laboratory equipment. As a result, its clinical applications have been continuously expanding across a wide range of indications. Based on a comprehensive review of the existing literature and current research evidence, this article provides an in-depth summary of the advancements in both basic science and clinical applications of plasmatrix in the context of implant dentistry. Particular attention is given to its classification from a materials science perspective, underlying molecular mechanisms, biological effects in promoting tissue regeneration, and its implementation under different clinical scenarios. Furthermore, the article discusses unresolved technical challenges and existing controversies, and outlines potential future directions for research and technological innovation, aiming to provide robust evidence-based guidance for clinical practice as well as a theoretical and methodological reference for future scientific investigations.
Humans ; Biocompatible Materials/therapeutic use* ; Dental Implants ; Tissue Scaffolds ; Fibrin/therapeutic use* ; Tissue Engineering/methods* ; Dental Implantation/methods* ; Dental Implantation, Endosseous/methods*

Metabolic dysfunction-associated fatty liver disease （MAFLD） has a relatively high prevalence rate around the world and is closely associated with the development of various extrahepatic malignancies， among which pancreatic cancer exhibits the highest mortality rate. However， the underlying mechanism between MAFLD and pancreatic cancer remains unclear. This article systematically introduces the latest epidemiological evidence of the association between MAFLD and pancreatic cancer， reviews the research advances in pathogenesis， and evaluates the impact of MAFLD severity and high-risk factors （such as nonalcoholic fatty pancreatic disease and intraductal papillary mucinous neoplasm） on the risk of pancreatic cancer. This article points out that insulin resistance， adipokines， and gut dysbiosis may be the key mechanisms of MAFLD promoting the onset of pancreatic cancer， and it also highlights the presence of heterogeneity in current studies. Large-scale prospective cohort studies are needed in the future to further validate the causal relationship and explore more effective strategies for risk stratification.

Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-β in PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβ in the PSC model.Unexpectedly,Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2-/-DDC mice.However,Lxrβ depletion intensified DDC-induced PSC in the Rag2-/-mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2-/-DDC mice,Lxrβ-/-Rag2-/-DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.

OBJECTIVE To investigate the mechanism of Yifei xuanfei jiangzhuo formula （YFXF） against vascular dementia （VD）. METHODS The differentially expressed genes of YFXF （YDEGs） were obtained by network pharmacology. High-risk genes were screened from YDEGs by using the nomogram model. The optimal machine learning models in generalized linear， support vector machine， extreme gradient boosting and random forest models were screened based on high-risk genes. VD model rats were established by bilateral common carotid artery occlusion， and were randomly divided into model group and YFXF group （12.18 g/kg， by the total amount of crude drugs）， and sham operation group was established additionally， with 6 rats in each group. The effects of YFXF on behavior （using escape latency and times of crossing platform as indexes）， histopathologic changes of cerebral cortex， and the expression of proteins related to the secreted phosphoprotein 1 （SPP1）/phosphoinositide 3-kinase （PI3K）/protein kinase B （aka Akt） signaling pathway and the mRNA expression of SPP1 in cerebral cortex of VD rats were evaluated. RESULTS A total of 6 YDEGs were obtained， among which SPP1， CCL2， HMOX1 and HSPB1 may be high-risk genes of VD. The generalized linear model based on high-risk genes had the highest prediction accuracy （area under the curve of 0.954）. Compared with the model group， YFXF could significantly shorten the escape latency of VD rats， significantly increase the times of crossing platform （P＜0.05）； improve the pathological damage of cerebral cortex， such as neuronal shrinkage and neuronal necrosis； significantly reduce the expressions of SPP1 protein and mRNA （P＜0.05）， while significantly increase the phosphorylation levels of PI3K and Akt （P＜0.05）. CONCLUSIONS VD high-risk genes SPP1， CCL2， HMOX1 and HSPB1 may be the important targets of YFXF. YFXF may play an anti-VD role by down-regulating the protein and mRNA expressions of SPP1 and activating PI3K/Akt signaling pathway.

Objective:To observe the effect of Tongguan Liqiao(opening orifices)needling plus tongue pressure resistance feedback training in treating post-stroke deglutition disorders. Methods:A prospective randomized controlled trial was conducted.A total of 120 patients with post-stroke deglutition disorders were divided into a control group and an observation group using the random number table method,with 60 cases in each group.Both groups were treated with routine treatments.The control group was treated with additional tongue pressure resistance feedback training,and the observation group was treated with additional Tongguan Liqiao needling based on the same intervention in the control group.After 4 weeks of treatment,the clinical efficacy was evaluated,and the complications that occurred during treatment were summarized.The FUJISHIMA Ichiro food intake level scale(FILS)and the swallowing quality of life questionnaire(SWAL-QOL)were scored before treatment and after 4 weeks of treatment. Results:The total effective rate of the observation group was higher than that of the control group(P<0.05).After 4 weeks of treatment,the FILS and SWAL-QOL scores in both groups were higher than those before treatment,and the scores in the observation group were higher than those in the control group(P<0.05).There was no statistical difference in the complication occurrence between the two groups(P>0.05). Conclusion:On the basis of routine treatments,Tongguan Liqiao needling plus tongue pressure resistance feedback training has a better effect in the treatment of post-stroke deglutition disorders.This method can effectively improve the swallowing function of patients,improve the quality of life,and is safe.

Objective:To treat the Crohn's disease(CD)patients with ustekinumab(UST),to eva-luate their clinical and endoscopic remission,and to evaluate their transmural response(TR)and trans-mural healing(TH)condition using intestinal ultrasonography(IUS).Methods:Retrospective analysis was made on patients diagnosed with CD in Peking University People's Hospital from January 2020 to Au-gust 2022,who were treated with UST for remission induction and maintenance therapy.All the patients were evaluated on both week 8 and week 16/20 after treatment,including clinical,biochemical indica-tors,colonoscopy and IUS examination.Results:A total of 13 patients were enrolled in this study,inclu-ding 11 males and 2 females.The minimum age was 23 years,the maximum age was 73 years and the mean age was 36.92 years.All the patients were in the active stage of disease before treatment,and the average Best Crohn's disease activity index(Best CDAI)score was 270.12±105.55.In week 8,the Best CDAI score of the patients decreased from 270.12±105.55 to 133.16±48.66(t=4.977,P＜0.001).Eight patients achieved clinical remission while 5 patients remained in the active stage.Nine patients underwent colonoscopy evaluation.The average simple endoscopic score for Crohn's disease(SES-CD)score decreased from 10.71±7.14 before treatment to 6.00±7.81(t=2.483,P=0.048)in week 16/20.Four patients achieved endoscopic remission while 5 patients did not.In week 8,5 pa-tients achieved TR,2 patients achieved TH,the other 6 patients did not get TR or TH.In week 16/20,6 patients achieved TR,3 patients achieved TH while the other 4 patients did not get TR or TH.There was no significant statistical difference in the TR effect of UST between small intestine and colon lesions(Fisher test,P＞0.999).The rate of UST transmural response in the patients who had had previous bio-logical agent therapy was lower than those with no previous biological agent therapy,but there was no sig-nificant statistical difference(Fisher test,P=0.491).Conclusion:After treatment of UST,the clinical and endoscopic conditions of the CD patients had been improved,and some patients could achieve clini-cal remission and endoscopic remission.UST had good TR and TH effects on CD.TR might appear in week 8,and the TR effect increased in week 16/20.There was no significant statistical difference in the TR effect between small intestine and colon lesions.TR effect of UST was better in the patients who had no previous biological agent therapy than those who had had other biological agents,but the result had no significant statistical difference.

Objective:To investigate the influence of varied oxygen (O 2) concentration environments on the phenotypic transformation of pulmonary artery smooth muscle cells (PASMC) and the mechanism of pulmonary hypertension. Methods:Primary rat PASMC were isolated and cultured through the process of enzymatic digestion. Following identification, the stable passaged PASMC were subjected to a 6-hour incubation in sealed containers with normal O 2 content (group C) and relative O 2 content comprising 55% (group H55), 75% (group H75), and 95% (group H95). mRNA and protein expression of α-Actin (α-SMA), smooth muscle 22α (SM22α), osteopontin (OPN), and matrix metalloproteinase-2 (MMP-2) were measured using real-time quantitative PCR and western blot analysis. Results:The H55 group displayed no significant difference from the C group in terms of mRNA and relative protein expression levels for α-SMA, SM22α, OPN, and MMP-2 (all P>0.05). On the other hand, groups H75 and H95 exhibited a reduction in mRNA and relative protein expression of α-SMA and SM22α, along with an increase in mRNA and relative protein expression of OPN and MMP-2 when compared with both the C and H55 groups (all P<0.05). The H95 group showed a higher relative mRNA expression of MMP-2 as compared to the H75 group ( P<0.05). Conclusions:Oxygen concentration environments of 75% or higher can serve as the foundation for the pathogenesis of pulmonary hypertension, essentially by inducing a phenotypic transformation in PASMC towards adopting a robust secretory function. This induction is contingent upon the concentration of oxygen present.