Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver injury of unknown etiology. The onset of this disease involves the activation and recruitment of diverse immune and non-immune cells, which in turn trigger hepatic damage. Immune checkpoint molecules (ICM) are expressed on the surface of multiple cell types. By regulating cellular functional states, they help limit the intensity and duration of immune responses, thereby preventing excessive inflammation and tissue damage, and maintaining immune homeostasis. In AIH, however, this natural "braking" mechanism is impaired, leading to aberrant activation of both immune and non-immune cells and the breakdown of immune homeostasis. Consequently, ICM are likely to play a critical role in the pathogenesis of AIH. A deeper understanding of the function of ICM in AIH not onlyadvances our insight into the disease mechanism, but also suggests that targeting these molecules may represent a promising therapeutic strategy for the treatment of AIH.

ObjectiveTo investigate the risk factors for rebleeding after endoscopic therapy for esophageal and gastric varices in liver cirrhosis patients， to construct a clinical predictive model， and to provide a reference for predicting rebleeding in the early stage， reducing the incidence rate of rebleeding， and improving the clinical outcome of patients. MethodsA retrospective analysis was performed for the clinical data of 194 liver cirrhosis patients with gastroesophageal variceal bleeding who received initial endoscopic therapy at Department of Gastroenterology， The Second People’s Hospital of Lanzhou， from January 1， 2021 to May 31， 2025. According to whether rebleeding occurred within 1 year after endoscopic therapy， the patients were divided into rebleeding group and non-rebleeding group. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. The patients enrolled were randomly divided into a training set and a validation set at a ratio of 7∶3. In the training set， the Lasso regression analysis was used to obtain optimal predictive variables， and the factors that might affect prognosis were included in the univariate and multivariate Logistic regression analyses to identify independent predictive factors for rebleeding after endoscopic therapy for esophageal and gastric varices in liver cirrhosis patients， which were used to construct a nomogram model. In both the training set and the validation set， the receiver operating characteristic （ROC） curve and the calibration curve were used to assess the discriminatory ability and calibration of the model， and decision curve analysis and the clinical impact curve were used to assess the clinical practicability of the model. ResultsAmong the 194 liver cirrhosis patients with esophageal and gastric varices， 116 （59.79%） experienced rebleeding within 1 year after endoscopic therapy， with 76 patients in the training set and 40 patients in the validation set. In the training set， the Lasso regression analysis and the univariate and multivariate Logistic regression analyses showed that etiology of liver cirrhosis （odds ratio ［OR］=3.540， 95% confidence interval ［CI］： 1.520 — 7.150， P<0.001）， Child-Pugh class （OR=3.560， 95%CI： 1.380 — 9.500， P=0.019）， severity of esophageal and gastric varices （OR=8.190， 95%CI： 3.568 — 17.850， P=0.026）， and main portal vein diameter （OR=2.954， 95%CI： 1.349 — 15.030， P=0.044） were independent predictive factors for rebleeding of esophageal and gastric varices in liver cirrhosis patients. A nomogram model was constructed based on the above independent predictive factors. The ROC curve analysis showed that this model had an area under the ROC curve of 0.845 （95%CI： 0.778 — 0.912） in the training set and 0.801 （95%CI： 0.798 — 0.868） in the validation set. The model had an index of concordance of 0.832 in the training set and 0.820 in the validation set， suggesting that the model had a good discriminatory ability. The Hosmer-Lemeshow test showed P values of 0.320 and 0.550 in the training set and validation set， respectively， the calibration curve indicated that the predicted probabilities of the nomogram model were in good concordance with the actual observed probabilities， suggesting that the model had good calibration. The decision curve analysis and the clinical impact curve showed that the model had good clinical utility. ConclusionThe nomogram model based on etiology of liver cirrhosis， Child-Pugh class， severity of esophageal and gastric varices， and main portal vein diameter has a certain clinical value in predicting the risk of rebleeding from esophageal and gastric varices in liver cirrhosis.

Platelet transfusion refractoriness (PTR) is one of the common problems in platelet transfusion, significantly impacting patient clinical outcomes and increasing the demand for allogeneic platelet transfusion. Both immune and non-immune factors contribute to PTR, among which the occurrence mechanism of immune platelet transfusion refractoriness (IPTR) involves humoral and cellular immune processes and is influenced by platelet storage, processing, and the patient's disease, therapy and immune status. This review comprehensively discusses the research related to the factors for alloimmune of IPTR, the mechanism of platelet clearance and its influencing factors. Furthermore, it explores feasible prevention and treatment measures such as platelet compatibility transfusion and clinical treatments. The aim is to provide a systematic cognition for a deeper understanding of the pathological process of platelet alloimmunization and clearance, and to provide a theoretical basis for the construction of precise clinical prevention and treatment strategies for IPTR, as well as to explore feasible research directions in this field in the future.

RNA-based gene therapy has been widely used for various diseases, and extensive studies have proved that suitable delivery routes greatly help the development of RNA therapeutics. Identifying a safe and effective delivery system is key to realizing RNA therapeutics' clinical translation. Inhalation is a non-invasive pulmonary delivery modality that can enhance the retention of therapeutic agents in the lungs with negligible toxicity, thereby improving patient compliance. Inhaled RNA therapeutics are increasingly becoming an area of focus for researchers; however, only several clinical trials have explored inhaled delivery of RNA for pulmonary diseases. This review presents an overview of recent advances in inhaled delivery systems for RNA therapeutics, including viral and nonviral systems, highlighting state of the art regarding inhalation in the messenger RNA (mRNA) field. We also summarize the applications of mRNA inhalants in infectious and other lung diseases. Simultaneously, the research progresses on small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and different types of RNA are also discussed to provide new strategies for developing RNA inhalation therapy. Finally, we clarify the challenges inhaled RNA-based therapeutics face before their widespread adoption and provide insights to help advance this exciting field to the bedside.

OBJECTIVES: To investigate the effect of orexin-A-mediated regulation of ionotropic glutamate receptors for promoting motor function recovery in rats with spinal cord injury (SCI). METHODS: Thirty-six newborn SD rats (aged 7-14 days) were randomized into 6 groups (n=6), including a normal control group, a sham-operated group, and 4 SCI groups with daily intrathecal injection of saline, DNQX, orexin-A, or orexin-A+DNQX for 3 consecutive days after PCI. Motor function of the rats were evaluated using blood-brain barrier (BBB) score and inclined plane test 1 day before and at 1, 3, and 7 days after SCI. For patch-clamp experiment, spinal cord slices from newborn rats in the control, sham-operated, SCI, and SCI+orexin groups were prepared, and ventral horn neurons were acutely isolated to determine the reversal potential and dynamic indicators of glutamate receptor-mediated currents under glutamate perfusion. RESULTS: At 3 and 7 days after SCI, the orexin-A-treated rats showed significantly higher BBB scores and grip tilt angles than those with other interventions. Compared with those treated with DNQX alone, the rats receiving the combined treatment with orexin and DNQX had significantly higher BBB scores and grip tilt angles on day 7 after PCI. In the patch-clamp experiment, the ventral horn neurons from SCI rat models exhibited obviously higher reversal potential and greater rise slope of glutamate current with shorter decay time than those from sham-operated and orexin-treated rats. CONCLUSIONS Orexin-A promotes motor function recovery in rats after SCI possibly by improving the function of the ionotropic glutamate receptors.
Animals ; Spinal Cord Injuries/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, Ionotropic Glutamate/metabolism* ; Recovery of Function/drug effects* ; Orexins/pharmacology* ; Male ; Female ; Animals, Newborn ; Neuropeptides/pharmacology* ; Intracellular Signaling Peptides and Proteins/pharmacology*

Hot melt extrusion(HME)technology employs thermodynamic and kinetic principles to mix pharmaceutical polymers with crystalline drugs at high temperatures and extrude them,embedding drug molecules within the polymer matrix to form solid dispersions.Due to its solvent-free nature,capability for one-step processing,and support for continuous operation,HME has garnered significant attention in the pharmaceutical industry in recent years.This article introduced the basic principles and development history of HME technology and its marketed drugs.It reviewed the research progress of HME technology in improving drug solubility,masking taste,controlled release,targeted release,oral dispersible films,implant formulations,semi-solid formulations,and 3D printed formulations.Additionally,the article summarized the advantages and limitations of HME technology and provided an outlook on its future development.

Objective To explore the protective effect of 7,8-dihydroxyflavone(7,8-DHF)on the retina of diabetic rats and its mechanism.Methods A total of 18 SPF-grade male Sprague-Dawley(SD)rats were selected and randomly divided into three groups:the normal group,the model group,and the experimental group,with six rats in each group.Rats in the normal group were fed with a normal diet,while those in the remaining two groups were fed with a high-fat emulsion through oral gavage continuously for 2 weeks to establish a diabetes model.Rats in the experimental group were provided with 7,8-DHF(5 mg?kg-1)by continuous intraperitoneal injection,while those in the normal and model groups were provided with an equal volume of normal saline.The rats in all groups received intervention once a day for 2 weeks.The changes in the body mass and fasting blood glucose(FBG)were observed before and after modeling.Besides,the changes in the retina of rats in each group were observed by fundus fluorescence angiography(FFA)after 2 weeks.Moreo-ver,the changes and apoptosis of retinal neuronal cells were detected by hematoxylin and eosin(HE)staining,CD31 im-munofluorescence,and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays.Results After 2 weeks of continuous intervention,compared with the normal group,the body mass of rats in the model and experimental groups decreased(both P＜0.05),and the FBG increased significantly(both P＜0.05);compared with the model group,the experimental group showed an increase in the body mass(P＜0.05)and a decrease in the FBG(P＜0.05).The fundus photography and FFA of rats in the three groups did not reveal any fundus features of diabetic retinopathy.The HE staining results showed that the retina of rats in the normal and experimental groups was structurally intact,with neatly arranged cells and uniform thickness;the retinal structure of rats in the model group remained clear.However,the thickness of the inner layers of the retina of rats in the model group was thinner compared with the normal and experimental groups,exhibi-ting significant differences(both P＜0.05).The CD31 immunofluorescence assay results indicated that the CD31 immuno-fluorescence intensity values of rats in the three groups were roughly comparable,without significant differences(all P＞0.05).The TUNEL assay results suggested that the apoptosis of retinal neurons increased in rats in the model group com-pared with the normal group,exhibiting significant differences(P＜0.001);compared with the model group,the apoptosis of retinal neurons of rats in the experimental group decreased significantly,displaying significant differences(P＜0.001).Conclusion The apoptosis of retinal neurons in diabetic rats may precede vascular endothelial cell injury.7,8-DHF can improve the body mass,decrease the blood glucose level,and protect the retinal neurons in diabetic rats.

OBJECTIVE To study the anti-fatigue effects of differently-cultivated Astragalus extract in a hypoxic environment of the plateau and explore the related mechanisms.METHODS Fifty-six male KM mice were randomly divided into the hypoxic swimming control(HSC)group,imitation wild Astragalus extract(IWA)430,860 and 1 720 mg·kg-1 groups,and cultivated Astragalus extract(CA)463,925 and 1 850 mg·kg-1 groups.The drug was administered by gavage once daily for 15 days,while body mass was monitored every three days.After 15 days of gavage,the mice were subjected to load swimming(5%body weight)in a hypobaric chamber(simulating a 4 000 m altitude),with exhaus-tive swimming time measured to identify the optimal dosage.Following randomization,fifty male KM mice were assigned to five groups:normoxic control(NC),hypoxic control(HC),HSC,IWA 860 and CA 925 mg·kg-1.All groups underwent daily gavage for 15 d before 90 min non-weight-bearing swimming was conducted in the HSC,IWA 860 and CA 925 mg·kg-1 groups within a hypobaric chamber,followed by immediate measurement of muscle strength.Hematoxylin-eosin(HE)staining was used to observe the histopathological changes in liver and gastrocnemius muscle tissues.Blood urea nitrogen(BUN),blood glucose(BG)and serum lactic acid(LA),glutathione(GSH),glutathione peroxidase(GSH-Px),malondialdehyde(MDA),superoxide dismutase(SOD),liver glycogen(LG)and muscle glycogen(MG)in livers and muscles,and total antioxidant capacity(T-AOC)and reactive oxygen species(ROS)in muscles were measured by commercial kits.Taurine and hypotaurine were measured by HPLC.Enzyme-linked immunosorbent assay(ELISA)was used for cysteine sulfenic acid decarboxylase(CSAD)measure-ment.Western blotting was used to detect protein expressions of phosphatidylinositol 3-kinase(PI3K),protein kinase B(Akt),nuclear factor E2-related factor 2(Nrf2),and heme oxygenase-1(HO-1)in skeletal muscles.RESULTS Compared with the HSC group,the swimming time was prolonged in IWA 463,IWA 860,CA 925 and CA 1 850 mg·kg-1 groups.Compared with the HSC group,the muscle strength of mice in the IWA 860 mg·kg-1 group and the CA 925 mg·kg-1 group was significantly increased,histo-pathological damage in the liver and gastrocnemius muscle was reduced,serum levels of LA and BUN were significantly decreased,levels of BG,LG and MG were significantly increased,levels of GSH,GSH-Px and SOD were significantly increased,contents of MDA were significantly decreased,expressions of CSAD were significantly increased in liver tissue,contents of GSH,T-AOC,taurine and hypotaurine were significantly increased,levels of ROS were significantly decreased,and protein expressions of PI3K,Akt,Nrf2,HO-1 were significantly upregulated in muscle tissues.CONCLUSION Under simulated high-altitude hypoxic conditions,extracts of Astragalus membranaceus cultivated by two methods consis-tently exhibit anti-fatigue effects.Its mechanisms may be mitigating oxidative stress,augmenting taurine and hypotaurine metabolic regulation,and activating PI3K/Akt and Nrf2/HO-1 signaling pathways.IWA has a better anti-fatigue effect than CA.