Ulcerative colitis （UC）， which is characterized by a complex and multifactorial etiology， remains one of the challenging disorders in the international field of digestive system diseases. In recent years， rectal administration preparations have made rapid progress in UC therapeutic applications. This study systematically reviews the dosage forms， mechanisms of action， and clinical applications of rectally-administered preparations for the treatment of UC. It is found that suppositories are the most commonly used dosage forms for rectal administration. The newer suppositories have the advantages of high bioavailability and good stability. Enemas can retain the drug in the intestine as much as possible to achieve the effects of diluting intestinal toxins， cleansing the bowel， and reducing inflammation. Gels can achieve a drug-sustained-release effect and effectively improve intestinal mucosal damage. The mechanism of action of this type of preparation is mainly to inhibit inflammatory cell infiltration， regulate intestinal microbial homeostasis， and increase the expression of tight-junction proteins， so as to play anti-inflammatory， regulate the intestinal bacterial flora， repair the intestinal mucosa， and other efficacies. The diversity of rectal administration forms provides a wide range of choices for the clinical treatment of UC， such as Mesalazine suppositories， Lianshao enemas， and temperature- sensitive gels loaded with drugs for UC.

Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma, accompanied by dynamic changes in the tumor microenvironment (TME). A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction (SBJDD) in preventing colorectal tumorigenesis. However, the mechanism remains unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry. Bulk RNA sequencing was utilized to assess the underlying mechanisms. Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc ^Min/+ mice and clinical patients. There was a marked accumulation of CCL22⁺ dendritic cells (DCs) and an enhanced immunosuppressive action, which SBJDD and berberine reversed. Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22⁺ DCs, which may represent "exhausted DCs". Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects. TMEM131 derived CCL22⁺ DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis. These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer (CRC), suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.

Objective:To explore the efficacy and safety of whole-brain low-dose radiotherapy(LDRT)combined with PD-1 inhibitor sin-tilimab and intrathecal pemetrexed(IP)for the treatment of refractory non-small cell lung cancer(NSCLC)with leptomeningeal metastases(LM).Methods:Retrospective analysies were was performed on eight NSCLC patients with LM at the West China Hospital of Sichuan Uni-versity from December 2022 to May 2024.Among the eight patients,there were four were males and four were females,with a median age of 49 years(rangeing,between 34 to 58 years).All patients were treated with whole-brain LDRT combined with immune checkpoint inhibit-or(ICI)and intrathecal chemotherapy regimens,and the therapeutic efficacy was evaluated according to the Response Assessment in Neuro-Oncology(RANO)criteria and the Karnofsky physical status(KPS)score.Adverse reactions were assessed according to the Common Criteria for the Evaluation of Adverse Events(CTCAE version 5.0).Survival analysis was performed using the Kaplan-Meier method.The classification proportion of cerebrospinal fluid subsets before and after treatment was analyzed using by single-cell sequencing,and the differential ana-lysis of gene expression in parallel cells was performed.Results:The best clinical treatment effects in eight patients were were evaluated us-ing the RANO criteria:five patients(62.5%)were evaluated as improved and three(37.5%)as stable.The median KPS score of the eight pa-tients was 30(20-50)before treatment,which was significantly improved to 60(40-90)after treatment(P=0.000 9).The remission rate of neurological symptoms was 100%(8/8)in eight patients.The median neurological progression-free survival(NPFS)was 12 months.The res-ults of single-cell sequencing in CSF of patientss(P1)showed that the proportion of T cells in the patient samples after whole-brain LDRT treatment was significantly higher than that before treatment(6.08%vs.68.87%),and the proportion of tumor cells was significantly lower(12.92%vs.0.6%).The differential analysis of gene expression showed that CCL5 and CXCL13 were significantly upregulated in T cells of CSF after WB-LDRT treatment.Conclusions:The combination of whole-brain LDRT with ICI and IP in the treatment of NSCLC with LM can signific-antly alleviate neurological symptoms,improve quality of life and prolong the NPFS of patients,which is a safe and effective treatment.

Objective To investigate the relationship between the changes in vasopressin(VP)level and disease severity and prognosis in patients with septic shock(SS).Methods A total of 96 patients with SS in the hospital from December 2021 to December 2022 were selected as the study group,and 95 healthy volun-teers in the hospital during the same period were selected as the control group.The plasma VP levels of the two groups were compared,and their correlation with multiple organ dysfunction syndrome(MODS)score,a-cute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score,serum C-reactive protein(CRP),and procalcitonin(PCT)levels were analyzed.The study group received shock treatment,and was divided into a good prognosis group and a poor prognosis group based on the prognosis after 28 days of hospitalization.The clinical data of the two groups were compared.Multivariate Logistic regression analysis was used to analyze the factors affecting poor prognosis.A new prediction scheme and a conventional prediction scheme were con-structed,and the predictive efficacy of different prediction schemes was evaluated using area under the curve(AUC),net reclassification index and comprehensive discrimination improvement index.Results Compared with the control group,the plasma VP level in the study group was significantly decreased,and MODS score,APACHE Ⅱ score,the levels of serum CRP and PCT were significantly increased,with statistical significance(P＜0.05).Pearson correlation analysis showed that plasma VP level was negatively correlated with MODS score,APACHE Ⅱ score,serum CRP and PCT level(r=-0.426,-0.519,-0.483,-0.395,P＜0.05).The proportion of diabetes mellitus,acute respiratory distress syndrome(ARDS),acute kidney injury(AKI),MODS score,APACHE Ⅱ score,serum CRP and PCT levels in the poor prognosis group were higher than those in the good prognosis group,while the plasma VP level was lower than that in the good prognosis group,with statistical significance(P＜0.05).Logistic regression analysis showed that concurrent ARDS,concurrent AKI,plasma VP,MODS score,APACHE Ⅱ score,serum CRP and PCT were all influential factors for poor prognosis of SS patients(P＜0.05).The AUC of plasma VP predicting poor prognosis of SS patients was 0.752,and the AUC of the new prediction scheme predicting poor prognosis of SS patients was greater than that of the conventional prediction scheme predicting poor prognosis of SS patients(P＜0.05).Conclu-sion Plasma VP level decrease in SS patients and closely relate to the severity of the condition.Based on the results of Logistic regression analysis,the new predictive model is established,which has certain predictive value for poor prognosis.

Objective To observe the value of left atrial strain combined with electrocardiogram(ECG)P-wave parameters for predicting recurrence of paroxysmal atrial fibrillation(PAF)after pulmonary vein isolation(PVI)using radiofrequency catheter.Methods Totally 88 PAF patients who planned to receive the first PVI were prospectively enrolled and divided into recurrence group(n=30)and non-recurrence group(n=58)according to results of ECG within 6 months after PVI.The patients'basic data,the transthoracic echocardiography(TTE)parameters,including left atrial reservoir strain(LASr),left atrial conduct strain(LAScd)and left atrial contraction strain(LASct),as well as ECG parameters including P-wave duration,PR interval and P/PR(the ratio of P-wave duration to PR interval)were compared between groups.Multivariate logistic regression analysis was performed of parameters being statistically different between groups to screen independent predictors for recurrence of PAF after PVI.The receiver operating characteristic curve and the area under the curve(AUC)were used to evaluate the predicting efficacy of individual independent predictors alone and their combination,and DeLong test was used for comparison.Results No significant difference of patients'basic data was found between groups(all P＞0.05).Compared with those in non-recurrence group,LASr and LAScd decreased while P/PR increased in recurrent group(all P＜0.05).LASr(OR=0.805),LAScd(OR=0.850)and P/PR(OR=1.119)were all independent predictors for recurrence of PAF after PVI(all P＜0.05),with AUC of 0.755,0.643 and 0.771,respectively,all lower than their combination(AUC=0.869)(all P＜0.05).Conclusion TTE and ECG parameters could be used to predict recurrence of PAF after PVI.The predicting efficacy of the combination of LASr,LAScd and P/PR was better than that of each alone.

AIM:To study the effect of NEDD8-conjugating enzyme UBE2F on lung adenocarcino-ma metastasis.METHODS:The expression of UBE2F in lung adenocarcinoma was analyzed using TIMER2.0,UALCAN and HPA databases.Kaplan-Mei-er Plotter database was used to analyze the rela-tionship between UBE2F expression and survival rate of lung adenocarcinoma.A UBE2F-knockout lung adenocarcinoma cell line was constructed us-ing CRISPR/Cas9 technology,and a UBE2F-knockout lung adenocarcinoma metastasis model was con-structed in nude mice to verify the effect of UBE2F knockout on lung adenocarcinoma metastasis.The effects of UBE2F knockout on invasion and migra-tion of lung adenocarcinoma cells were examined by cell scratch assay and Transwell invasion and mi-gration assays.The effect of down-regulated UBE2F expression on snail expression,a key marker of epi-thelial-mesenchymal transition(EMT),was detect-ed by Western blot and Real time PCR.RESULTS:Multiple database analysis showed that UBE2F was highly expressed in lung cancer,and Kaplan-Meier Plotter analysis showed that high expression of UBE2F in lung adenocarcinoma had better progno-sis than low expression.In vivo experiments showed that compared with control group,the number of nodules metastasized on the lung sur-face of nude mice after UBE2F knockout was signifi-cantly increased(P<0.05).Cell scratch assay and Transwell assay showed that UBE2F enhanced the migration and invasion ability of lung cancer cells after knockout,and the difference were statistically significant(P<0.05).Western blot and Real time PCR results indicated that the level of EMT tran-scription factor snail protein and mRNA increased after UBE2F knockout.CONCLUSION:In lung ade-nocarcinoma cells,UBE2F down-regulation leads to Snail accumulation and promotes invasion and me-tastasis of lung adenocarcinoma cells.

ObjectiveTo investigate the possible mechanism of Wenfei Huaxian Decoction （温肺化纤汤） in treatment of pulmonary fibrosis in systemic sclerosis-associated interstitial lung disease （SSc-ILD）. MethodsSixty C3H/He female rats were randomly divided into a control group， a model group， a pirfenidone group， and low-， medium-， and high-dose Wenfei Huaxian Decoction groups. The SSc-ILD model mice was established by subcutaneous injection of bleomycin solution 0.04 mg/d into the back of mice for 28 days in all groups but the control group. After successful modelling， the pirfenidone group was given pirfenidone capsule 300 mg/（kg·d） by gavage， the low-， medium- and high-dose Wenfei Huaxian Decoction groups were given Wenfei Huaxian Decoction 7.81， 15.62， and 31.24 g/（kg·d） by gavage， respectively， and the control group as well as the model group were given normal saline 0.1 ml/10 g by gavage， for a total of 21 days. At the end of the intervention， HE staining and Masson staining were used to observe the pathological changes in the skin and lung tissues； the hydroxyproline content of the skin and lung tissues was detected； the protein expression levels of endoplasmic reticulum stress-related proteins glucose-regulated protein 78 （BIP） and C/EBP homologous protein （CHOP） as well as those of nuclear factor kappa B （NF-κB） pathway p65 were measured by western blot； ELISA was performed to determine the expression levels of interferon gamma （IFN-γ）， interleukin 6 （IL-6） and tumour necrosis factor alpha （TNF-α） in serum of rats. ResultsThe results of HE and Masson staining indicated that compared with the control group， the dermis significantly thickened， the number of collagen fibers significantly enlarged， and the number of inflammatory cells significantly increased in the model group； the lung tissue showed a marked inflammatory cellular response with massive collagen fibre proliferation with inflammatory cell infiltration. Compared with the model group， the skin tissue and lung tissue collagen fibre proliferation significantly reduced and inflammatory cell infiltration reduced in the pirfenidone group and all dose groups of Wenfei Huaxian Decoction， and the effects of pirfenidone group and Wenfei Huaxian Decoction medium- and high-dose groups were basically comparable. Compared with the model group， the content of hydroxyproline in skin and lung tissue， the serum level of IFN-γ， IL-6 and TNF-α， and the expression levels of BIP and CHOP protein in lung tissue increased in model group （P＜0.05）. Compared with model group， the content of hydroxyproline in skin tissue of pirfenidone group， low-and medium-dose Wenfei Huaxian Decoction groups decreased， and the content of hydroxyproline in lung tissue of medium-dose Wenfei Huaxian Decoction group decreased. The serum level of IFN-γ， IL-6， TNF-α and the expression levels of BIP， CHOP and p65 protein in lung tissue of rats in pirfenidone group and high-dose Wenfei Huaxian Decoction group decreased （P＜0.05）. The content of hydroxyproline in lung tissue of medium-dose Wenfei Huaxian Decoction group was significantly lower than that of low-dose and high-dose Wenfei Huaxian Decoction group， and the serum level of IFN-γ， IL-6， TNF-α in low- and medium-dose Wenfei Huaxian Decoction group were higher than those in high-dose Wenfei Huaxian Decoction group. The expression level of BIP protein in high-dose group was significantly lower than that in low- and medium-dose Wenfei Huaxian Decoction groups （P＜0.05）. ConclusionWenfei Huaxian Decoction can improve the skin and lung fibrosis of SSc-ILD rats， which may act through anti-inflammation， inhibition of NF-κB pathway， and then inhibition of endoplasmic reticulum stress， which ultimately blocked the fibrotic process.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.