Pure Total Flavonoids From Citrus Protect Against Nonsteroidal Anti-inflammatory Drug-Induced Small Intestine Injury by Promoting Autophagy in vivo and in vitro.

Small intestine injury is an adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) that urgently needs to be addressed for their safe application. Although pure total flavonoids from citrus (PTFC) have been marketed for the treatment of digestive diseases, their effects on small intestine injury and the underlying mechanism of action remain unknown. This study aimed to investigate the potential role of autophagy in the mechanism of NSAID (diclofenac)-induced intestinal injury in vivo and in vitro and to demonstrate the protective effects of PTFC against NSAID-induced small intestine disease. The results of qRT-PCR, western blotting, and immunohistochemistry showed that the expression levels of autophagy-related 5 (Atg5), light chain 3 (LC3)-II, and tight junction (TJ) proteins ZO-1, claudin-1, and occludin were decreased in rats with NSAID-induced small intestine injury and diclofenac-treated IEC-6 cells compared with the control groups. In the PTFC group, Atg5 and LC3-II expression, TJ protein expression, and the LC3-II/LC3-I ratio increased. Furthermore, the mechanism by which PTFC promotes autophagy in vivo and in vitro was evaluated by western blotting. Expression levels of p-PI3K and p-Akt increased in the intestine disease-induced rat model group compared with the control, but decreased in the PTFC group. Autophagy of IEC-6 cells was upregulated after treatment with a PI3K inhibitor, and the upregulation was significantly more after PTFC treatment, suggesting PTFC promoted autophagy through the PI3K/Akt signaling pathway. In conclusion, PTFC protected intestinal barrier integrity by promoting autophagy, which demonstrates its potential as a therapeutic candidate for NSAID-induced small intestine injury.

Effects of Mast Cells Induced by NSAIDs Impair Intestinal Epithelial Barrier Function In Vivo and In Vitro.

To explore the correlation between altered expression of mast cells and PAR-2 and impaired mucosal barrier in NSAIDs enteropathy through animal and cell experiments, and to elucidate the role of mast cells and PAR-2 in the pathogenesis of NSAIDs enteropathy and the regulatory mechanism of the tight junction of intestinal epithelium. Animal experiments: the NSAIDs-related small intestine injury model was established by intragastric administration of diclofenac sodium, and mast cells were detected by toluidine blue staining. Cell experiments: Intestinal epithelial cell line (IEC-6) was applied with diclofenac sodium and its activity was detected by CCK-8.IEC-6 and RBL-2H3 were co-cultured to evaluate the permeability of intestinal epithelial cells by detecting the concentration of potassium ion and LDH. The expressions of tight junction proteins (zo-1, claudin-1, occludin), cytoskeletal components (actin, tubulin, keratin) and par-2 were analyzed by Western Blot. In animal experiments, the number of mast cells was significantly increased after 24 h of action of diclofenac sodium. In cell experiments, the survival rate of IEC-6 cells decreased significantly when the concentration of diclofenac sodium is more than 50 µg/mL; after 24 h of co-culture, the potassium and LDH concentration in the co-culture group were significantly higher, and the expression of ZO-1, claudin-1, occludin, tubulin, and keratin was decreased. Mast cells activate PAR-2 in intestinal epithelial cells, downregulate the related proteins of cell tight junctions and cytoskeletal proteins, and increase the permeability of intestinal epithelial cells.

Real-world data on the use of secukinumab as treatment for moderate-to-severe psoriasis in Chinese patients.

BACKGROUND: The efficacy and safety of secukinumab, an interleukin-17 inhibitor, as systemic treatment for patients with moderate-to-severe psoriasis have been demonstrated, but real-world data pertaining to this is limited in China. OBJECTIVE: To evaluate the efficacy and safety of secukinumab in clinical practice in Chinese psoriasis patients with or without psoriatic arthritis (PsA) and identify potential baseline factors that affect the response of patients to secukinumab treatment. MATERIALS & METHODS: Data from 81 patients treated with secukinumab for at least 16 weeks were analysed in a retrospective observational study. RESULTS: After 16 weeks of treatment with secukinumab, 91.1%, 73%, and 38.3% of patients achieved a PASI 75 (75% improvement based on the Psoriasis Area and Severity Index), PASI 90, and PASI 100, respectively. A significant improvement in the quality of life of patients was also observed. Notably, baseline factors, such as young age, lower BMI, no scalp involvement and absence of concomitant PsA, were associated with better clinical response to secukinumab. Approximately 42% of patients (34/81) experienced adverse events, of which the most common was pruritus. CONCLUSION: The results demonstrated that secukinumab appears to be an effective treatment alternative for the majority of Chinese plaque psoriasis patients. Baseline factors, including age, BMI, scalp involvement and concomitant presence of PsA, were associated with response to secukinumab.

Annular epidermolytic ichthyosis with palmoplantar keratosis: a unique phenotype associated with interfamilial phenotypic heterogeneity.

BACKGROUND: Annular epidermolytic ichthyosis (AEI) is a rare autosomal dominant ichthyosis that was recently described in 10 separate families in the English literature. There are no reports on the phenotypic heterogeneity of AEI. OBJECTIVES: We investigated, for the first time, a large Chinese AEI pedigree exhibiting interfamilial phenotypic heterogeneity. MATERIALS AND METHODS: We collected clinical data and DNA from the members of the family, and skin lesions were obtained from two patients with different phenotypes. Skin imaging examinations were performed. Whole-exome sequencing (WES) and Sanger sequencing were used to detect gene mutations. RESULTS: The characteristic features of granular layer degeneration in the two biopsies were verified via histological methods. The missense mutation c.1436T > C in KRT1 was detected in all nine patients. CONCLUSION: This study demonstrates that AEI may present with different clinical phenotypes and that mutation analysis for suspected cases is necessary to obtain a precise diagnosis.

The decreased expression of IKBKE in systemic lupus erythematosus.

OBJECTIVE: The IKBKE has been proven to be associated with systemic lupus erythematosus (SLE) in a genome-wide association study (GWAS) conducted by our group. The objective of the recent study is to investigate the contribution of IKBKE functional variants (rs2297550) to SLE. METHODS: We detected the regulatory effect of rs2297550 on IKBKE expression by expression quantitative trait loci (eQTL) study. Then, we investigated the differences of IKBKE mRNA expression levels in peripheral blood mononuclear cells (PBMCs) between 135 SLE patients and 130 healthy controls using quantitative real-time PCR (qRT-PCR). We further analyzed the association of SLE clinical characteristics with IKBKE mRNA expression and rs2297550 polymorphisms. RESULTS: The results of eQTL indicated the genotype "GG" of single-nucleotide polymorphism (SNP) rs2297550 was associated with lower expression levels of IKBKE (P = 0.022) in normal controls. Compared with the healthy control group, the expression levels of IKBKE mRNA in patients with SLE were significantly decreased (P = 2.32 × 10-12). In clinical characteristics, we found that IKBKE mRNA expression levels were associated with vasculitis (P = 0.015) and increased C-reactive protein (CRP) (P = 0.021) in SLE patients. CONCLUSION: In this study, we not only detected that the variant rs2297550 of IKBKE may be closely related to SLE, but also proposed functional hypotheses for the association signals. Key Points • The rs2297550 is located in a region with transcriptional regulatory function and may regulate the expression of IKBKE via these regulatory elements. • The genotype "GG" of SNP rs2297550 was associated with lower expression levels of IKBKE. • The expression of IKBKE mRNA was decreased in SLE patients compared with healthy controls. • IKBKE contributes to the clinical characteristics of SLE.

The prevalence of human papillomavirus in colorectal cancer and adenoma: A meta-analysis.

OBJECTIVE: The objective of this study is to further clarify the correlation between colorectal cancer (CRC) and human papillomavirus (HPV) through literature search and meta-analysis, which is conducive to the formulation of further prevention programs. METHODS: Searching Web of Science, PubMed, MEDLINE, Scopus, and CENTRAL for studies investigating the relationship between CRC and HPV. All analyses were performed through Revman (version 5.3, the Cochrane Collaboration, Oxford, UK). Data from selected studies were extracted into two by two tables. Moreover, all included studies were weighted and summarized. RESULTS: Eighteen studies were included. The expression of HPV in CRC tissues was obviously higher than that in nonmalignant tissues (odds ratio [OR] = 5.56, 95% confidence interval [CI] = 3.18-9.72, Z = 6.02, P < 0.00001). The expression of HPV in CRC tissues and adenoma tissues showed no significant abnormalities (OR = 1.74, 95% CI = 0.92-3.29, Z = 1.70, P = 0.09). The expression of HPV in CRC tissues was obviously higher than that in normal tissues (OR = 7.23, 95% CI = 3.89-13.42, Z = 6.27, P < 0.00001). CONCLUSION: HPV infection in CRC tissues was obviously higher than that in nonmalignant tumor tissues and normal colon tissues, but there were no statistically significant abnormalities between CRC tissues and adenoma tissues.

Exome-Wide Rare Loss-of-Function Variant Enrichment Study of 21,347 Han Chinese Individuals Identifies Four Susceptibility Genes for Psoriasis.

Most psoriasis-related genes or loci identified by GWAS represent common clusters and are located in noncoding regions of the human genome, providing only limited evidence for the roles of rare coding variants in psoriasis. Two exome-wide case-control genotyping data sets (11,245 cases and 11,177 controls) were obtained from our previous study. Quality controls were established for each data set, and the markers remaining in each set were annotated using ANNOVAR. Gene-based analysis was performed on the annotation results. A total of 250 and 35 genes in the Exome_Fine and Exome_Asian array cohorts, respectively, exceeded the threshold (P < 4.43 × 10-6). Merged gene-based analysis was then conducted on the same set of SNPs from seven genes common to both arrays, and the chi-square test was used to confirm all gene-based results. Ultimately, four susceptibility genes were identified: BBS7 (Pcombine = 1.38 × 10-29), GSTCD (Pcombine = 8.35 × 10-47), LIPK (Pcombine = 1.02 × 10-19), and PPP4R3B (Pcombine = 1.79 × 10-33). This study identified four susceptibility genes for psoriasis via a gene-based method using rare variants, contributing to our understanding of the pathogenesis of psoriasis.