Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Aim To investigate the effect of exogenous growth differentiation factor 11(GDF11)on vascular re-modeling in hypertensive rats through regulating the endoplasmic reticulum stress pathway mediated by lectin-like oxidized low density lipoprotein receptor-1(LOX-1).Methods Rats were randomly divided into control group,model group(Ang Ⅱ-induced hypertension rat model group),r-GDF11 group,Ab-LOX-1 group,r-GDF11+r-LOX-1 group,with 10 rats in each group.The changes of caudal arterial blood pressure in rats were detected by animal non-invasive blood pres-sure meter;the morphology of aortic vessels was evaluated by hematoxylin-eosin(HE)staining;the collagen deposition in aortic tissue was evaluated by Masson staining;the expression of GDF11,LOX-1 and endoplasmic reticulum(ER)stress related proteins in aortic tissues were detected by Western blot.Results Compared with the control group,the blood pressure of rats in the model group was increased,the media thickness(MT)and MT/lumen diameter(LD)of aortic tis-sue were increased,and the LD of aortic tissue was decreased(all P＜0.05);Collagen volume fraction(CVF)value,the expression of glucose regulated protein 78(GRP78)and activating transcription factor 6(ATF6)protein,the ratio of phosphorylated PKR-like endoplasmic reticulum regulating kinase(p-PERK)/PERK and phosphorylated inositol requiring enzyme 1α(p-IRE1α)/IRE1α in aortic tissue were increased(all P＜0.05).Compared with the model group,the blood pressure of rats in the r-GDF11 group and Ab-LOX-1 group was decreased,the MT and MT/LD of aortic tissue were de-creased,and the LD of aortic tissue was increased(all P＜0.05);CVF value,the expression of GRP78 and ATF6 protein,p-PERK/PERK and p-IRE1α/IRE1α in aortic tissue were decreased(all P＜0.05).Compared with the r-GDF11 group,the blood pressure of rats in the r-GDF11+r-LOX-1 group was increased,the MT and MT/LD of aortic tissue were increased,and the LD of aortic tissue was decreased(all P＜0.05);CVF value,the expression of GRP78 and ATF6 protein,the p-PERK/PERK and p-IRE1α/IRE1α in aortic tissue were increased(all P＜0.05).Conclusion Exogenous GDF11 im-proves vascular remodeling in hypertensive rats through inhibiting LOX-1-mediated endoplasmic reticulum stress pathway.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Diabetic keratopathy is a chronic complication of diabetes caused by abnormal metabolites accumulation, oxidative stress, abnormal inflammation and corneal neuropathy.It can result in delayed corneal epithelial healing and decreased corneal sensitivity under the stimulation of ocular trauma or surgery which bring great challenges to clinicians.Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammatory is one of the factors that cause chronic complications of diabetes, and is also an important factor for delaying the healing of diabetic wounds.The NLRP3 inflammatory signaling pathway is closely related to corneal oxidative stress, delayed epithelium healing and development of corneal neuropathy.In this paper, the research status and prospects of NLRP3 inflammatory signaling pathway and diabetic keratopathy were reviewed to provide new ideas for studying the mechanism and treatment of diabetic keratopathy.

Objective:To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT).Methods:A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ 2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results:A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment.Conclusion:ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

  Objective  This study aimed at describing the frequency of rare variants of monogenic cerebral small vessel diseases (CSVD) in a cohort of patients with CSVD, and to explore its clinical relevance.  Methods  This study included CSVD patients visiting the Neurology Department of Peking Union Medical College Hospital(PUMCH) from March 2017 to January 2022, collecting their demographic and clinical information and DNA samples for whole-exome sequencing. Descriptive analysis and statistical analysis were conducted exploring the differences between monogenic CSVD-related gene mutation carriers and noncarriers.  Results  A total of 292 patients were included, 51.03% of whom carried one or more rare variants of monogenic CSVD-related genes. The most common rare low-frequency variants were located in the NOTCH3 gene (70 patients, 23.97%), followed by HTRA1 and COL4A1/COL4A2 (22 patients, 7.53%) respectively. Among the subgroup of patients without a family history of stroke (n=176), the frequency of rare variants was as high as 47.16%. Compared with non-carriers, the carriers were diagnosed at a younger age (58.76±13.71 vs. 63.46±13.21, P=0.003). No difference was found in phenotypes among single-SNP carriers, multiple-SNPs carriers, and noncarriers.  Conclusions  The frequency of rare mutation of monogenic CSVD-related genes were relatively high in Chinese CSVD cohort. The most common rare variant was within the NOTCH3, followed by HTRA1 and COL4A1/COL4A2 genes. For CSVD patients of unknown causes, genetic screening should not be neglected even if there is not a family history of the disease.

Objective:To analyze the clinical features of patients with COVID-19 in Chongqing Municipality.Methods:The clinical data, laboratory tests and chest imaging findings of 153 patients COVID-19 admitted in Chongqing Public Health Medical Center from January 26 to February 5, 2020 were retrospectively reviewed. According to the relevant diagnostic criteria, patients were divided into non-severe group (n=132) and severe group (n=21). The correlation between serum index changes and disease severity was analyzed.Results:The proportion of patients with underlying diabetes or chronic respiratory diseases in severe group was significantly higher than that in non-severe group ( χ2=11.04 and 6.94, P<0.05). The proportion of symptom-free patients in non-severe group was significantly higher than that in severe group ( χ2=4.09, P<0.05). The symptoms of fever, fatigue and muscle soreness in the severe group were more common than those in the non-severe group ( χ2=4.40, 14.42 and 22.67, P<0.05). Among the concomitant symptoms, the proportion of cough and shortness of breath in the severe group was higher than that in the non-severe group ( χ2=8.46 and 4.80, P<0.05). C-reactive protein and D-Dimer levels were higher in the severe group than those in the non-severe group ( Z=-4.39 and -1.96, P<0.05), and the number of CD3 + T lymphocyte cells, CD4 + T lymphocyte cells and CD8 + T lymphocyte cells in the severe group was lower than that in the non-severe group ( Z=27.25, 20.60 and 17.36, P<0.05). Compared with the non-severe group, both lungs and the right lung lower lobe were more susceptible to be involved( χ2=9.71和23.61, P<0.05). Conclusions:There are significant differences in underlying diseases, clinical symptoms, imaging manifestations and laboratory findings between severe and non-severe patients with COVID-19.