White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.

Periodontitis disease (PD) is associated with a systemic disorder of inflammatory bowel disease (IBD). The immune response is the common feature of the two conditions, but the more precise mechanisms remain unclear. Differential expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA) were performed on PD and Crohn's disease (CD) data sets to identify crosstalk genes linking the two diseases. The proportions of infiltrating immune cells were calculated by using Single-sample Gene Set Enrichment Analysis. In addition, a data set of isolated neutrophils from the circulation was performed via WGCNA to obtain PD-related key modules. Then, single-cell gene set enrichment scores were computed for the key module and grouped neutrophils according to score order in the IBD scRNA-seq data set. Single-cell gene enrichment analysis was used to further explore the biological process of the neutrophils. A total of 13 crosstalk genes (IL1B, CSF3, CXCL1, CXCL6, FPR1, FCGR3B, SELE, MMP7, PROK2, SRGN, FCN1, TDO2 and CYP24A1) were identified via DEGs analysis and WGCNA by combining PD and CD data sets. The enrichment analysis showed that these genes were involved in interleukin-10 signaling and inflammatory response. The immune infiltration analysis showed a significant difference in the proportion of neutrophils in PD and CD compared with healthy patients. Neutrophils were scored based on the expression of a periodontitis-related gene set in the scRNA-seq data set of IBD. The enrichment analysis demonstrated that inflammatory response, TNFα signaling via NF-κB and interferon-gamma response were upregulated in the high-score group, which expressed more pro-inflammatory cytokines and chemokines compared with the low-score group. This study reveals a previously unrecognized mechanism linking periodontitis and IBD through crosstalk genes and neutrophils, which provides a theoretical framework for future research.

Purpose: Consensus molecular subtypes (CMS) are mainly used for biological interpretability and clinical stratification of colorectal cancer (CRC) in primary tumors (PT) but few in metastases. The heterogeneity of CMS distribution in metastases and the concordance of CMS between PT and metastases still lack sufficient study. We used CMS to classify CRC metastases and combine it with histopathological analysis to explore differences between PT and distant metastases. Patients and Methods: We obtained gene expression profiles for 942 PT samples from TCGA database (n=376) and GEO database (n=566), as well as 442 metastasis samples from GEO database. Among these, 765 PT samples and 442 metastasis samples were confidently identified with CMS using the “CMS classifier” and enrolled for analysis. Clinicopathological manifestation and CMS classification of CRC metastases were assessed with data from GEO, TCGA, and cBioPortal. Overall, 105 PT-metastasis pairs were extracted from 10 GEO datasets to assess CMS concordance. Tumor microenvironment (TME) features between PT and metastases were analyzed by immune-stromal infiltration with ESTIMATE and xCell algorithms. Finally, TME features were validated with multiplex immunohistochemistry in 27 PT-metastasis pairs we retrospectively collected. Results: Up to 64% of CRC metastases exhibited concordant CMS groups with matched PT, and the TME of metastases was similar to that of PT. For most common distant metastases, liver metastases were predominantly CMS2 and lung and peritoneal metastases were mainly CMS4, highlighting “seed” of tumor cells of different CMS groups had a preference for metastasis to “soil” of specific organs. Compared with PT, cancer-associated fibroblasts (CAF) reduced in liver metastases, CD4+T cells and M2-like macrophages increased in lung metastases, and M2-like macrophages and CAF increased in peritoneal metastases. Conclusion: Our findings underscore the importance of CMS-guided specific organ monitoring and treatment post-primary tumor surgery for patients. Differences in immune-stromal infiltration among different metastases provide targeted therapeutic opportunities for metastatic CRC.

Introduction. Previous studies of coronavirus disease 2019 (COVID-19) have focused on the general population. However, diabetes (DM) as one of the most common comorbidities is rarely studied in detail. This study is aimed at describing clinical characteristics and determining risk factors of ICU admission for COVID-19 patients with DM. Methods. Data were extracted from 288 adult patients with laboratory-confirmed COVID-19 from Guangzhou Eighth People’s Hospital. Demographic characteristics, laboratory results, radiographic findings, complications, and treatments were collected and compared between DM and non-DM groups. Binary logistic regression was used to identify the risk factors associated with ICU admission for COVID-19 patients with DM or non-DM. Results. COVID-19 patients with DM showed as older ages, higher levels of C-reactive protein (CRP), myoglobin, alanine transaminase (ALT), and aspartate transaminase (AST). They were also more prone to transfer to the intensive care unit (ICU) for treatment. Multiple regression analysis showed that the following were the independent risk factors for COVID-19 patients with DM that received ICU admission: each 1-year increase in age (odds ratio (OR), 1.07; 95% CI, 1.02-1.13; ), respiratory rate over 24 times per minute (OR, 5.22; 95% CI, 2.26-16.58; ), HbA1c greater than 7% (OR, 4.58; 95% CI, 1.82-10.55; ), and AST higher than 40 U/L (OR, 2.96; 95% CI, 1.58-8.85; ). In addition, each 1-year increase in age (OR, 1.05; 95% CI, 1.01-1.10; ), diarrhea (OR, 4.62; 95% CI, 2.01-9.36; ), respiratory rate over 24 times per minute (OR, 5.13; 95% CI, 1.18-16.82; ), CRP greater than 10 mg/L (OR, 5.19; 95% CI, 1.37-13.25, ), and TnI higher than 0.03 μg/L (OR, 6.48; 95% CI, 1.17-21.38; ) were risk factors for ICU admission of COVID-19 patients with non-DM. Conclusions. The older age, respiratory rate over 24 times per minute, HbA1c greater than 7%, and AST higher than 40 U/L were risk factors of ICU admission for COVID-19 patients with diabetes. Investigating and monitoring these factors could assist in the risk stratification of COVID-19 patients with DM at an early stage.