GSDME-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation.

OBJECTIVE: Psoriasis is a common, chronic inflammatory disease with unclear etiology. Keratinocytes in psoriasis are susceptible to exogenous triggers that induce inflammatory cell death. This study investigated whether GSDME-mediated pyroptosis in keratinocytes contributes to the pathogenesis of psoriasis. METHODS: Skin samples from patients with psoriasis and healthy controls were collected to evaluate the expression of GSDME, cleaved-caspase-3, and inflammatory factors. We then analyzed the data series, GSE41662, to further compare the expression of GSDME between lesional and non-lesional skin samples in those with psoriasis. In vivo, caspase-3 inhibitor and GSDME deficiency mice (Gsdme-/-) were applied to block caspase-3/GSDME activation in the imiquimod-induced psoriasis model. Skin inflammation, disease severity, and pyroptosis-related proteins were analyzed. In vitro, tumor necrosis factor-α (TNF-α)-induced caspase-3/GSDME-mediated pyroptosis in the HACAT cell line was explored. RESULTS: Our analysis of the GSE41662 data series found that GSDME were upregulated in psoriasis lesions, compared to normal skin. High levels of inflammatory cytokines such as IL-1ß, IL-6, and TNF-α were also found in psoriasis lesions. In mice of Gsdme-/- and caspase-3 inhibitor groups, the severity of skin inflammation was attenuated, and GSDME and C-caspase-3 levels decreased after imiquimod treatment. Similarly, IL-1ß, IL-6, and TNF-α were decreased in Gsdme-/- and caspase-3 inhibitor groups. In vitro, TNF-α induced HACAT cell pyroptosis through caspase-3/GSDME pathway activation, which was suppressed by blocking caspase-3 or silencing GSDME. CONCLUSION: Our study provides a novel explanation that TNF-α/caspase-3/GSDME-mediated keratinocyte pyroptosis is highly responsible for the initiation and acceleration of skin inflammation and progression of psoriasis.

Identification of Key Biomarkers and Immune Infiltration in Liver Tissue after Bariatric Surgery.

Background: Few drugs are clearly available for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH); nevertheless, mounting studies have provided sufficient evidence that bariatric surgery is efficient for multiple metabolic diseases, including NAFLD and NASH, while the molecular mechanisms are still poorly understood. Methods: The mRNA expression profiling of GSE48452 and GSE83452 were retrieved and obtained from the Gene Expression Omnibus (GEO) database. The limma package was employed for identifying differentially expressed genes (DEGs), followed by clusterProfiler for performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and GSEA software for performing GSEA analyses. The PPI network analyses were constructed using Metascape online analyses. WGCNA was also utilized to identify and verify the hub genes. CIBERSORT tools contributed to the analysis of immune cell infiltration of liver diseases. Results: We identify coexpressed differential genes including 10 upregulated and 55 downregulated genes in liver tissue after bariatric surgery. GO and KEGG enrichment analyses indicated that DEGs were remarkably involved in the immune response. GSEA demonstrated that DEGs were markedly enriched in the immune response before surgery, while most were enriched in metabolism after surgery. Seven genes were screened through the MCC algorithm and KME values, including SRGN, CD53, EVI2B, MPEG1, NCKAP1L, LCP1, and TYROBP. The mRNA levels of these genes were verified in the Attie Lab Diabetes Database, and only LCP1 was found to have significant differences and correlation with certain immune cells. Conclusion: Our knowledge of the mechanisms by which bariatric surgery benefits the liver and the discovery of LCP1 is expected to serve as potential biomarkers or therapeutic targets for NAFLD and NASH.

Dapagliflozin alleviates advanced glycation end product induced podocyte injury through AMPK/mTOR mediated autophagy pathway.

Excessive accumulation of advanced glycation end products (AGEs) contributes to autophagy interruption on podocytes and insufficient autophagy on podocytes is accountable to podocyte injury and eventually accelerates the advancement of DN. SGLT2 inhibitors have been confirmed excellent renoprotection in DN whereas the mechanism for such benefit is not fully illustrated. Here, we report dapagliflozin, an SGLT2 inhibitor, ameliorated the pro-inflammatory cytokines release and apoptosis level concomitant with increasing Synaptopodin level on AGE-induced podocytes. Furthermore, dapagliflozin manifested autophagy promotion on AGE-induced podocytes as evident by the upregulated Beclin and LC3II/LC3I ratio levels attendant with the shrunk p62 level. However, The protective effect of dapagliflozin was blunted by 3-MA, an autophagy inhibitor. Additionally, the effect of dapagliflozin on autophagy was relevant to the regulation of the AMPK-mTOR signal pathway. Taken together, dapagliflozin effectively mitigated AGE-induced podocyte injury through AMPK-mTOR mediated upregulation of autophagy. It may offer a novel mechanism to further elucidate the renoprotective effect on SGLT2 inhibitors.

Association of the Coronavirus Disease 2019 Outbreak on the Diabetes Self-Management in Chinese Patients: An Analytical Cross-Sectional Study.

Background: The coronavirus disease 2019 (COVID-19) outbreak has seriously affected people's lives, especially those with chronic diseases. Diabetes self-management, which plays an important role in glycaemic control and reducing the risk of acute and long-term complications, may be discouraged by social distancing. Purpose: To evaluate the level of self-management activities in Chinese patients with type 2 diabetes mellitus (T2DM) during the COVID-19 pandemic. Patients and Methods: A survey of with 872 patients with T2DM in the inpatient and outpatient departments through face-to-face interviews was conducted from 1 July, 2020 to 30 September, 2020. The main outcome measures were glycaemic control status and level of self-management activities during the pandemic. Results: In terms of glycaemic control, the data showed that patients with fasting plasma glucose (FPG) < 7.0 mmol/L (36.4%), postprandial plasma glucose (PPG) < 10.0 mmol/L (26.3%), or glycosylated haemoglobin (HbA1c) < 7.0% (18.6%) in our investigation has well-controlled blood glucose level, and 11.9% of patients experienced blood glucose <3.9 mmol/L during the outbreak. The diabetes self-management of Chinese patients decreased and the final diabetes self-management score of the Chinese patients was 3.4 ± 1.45. Patients with higher education, diabetes education, comorbidities, and online consultations had higher diabetes self-management scores (P <0.05). Adherence to diabetes self-management in the normal glycaemic control group was higher than that in the substandard glycaemic control group (P<0.05). Among all participants, 72.1% of the patients reduced the frequency of hospital visits, and 44.8% considered that they had diabetes-related stress during the pandemic. The mean anxiety level score rated by 286 patients was 5.3±2.8. Conclusion: The COVID-19 pandemic has affected diabetes self-management, including substandard glycemic control, increased diabetes-related stress, limited exercise range and medical visits. Therefore, future interventions should focus on the online management of chronic diseases and support online consultation' development and promotion, which can overcome physical distance and provide personalized services conveniently.

High-altitude gastrointestinal bleeding: an observation in Qinghai-Tibetan railroad construction workers on Mountain Tanggula.

AIM: To investigate the gastrointestinal bleeding (GIB) in people from lowland to high altitude and in workers on Mountain Tanggula and its causes as well as treatment and prophylaxis. METHODS: From 2001 to October 2003, we studied GIB in 13502 workers constructing the railroad on Mountain Tanggula which is 4905 m above the sea level. The incidence of GIB in workers at different altitudes was recorded. Endoscopy was performed when the workers evacuated to Golmud (2808 m) and Xining (2261 m). The available data on altitude GIB were analyzed. RESULTS: The overall incidence of GIB was 0.49% in 13502 workers. The incidence increased with increasing altitude. The onset of symptoms in most patients was within three weeks after arrival at high altitude. Bleeding manifested as hematemesis, melaena or hematochezia, and might be occult. Endoscopic examination showed that the causes of altitude GIB included hemorrhage gastritis, gastric ulcer, duodenal ulcer, and gastric erosion. Experimental studies suggested that acute gastric mucosal lesion (AGML) could be induced by hypoxic and cold stress, which might be the pathogenesis of altitude GIB. Those who consumed large amount of alcohol, aspirin or dexamethasone were at a higher risk of developing GIB. Persons who previously suffered from peptic ulcer or high-altitude polycythemia were also at risk of developing GIB. Early diagnosis, evacuation, and treatment led to early recovery. CONCLUSION: GIB is a potentially life threatening disease, if it is not treated promptly and effectively. Early diagnosis, treatment and evacuation lead to an early recovery. Death due to altitude GIB can be avoided if early symptoms and signs are recognized.

Ataxia: an early indicator in high altitude cerebral edema.

Wu, Tianyi, Shouquan Ding, Jinliang Liu, Jianhou Jia, Ruichen Dai, Baozhu Liang, Jizhui Zhao, and Detang Qi. Ataxia: an early indicator in high altitude cerebral edema. High Alt. Med. Biol. 7:275-280, 2006.--As a result of industrial development in the western region of China, in 2001 the Chinese government decided to build Qinghai-Tibetan Railway. The new railroad stretches 1118 km from Golmud (2808 m) to Lhasa (3658 m), with more than three-quarter of the distance above 4000 m, through the Mt. Kun Lun and Tanggula ranges. From the beginning of the project on June, 29, 2001, to the end of the year of 2003, about 74,735 construction workers worked in the harsh climate, in adverse circumstances and a low-barometric-pressure environment. The construction provided an opportunity for the investigation and study of acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE). These altitude illnesses were very common in the construction workers. From July 1, 2001, to October 31, 2003, the overall incidence of AMS, HAPE, and HACE in the total workers was approximately 45%-95%, 0.49%, and 0.26%, respectively. Altitude illnesses were studied at two hospitals near the construction site. One hospital is located on the Fenghuoshan (Mt. Wind-gap) at an altitude of 4779 m (PB 428 torr), and the second hospital is situated in the Kekexili area at an altitude of 4505 m (PB 440 torr). Kekexili is a sparsely populated zone because the weather conditions are very bad all year round. These two hospitals received patients from the construction sites, where workers were working at altitudes between 4464 and 4905 m. A total of 8014 workers were treated at Fenghuoshan and 5488 were in Kekexili over the past 3 years. According to local guidance about proper medical care, workers ascending to high altitude should be examined physically, complete an AMS questionnaire, and be monitored for ataxia as an early warning sign of the impending, more serious aspects of HACE. The onset of HACE is frequently characterized by an ataxic gait, as reported since the middle of the 20th century (Gray et al., 1971; Wilson, 1973; Houston and Dickinson, 1975; Dickinson, 1979; Clarke, 1988; Hackett and Oelz, 1992; Hackett, 2002; Hackett and Roach, 2004). However, there are no detailed analyses of ataxia in HACE. This paper considers the relation between ataxia and HACE and its frequency, significance, and importance.