Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

A novel capsule endoscopy for upper and mid-GI tract: the UMGI capsule.

BACKGROUNDS AND AIMS: Complete and consecutive observation of the gastrointestinal (GI) tract continues to present challenges for current endoscopy systems. We developed a novel upper and mid gastrointestinal (UMGI) capsule endoscopy using the modified detachable string magnetically controlled capsule endoscopy (DS-MCE) and inspection method and aimed to assess the clinical application. METHODS: Patients were recruited to undergo UMGI capsule endoscopy followed by esophagogastroduodenoscopy. All capsule procedures in the upper gastrointestinal (UGI) tract were conducted under the control of magnet and string. The main outcome was technical success, and the secondary outcomes included visualization of the UMGI tract, examination time, diagnostic yield, compliance, and safety evaluation. RESULTS: Thirty patients were enrolled and all UMGI capsule procedures realized repeated observation of the esophagus and duodenum with detection rates of 100.0%, 80.0%, and 86.7% of Z-line, duodenal papilla, and reverse side of pylorus, respectively. String detachment was succeeded in 29 patients (96.7%) and the complete examination rate of UMGI tract was 95.45% (21/22). All UMGI capsule procedures were well tolerated with low discomfort score, and had a good diagnostic yield with per-lesion sensitivity of 96.2% in UGI diseases. No adverse events occurred. CONCLUSIONS: This new capsule endoscopy system provides an alternative screening modality for the UMGI tract, and might be indicated in cases of suspected upper and small bowel GI bleeding. Trial registration DS-MCE-UGI and SB, NCT04329468. Registered 27 March 2020, https://clinicaltrials.gov/ct2/results?cond=&term=NCT04329468 .

The Impacts of Genetic and Environmental Factors on the Progression of Chronic Pancreatitis.

BACKGROUND & AIMS: Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive. METHODS: A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed. RESULTS: A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P < .001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P < .001) and alcohol consumption (HR, 1.86; P < .001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea. CONCLUSIONS: Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297).

Magnetically controlled capsule endoscopy in one-time gastro-small intestinal joint examination: a two-centre experience.

BACKGROUND: The lesions of certain diseases are widely distributed in both stomach and small intestine, while the step-by-step strategy of gastroscopy followed by enteroscopy can be burdensome and costly. We aimed to determine if magnetically controlled capsule endoscopy (MCE) could be used in one-time gastro-small intestine (GSI) joint examination. METHODS: In this study, data of patients in Chinese PLA General Hospital and Changhai Hospital who underwent MCE GSI examination from January 2020 to August 2021 were retrospectively analysed. The primary outcome of this study was the success rate of one-time GSI joint examination, and secondary outcomes included visualization and cleanliness of gastrointestinal tract, gastrointestinal transit times, diagnostic yield and safety of MCE examination. RESULTS: A total of 768 patients were included. The success rate of one-time GSI joint examination was 92.58%. There were 94.92% MCEs observed > 90% gastric mucosa in the 6 anatomic landmarks. The rate of complete small bowel examination was 97.40%. The median gastric examination time, gastric transit time and small intestine transit time were 8.18 min, 63.89 min and 4.89 h, respectively. Magnetic steering of MCE significantly decreased gastric transit time (8.92 min vs. 79.68 min, P = 0.001) and increased duodenal lesion detection rate (13.47% vs. 6.26%, P = 0.001) when compared with non-magnetic steering group. Two capsules were retained and were removed by enteroscopy or spontaneously excreted. CONCLUSIONS: MCE is feasible to complete GSI joint examination and the detection of both gastric and small intestinal diseases can be achieved simultaneously. Trial registration Clinical Trial Registration ClinicalTrials.gov, ID: NCT05069233.

SPINK1 mutations and risk of pancreatic cancer in a Chinese cohort.

OBJECTIVE: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). METHODS: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients' demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. RESULTS: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. CONCLUSIONS: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP.

Prevalence and Risk Factors for Osteopathy in Chronic Pancreatitis.

BACKGROUND AND AIMS: The high incidence of osteopathy among patients with chronic pancreatitis (CP) has garnered increased attention over recent years. The aims of this study were to assess the prevalence and risk factors for osteopathy in Chinese patients with CP. METHODS: This was a cross-sectional study of CP patients from a large center in China; patients were recruited between 31 January 2017 and 31 January 2018. Bone density and laboratory tests, including bone-related biochemical, inflammatory, and hormone parameters, were assessed prospectively. Differences between patients with and without osteopathy were analyzed. Logistic regression analysis was used to investigate associations between variables. RESULTS: In total, 104 CP patients were enrolled in this study (68.3% idiopathic and 31.7% alcoholic). According to the M-ANNHEIM classification, 87.5% of the patients were at an early stage (0-II). Osteopenia was diagnosed in 30.8% of patients and osteoporosis in 5.8%; thus, a total of 36.5% of patients presented with osteopathy. In multivariate analysis, the independent risk factors for osteopathy in CP patients were age (OR = 1.04; 95% CI = 1.00-1.08; P = 0.030), BMI (OR = 0.72; 95% CI = 0.58-0.89; P = 0.003), and PTH (OR = 0.96; 95% CI = 0.93-1.00; P = 0.022). CONCLUSIONS: This study is the first to report the prevalence of osteopathy in Chinese patients with CP. It found that age and low BMI are significant risk factors for osteopathy. Low PTH (but within the normal range) showed a weak association with osteopathy, which warrants further exploration.

Second-generation magnetically controlled capsule gastroscopy with improved image resolution and frame rate: a randomized controlled clinical trial (with video).

BACKGROUND AND AIMS: Compared with conventional endoscopy, magnetically controlled capsule gastroscopy (MCCG) can be further optimized in gastric examination time and complete visualization of upper GI (UGI) mucosa. The second-generation MCCG (MCCG-2) was developed with higher image resolution and adaptive frame rate, and we aimed to evaluate its clinical availability for UGI examination in this study. METHODS: Consecutive patients undergoing MCCG examination between May to June 2019 were prospectively enrolled and randomized to swallow the first-generation MCCG (MCCG-1) or MCCG-2 in a 1:1 ratio. The main outcomes included visualization of the esophagus and duodenum, operation-related parameters, image quality, maneuverability, detection of lesions, and safety evaluation. RESULTS: Eighty patients were enrolled. In the MCCG-2 group, frames captured for esophageal mucosa and Z-line were 171.00 and 2.00, significantly increased from those in the MCCG-1 group (97.00 [P = .002] and .00 [P = .028], respectively). The gastric examination time was shortened from 7.78 ± .97 minutes to 5.27 ± .74 minutes (P < .001), with the total running time of the capsule extended from 702.83 minutes to 1001.99 minutes (P < .001). MCCG-2 also greatly improved the image quality (P < .001) and maneuverability (P < .01). No statistical difference existed in the detection of lesions between the 2 groups, and no adverse events occurred. CONCLUSIONS: MCCG-2 showed better performance in mucosal visualization, examination duration, and maneuverability, making better diagnosis of UGI diseases a possibility. (Clinical trial registration number: NCT03977935.).

Adverse events of video capsule endoscopy over the past two decades: a systematic review and proportion meta-analysis.

BACKGROUND: A full spectrum of video capsule endoscopy (VCE) adverse events over the past two decades has not been evaluated. We aimed to determine pooled rates, predictors and temporal-trend of VCE adverse events over the past two decades. METHODS: Systematic search of PubMed and EMBASE for English-language publications reporting VCE adverse events (January 1, 2000 to March 31, 2019). Data were extracted independently by two investigators. Pooled VCE adverse event rates were calculated using the random or fixed model as appropriate. Predictors and temporal-trend of each adverse event were performed by meta-regression analyses. RESULTS: In total, 402 studies were identified, including 108,079 VCE procedures. Rate of retention, swallow disorder, aspiration, technical failure, and procedural adverse events were 0.73% (95% confidence interval [CI] 0.59-0.89%), 0.75% (95% CI 0.43-1.13%), 0.00% (95% CI 0.00-0.00%), 0.94% (95% CI 0.65-1.28%), 0.67% (95% CI 0.32-1.10%), respectively; incomplete examination rate of esophagus, stomach, small bowel, and colon were 9.05%, 7.69%, 12.08%, 19.19%, respectively. Patency capsule reduced retention rate by 5.04%, whereas known inflammatory bowel disease increased retention rate by 4.29%. Elder was the risk and protective factor for small bowel incomplete examination (0.30%) and swallow disorder (- 0.72%), respectively. Rates of retention and small bowel incomplete examination significantly declined over time (P = .0006 and P < .0001).. CONCLUSIONS: VCE adverse event rates were generally low, and retention and small bowel incomplete examination rates declined over the past two decades. Patients with known inflammatory bowel disease or elder should be alerted to high risk of retention or small bowel incomplete examination (PROSPERO: CRD42019139595).

CREB/Wnt10b mediates the effect of COX-2 on promoting BMP9-induced osteogenic differentiation via reducing adipogenic differentiation in mesenchymal stem cells.

Bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic factors, which may be a potential candidate for bone tissue engineering. However, the osteogenic capacity of BMP9 still need to be further enhanced. In this study, we determined the effect of Wnt10b on BMP9-induced osteogenic differentiation in mesenchymal stem cell (MSCs) and the possible mechanism underlying this process. We introduced the polymerase chain reaction (PCR), Western blot analysis, histochemical stain, ectopic bone formation, and microcomputed tomography analysis to evaluate the effect of Wnt10b on BMP9-induced osteogenic differentiation. Meanwhile, PCR, Western blot analysis, chromatin immunoprecipitation, and immunoprecipitation were used to analyze the possible relationship between BMP9 and Wnt10b. We found that BMP9 upregulates Wnt10b in C3H10T1/2 cells. Wnt10b increases the osteogenic markers and bone formation induced by BMP9 in C3H10T1/2 cells, and silencing Wnt10b decreases these effects of BMP9. Meanwhile, Wnt10b enhances the level of phosphorylated Smad1/5/8 (p-Smad1/5/8) induced by BMP9, which can be reduced by silencing Wnt10b. On the contrary, Wnt10b inhibits adipogenic markers induced by BMP9, which can be decreased by silencing Wnt10b. Further analysis indicated that BMP9 upregulates cyclooxygenase-2 (COX-2) and phosphorylation of cAMP-responsive element binding (p-CREB) simultaneously. COX-2 potentiates the effect of BMP9 on increasing p-CREB and Wnt10b, while silencing COX-2 decreases these effects. p-CREB interacts with p-Smad1/5/8 to bind the promoter of Wnt10b in C3H10T1/2 cells. Our findings suggested that Wnt10b can promote BMP9-induced osteogenic differentiation in MSCs, which may be mediated through enhancing BMP/Smad signal and reducing adipogenic differentiation; BMP9 may upregulate Wnt10b via the COX-2/p-CREB-dependent manner.

Melatonin safeguards against fatty liver by antagonizing TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

Wnt11 promotes BMP9-induced osteogenic differentiation through BMPs/Smads and p38 MAPK in mesenchymal stem cells.

Bone morphogenetic protein 9 (BMP9), as one of the most potent osteogenic factors, is a promising cytokine for bone tissue engineering. Wnt11 can regulate the development of the skeletal system and is related to high bone mass syndrome. However, the effect of Wnt11 on BMP9-induced osteogenic differentiation remains unknown. In this study, we investigated the relationship between Wnt11- and BMP9-induced osteogenic differentiation in mesenchymal stem cells (MSCs). We recapitulated the osteogenic potential of BMP9 in C3H10T1/2 cells. The messenger RNA expression of Wnt11 is detectable in the available progenitor cells, and BMP9 can obviously increase the protein level of Wnt11 in these cells. Exogenous Wnt11 potentiates the effect of BMP9 on increasing alkaline phosphatase (ALP) activities, the expression of osteopontin (OPN), and Runt-related transcription factor 2 (Runx2), so does matrix mineralization in C3H10T1/2 cells. Although Wnt11 cannot increase the BMP9-induced ectopic bone formation, it can increase the bone density induced by BMP9 apparently. Wnt11 increases the level of p-Smad1/5/8, as well as p-p38. Meanwhile, Wnt11 promotes the effect of BMP9 on increasing the levels of p-Smad1/5/8 and p-p38. Inhibition of p38 decreases the BMP9-induced ALP activities, the expression of OPN, and the mineralization in C3H10T1/2 cells. However, all of these effects of the p38 inhibitor on BMP9-induced osteogenic markers can be almost reversed by the overexpression of Wnt11. Our findings suggested that Wnt11 can enhance the osteogenic potential of BMP9 in MSCs, and this effect may be partly mediated through enhancing BMPs/Smads and the p38 MAPK signal, which was induced by BMP9.

BMP9/COX-2 axial mediates high phosphate-induced calcification in vascular smooth muscle cells via Wnt/ß-catenin pathway.

Vascular calcification is a notable risk factor for cardiovascular system. High phosphate can induce calcification in vascular smooth muscle cells (VSMCs), but the detail mechanism underlying this process remains unclear. In the present study, we determined the relationship between high phosphate and bone morphogenetic protein 9 (BMP9) in VSMCs, the effect of BMP9 on calcification in VSMCs and the effect of COX-2 on BMP9 induced calcification in VSMCs, as well as the possible mechanism underlying this biological process. We found that high phosphate obviously up-regulates the expression of BMP9 in VSMCs. Over-expression of BMP9 decreases the level of alpha-smooth muscle cell actin (α-SMA) apparently, but increases the level of Runx-2, Dlx-5, and ALP in VSMCs. Meanwhile, BMP9 increases the level of OPN and OCN, promotes mineralization in VSMCs and induces calcification in thoracic aorta. High phosphate and over-expression of BMP9 increases the level of COX-2. Over-expression of COX-2 enhances the inhibitory effect of BMP9 on α-SAM and increases the level of OPN and OCN induced by BMP9. However, inhibition of COX-2 decreases the BMP9-induced calcification in VSMCs and thoracic aorta. For mechanism, we found that high phosphate or BMP9 increases the level of ß-catenin and p-GSK3ß in VSMCs, but no substantial effect on GSK3ß. However, COX-2 inhibitor decreases the expression of ß-catenin induced by BMP9. Our findings indicated that BMP9 is involved in the phosphate-induced calcification in VSMCs and COX-2 partly mediates the BMP9-induced calcification in VSMCs through activating Wnt/ß-catenin pathway.

Dynamic Acoustic Beamshaping with Coupling-Immune Moiré Metasurfaces.

Moiré effects arising from mutually twisted metasurfaces have showcased remarkable wave manipulation capabilities, unveiling tantalizing emerging phenomena such as acoustic moiré flat bands and topological phase transitions. However, the pursuit of strong near-field coupling in layers has necessitated acoustic moiré metasurfaces to be tightly stacked at narrow distances in the subwavelength range. Here, moiré effects beyond near-field interlayer coupling in acoustics are reported and the concept of coupling-immune moiré metasurfaces is proposed. Remote acoustic moiré effects decoupled from the interlayer distance are theoretically, numerically, and experimentally demonstrated. Tunable out-of-plane acoustic beam scanning is successfully achieved by dynamically controlling twist angles. The engineered coupling-immune properties are further extended to multilayered acoustic moiré metasurfaces and manipulation of acoustic vortices. Good robustness against external disturbances is also observed for the fabricated coupling-immune acoustic moiré metasurfaces. The presented work unlocks the potential of twisted moiré devices for out-of-plane acoustic beam shaping, enabling practical applications in remote dynamic detection, and multiplexed underwater acoustic communication.

Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

The associations between DNA methylation and depression: A systematic review and meta-analysis.

BACKGROUND: Growing evidence suggests that epigenetic modification is vital in biological processes of depression. Findings from studies exploring the associations between DNA methylation and depression have been inconsistent. METHODS: A systematical search of EMBASE, PubMed, Web of Science, and PsycINFO databases was conducted to include studies focusing on the associations between DNA methylation and depression (up to November 1st 2021) according to PRISMA guidelines with registration in PROSPERO (CRD42021288664). RESULTS: A total of 47 studies met inclusion criteria and 31 studies were included in the meta-analysis. This meta-analysis found that genes hypermethylation, including BDNF (OR: 1.15, 95%CI: 1.01-1.32, I2 = 90 %), and NR3C1 (OR: 1.43, 95%CI: 1.09-1.87, I2 = 88 %) was associated with increased risk of depression. Significant association of SLC6A4 hypermethylation with depression was only found in the subgroup of using original data (OR: 1.09, 95%CI: 1.01-1.19, I2 = 52 %). BDNF hypermethylation could increase the risk of depression only in the Asian population (OR: 1.18, 95%CI: 1.01-1.40, I2 = 91 %), and significant associations of NR3C1 hypermethylation with depression were found in the group for depressive symptoms (OR: 1.34, 95%CI: 1.08-1.67, I2 = 85 %), but not for depressive disorder (OR: 1.89, 95%CI: 0.54-6.55, I2 = 94 %). LIMITATIONS: More studies are needed to explore the factors that might influence the estimates owing to the contextual heterogeneity of the pooling of included studies. CONCLUSIONS: It is noted that DNA hypermethylation, namely BDNF and NR3C1, is associated with increased risk of depression. The findings in this study could provide some material evidence for preventing and diagnosing of depression.

Diffuse arterial atherosclerosis presenting with acute ischemic gastritis: A case report.

BACKGROUND: Ischemic gastritis is a clinically rare disease with high mortality that infrequently reported in the medical literature and under-recognized clinically and histopathologically. Early diagnosis and treatment can only be achieved through upper gastrointestinal endoscopy after symptoms appear. CASE SUMMARY: A 68-year-old woman with a history of intracranial aneurysm developed dizziness, chest tightness and unconsciousness for 2 d. Computed tomography angiography showed diffuse coronary atherosclerosis, moderate to severe stenosis in the proximal end of the left anterior descending branch, multiple calcified plaques in the proximal end of the circumflex branch and right coronary artery, and mild to moderate stenosis. The patient also developed diffuse atherosclerosis in the splenic and mesenteric arteries, with mild lumen stenosis and atherosclerosis in the abdominal aorta and its branches. Endoscopy showed submucosal congestion and damage of the entire gastric mucosa, of which the fundus and body of the stomach were most seriously affected. The mucosa was swollen, with a deep purple color, surface erosion and dark red oozing blood. Pathological examination showed bleeding and necrosis of the gastric mucosa, with residual contours of the gastric glands, consistent with ischemic gastritis. CONCLUSION: Ischemic gastritis is a rare disease that may be difficult to diagnose as its symptoms may be similar to those of other gastrointestinal diseases. Diagnosis is usually based on endoscopic and pathological examinations, which show insufficient blood supply to the gastric mucosa leading to mucosal damage and necrosis.

The Impact of Physical Activity Intensity on the Dynamic Progression of Cardiometabolic Multimorbidity: Prospective Cohort Study Using UK Biobank Data.

BACKGROUND: Although many studies have reported on the associations between the amount of physical activity (PA) and the transitions of cardiometabolic multimorbidity (CMM), the evidence for PA intensity has not been fully evaluated. OBJECTIVE: This study aimed to explore the impact of PA intensity on the dynamic progression of CMM. METHODS: The prospective cohort of this study using data from the UK Biobank included 359,773 participants aged 37-73 years who were recruited from 22 centers between 2006 and 2010. The diagnoses of CMM, which included the copresence of type 2 diabetes (T2D), ischemic heart disease, and stroke, were obtained from first occurrence fields provided by the UK Biobank, which included data from primary care, hospital inpatient record, self-reported medical condition, and death registers. The PA intensity was assessed by the proportion of vigorous PA (VPA) to moderate to vigorous PA (MVPA). Multistate models were used to evaluate the effect of PA intensity on the dynamic progression of CMM. The first model (model A) included 5 transitions, namely free of cardiometabolic disease (CMD) to first occurrence of CMD (FCMD), free of CMD to death, FCMD to CMM, FCMD to mortality, and CMM to mortality. The other model (model B) used specific CMD, namely T2D, ischemic heart disease, and stroke, instead of FCMD and included 11 transitions in this study. RESULTS: The mean age of the included participants (N=359,773) was 55.82 (SD 8.12) years at baseline, and 54.55% (196,271/359,773) of the participants were female. Compared with the participants with no VPA, participants with intensity levels of >0.75 to <1 for VPA to MVPA had a 13% and 27% lower risk of transition from free of CMD to FCMD (hazard ratio [HR] 0.87, 95% CI 0.83-0.91) and mortality (HR 0.73, 95% CI 0.66-0.79) in model A, respectively. The HR for the participants with no moderate PA was 0.82 (95% CI 0.73-0.92) compared with no VPA. There was a substantially protective effect of higher PA intensity on the transitions from free of CMD to T2D and from T2D to mortality, which reveals the importance of PA intensity for the transitions of T2D. More PA and greater intensity had a synergistic effect on decreasing the risk of the transitions from free of CMD to FCMD and mortality. Male participants, younger adults, adults with a higher BMI, current or previous smokers, and excessive alcohol drinkers could obtain more benefits from higher PA intensity for the lower risk of at least 1 transition from free of CMD, then to CMM, and finally to mortality. CONCLUSIONS: This study suggests that higher PA intensity is an effective measure for preventing CMM and mortality in the early period of CMM development. Relevant interventions related to higher PA intensity should be conducted.

Central and peripheral analgesic active components of triterpenoid saponins from Stauntonia chinensis and their action mechanism.

Triterpenoid saponins from Stauntonia chinensis have been proven to be a potential candidate for inflammatory pain relief. Our pharmacological studies confirmed that the analgesic role of triterpenoid saponins from S. chinensis occurred via a particular increase in the inhibitory synaptic response in the cortex at resting state and the modulation of the capsaicin receptor. However, its analgesic active components and whether its analgesic mechanism are limited to this are not clear. In order to further determine its active components and analgesic mechanism, we used the patch clamp technique to screen the chemical components that can increase inhibitory synaptic response and antagonize transient receptor potential vanilloid 1, and then used in vivo animal experiments to evaluate the analgesic effect of the selected chemical components. Finally, we used the patch clamp technique and molecular biology technology to study the analgesic mechanism of the selected chemical components. The results showed that triterpenoid saponins from S. chinensis could enhance the inhibitory synaptic effect and antagonize the transient receptor potential vanilloid 1 through different chemical components, and produce central and peripheral analgesic effects. The above results fully reflect that "traditional Chinese medicine has multi-component, multi-target, and multi-channel synergistic regulation".

Increased severity of complications after therapeutic ERCP in geriatric patients with chronic pancreatitis: An observational study.

Studies of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in geriatric patients have mainly examined patients with biliary diseases, rather than chronic pancreatitis (CP). This study aimed to evaluate the safety and success rate of therapeutic ERCP in geriatric patients with CP. The medical records of patients with CP aged over 65 years (group A) were retrospectively collected in a tertiary hospital from January 2013 to December 2018. Sex-matched CP patients under 65 years (group B) were randomly selected into the control group (matching ratio = 1:2). The success rate and the complication rate of therapeutic ERCP in 2 groups were compared. The risk factors for post-ERCP pancreatitis were investigated by univariate and multivariate analyses. A total of 268 ERCPs were performed in 179 patients of group A and 612 ERCPs in 358 patients of group B. The success rate of ERCP in group A was similar to that of group B (92.16% vs 92.32%; P = .936). The overall incidence of post-ERCP complications was 7.09% (19/268) and 5.72% (35/612) in group A and B, respectively (P = .436). However, geriatric patients had a significantly increased occurrence of moderate to severe complications (2.61% vs 0.16%; P = .002). Female gender (odds ratio [OR] = 3.40; P = .046), pancreas divisum (OR = 7.15; P = .049), dorsal pancreatogram (OR = 7.40; P = .010), and lithotripsy (OR = 0.15; P = .016) were significantly associated with risk of post-ERCP pancreatitis in geriatric patients. Therapeutic ERCP is safe and feasible in elderly patients with CP. However, occurrence of moderate to severe complications after ERCP increased in geriatric patients.

Ancillary ligand-regulated Ti(IV)-based metallocalixarene coordination cages for photocatalytic H2 evolution.

High-valence Ti(IV)-based metallocalixarene coordination cages that are linked by oriented ancillary ligands are unknown so far. Herein, the first family of tunable calixarene-based coordination cages of Ti(IV) with a framework formula [Ti12(OiPr)12(TBC[4])6L6] have been assembled from six {Ti2(OiPr)2(TBC[4])}2+ nodes and six pyridinedicarboxylic ligands. Furthermore, the {Ti12L6} cage showed strong photocatalytic H2 evolution activity, and DFT studies were performed to explore its electronic structure.