Corrigendum: Gut microbiome alterations during gastric cancer: evidence assessment of case-control studies.

[This corrects the article DOI: 10.3389/fmicb.2024.1406526.].

Combined UPLC-QqQ-MS/MS and AP-MALDI Mass Spectrometry Imaging Method for Phospholipidomics in Obese Mouse Kidneys: Alleviation by Feeding Sea Cucumber Phospholipids.

Sea cucumber phospholipids have ameliorative effects on various diseases related to lipid metabolism. However, it is unclear whether it can ameliorate obesity-associated glomerulopathy (ORG) induced by a high-fat diet (HFD). The present study applied UPLC-QqQ-MS/MS and atmospheric pressure matrix-assisted laser desorption ionization mass spectrometry imaging (AP-MALDI MSI) to investigate the effects of sea cucumber phospholipids, including plasmalogen PlsEtn and plasmanylcholine PakCho, on phospholipid profiles in the HFD-induced ORG mouse kidney. Quantitative analysis of 135 phospholipids revealed that PlsEtn and PakCho significantly modulated phospholipid levels. Notably, PlsEtn modulated kidney overall phospholipids better than PakCho. Imaging the "space-content" of 9 phospholipids indicated that HFD significantly increased phospholipid content within the renal cortex. Furthermore, PlsEtn and PakCho significantly decreased the expression of transport-related proteins CD36, while elevating the expression of fatty acid ß-oxidation-related protein PPAR-α in the renal cortex. In conclusion, sea cucumber phospholipids reduced renal lipid accumulation, ameliorated renal damage, effectively regulated the content and distribution of renal phospholipids, and improved phospholipid homeostasis, exerting an anti-OGR effect.

Determination of 16 ultraviolet-absorbing compounds in marine invertebrates by using LC-USI-MS/MS coupled with QuEChERS.

In this study, we examined multiple endocrine-disrupting ultraviolet-absorbing compounds (UVACs) in marine invertebrates used in personal care products and packaging. Modified QuEChERS and liquid chromatography UniSpray ionization tandem mass spectrometry were used to identify 16 UVACs in marine invertebrates. Matrix-matched calibration curves revealed high linearity (r ≥ 0.9929), with limits of detection and quantification of 0.006-1.000 and 0.020-3.000 ng/g w.w., respectively. In oysters, intraday and interday analyses revealed acceptable accuracy (93%-120%) and precision (≤18%), except for benzophenone (BP) and ethylhexyl 4-(dimethylamino) benzoate. Analysis of 100 marine invertebrate samples revealed detection frequencies of 100%, 98%, 89%, 64%, and 100% for BP, 4-hydroxybenzophenone, 4-methylbenzophenone, 4-methylbenzylidene camphor, and benzophenone-3 (BP-3), respectively. BP and BP-3 were detected at concentrations of 4.40-27.39 and < 0.020-0.560 ng/g w.w., respectively, indicating their widespread presence. Overall, our proposed method successfully detected UVACs in marine invertebrates, raising concerns regarding their potential environmental and health effects.

Identification of metabolites reproducibly associated with Parkinson's Disease via meta-analysis and computational modelling.

Many studies have reported metabolomic analysis of different bio-specimens from Parkinson's disease (PD) patients. However, inconsistencies in reported metabolite concentration changes make it difficult to draw conclusions as to the role of metabolism in the occurrence or development of Parkinson's disease. We reviewed the literature on metabolomic analysis of PD patients. From 74 studies that passed quality control metrics, 928 metabolites were identified with significant changes in PD patients, but only 190 were replicated with the same changes in more than one study. Of these metabolites, 60 exclusively increased, such as 3-methoxytyrosine and glycine, 54 exclusively decreased, such as pantothenic acid and caffeine, and 76 inconsistently changed in concentration in PD versus control subjects, such as ornithine and tyrosine. A genome-scale metabolic model of PD and corresponding metabolic map linking most of the replicated metabolites enabled a better understanding of the dysfunctional pathways of PD and the prediction of additional potential metabolic markers from pathways with consistent metabolite changes to target in future studies.

Effect of cytochrome c release on the mitochondrial-dependent apoptosis and quality deterioration of black rockfish (Sebastes schlegelii) postmortem storage.

Apoptosis was associated with decreased sensory quality attributes of fish during postmortem storage. Based on cytochrome c (cyt-c) release plays a crucial role in apoptosis, the study aims to investigate the factors regulating cyt-c release and whether cyt-c acts as an endogenous pro-oxidant to trigger lipid oxidation. Within 12 h postmortem, dramatic changes in the intramuscular environment (glycogen from 1.57 mg/g to 0.65 mg/g; ATP reduced by 92.91%; pH value reaching the lowest (pH = 7.14)) and the mitochondrial environment (accumulation of mitochondrial ROS and Ca2+ levels) are induced mitochondrial swelling and opening of the MPTP (increased 34.35% and 31.91%), leading to the release of cyt-c from the mitochondria into the cytoplasm and the activation of caspase-3. This leads to lipid oxidation and degradation of myofibrillar proteins, accelerating quality deterioration in color and texture. The results suggest that cyt-c is involved in lipid oxidation during postmortem through the apoptotic mitochondrial pathway.

PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

The State-of-the-Art Antibacterial Activities of Glycyrrhizin: A Comprehensive Review.

Licorice (Glycyrrhiza glabra) is a plant of the genus Glycyrrhiza in the family Fabaceae/Leguminosae and is a renowned natural herb with a long history of medicinal use dating back to ancient times. Glycyrrhizin (GLY), the main active component of licorice, serves as a widely utilized therapeutic agent in clinical practice. GLY exhibits diverse medicinal properties, including anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, intestinal environment maintenance, and liver protection effects. However, current research primarily emphasizes GLY's antiviral activity, while providing limited insight into its antibacterial properties. GLY demonstrates a broad spectrum of antibacterial activity via inhibiting the growth of bacteria by targeting bacterial enzymes, impacting cell membrane formation, and altering membrane permeability. Moreover, GLY can also bolster host immunity by activating pertinent immune pathways, thereby enhancing pathogen clearance. This paper reviews GLY's inhibitory mechanisms against various pathogenic bacteria-induced pathological changes, its role as a high-mobility group box 1 inhibitor in immune regulation, and its efficacy in combating diseases caused by pathogenic bacteria. Furthermore, combining GLY with other antibiotics reduces the minimum inhibitory concentration, potentially aiding in the clinical development of combination therapies against drug-resistant bacteria. Sources of information were searched using PubMed, Web of Science, Science Direct, and GreenMedical for the keywords "licorice", "Glycyrrhizin", "antibacterial", "anti-inflammatory", "HMGB1", and combinations thereof, mainly from articles published from 1979 to 2024, with no language restrictions. Screening was carried out by one author and supplemented by others. Papers with experimental flaws in their experimental design and papers that did not meet expectations (antifungal papers, etc.) were excluded.

Dynamics of endothelial cells migration in nature-mimicking blood vessels.

Endothelial cells (ECs) migration is a crucial early step in vascular repair and tissue neovascularization. While extensive research has elucidated the biochemical drivers of endothelial motility, the impact of biophysical cues, including vessel geometry and topography, remains unclear. Herein, we present a novel approach to reconstruct 3D self-assembly blood vessels-on-a-chip that accurately replicates real vessel geometry and topography, surpassing conventional 2D flat tube formation models. This vessels-on-a-chip system enables real-time monitoring of vasculogenesis and ECs migration at high spatiotemporal resolution. Our findings reveal that ECs exhibit increased migration speed and directionality in response to narrower vessel geometries, transitioning from a rounded to a polarized morphology. These observations underscore the critical influence of vessel size in regulating ECs migration and morphology. Overall, our study highlights the importance of biophysical factors in shaping ECs behavior, emphasizing the need to consider such factors in future studies of endothelial function and vessel biology.

Corrigendum: Positive association between blood ethylene oxide levels and metabolic syndrome: NHANES 2013-2020.

[This corrects the article DOI: 10.3389/fendo.2024.1365658.].

Using CO2 and oxidants for in situ regeneration of permeable reactive barriers for leachate-contaminated groundwater.

Groundwater contamination near landfills is commonly caused by leachate leakage, and permeable reactive barriers (PRBs) are widely used for groundwater remediation. However, the deactivation and blockage of the reactive medium in PRBs limit their long-term effectiveness. In the current study, a new methodology was proposed for the in situ regeneration of PRB to remediate leachate-contaminated groundwater. CO2 coupled with oxidants was applied for the dispersion and regeneration of the fillers; by injecting CO2 to disperse the fillers, the permeability of the PRB was increased and the oxidants could flow evenly into the PRB. The results indicate that the optimum filler proportion was zero-valent iron (ZVI)/zeolites/activated carbon (AC) = 3:8:10 and the optimum oxidant proportion was COD/Na2S2O8/H2O2/Fe2+ = 1:5:6:5; the oxidation system of Fe2+/H2O2/S2O82- has a high oxidation efficiency and persistence. The average regeneration rate of zeolites was 72.71%, and the average regeneration rate of AC was 68.40%; the permeability of PRB also increased. This technology is effective for the remediation of landfills in China that have large contaminated areas, an uneven pollutant concentration distribution, and a long pollution duration. The purification mode of long-term adsorption and short-time in situ oxidation can be applied to the remediation of long-term high-concentration organically polluted groundwater, where pollution sources are difficult to cut off.

Self-Evolving Hierarchical Hydrogel Fibers with Circadian Rhythms and Memory Functions.

The fusion of hierarchical tissues at interfaces, incorporating ultrafast selective transport channels, enables efficient matter exchange and energy transfer across multiscale structures in living organisms. However, achieving these characteristics simultaneously in an artificial multimaterial system is challenging. Here, this work presents a multimaterial hydrogel fiber with a hierarchical structure of interface fusion, which forms spontaneously through in situ hierarchy evolution induced by ionic cross-linking and molecular shear flow. Water transport occurs in the angstrom-scale confined slits created by aligned cellulose nanocrystals (CNCs) by direct Coulomb knock-on, resembling Newton's cradle motion. The fusion of interfaces enables high-efficiency water transport across multiscale layers, combined with Newton's cradle-like collective water motion, creating a highly sensitive negative feedback loop within the fiber. These fibers exhibit integrated behaviors of time-space perception, short-term memory and adaptive changes in shape. Additionally, they demonstrate rhythm characteristics, changing periodically in a 24-h day-night cycle. Composed of natural building blocks, these hierarchical hydrogel fibers exhibit a memristor effect similar to that of an elementary neuron, making them promising for applications in seamless on-skin and implantable bioelectronics.

Methods and computational tools to study eukaryotic cell migration in vitro.

Cellular movement is essential for many vital biological functions where it plays a pivotal role both at the single cell level, such as during division or differentiation, and at the macroscopic level within tissues, where coordinated migration is crucial for proper morphogenesis. It also has an impact on various pathological processes, one for all, cancer spreading. Cell migration is a complex phenomenon and diverse experimental methods have been developed aimed at dissecting and analysing its distinct facets independently. In parallel, corresponding analytical procedures and tools have been devised to gain deep insight and interpret experimental results. Here we review established experimental techniques designed to investigate specific aspects of cell migration and present a broad collection of historical as well as cutting-edge computational tools used in quantitative analysis of cell motion.

Dual-channel end-to-end network with prior knowledge embedding for improving spatial resolution of magnetic particle imaging.

Magnetic particle imaging (MPI) is an emerging non-invasive medical imaging tomography technology based on magnetic particles, with excellent imaging depth penetration, high sensitivity and contrast. Spatial resolution and signal-to-noise ratio (SNR) are key performance metrics for evaluating MPI, which are directly influenced by the gradient of the selection field (SF). Increasing the SF gradient can improve the spatial resolution of MPI, but will lead to a decrease in SNR. Deep learning (DL) methods may enable obtaining high-resolution images from low-resolution images to improve the MPI resolution under low gradient conditions. However, existing DL methods overlook the physical procedures contributing to the blurring of MPI images, resulting in low interpretability and hindering breakthroughs in resolution. To address this issue, we propose a dual-channel end-to-end network with prior knowledge embedding for MPI (DENPK-MPI) to effectively establish a latent mapping between low-gradient and high-gradient images, thus improving MPI resolution without compromising SNR. By seamlessly integrating MPI PSF with DL paradigm, DENPK-MPI leads to a significant improvement in spatial resolution performance. Simulation, phantom, and in vivo MPI experiments have collectively confirmed that our method can improve the resolution of low-gradient MPI images without sacrificing SNR, resulting in a decrease in full width at half maximum by 14.8%-23.8 %, and the accuracy of image reconstruction is 18.2 %-27.3 % higher than other DL methods. In conclusion, we propose a DL method that incorporates MPI prior knowledge, which can improve the spatial resolution of MPI without compromising SNR and possess improved biomedical application.

Trends in cardiovascular health metrics and associations with long-term mortality among US adults with coronary heart disease.

BACKGROUND AND AIMS: Our study examined the trends of cardiovascular health metrics in individuals with coronary heart disease (CHD) and their associations with all-cause and cardiovascular disease mortality in the US. METHODS AND RESULTS: The cohort study was conducted based on the National Health and Nutrition Examination Survey 1999-2018 and their linked mortality files (through 2019). Baseline CHD was defined as a composite of self-reported doctor-diagnosed coronary heart disease, myocardial infarction, and angina pectoris. Cardiovascular health metrics were assessed according to the American Heart Association recommendations. Long-term all-cause and cardiovascular disease mortality were the primary outcomes. Survey-adjusted Cox regression models were used to estimate hazard ratios and corresponding 95% confidence intervals for the associations between cardiovascular health metrics and all-cause and cardiovascular disease mortality. The prevalence of one or fewer ideal cardiovascular health metrics increased from 14.15% to 22.79% (P < 0.001) in CHD, while the prevalence of more than four ideal cardiovascular health metrics decreased from 21.65% to 15.70 % (P < 0.001) from 1999 to 2018, respectively. Compared with CHD participants with one or fewer ideal cardiovascular health metrics, those with four or more ideal cardiovascular health metrics had a 35% lower risk (hazard ratio, 0.65; 95% confidence interval: 0.51, 0.82) and a 44% lower risk (0.56; 0.38, 0.84) in all-cause and cardiovascular disease mortality, respectively. CONCLUSION: Substantial declines were noted in ideal cardiovascular health metrics in US adults with CHD. A higher number of cardiovascular health metrics was associated with lower all-cause and cardiovascular disease mortality in them.

Association of cardiovascular health metrics with all-cause and cardiovascular disease mortality in chronic kidney disease: A cohort study.

BACKGROUND AND AIMS: Since the global burden of chronic kidney disease (CKD) is rising rapidly, the study aimed to assess the association of cardiovascular health (CVH) metrics with all-cause and cardiovascular disease (CVD) mortality among individuals with CKD. METHODS AND RESULTS: The cohort study included 5834 participants with CKD from the National Health and Nutrition Examination Survey 1999-2018. A composite CVH score was calculated based on smoking status, physical activity, body mass index, blood pressure, total cholesterol, diet quality, and glucose control. Primary outcomes were all-cause and CVD mortality as of December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to estimate the association between CVH metrics and deaths in CKD patients. During a median follow-up of 7.2 years, 2178 all-cause deaths and 779 CVD deaths were documented. Compared to participants with ideal CVH, individuals with intermediate CVH exhibited a 46.0% increase in all-cause mortality (hazard ratio, 1.46; 95% confidence interval: 1.17, 1.83), while those with poor CVH demonstrated a 101.0% increase (2.01; 1.54, 2.62). For CVD mortality, individuals with intermediate CVH experienced a 56.0% increase (1.56; 1.02, 2.39), and those with poor CVH demonstrated a 143.0% increase (2.43; 1.51, 3.91). Linear trends were noted for the associations of CVH with both all-cause mortality (P for trend <0.001) and CVD mortality (P for trend = 0.02). CONCLUSIONS: Lower CVH levels were associated with higher all-cause and CVD mortality in individuals with CKD, which highlights the importance of maintaining good CVH in CKD patients.

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Positive association between blood ethylene oxide levels and metabolic syndrome: NHANES 2013-2020.

Purpose: The exposure of Ethylene oxide (EO) is linked to systemic inflammatory response and various cardiovascular risk factors. Hemoglobin's binding to ethylene oxide (HbEO) was used to measure serum EO level. This research aims to explore the association between metabolic syndrome (MetS) and HbEO, and between HbEO and components of metabolic syndrome. Method: This research included 1842 participants from 2013 to 2020 in National Health and Nutrition Examination Survey (NHANES) database. Weighted logistic regression models were used to analyze the relationship between HbEO and metabolic syndrome risk, using odds ratio (OR) and 95% confidence interval (CI). The restricted cubic spline plot explores whether there is a dose-response relationship between HbEO and MetS risk. Subgroup analysis was performed to analyze study heterogeneity. Results: Significant differences were found in gender, educational level, marital status, diabetes status and hypertension among different groups (P < 0.001, P = 0.007, P = 0.003, P < 0.001, P < 0.001, respectively). The serum HbEO level exhibited positive correlation with metabolic syndrome risk in Q2 level (OR=1.64, 1.04~2.48), Q3 level (OR=1.99, 1.29~3.08), and Q4 level (OR=2.89, 1.92~4.34). The dose-response association suggested a possible linear association between serum HbEO and metabolic syndrome risk (P-overall=0.0359, P-non-linear=0.179). L-shaped association was found between HbEO and the risk of MetS in female population, obese population and mid-age and elder population (P-overall<0.001, P-non-linear=0.0024; P-overall=0.0107, P-non-linear=0.0055 P-overall<0.001 P-non-linear=0.0157). Conclusion: This study indicates a linear correlation between MetS and HbEO, with MetS risk escalating as HbEO levels increase. The prevalence of MetS varies depending on BMI, age and gender, and these factors can also influence MetS prevalence when exposed to EO.

Gut microbiome alterations during gastric cancer: evidence assessment of case-control studies.

Objectives: The study aims to systematically identify the alterations in gut microbiota that observed in gastric cancer through comprehensive assessment of case-control studies. Methods: The systematic literature search of PubMed, Embase, Cochrane Library, and Web of Science was conducted to identify case-control studies that compared the microbiomes of individuals with and without gastric cancer. Quality of included studies was evaluated with the Newcastle-Ottawa Quality Assessment Scale (NOS). Meta-analyses utilized a random-effects model, and subgroup and sensitivity analyses were performed to assess study heterogeneity. All data analyses were performed using the "metan" package in Stata 17.0, and the results were described using log odds ratios (log ORs) with 95% confidence intervals (CIs). Results: A total of 33 studies involving 4,829 participants were eligible for analysis with 29 studies provided changes in α diversity and 18 studies reported ß diversity. Meta-analysis showed that only the Shannon index demonstrated statistical significance for α-diversity [-5.078 (-9.470, -0.686)]. No significant differences were observed at the phylum level, while 11 bacteria at genus-level were identified significant changed, e.g., increasing in Lactobacillus [5.474, (0.949, 9.999)] and Streptococcus [5.095, (0.293, 9.897)] and decreasing in Porphyromonas and Rothia with the same [-8.602, (-11.396, -5.808)]. Sensitivity analysis indicated that the changes of 9 bacterial genus were robust. Subgroup analyses on countries revealed an increasing abundance of Helicobacter and Streptococcus in Koreans with gastric cancer, whereas those with gastric cancer from Portugal had a reduced Neisseria. Regarding the sample sources, the study observed an increase in Lactobacillus and Bacteroides in the gastric mucosa of people with gastric cancer, alongside Helicobacter and Streptococcus. However, the relative abundance of Bacteroides decreased compared to the non-gastric cancer group, which was indicated in fecal samples. Conclusion: This study identified robust changes of 9 bacterial genus in people with gastric cancer, which were country-/sample source-specific. Large-scale studies are needed to explore the mechanisms underlying these changes. Systematic Review: Unique Identifier: CRD42023437426 https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023437426.

Emodin Attenuates Sepsis-induced Intestinal Injury by Regulating TRPM7 Expression.

Background: Sepsis is a potentially lethal organ immune dysfunction induced by infection, with the stomach being the first organ to be attacked. Emodin has anti-inflammatory and gastrointestinal functions, but its therapeutic effect on intestinal injury in sepsis remains unclear. This study sought to investigate the role of emodin in treating intestine damage brought on by sepsis. Methods: Between June 2021 and July 2023, Lipopolysaccharide (LPS) was used to stimulate human intestinal epithelial cells NCM460 to create a septic cell model, and treatment was regulated by rhodopsin. Transient receptor potential melastatin 7 (TRPM7) expression was used to check that the LPS induction conditions were acceptable. About the proliferation of the NCM460 cells, the effects of overexpressing TRPM7 and silencing TRPM7 were assessed. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide test. Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 expression in the cells was detected using enzyme-linked immunosorbent assays. TRPM7 messenger RNA expression was detected using real-time quantitative polymerase chain reaction (RT-qPCR). Western blot determined the levels of TRPM7, Bcl2-associated X (Bax), and B-cell lymphoma-2 (Bcl2) protein expression levels. The terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL) technique was used to measure the apoptosis rate. Results: The levels of the inflammatory factors and Bax expression in the cells and the cell apoptosis rate steadily increased as the LPS-induced concentration increased. In contrast, cell viability and the Bcl2 expression levels gradually decreased. In this study, we treated the cells with LPS at a concentration of 25 µg/mL for 12 hours. It was detected that the knockdown of TRPM7 expression decreased the effect of LPS induction, while boosting the expression of TRPM7 boosted the effectiveness. Treatment with emodin lowered TRPM7 expression, increasing cell survival, and Bcl2 expression levels while decreasing the apoptosis rate, inflammatory factors, and Bax expression levels. Conclusion: Emodin may alleviate sepsis-induced intestinal injury by down-regulating the TRPM7 gene. These findings suggest that emodin may hold promise as a therapeutic agent for treating intestinal injury in sepsis. If further validated through additional research and clinical trials, emodin or similar compounds could potentially be developed into safe and effective medications for sepsis patients.

Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes.

AIMS/HYPOTHESIS: Mutations in Isl1, encoding the insulin enhancer-binding protein islet-1 (ISL1), may contribute to attenuated insulin secretion in type 2 diabetes mellitus. We made an Isl1E283D mouse model to investigate the disease-causing mechanism of diabetes mellitus. METHODS: The ISL1E283D mutation (c. 849A>T) was identified by whole exome sequencing on an early-onset type 2 diabetes family and then the Isl1E283D knockin (KI) mouse model was created and an IPGTT and IPITT were conducted. Glucose-stimulated insulin secretion (GSIS), expression of Ins2 and other ISL1 target genes and interacting proteins were evaluated in isolated pancreas islets. Transcriptional activity of Isl1E283D was evaluated by cell-based luciferase reporter assay and electrophoretic mobility shift assay, and the expression levels of Ins2 driven by Isl1 wild-type (Isl1WT) and Isl1E283D mutation in rat INS-1 cells were determined by RT-PCR and western blotting. RESULTS: Impaired GSIS and elevated glucose level were observed in Isl1E283D KI mice while expression of Ins2 and other ISL1 target genes Mafa, Pdx1, Slc2a2 and the interacting protein NeuroD1 were downregulated in isolated islets. Transcriptional activity of the Isl1E283D mutation for Ins2 was reduced by 59.3%, and resulted in a marked downregulation of Ins2 expression when it was overexpressed in INS-1 cells, while overexpression of Isl1WT led to an upregulation of Ins2 expression. CONCLUSIONS/INTERPRETATION: Isl1E283D mutation reduces insulin expression and secretion by regulating insulin and other target genes, as well as its interacting proteins such as NeuroD1, leading to the development of glucose intolerance in the KI mice, which recapitulated the human diabetic phenotype. This study identified and highlighted the Isl1E283D mutation as a novel causative factor for type 2 diabetes, and suggested that targeting transcription factor ISL1 could offer an innovative avenue for the precise treatment of human type 2 diabetes.