Association of circulating long-chain free fatty acids and incident diabetes risk among normoglycemic Chinese adults: a prospective nested case-control study.

BACKGROUND: Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking. OBJECTIVES: Our study aimed to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults. METHODS: This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using a targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes. RESULTS: The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1, and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95% CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18-26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95% CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR: 0.85; 95% CI: 0.76, 0.94), PUFAs 20:4 (OR: 0.84; 95% CI: 0.75, 0.94), and 24:2 (OR: 0.87; 95% CI: 0.78, 0.97) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 (95% CI: 0.61, 0.99; P = 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset. CONCLUSIONS: These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Platelet Concentrates Preconditioning of Mesenchymal Stem Cells and Combined Therapies: Integrating Regenerative Strategies for Enhanced Clinical Applications.

This article presents a comprehensive review of the factors influencing the efficacy of mesenchymal stem cells (MSCs) transplantation and its association with platelet concentrates (PCs). It focuses on investigating the impact of PCs' composition, the age and health status of platelet donors, application methods, and environmental factors on the outcomes of relevant treatments. In addition, it delves into the strategies and mechanisms for optimizing MSCs transplantation with PCs, encompassing preconditioning and combined therapies. Furthermore, it provides an in-depth exploration of the signaling pathways and proteomic characteristics associated with preconditioning and emphasizes the efficacy and specific effects of combined therapy. The article also introduces the latest advancements in the application of biomaterials for optimizing regenerative medical strategies, stimulating scholarly discourse on this subject. Through this comprehensive review, the primary goal is to facilitate a more profound comprehension of the factors influencing treatment outcomes, as well as the strategies and mechanisms for optimizing MSCs transplantation and the application of biomaterials in regenerative medicine, offering theoretical guidance and practical references for related research and clinical practice.

Human amniotic mesenchymal stromal cell-derived exosomes promote neuronal function by inhibiting excessive apoptosis in a hypoxia/ischemia-induced cerebral palsy model: A preclinical study.

BACKGROUND: Cerebral palsy (CP) is a condition resulting from perinatal brain injury and can lead to physical disabilities. Exosomes derived from human amniotic mesenchymal stromal cells (hAMSC-Exos) hold promise as potential therapeutic options. OBJECTIVE: This study aimed to investigate the impact of hAMSC-Exos on neuronal cells and their role in regulating apoptosis both in vitro and in vivo. METHODS: hAMSC-Exos were isolated via ultracentrifugation and characterized via transmission electron microscopy, particle size analysis, and flow cytometry. In vitro, neuronal damage was induced by lipopolysaccharide (LPS). CP rat models were established via left common carotid artery ligation. Apoptosis levels in cells and CP rats were assessed using flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR), Western blotting, and TUNEL analysis. RESULTS: The results demonstrated successful isolation of hAMSC-Exos via ultracentrifugation, as the isolated cells were positive for CD9 (79.7%) and CD63 (80.2%). Treatment with hAMSC-Exos significantly mitigated the reduction in cell viability induced by LPS. Flow cytometry revealed that LPS-induced damage promoted apoptosis, but this effect was attenuated by treatment with hAMSC-Exos. Additionally, the expression of caspase-3 and caspase-9 and the Bcl-2/Bax ratio indicated that excessive apoptosis could be attenuated by treatment with hAMSC-Exos. Furthermore, tail vein injection of hAMSC-Exos improved the neurobehavioral function of CP rats. Histological analysis via HE and TUNEL staining showed that apoptosis-related damage was attenuated following hAMSC-Exo treatment. CONCLUSIONS: In conclusion, hAMSC-Exos effectively promote neuronal cell survival by regulating apoptosis, indicating their potential as a promising therapeutic option for CP that merits further investigation.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

Differential influences of forest floor-pyrolyzed biochar-derived and leached dissolved organic matter interaction with natural iron-bearing minerals in forest subsoil on the formation of mineral-associated soil organic matter.

The vertical sequestration of dissolved organic matter (DOM) by iron minerals along the soil profile is assumed to be central to the long-term storage of the soil organic matter (SOM) pool. However, there is limited information available about how the interaction between DOM and natural iron-bearing minerals shape mineral SOM associations quantitatively and qualitatively in forest subsoils. Here, we systematically investigated the influences of forest organic layer-pyrolyzed biochar-derived DOM (BDOM) and leached DOM (LDOM) on quantity, molecular composition, and diversity of deposition layer-derived iron minerals-associated OM by using Fourier transform ion cyclotron resonance mass spectrometry and other complementary spectroscopy. Results indicated natural iron minerals (FeOx1 and FeOx2) had a greater capacity for sorbing LDOM with higher aromaticity and molecular weight than those of BDOM, and the higher proportion of goethite and short-order-range phase in natural iron minerals was closely related to the increased OM adsorption capacity. We also observed the preferential sorption of oxygen/nitrogen-rich polycyclic aromatic compounds and carboxylic-containing compounds in LDOM and concurrent the potential release of lignin-like/aromatics compounds and carboxyl/nitrogen-less aliphatic compounds from native OM coprecipitates into the solution. However, unsaturated and oxidized phenolic compounds in BDOM had a stronger affinity for FeOx through hydrophobic partitioning and specific polar interactions, and concomitantly the partial release of nitrogen-free aliphatic and other carboxyl-rich compounds. More nitrogen structures in aromatic-containing compounds can improve the saturation level and polarity of BDOM. Compared with BDOM, LDOM exerted a stronger control over the exchange of native OM from subsoil natural iron-bearing minerals and substantially enhanced the molecular diversity of the reconstituted mineral-associated OM during the adsorptive fractionation. Overall, these findings suggest the compositional evolution of DOM profoundly shapes SOM formation and persistence in forest subsoils, which is the key to understanding DOM cycling and contaminant fate during its passage through the soil.

BiTiS3 bio-transducer with explosive on-demand generation of NO gas for synergetic cancer therapy.

Combined photothermal therapy and nitric oxide (NO)-mediated gas therapy has shown great potential as a cancer treatment. However, the on-demand release of NO at a high concentration presents a challenge owing to the lack of an ideal bio-transducer with a high loading capacity of NO donors and sufficient energy to induce NO release. Here, we present a new 2D BiTiS3 nanosheet that is synthesized, loaded with the NO donor (BNN6), and conjugated with PEG-iRGD to produce a multifunctional bio-transducer (BNN6-BiTiS3-iRGD) for the on-demand production of NO. The BiTiS3 nanosheets not only have a high loading capacity of NO donors (750%), but also exhibit a high photothermal conversion efficiency (59.5%) after irradiation by a 1064-nm laser at 0.5 W/cm2. As a result of the above advantages, the temporal-controllable generation of NO within a large dynamic range (from 0 to 344 µM) is achieved by adjusting power densities, which is among the highest efficiency values reported for NO generators so far. Moreover, the targeted accumulation of BNN6-BiTiS3-iRGD at tumor sites leads to spatial-controllable NO release. In vitro and in vivo assessments demonstrate synergistic NO gas therapy with mild photothermal therapy based on BNN6-BiTiS3-iRGD. Our work provides insights into the design and application of other 2D nanomaterial-based therapeutic platforms.

Transformation of Black Phosphorus through Lattice Reconstruction for NIR-II-Responsive Cancer Therapy.

The photothermal performance of black phosphorus (BP) in the near infrared (NIR)-II bio-window (1000-1500 nm) is low, which limits its biomedical applications. Herein, ultrasmall nickel phosphide quantum dots (Ni2 P QDs) are synthesized with BP quantum dots (BPQDs) as the template by topochemical transformation. The size of Ni2 P QDs is ≈3.5 nm, similar to that of BPQDs, whereas the absorption and photothermal conversion efficiency of Ni2 P QDs at 1064 nm (43.5%) are significantly improved compared with those of BPQDs. To facilitate in vivo applications, an Ni2 P QDs-based liposomal nano-platform (Ni2 P-DOX@Lipo-cRGD) is designed by incorporation of Ni2 P QDs and doxorubicin (DOX) into liposomal bilayers and the interior, respectively. The encapsulated DOX is responsively released from liposomes upon 1064-nm laser irradiation owing to the photothermal effect of Ni2 P QDs, and the drug release rate and amount are controlled by the light intensity and exposure time. In vivo, experiments show that Ni2 P-DOX@Lipo-cRGD has excellent tumor target capability and biocompatibility, as well as complete tumor ablation through the combination of photothermal therapy and chemotherapy. The work provides a new paradigm for the NIR-II transformation of nano-materials and may shed light on the construction of multifunctional nano-platforms for cancer treatment.

Associations of sleeping patterns and isotemporal substitution of other behavior with the prevalence of CKD in Chinese adults.

Studies have found a U-shaped relationship between sleep duration and chronic kidney disease (CKD) risk, but limited research evaluated the association of reallocating excessive sleep to other behavior with CKD. We included 104 538 participants from the nationwide cohort of the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study, with self-reported time of daily-life behavior. Using isotemporal substitution models, we found that substituting 1 h of sleeping with sitting, walking, or moderate-to-vigorous physical activity was associated with a lower CKD prevalence. Leisure-time physical activity displacement was associated with a greater prevalence reduction than occupational physical activity in working population. In stratified analysis, a lower CKD prevalence related to substitution toward physical activity was found in long sleepers. More pronounced correlations were observed in long sleepers with diabetes than in those with prediabetes, and they benefited from other behavior substitutions toward a more active way. The U-shaped association between sleep duration and CKD prevalence implied the potential effects of insufficient and excessive sleep on the kidneys, in which the pernicious link with oversleep could be reversed by time reallocation to physical activity. The divergence in the predicted effect on CKD following time reallocation to behavior of different domains and intensities and in subpopulations with diverse metabolic statuses underlined the importance of optimizing sleeping patterns and adjusting integral behavioral composition.

Early adulthood weight change, midlife "Life's essential 8" health status and risk of cardiometabolic diseases: a chinese nationwide cohort study.

BACKGROUND: The association between weight change during early adulthood and cardiometabolic diseases remains uncertain in Chinese population. Whether the association varies with comprehensive cardiovascular health (CVH) in midlife assessed by "Life's Essential 8" has not been characterized. We aim to examine the associations of early adulthood weight change and midlife "Life's Essential 8" CVH status with cardiometabolic outcomes in a Chinese cohort. METHODS: The study participants were from the China Cardiometabolic Disease and Cancer Cohort (4 C) Study. This analysis included 72,610 middle-aged and older participants followed for a median of 3.6 years. At baseline, the participants recalled body weight at age 20 and 40 years, and we calculated change in weight and BMI between 20 and 40 years of age. Health behaviors information in "Life's Essential 8" was collected by questionnaire, and health factors were measured in the study center. During follow-up, we ascertained incident cardiovascular events based on medical records, and diagnosed incident diabetes according to the American Diabetes Association 2010 criteria. RESULTS: 72,610 study participants were included with a mean age of 56.0 ± 8.8 years and 29% of them were males. Weight gain of more than 10 kg between 20 and 40 years of age was associated with 22% increased risk of incident cardiovascular events (HR: 1.22; 95%CI: 1.04-1.43) and 38% increased risk of diabetes (HR: 1.38; 95%CI: 1.25-1.53) compared to stable weight. Besides, the association of weight gain more than 10 kg in early adulthood with cardiometabolic risk was even stronger in those with low CVH score in midlife (HR: 2.44; 95%CI: 2.01-2.97 for incident cardiovascular events; HR: 2.20; 95%CI: 1.90-2.55 for incident diabetes) or with few ideal cardiovascular health metrics in midlife. CONCLUSIONS: Our study indicated that weight gain in early adulthood was associated with significantly increased risk of cardiometabolic diseases. And the association could be stronger in those with poor CVH profiles in midlife. These findings confirmed the significance of weight management during early adulthood and suggested that individuals who experienced substantial weight gain in early life should be encouraged to maintain good CVH status in Chinese population.

The Impact of Sedentary Behavior on Renal Function Decline in 132,123 Middle Aged and Older Adults: A Nationwide Cohort Study.

BACKGROUND Prior studies suggest that sedentary behavior is a well-known risk factor for cardiometabolic diseases. However, the longitudinal association between overall siting time and kidney function decline is not known. MATERIAL AND METHODS We performed a nationwide prospective cohort study in individuals aged more than 40 years enrolled in the China Cardiometabolic Disease and Cancer Cohort (4C) study. A total of 132 123 individuals were included in this study. Sitting time was measured with the short version of the International Physical Activity Questionnaire (IPAQ). Kidney function decline was defined as an eGFR <60 mL/min/1.73 m² or more than a 30% decrease in eGFR from baseline. Multivariate Cox proportional hazards regression analyses were conducted to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of the relation between kidney function decline and sitting time. RESULTS During a mean follow-up of 3.8 years, 3890 (2.9%) participants experienced kidney function decline. Longer sitting time was significantly associated with the risk of kidney function decline (aHR, 1.136; 95% CI, 1.036-1.247, P=0.007, comparing participants with baseline sitting time in the lowest quartile with those in the highest quartile) after adjustment for potential confounders. CONCLUSIONS Longer sitting time was independently and prospectively associated with a higher risk of kidney function decline. Sedentary behavior might represent a modifiable risk factor for chronic kidney disease (CKD) prevention.

LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

Long noncoding RNA DLEU1 promotes proliferation and glycolysis of gastric cancer cells via APOC1 upregulation by recruiting SMYD2 to induce trimethylation of H3K4 modification.

OBJECTIVES: APOC1 has been reported to promote tumor progression. Nevertheless, its impact on cell proliferation and glycolysis in gastric cancer (GC) remains to be probed. Hence, this study explored the related impacts and mechanisms. METHODS: DLEU1, SMYD2, and APOC1 expression was detected in GC cells. Afterward, ectopic expression and knockdown experiments were conducted in GC cells, followed by measurement of cell proliferation, glucose uptake capability, lactic acid production, ATP content, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), and GLUT1, HK2, and LDHA expression. In addition, interactions between DLEU1 and SMYD2 were analyzed with RIP and RNA pull down assays, and the binding of SMYD2 to APOC1 promoter and the methylation modification of SMYD2 in H3K4me3 were assessed with a ChIP assay. The ectopic tumor formation experiment in nude mice was conducted for in vivo validation. RESULTS: DLEU1, SMYD2, and APOC1 were highly expressed in GC cells. The downregulation of DLEU1 or APOC1 inhibited glucose uptake capability, lactic acid production, ECAR, the expression of GLUT1, HK2, and LDHA, ATP contents, and proliferation but augmented OCR in GC cells, which was also verified in animal experiments. Mechanistically, DLEU1 interacted with SMYD2 and recruited SMYD2 to APOC1 promoter to promote H3K4me3 modification, thus facilitating APOC1 expression. Furthermore, the effects of DLEU1 silencing on GC cell proliferation and glycolysis were negated by overexpressing SMYD2 or APOC1. CONCLUSION: LncRNA DLEU1 recruited SMYD2 to upregulate APOC1 expression, thus boosting GC cell proliferation and glycolysis.

Biodegradable FePS3 nanoplatform for efficient treatment of osteosarcoma by combination of gene and NIR-II photothermal therapy.

As a common tumor with high incidence, osteosarcoma possesses extremely poor prognosis and high mortality. Improving the survival of osteosarcoma patients is still a great challenge due to the precipice of advancement in treatment. In this study, a combination strategy of gene therapy and photothermal therapy (PTT) is developed for efficient treatment of osteosarcoma. Two-dimensional (2D) FePS3 nanosheets are synthesized and functionalized by poly-L-lysine-PEG-folic acid (PPF) to fabricate a multifunctional nanoplatform (FePS@PPF) for further loading microRNAs inhibitor, miR-19a inhibitor (anti-miR-19a). The photothermal conversion efficiency of FePS@PPF is up to 47.1% under irradiation by 1064 nm laser. In vitro study shows that anti-miR-19a can be efficiently internalized into osteosarcoma cells through the protection and delivery of FePS@PPF nanaocarrier, which induces up-regulation of PTEN protein and down-regulation p-AKT protein. After intravenous injection, the FePS@PPF nanoplatform specifically accumulates to tumor site of osteosarcoma-bearing mice. The in vitro and in vivo investigations reveal that the combined PTT-gene therapy displays most significant tumor ablation compared with monotherapy. More importantly, the good biodegradability promotes FePS@PPF to be cleared from body avoiding potential toxicity of long-term retention. Our work not only develops a combined strategy of NIR-II PTT and gene therapy mediated by anti-miR-19a/FePS@PPF but also provides insights into the design and applications of other nanotherapeutic platforms.

Case report: Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2.

Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date. Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.

Comprehensive analysis identifies cuproptosis-related gene DLAT as a potential prognostic and immunological biomarker in pancreatic adenocarcinoma.

BACKGROUND: Cuproptosis is a regulated cell death form associated with tumor progression, clinical outcomes, and immune response. However, the role of cuproptosis in pancreatic adenocarcinoma (PAAD) remains unclear. This study aims to investigate the implications of cuproptosis-related genes (CRGs) in PAAD by integrated bioinformatic methods and clinical validation. METHODS: Gene expression data and clinical information were downloaded from UCSC Xena platform. We analyzed the expression, mutation, methylation, and correlations of CRGs in PAAD. Then, based on the expression profiles of CRGs, patients were divided into 3 groups by consensus clustering algorithm. Dihydrolipoamide acetyltransferase (DLAT) was chosen for further exploration, including prognostic analysis, co-expression analysis, functional enrichment analysis, and immune landscape analysis. The DLAT-based risk model was established by Cox and LASSO regression analysis in the training cohort, and then verified in the validation cohort. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) assays were performed to examine the expression levels of DLAT in vitro and in vivo, respectively. RESULTS: Most CRGs were highly expressed in PAAD. Among these genes, increased DLAT could serve as an independent risk factor for survival. Co-expression network and functional enrichment analysis indicated that DLAT was engaged in multiple tumor-related pathways. Moreover, DLAT expression was positively correlated with diverse immunological characteristics, such as immune cell infiltration, cancer-immunity cycle, immunotherapy-predicted pathways, and inhibitory immune checkpoints. Submap analysis demonstrated that DLAT-high patients were more responsive to immunotherapeutic agents. Notably, the DLAT-based risk score model possessed high accuracy in predicting prognosis. Finally, the upregulated expression of DLAT was verified by RT-qPCR and IHC assays. CONCLUSIONS: We developed a DLAT-based model to predict patients' clinical outcomes and demonstrated that DLAT was a promising prognostic and immunological biomarker in PAAD, thereby providing a new possibility for tumor therapy.

Association of Spousal Diabetes Status and Ideal Cardiovascular Health Metrics With Risk of Incident Diabetes Among Chinese Adults.

Importance: Spouses share common socioeconomic, environmental, and lifestyle factors, and multiple studies have found that spousal diabetes status was associated with diabetes prevalence. But the association of spousal diabetes status and ideal cardiovascular health metrics (ICVHMs) assessed by the American Heart Association's Life's Essential 8 measures with incident diabetes has not been comprehensively characterized, especially in large-scale cohort studies. Objective: To explore the association of spousal diabetes status and cardiovascular health metrics with risk of incident diabetes in Chinese adults. Design, Setting, and Participants: This cohort study included individuals in the China Cardiovascular Disease and Cancer Cohort without diabetes who underwent baseline and follow-up glucose measurements and had spouses with baseline glucose measurements. The data were collected in January 2011 to December 2012 and March 2014 to December 2016. The spousal study had a mean (SD) follow-up of 3.6 (0.9) years (median [IQR], 3.2 [2.9-4.5] years). Statistical analysis was performed from July to November 2022. Exposure: Spousal diabetes status was diagnosed according to the 2010 American Diabetes Association (ADA) criteria. All participants provided detailed clinical, sociodemographic, and lifestyle information included in cardiovascular health metrics. Main Outcomes and Measures: Incident diabetes, diagnosed according to 2010 ADA criteria. Results: Overall, 34 821 individuals were included, with a mean (SD) age of 56.4 (8.3) years and 16 699 (48.0%) male participants. Spousal diabetes diagnosis was associated with an increased risk of incident diabetes (hazard ratio [HR], 1.15; 95% CI, 1.03-1.30). Furthermore, participants whose spouses had uncontrolled glycated hemoglobin (HbA1c) had a higher risk of diabetes (HR, 1.20; 95% CI, 1.04-1.39) but the risk of diabetes in participants whose spouses had controlled HbA1c did not increase significantly (HR, 1.10; 95% CI, 0.92-1.30). Moreover, this association varied with composite cardiovascular health status. Diabetes risk in individuals who had poor cardiovascular health status (<4 ICVHMs) was associated with spousal diabetes status (3 ICVHMs: HR, 1.50; 95% CI, 1.15-1.97), while diabetes risk in individuals who had intermediate to ideal cardiovascular health status (≥4 ICVHMs) was not associated with it (4 ICVHMs: HR, 1.01; 95% CI, 0.69-1.50). Conclusions and Relevance: In this study, spousal diabetes diagnosis with uncontrolled HbA1c level was associated with increased risk of incident diabetes, but strict management of spousal HbA1c level and improving ICVHM profiles may attenuate the association of spousal diabetes status with diabetes risk. These findings suggest the potential benefit of couple-based lifestyle or pharmaceutical interventions for diabetes.

Microencapsulation of Lead-Halide Perovskites in an Oil-in-Fluorine Emulsion for Cell Imaging.

The superior optical properties of lead-halide perovskites (LHPs) inspired significant research in cell imaging applications; many encapsulating processes have improved perovskite stabilities with comparable biosafety. Herein, facile solvent evaporation encapsulation based on an oil-in-fluorine emulsion for aqueous-stable and extremely nontoxic LHP microcapsules is described. Perfluorooctane dispersed the emulsifier fluorocarbon surfactant to form a continuous fluorine phase, while LHPs and polymethylmethacrylate (PMMA) were dispersed in 1,2-dichloroethane, then emulsified in the fluorine phase to form an oil-in-fluorine emulsion. CsPbBr3 microcapsules with a dense PMMA shell that protect fragile CsPbBr3 from the external environment and inhibit lead ion release were obtained after solvent evaporation. The CsPbBr3 microcapsules not only retained 91% of fluorescence intensity after exposure to water for 30 d but also possess extremely low cytotoxicity for MCF-7 cells. After exposure to 2 mg/mL of CsPbBr3 microcapsules for 48 h, the cell viability remained >90%. The intracellular uptake of CsPbBr3 microcapsules indicates its potential use in cell imaging.

Irisin attenuates ethanol-induced behavioral deficits in mice through activation of Nrf2 and inhibition of NF-κB pathways.

This study aims to investigate the effect of irisin on ethanol-induced behavioral deficits and explore the underlying mechanisms. A mouse model of ethanol addiction/withdrawal was constructed through chronic ethanol administration. Depressive-like behaviors were evaluated by the tail suspension test and forced swimming test, and anxiety-like behaviors were evaluated by the marble-burying test and elevated plus maze test. The expression of Nrf2 was measured by western blotting. Levels of inflammatory mediators (NF-κB, TNF-α, IL-1ß and IL-6) and oxidative stress factors (ROS, MDA, GSH and SOD) were detected by ELISA. The ethanol-induced PC12/BV2 cell injury model was used to elucidate whether the effect of irisin on ethanol-induced neurological injury was related to anti-inflammatory and antioxidant mechanisms. Ethanol-induced ethanol preference and emotional deficits were improved by chronic irisin treatment; however, these improvements were partly reversed by cotreatment with the Nrf2 inhibitor ML385. Further results implied that the improvement effect of irisin on behavioral abnormalities may be related to its anti-inflammatory and antioxidant effects. In detail, irisin inhibited ethanol-induced abnormal expression of ROS and MDA and upregulated the expression of GSH and SOD. Meanwhile, irisin treatment inhibited ethanol-induced overexpression of NF-κB, TNF-α, IL-1ß and IL-6 in the hippocampus and cerebral cortex. The regulation of oxidative stress factors by irisin was reversed after ML385 treatment. In the in vitro study, overexpression of oxidative stress factors in ethanol-treated PC12 cells was inhibited by irisin treatment; however, the prevention was reversed after the knockdown of Nrf2 siRNA. Moreover, ethanol-induced overexpression of inflammatory mediators in BV2 cells was also inhibited by irisin treatment. Irisin improved depressive and anxiety-like behaviors induced by ethanol addiction/withdrawal in mice, and this protection was greatly associated with the NF-κB-mediated anti-inflammatory signaling pathway and Nrf2-mediated antioxidative stress signaling pathway.

Data-driven subgroups of prediabetes and the associations with outcomes in Chinese adults.

Prediabetes and its pathophysiology remain important issues. We aimed to examine the cluster characteristics of prediabetes and explore their associations with developing diabetes and its complications based on 12 variables representing body fat, glycemic measures, pancreatic ß cell function, insulin resistance, blood lipids, and liver enzymes. A total of 55,777 individuals with prediabetes from the China Cardiometabolic Disease and Cancer Cohort (4C) were classified at baseline into six clusters. During a median of 3.1 years of follow-up, significant differences in the risks of diabetes and its complications between clusters were observed. The odds ratios of diabetes stepwisely increase from cluster 1 to cluster 6. Clusters 1, 4, and 6 have increased chronic kidney diseases risks, while the prediabetes in cluster 4, characterized by obesity and insulin resistance, confers higher risks of cardiovascular diseases compared with others. This subcategorization has potential value in developing more precise strategies for targeted prediabetes prevention and treatment.