FASEB bioAdvances最新文献

Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long-chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high-energy content and lipotoxicity. In contrast, medium-chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from in vitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles in vivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84-deficient mice. Although Gpr84-deficient mice were lean and had increased endogenous MCFAs under high-fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon-like peptide-1 (GLP-1) levels compared with wild-type mice. Medium-chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP-1 levels in wild-type mice; however, these effects were partially attenuated in Gpr84-deficient mice. Our results indicate that long-term MCFA-mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes.

Transmembrane protein 182 (TMEM182) is notably abundant in muscle and adipose tissue, but its role in the heart remains unknown. This study examined the contribution of TMEM182 in the differentiation of human induced pluripotent stem cells (hiPSCs) into cardiomyocytes. For this, we generated hiPSCs overexpressing TMEM182 in a doxycycline-inducible manner and induced their differentiation into cardiomyocytes. On Day 12 of differentiation, expression of the cardiomyocyte markers, TNNT2 and MYH6, was significantly decreased in TMEM182-overexpressing cells. Additionally, we found that phosphorylation of GSK-3β (Ser9) and β-catenin (Ser552) was increased during TMEM182 overexpression, suggesting activation of Wnt/β-catenin signaling. We further focused on integrin-linked kinase (ILK) as the mechanism by which TMEM182 activates Wnt/β-catenin signaling. Evaluation showed that ILK expression was increased in cells overexpressing TMEM182. These results suggest that TMEM182 maintains Wnt/β-catenin signaling in an activated state after mesoderm formation by increasing ILK expression, thereby suppressing hiPSCs differentiation into cardiomyocytes.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by the progressive deterioration of articular cartilage and concomitant alterations in subchondral bone architecture. However, the precise mechanisms underlying the initiation and progression of OA remains poorly understood. In the present study, we explored whether the calcification in the articular cartilage occurred in the early stage of mouse OA model, generated by the surgery destabilization of the medial meniscus (DMM), via the intra-articular injection of alizarin complexone due to its anionic nature for binding calcium-containing crystals. Although we did not observe the calcification in the articular cartilage of early stage of DMM mice, we unexpectedly identified alizarin complexone had the diffusion capacity for detecting the permeability from the articular cartilage to subchondral bone. Our data showed that the diffusion of alizarin complexone from the articular cartilage to calcified cartilage was greater in the early stage of DMM mice than that in sham controls. Additionally, we observed enhanced penetration of alizarin complexone through the periosteum in DMM mice compared to sham mice. In summary, we developed a novel imaging method that offers a valuable tool for further exploration of biochemical communication underlying OA development. Our findings provided new evidence that increased molecular interactions between the articular cartilage and subchondral bone is involved in the pathogenesis of OA progression.

Core facilities are crucial for cutting-edge scientific research in academic institutions, yet they place a significant financial burden on budgets. The viability of these facilities can be improved through cross-institutional collaborations, although initiating and sustaining such partnerships poses challenges. Insights from Israel's recent nationwide organization of core facilities could offer valuable lessons for fostering similar cooperation elsewhere. Despite the chronic shortfall in public research funding, Israeli research institutions were slow to fully embrace infrastructure sharing. This gap led to the creation of the Israel Research Core Facilities (IRCF) in 2022, which linked core facilities across the country through a bottom-up approach. IRCF facilitated the formation of numerous specialized nation-wide networks for intellectual exchange, and supported training workshops and meetings aimed at core technology providers. These initiatives serve dual purposes: they ensure the ongoing advancement of technological capabilities across facilities, regardless of their size or location, and they strengthen the commitment to the IRCF mission by motivating the maintenance of the IRCF database. As a result, a model of “capacity sharing” emerged, connecting all of Israel's core facility centers. This model enhances infrastructure use, supports strategic planning, and fosters growth. With over 450 core experts offering over 1100 scientific services consolidated into a publicly accessible database, IRCF supports research in universities, hospitals, government, and industry. This strategy could act as a model for creating regional core facility organizations to elevate research quality and ensure efficient infrastructure development.

Behavioral and environmental risk factors are critical in the development and progression of cardiovascular disease (CVD). Understanding the molecular mechanisms underlying these risk factors will offer valuable insights for targeted preventive and therapeutic strategies. Epigenetic modifications, including DNA methylation, histone modifications, chromatin remodeling, noncoding RNA (ncRNA) expression, and epitranscriptomic modifications, have emerged as key mediators connecting behavioral and environmental risk factors to CVD risk and progression. These epigenetic alterations can profoundly impact on cardiovascular health and susceptibility to CVD by influencing cellular processes, development, and disease risk over an individual's lifetime and potentially across generations. This review examines how behavioral and environmental risk factors affect CVD risk and health outcomes through epigenetic regulation. We review the epigenetic effects of major behavioral risk factors (such as smoking, alcohol consumption, physical inactivity, unhealthy diet, and obesity) and environmental risk factors (including air and noise pollution) in the context of CVD pathogenesis. Additionally, we explore epigenetic biomarkers, considering their role as causal or surrogate indicators, and discuss epigenetic therapeutics targeting the mechanisms through which these risk factors contribute to CVD. We also address future research directions and challenges in leveraging epigenetic insights to reduce the burden of CVD related to behavioral and environmental factors and improve public health outcomes. This review aims to provide a comprehensive understanding of behavioral and environmental epigenetics in CVD and offer valuable strategies for therapeutic intervention.

The human placenta is a vital organ, encompassing many distinct cell types, that maintains the growth and development of the fetus and is essential for substance exchange, defense, synthesis, and immunity. Abnormalities in placental cells can lead to various pregnancy complications, but the mechanisms remain largely unclear. Single-cell and spatial transcriptomics technologies have been developed in recent years to demonstrate placental cell heterogeneity and spatial molecular localization. Here, we review and summarize the current literature, demonstrating these technologies and showing the heterogeneity of various placenta cells and cell–cell communication of normal human placenta, as well as placenta-related diseases, such as preeclampsia, gestational diabetes mellitus, advanced maternal age, recurrent pregnancy loss, and placenta accreta spectrum disorders. Meanwhile, current weaknesses and future direction were discussed.

In recent years, the scientific community has shown interest in the role of gut microbiota in the development of autoimmune diseases (AID). Although observational studies have revealed significant associations between gut microbiota and AID like rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, these connections do not necessarily imply causality. Mendelian randomization (MR) approach has been extensively employed to investigate the causal relationship. Relevant MR study findings indicate that a reduction in beneficial microbial populations, particularly Bifidobacterium and Lactobacillus, and an increase in potential pathogenic microbes, is correlated with an elevated AID risk. Given the innovative potential of MR in unraveling the etiopathogenesis of AIDs, this article offers an overview of this methodological approach and its recent applications in AID research.

Mitochondria are vital for retinal cell function and survival, and there is growing evidence linking mitochondrial dysfunction to retinal degenerations. Although ARL3 mutations have been linked to multiple forms of retinal degeneration, the relationship between ARL3 and mitochondria remains unexplored. Herein, we investigated the effects of ARL3^T31A, ARL3^C118F, and ARL3^T31A/C118F mutations on mitochondrial function in fibroblasts obtained from patients with ARL3-related rod-cone dystrophy. Our findings revealed that these mutations led to a decrease in mitochondrial respiration, an increase in the accumulation mitochondrial reactive oxygen species (ROS), and induction of apoptosis in fibroblasts. Additionally, we conducted a comparative analysis of the effects of ARL3^T31A, ARL3^C118F, and ARL3^T31A/C118F proteins on mitochondria in ARPE-19 cells. Results showed that ARL3^T31A and ARL3^T31A/C118F not only affected mitochondrial function but also induced apoptosis in ARPE-19 cells. Conversely, ARL3^C118F primarily influenced cell apoptosis with minimal effects on mitochondrial function in ARPE-19 cells. Transcriptome analysis further suggested the involvement of respiratory electron transport, response to ROS, and apoptotic signaling pathways in ARL3^T31A/C118F cells. Our study demonstrated that ARL3-related mutations play a significant role in the diversity of mitochondrial function, providing novel insights into the functional analysis of ARL3-related mutations.

Neutrophil extracellular traps (NETs) have been implicated in the pathology of various inflammatory conditions. In cancer, NETs have been demonstrated to induce systemic inflammation, impair peripheral vessel and organ function and promote metastasis. Here we show that the plasma level of NETs is significantly higher in patients with metastatic breast cancer compared to those with local disease, or those that were considered cured at a 5-year follow-up, confirming NETs as interesting therapeutic targets in metastatic breast cancer. Administration of DNase I is one strategy to eliminate NETs but long-term treatment requires repeated injections and species-specific versions of the enzyme. To enhance administration and therapeutic efficacy, we have developed an adeno-associated virus (AAV) vector system for delivery of murine DNase I and addressed its potential to counteract cancer-associated pathology in the murine MMTV-PyMT model for metastatic mammary carcinoma. The AAV vector is comprised of capsid KP1 and an expression cassette encoding hyperactive murine DNase I (AAV-mDNase I) under the control of a liver-specific promotor. This AAV-mDNase I vector could support elevated expression and serum activity of murine DNase I over at least 8 months. Neutrophil Gelatinase-Associated Lipocalin (NGAL), a biomarker for kidney hypoperfusion that is upregulated in urine from MMTV-PyMT mice, was suppressed in mice receiving AAV-mDNase I compared to an AAV-null control group. Furthermore, the proportion of mice that developed lung metastasis was reduced in the AAV-mDNase I group. Altogether, our data indicate that AAV-mDNase I has the potential to reduce cancer-associated impairment of renal function and development of metastasis. We conclude that AAV-mDNase I could represent a promising therapeutic strategy in metastatic breast cancer.

Despite advancement in anti-seizure medications, 30% of patients continue to experience recurrent seizures. Previous data indicated the antiepileptic properties of melatonin and its agonists in several animal models. However, the underlying mechanisms of melatonin and its agonists on cellular excitability remain poorly understood. In this study, we demonstrated the electrophysiological changes of two main kinds of ion channels that are responsible for hyperexcitability of neurons after introduction of melatonin agonists- ramelteon (RAM). In Neuro-2a cells, the amplitude of voltage-gated Na⁺ (I_Na) and delayed-rectifier K⁺ currents (I_{K (DR)}) could be suppressed under RAM. The IC₅₀ values of 8.7 and 2.9 μM, respectively. RAM also diminished the magnitude of window Na⁺ current (I_{Na (W)}) elicited by short ascending ramp voltage, with unchanged the overall steady-state current–voltage relationship. The decaying time course of I_Na during a train of depolarizing pulses arose upon the exposure to RAM. The conditioning train protocol which blocked I_Na fitted the recovery time course into two exponential processes and increased the fast and slow time constant of recovery the presence of RAM. In pituitary tumor (GH₃) cells, I_Na amplitude was also effectively suppressed by the RAM. In addition, GH3-cells exposure to RAM decreased the firing frequency of spontaneous action potentials observed under current-clamp conditions. As a result, the RAM-mediated effect on INa was closely associated with its ability to decrease spontaneous action potentials. Collectively, we found the direct attenuation of I_Na and I_{K (DR)} caused by RAM besides the agonistic action on melatonin receptors, which could partially explain its anti-seizure activity.