UNASSIGNED: Metabolic dysregulation following sepsis can significantly compromise patient prognosis by altering immune-inflammatory responses. Despite its clinical relevance, the exact mechanisms of this perturbation are not yet fully understood.
UNASSIGNED: Single-cell RNA sequencing (scRNA-seq) was utilized to map the immune cell landscape and its association with metabolic pathways during sepsis. This study employed cell-cell interaction and phenotype profiling from scRNA-seq data, along with pseudotime trajectory analysis, to investigate neutrophil differentiation and heterogeneity. By integrating scRNA-seq with Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning techniques, key genes were identified. These genes were used to develop and validate a risk score model and nomogram, with their efficacy confirmed through Receiver Operating Characteristic (ROC) curve analysis. The model\'s practicality was further reinforced through enrichment and immune characteristic studies based on the risk score and in vivo validation of a critical gene associated with sepsis.
UNASSIGNED: The complex immune landscape and neutrophil roles in metabolic disturbances during sepsis were elucidated by our in-depth scRNA-seq analysis. Pronounced neutrophil interactions with diverse cell types were revealed in the analysis of intercellular communication, highlighting pathways that differentiate between proximal and core regions within atherosclerotic plaques. Insight into the evolution of neutrophil subpopulations and their differentiation within the plaque milieu was provided by pseudotime trajectory mappings. Diagnostic markers were identified with the assistance of machine learning, resulting in the discovery of PIM1, HIST1H1C, and IGSF6. The identification of these markers culminated in the development of the risk score model, which demonstrated remarkable precision in sepsis prognosis. The model\'s capability to categorize patient profiles based on immune characteristics was confirmed, particularly in identifying individuals at high risk with suppressed immune cell activity and inflammatory responses. The role of PIM1 in modulating the immune-inflammatory response during sepsis was further confirmed through experimental validation, suggesting its potential as a therapeutic target.
UNASSIGNED: The understanding of sepsis immunopathology is improved by this research, and new avenues are opened for novel prognostic and therapeutic approaches.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical innate immune pathway primarily due to its vital DNA sensing mechanism in pathogen defence. Recent research advances have shown that excessive activation or damage to the cGAS-STING pathway can exacerbate chronic inflammatory responses, playing a significant role in metabolic dysfunction and aging, leading to the development of related diseases such as obesity, osteoporosis, and neurodegenerative diseases. This article reviews the structure and biological functions of the cGAS-STING signaling pathway and discusses in detail how this pathway regulates the occurrence and development of metabolic and age-related diseases. Additionally, this article introduces potential small molecule drugs targeting cGAS and STING, aiming to provide new research perspectives for studying the pathogenesis and treatment of metabolic-related diseases.

Prolonged confinement in cramped spaces can lead to derangements in brain function/structure, yet the underlying mechanisms remain unclear. To investigate, we subjected mice to restraint stress to simulate long-term narrow and enclosed space confinement, assessing their mental state through behavioral tests. Stressed mice showed reduced center travel and dwell time in the Open Field Test and increased immobility in the Tail Suspension Test. We measured lower hippocampal brain-derived neurotrophic factor levels and cortical monoamine neurotransmitters (5-HT and NE) in the stressed group. Further examination of the body\'s immune levels and serum metabolism revealed immune dysregulation and metabolic imbalance in the stressed group. The results of the metabolic network regulation analysis indicate that the targets affected by these differential metabolites are involved in several metabolic pathways that the metabolites themselves participate in, such as the \"long-term depression\" and \"purine metabolism\" pathways. Additionally, these targets are also associated with numerous immune-related pathways, such as the TNF, NF-κB, and IL-17 signaling pathways, and these findings were validated using GEO dataset analysis. Molecular docking results suggest that differential metabolites may regulate specific immune factors such as TNF-α, IL-1β, and IL-6, and these results were confirmed in experiments. Our research findings suggest that long-term exposure to confined and narrow spaces can lead to the development of psychopathologies, possibly mediated by immune system dysregulation and metabolic disruption.

Sarcopenia is a significant geriatric syndrome that involves the loss of skeletal muscle mass and strength. Due to its substantial endocrine role, the metabolic microenvironment of skeletal muscle undergoes changes with age. Examining the pathogenesis of sarcopenia through focusing on metabolic dysregulation could offer insights for developing more effective intervention strategies. In this study, we analyzed the transcriptomics data to identify specific genes involved in the regulation of metabolism in skeletal muscle during the development of sarcopenia. Three machine learning algorithms were employed to screen key target genes exhibiting strong correlations with metabolism, which were further validated using RNA-sequencing data and publicly accessible datasets. Among them, the metabolic enzyme nicotinamide N-methyltransferase (NNMT) was elevated in sarcopenia, and predicted sarcopenia with an area under the curve exceeding 0.7, suggesting it as a potential therapeutic target for sarcopenia. As expected, inhibition of NNMT improved the grip strength in aging mice and alleviated age-related decline in the mass index of the quadriceps femoris muscles and whole-body lean mass index. Additionally, the NNMTi treatment increased the levels of nicotinamide adenine dinucleotide (NAD+) content, as well as PGC1α and p-AMPK expression in the muscles of both the D-galactose-treated mouse model and naturally aging mouse model. Overall, this work demonstrates NNMT as a promising target for preventing age-related decline in muscle mass and strength.

As a terminal stage of various cardiovascular diseases, heart failure is of great concern due to its high mortality rate and limited treatment options. Researchers are currently focusing their efforts on investigating the metabolism of carbohydrates, fatty acids, and amino acids to enhance the prognosis of cardiovascular diseases. Simultaneously, branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, play significant roles in blood glucose regulation, protein synthesis, and insulin sensitivity. However, disrupted BCAAs metabolism has been associated with conditions such as hypertension, obesity, and atherosclerosis. This article explores intricate metabolic pathways, unveiling the connection between disrupted BCAAs metabolism and the progression of heart failure. Furthermore, the article discusses therapeutic strategies, assesses the impact of BCAAs on cardiac dysfunction, and examines the potential of modulating BCAAs metabolism as a treatment for heart failure. BCAAs and their metabolites are also considered as biomarkers for evaluating cardiac metabolic risk. In conclusion, this article elucidates the multifaceted roles of BCAAs in heart failure and cardiovascular health, providing guidance for future research and intervention measures.

The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and is characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression\'s development. Given that obesity and depression mutually increase each other\'s risk of development by 50-60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines and C-reactive protein (CRP). As pharmacotherapy fails in at least 30-40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further efforts directed at implementing these strategies in clinical practice could contribute to improved outcomes in patients with depression, comorbid obesity, and/or metabolic dysregulation.

Chronic hepatitis C virus (HCV) infection is an important public health issue. However, knowledge on how the virus remodels the metabolic and immune response toward hepatic pathologic environment is limited. The transcriptomic and multiple evidences reveal that the HCV core protein-intestine-specific homeobox (ISX) axis promotes a spectrum of metabolic, fibrogenic, and immune modulators (e.g., kynurenine, PD-L1, and B7-2), regulating HCV-infection relevant pathogenic phenotype in vitro and in vivo. In a transgenic mice model, the HCV core protein-ISX axis enhance metabolic disturbance (particularly lipid and glucose metabolism) and immune suppression, and finally, chronic liver fibrosis in a high-fat diet (HFD)-induced disease model. Mechanistically, cells with HCV JFH-1 replicons upregulate ISX and, consequently, the expressions of metabolic, fibrosis progenitor, and immune modulators via core protein-induced nuclear factor-κB signaling. Conversely, cells with specific ISX shRNAi inhibit HCV core protein-induced metabolic disturbance and immune suppression. Clinically, the HCV core level is significantly correlated with ISX, IDOs, PD-L1, and B7-2 levels in HCC patients with HCV infection. Therefore, it highlights the significance of HCV core protein-ISX axis as an important mechanism in the development of HCV-induced chronic liver disease and can be a specific therapeutic target clinically.

UNASSIGNED: Accumulating studies suggested that major depressive disorder (MDD) was closely related to metabolic syndrome (MetS). Important endogenous regulators fibroblast growth factors (FGFs) 19 and 21 were also reported to participate in psychiatric disorders. This study aimed to investigate the role of FGF19 and FGF21 in MDD and to explore the possible pathogenic mechanism of metabolic and cognitive dysregulation in depression.
UNASSIGNED: A total of 59 MDD patients and 55 healthy control participants were recruited. The serum levels of FGF19 and FGF21 and lipid profiles were measured by means of enzymatic methods. Cognitive function was measured by repeatable battery for the assessment of neuropsychological status (RBANS) scores. The gene expression of PGC-1α and FNDC5 was determined by quantitative polymerase chain reaction (PCR).
UNASSIGNED: We found that plasma FGF19 and FGF21 levels were significantly decreased in patients with MDD. Meanwhile, triglyceride (TG) was significantly elevated and PGC-1α was significantly downregulated in MDD patients. Correlation analyses showed negative associations between TG and FGF19 levels. As for cognitive performance, both FGF19 and FGF21 levels were positively correlated with immediate memory. However, FGF19 levels were negatively correlated with language, and FGF21 levels were also negatively correlated with attention and delayed memory. Additionally, negative associations were found between FGF19 levels and PGC-1α. FGF21 levels were positively associated with PGC-1α and negatively associated with FNDC5.
UNASSIGNED: This study elucidated the role of FGF19 and FGF21 in MDD. MDD patients were confirmed to have metabolic and cognitive dysregulation, and this abnormality was linked to the decreased concentrations of FGF19 and FGF21 through the PGC-1α/FNDC5 pathway. Our results showed that the alterations of FGF19 and FGF21 levels may be a common pathogenic mechanism of metabolic and cognitive disturbances in patients with MDD.

Red wine polyphenolic complexes have attracted increasing attention as potential modulators of human metabolic disease risk. Our previous study discovered that red wine high-molecular-weight polymeric polyphenolic complexes (HPPCs) could inhibit key metabolic syndrome-associated enzymes and favorably modulate human gut microbiota (GM) in simulated colonic fermentation assay in vitro. In this work, the efficacy of HPPC supplementation (150 and 300 mg/kg/day, respectively) against high-fat diet (HFD)-induced metabolic disturbance in mice was investigated. HPPCs effectively attenuated HFD-induced obesity, insulin resistance, and lipid and glucose metabolic dysregulation and ameliorated inflammatory response and hepatic and colonic damage. It also improved the relative abundance of Bacteroidetes and Firmicutes, consistent with an anti-obesity phenotype. The favorable modulation of GM was further supported by improvement in the profile of fecal short-chain fatty acids. The higher dosage generally had a better performance in these effects than the low dosage. Moreover, serum metabolite profiling and pathway enrichment analysis revealed that HPPCs significantly modulated vitamin B metabolism-associated pathways and identified N-acetylneuraminic acid and 2-methylbutyroylcarnitine as potential biomarkers of the favorable effect on HFD-induced metabolic dysregulation. These findings highlight that dietary supplementation with red wine HPPCs is a promising strategy for the management of weight gain and metabolic dysregulation associated with HFD.

Previous research has shown a significant association between weight and telomere length, but did not take into consideration weight range. The study was to investigate the association of weight range with telomere length.
Data of 2918 eligible participants aged 25-84 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 cycle were analyzed. Information about demographic variables, lifestyle factors, anthropometric variables, and medical comorbidities were included. Univariate and multivariate linear regression model with adjustments for potential confounders were employed to determine the association between weight range and telomere length. A non-parametrically restricted cubic spline model was used to illustrate the possible non-linear relationship.
In univariate linear regression, BMImax, BMI range, and weight range all revealed significant negative associations with telomere length. However, annual rate of BMI/weight range showed a significant positive associations with telomere length. There was no significant association between telomere length and BMImin. After adjusting for potential confounders, the inverse associations persisted in BMImax (β=-0.003, P<0.001), BMI range (β=-0.002, P=0.003), and weight range (β=-0.001, P=0.001). Furthermore, annual rate of BMI range (β=-0.026, P=0.009) and weight range (β=-0.010, P=0.007) presented negative associations with telomere length, after adjusting for covariates in Model 2-4. The association between BMImin (β =-0.002, P=0.237) and telomere length still could not reach statistical significance in multivariate linear regression model. The results of restricted cubic spline analysis showed that BMImax (P for nonlinear =0.026), BMI range (P for nonlinear =0.022), weight range (P for nonlinear =0.035), annual rate of BMI range (P for nonlinear =0.030), and annual rate of weight range (P for nonlinear =0.027) all had nonlinear inverse associations with telomere length.
The study suggests that weight range is inversely associated with telomere length in U.S. adults. Larger weight fluctuation may accelerate telomere shortening and aging.