Metabolic Inflammation Research Articles

Sestrin2 serves as a scaffold protein to maintain cardiac energy and metabolic homeostasis during pathological stress.

Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide. Metabolic imbalances and pathological stress often contribute to increased mortality. Sestrin2 (Sesn2) is a stress-inducible protein crucial in maintaining cardiac energy and metabolic homeostasis under pathological conditions. Sesn2 is upregulated in response to various stressors, including oxidative stress, hypoxia, and energy depletion, and mediates multiple cellular pathways to enhance antioxidant defenses, promote autophagy, and inhibit inflammation. This review explores the mechanisms through which Sesn2 regulates these pathways, focusing on the AMPK-mTORC1, Sesn2-Nrf2, and HIF1α-Sesn2 pathways, among others. We can identify the potential therapeutic targets for treating CVDs and related metabolic disorders by comprehending these complex mechanisms. Sesn2's unique ability to respond thoroughly to metabolic challenges, oxidative stress, and inflammation makes it a promising prospect for enhancing cardiac health and resilience against pathological stress.

Comparative assessment of phenotypic markers in patients with chronic inflammation: Differences on Bifidobacterium concerning liver status.

The relationship between systemic lupus erythematosus (SLE) and low-grade metabolic inflammation (MI) with the microbiota is crucial for understanding the pathogenesis of these diseases and developing effective therapeutic interventions. In this context, it has been observed that the gut microbiota plays a key role in the immune regulation and inflammation contributing to the exacerbation through inflammatory mediators. This research aimed to describe similarities/differences in anthropometric, biochemical, inflammatory, and hepatic markers as well as to examine the putative role of gut microbiota concerning two inflammatory conditions: SLE and MI. Data were obtained from a cohort comprising adults with SLE and MI. Faecal samples were determined by 16S technique. Statistical analyses compared anthropometric and clinical variables, and LEfSe and MetagenomeSeq were used for metagenomic data. An interaction analysis was fitted to investigate associations of microbiota with fatty liver index (FLI) depending on the inflammatory condition. Participants with low-grade MI showed worse values in anthropometry and biochemicals compared with patients with SLE. The liver profile of patients with MI was unhealthier, while no relevant differences were found in most of the inflammatory markers between groups. LEfSe analysis revealed an overrepresentation of Bifidobacteriaceae family in SLE group. An interactive association between gut Bifidobacterium abundance and type of disease was identified for FLI values, suggesting an effect modification of the gut microbiota concerning liver markers depending on the inflammatory condition. This study found phenotypical and microbial similarities and disparities between these two inflammatory conditions, evidenced in clinical and hepatic markers, and showed the interactive interplay between gut Bifidobacterium and liver health (measured by FLI) that occur in a different manner depending on the type of inflammatory disease. These results underscore the importance of personalized approaches and individual microbiota in the screening of different inflammatory situations, considering unique hepatic and microbiota profiles.

Integrated plasma proteomics and myocardial tissue transcriptomics reveal elevated fibrosis markers in arrhythmogenic cardiomyopathy patients

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is characterized by myocardial fibrofatty replacement and ventricular arrhythmias, with potential progression to heart failure. This study aims to identify ACM-specific biomarkers for improved prognosis and possible treatment strategies. Methods RNA sequencing and transcriptome analyses were performed in cardiomyocytes of 10 ACM patients, 10 dilated cardiomyopathy patients and 10 healthy controls. Analyses were performed using liquid chromatography and mass spectrometry. Additionally, plasma protein expression was assessed in 38 ACM patients and 24 healthy controls using the Proximity Extension Assay (Olink®). A standardized bicycle exercise test was performed in 11 ACM patients and controls and blood was obtained before and after exercise. Results Myocardial tissue transcriptomics identified several upregulated molecules associated with extracellular matrix formation and immune response in ACM. Plasma protein sequencing revealed upregulation of proteins involved in metabolic pathways, inflammation, and fibrosis. Integration of these analyses identified key soluble profibrotic markers such as Fibulin-3, Endostatin and C-X-C motif chemokine 10 (CXCL10) in plasma of ACM patients. After exercise, Fibulin-3 levels increased in ACM patients compared to controls. These findings were further validated using enzyme-linked immunosorbent assay (ELISA). Conclusion This comprehensive analysis revealed distinct proteomic and transcriptomic signatures in ACM patients' plasma and cardiomyocytes. The integrative analysis identified several upregulated profibrotic markers in ACM. Our Findings may advance diagnostic and prognostic strategies and offer potential therapeutic targets.

Proteomic profiling of extracellular vesicles in takotsubo syndrome

Abstract Background/Purpose Takotsubo syndrome (TS) is an acute form of heart failure characterized by transient regional wall motion abnormalities triggered by a stressful event. The mechanisms underlying its development and recovery are poorly understood, resulting in a lack of disease-specific treatments and diagnostic markers. Extracellular vesicles (EVs) play a significant role in cellular communication and have been shown to be important in various diseases. Their involvement in cardiac conditions like TS is an emerging area of research. The primary objective of this study is to isolate and characterize EVs, as well as profile their proteomic profile, from the heart tissue of rats induced with TS. Methods Rats underwent TS induction through the infusion of 1 mg/kg isoprenaline over 15 minutes (TS24h), or were given saline (control). High-resolution echocardiography verified apical ballooning at 6 hours. After 24 hours, heart tissues from apical and basal segments were collected and processed. EV isolation involved tissue slicing, enzymatic digestion, and differential centrifugation steps, including a final iodixanol cushion separation for large and small EVs (Figure 1). Tandem mass tags and mass spectrometry were utilized for global proteomics and any differentially expressed proteins (DEPs) were identified. Analytical techniques such as volcano plots, heatmaps, enrichment analysis, and protein clustering/networks were employed. The strongest clusters (lowest False Discovery Rate and highest intensity) were selected, and their Gene Ontology (GO) terms/pathways were identified. Results Pure, cup-shaped, vesicles ranging from 50-800nm were successfully isolated (figure 1). EVs from apex of control and TS24h hearts had lower protein concentrations compared to their corresponding basal segments. Global proteomic analysis revealed a distinct protein profile in EVs from the apical segment of TS hearts at 24 hours. A total of 256 (TS24h-apex vs control-apex) and 561 proteins (TS24h-apex vs TS24h-base) were differentially expressed. No DEPs were observed when comparing the basal segments of TS24h and control hearts. Functional enrichment analysis of the DEPs showed an abundant change of biological processes related to metabolic lipid processes, inflammatory response, complement activation, reorganization of extracellular matrix. A downregulation was seen for biological processes related to mitochondrial ATP synthesis coupled electron transport and muscle contraction. Conclusion This study demonstrates a distinct EV protein profile in the apical segments of TS hearts, with marked changes in proteins related to metabolic lipid processes, inflammation, and mitochondrial activity. This extensive catalogue of novel proteins sets the stage for future research aimed at identifying potential therapeutic targets and diagnostic biomarkers, and enabling proof-of-concept studies in TS.

MiR-375: it could be a general biomarker of metabolic changes and inflammation in type 1 diabetes patients and their siblings.

Type 1 diabetes (T1D) is a chronic autoimmune illness that results in loss of pancreatic beta cells and insulin insufficiency. MicroRNAs (miRNAs) are linked to immune system functions contributing to the pathophysiology of T1D, miRNA-375 is significantly expressed in the human pancreas and its circulatory levels might correspond to beta cell alterations. Pancreatic islet cell antibodies (ICA) and Glutamic acid decarboxylase antibodies (GADA) have roles in autoimmune pathogenesis and are predictive markers of T1D. The aim of this work was to detect serum level changes of miRNA-375, ICA, and GADA in T1D patients, and their siblings compared to healthy controls and correlate them with T1D biochemical parameters. The study included 66 T1D patients (32 males and 34 females; age range 3-18 years), 22 patients' siblings (13 males and 9 females; age range 4-17 years), and 23 healthy controls (7 males and 16 females; age range 4-17 years). MiRNA-375 levels were measured using quantitative reverse transcription polymerase chain reaction (RT-qPCR), while ICA and GADA levels were measured using enzyme-linked immunosorbent assay (ELISA). Data analysis was done utilizing SPSS-17 software. MiR-375 levels were downregulated in T1D patients and further decreased in their siblings when compared to healthy controls. Furthermore, miR-375 exhibited inverse correlations with HbA1c levels but no correlations with Total Insulin Dose, disease duration, or autoantibodies (GADA & ICA). Our study indicates that miR-375 is significantly downregulated in children with T1D and their siblings, suggesting its potential role as a biomarker for beta-cell function and glycemic control.

Evaluation of fenugreek (Trigonella foenum-graecum L.) powder supplementation on metabolic syndrome, oxidative stress and inflammation in high fat diet fed rats

As an anti-diabetic medicinal plant, fenugreek seed (FG) (Trigonella foenum-graecum L.) has long been utilized and has many therapeutic uses. The current investigation sought to ascertain the effects of FG powder supplementation on insulin resistance, dyslipidemia, and oxidative stress in rats given a high-fat (HF) diet. Measurements of biochemical and antioxidant indicators were made in animal blood and tissue samples, including malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), reduced glutathione (GSH), superoxide dismutase (SOD), triglycerides (TG), and catalase (CAT). Furthermore, the tissues of the kidney, heart, and liver were stained histologically. HF diet feeding in rats declined in antioxidant enzyme activities, along with a rise in MDA and other indicators of oxidative stress, which were mitigated by the supplementation of FG. Additionally, FG supplementation enhanced the expression of genes corresponding to antioxidants in the liver of rats given HF diet. FG supplements in HF diet-fed rats displayed altered gene expression in the livers that metabolized fat. Histological staining of the liver demonstrated that FG supplementation reduced necrosis and the accumulation of fat droplets in the liver of rats given HF diets. In conclusion, this finding showed that FG supplementation in HF diet fed rats reduced the plasma lipids, decreased oxidative stress and raised antioxidant enzyme activities. FG may therefore aid in reducing the chronic complications linked to the HF diet in experimental rats.

Comparison of Metabolic Syndrome, Autoimmune and Viral Distinctive Inflammatory Related Conditions as Affected by Body Mass Index

Background: Metabolic inflammation (MI), long COVID (LC) and systemic lupus erythematosus (SLE) share some metabolic common manifestations and inflammatory pathophysiological similarities. Health-related quality of life (HRQoL) and metabolic age are indicators of health status. The “METAINFLAMMATION-CM Y2020/BIO-6600” project, a prospective controlled study, aimed to identify differential diagnostic tools and clinical features among three inflammatory conditions by comparing obesity status (low BMI vs. high BMI). Methods: A total of 272 adults of both Caucasian and Hispanic descent, diagnosed with MI, LC or SLE, and a range of BMI, were recruited. Clinical and phenotypic traits were measured to analyze body composition, metabolic and inflammatory markers, HRQoL data, metabolic age and lifestyle habits using a 3 × 2 (disease × BMI) factorial design. Results: Some inflammatory related variables, such as fibrinogen, RDW (red cell blood distribution width), ESR (erythrocyte sedimentation rate) and NLR (neutrophil/lymphocyte ratio), showed effect modifications depending on the BMI and disease type. In relation to HRQoL, the Physical Component Summary (PCS12) showed no relevant changes, while the Mental Component Summary (MCS12) showed a significant effect modification according to the disease type and BMI (p < 0.05). Furthermore, a significant interaction was identified between the disease type and BMI in relation to metabolic age (p = 0.02). Conclusions: Assessing the impact of BMI on these three inflammatory diseases may help to prevent clinical complications and to design personalized treatments, especially for patients with SLE, who have a worse prognosis with an increased BMI compared to the other two inflammatory diseases.

Glibenclamide Prevents Inflammation by Targeting NLRP3 Inflammasome Activation In Vitro

The NLRP3 inflammasome is known to play a significant role in the development of neurodegeneration and physiological aging, as well as the development of metabolic inflammation, which has generated significant interest in the scientific community in finding effective inhibitors of the NLRP3 inflammasome and assessing their effects. The purpose of this study was to evaluate the effect of pharmacological modulation of NLRP3 activity using an indirect NLRP3 inflammasome inhibitor, glibenclamide, on the expression of metaflammasome components in in vitro brain cells obtained from middle-aged mice. The study revealed that glibenclamide reduces the expression of pro-inflammatory markers NLRP3 and IL18 in cell culture, which in turn leads to the prevention of phosphorylation of protein kinases of the metaflammasome complex – PKR and IKKβ. However, we did not observe changes in the expression of pathologically phosphorylated IRS, as well as in the number of senescent cells in cultures after the exposure to glibenclamide.

The Associations between Asprosine, Clusterin, Zinc Alpha-2-Glycoprotein, Nuclear Factor Kappa B, and Peroxisome Proliferator-Activated Receptor Gamma in the Development of Complications in Type 2 Diabetes Mellitus.

Objectives: The aim of this study was to investigate the circulating levels of asprosin, clusterin, zinc-alpha-2-glycoprotein (ZAG), nuclear factor-kappa B (NF-κB), and peroxisome proliferator-activated receptor-gamma (PPAR-γ) in patients with T2DM in relation to microvascular and macrovascular complications. Measuring these biomarkers may provide insight into the pathophysiology of T2DM and indicate novel targets for the therapy of diabetes-related complications. Methods: A total of 260 subjects consisting of four groups: healthy controls (Group-1), T2DM patients without complications (Group-2), T2DM patients with microvascular complications (Group-3), and T2DM patients with macrovascular complications (Group-4). Results: The mean age of all subjects was 52.96 ± 6.4, 127 of whom were male. Asprosin, clusterin, and NF-κB levels were significantly higher, while ZAG and PPAR-γ levels were significantly lower in diabetic patients than healthy subjects (p < 0.01, for all). Asprosin (p < 0.01), clusterin (p < 0.01), and NF-κB (p: 0.002) levels were significantly higher and PPAR-γ (p < 0.01) level was significantly lower (p < 0.001) in Group-3 than Group-2. Asprosin (p < 0.01) and NF-κB (p: 0.011) levels were significantly higher while ZAG (p < 0.01) level was significantly lower in Group-4 than Group-2. Serum ZAG level was found lower in Group-4 than in Group-3 (p = 0.037). Further, the biomarkers presented significant correlation with biomarkers like HbA1c and HOMA-IR. It was observed that increasing serum asprosin, clusterin, and NF-κB levels and decreasing serum PPAR-γ levels were effective in the development of microvascular complications while the increased asprosin levels and decreased ZAG levels had a significant effect on the development of macrovascular complications in the binary logistic regression analysis. Conclusions: This study confirms that altered levels of asprosin, clusterin, ZAG, NF-κB, and PPAR-γ are associated with T2DM and its complications. These biomarkers reflect the pathophysiological processes of metabolic disturbance and inflammation in T2DM and, therefore, have the potential for use in targeted interventions to prevent and manage diabetes-related complications.

Obesity alters circadian and behavioral responses to constant light in male mice

Exposure to artificial light during the night is known to promote disruption to the biological clock, which can lead to impaired mood and metabolism. Metabolic hormone secretion is modulated by the circadian pacemaker and recent research has shown that hormones such as insulin and leptin can also directly affect behavioral outcomes and the circadian clock. In turn, obesity itself is known to modulate the circadian rhythm and alter emotionality. This study investigated the behavioral and metabolic effects of constant light exposure in two models of obesity – a leptin null mutant (OB) and diet-induced obesity via high-fat diet. For both experiments, mice were placed into either a standard Light:Dark cycle (LD) or constant light (LL) and their circadian locomotor rhythms were continuously monitored. After 10 weeks of exposure to their respective lighting conditions, all mice were subjected to an open field assay to assess their explorative behaviors. Their metabolic hormone levels and inflammation levels were also measured. Behaviorally, exposure to constant light led to increased period lengthening and open field activity in the lean mice compared to both obesity models. Metabolically, LL led to increased cytokine levels and poorer metabolic outcomes in both lean and obese mice, sometimes exacerbating the metabolic issues in the obese mice, independent of weight gain. This study illustrates that LL can produce altered behavioral and physiological outcomes, even in lean mice. These results also indicate that obesity induced by different reasons can lead to shortened circadian rhythmicity and exploratory activity when exposed to chronic light.

Pediatric migraine is characterized by traits of ecological and metabolic dysbiosis and inflammation.

Recently, there has been increasing interest in the possible role of the gut microbiota (GM) in the onset of migraine. Our aim was to verify whether bacterial populations associated with intestinal dysbiosis are found in pediatric patients with migraine. We looked for which metabolic pathways, these bacteria were involved and whether they might be associated with gut inflammation and increased intestinal permeability. Patients aged between 6 and 17years were recruited. The GM profiling was performed by the 16S rRNA metataxonomics of faecal samples from 98 patients with migraine and 98 healthy subjects. Alpha and beta diversity analyses and multivariate and univariate analyses were applied to compare the gut microbiota profiles between the two group. To predict functional metabolic pathways, we used phylogenetic analysis of communities. The level of indican in urine was analyzed to investigate the presence of metabolic dysbiosis. To assess gut inflammation, increased intestinal permeability and the mucosal immune activation, we measured the plasmatic levels of lipopolysaccharide, occludin and IgA, respectively. The α-diversity analysis revealed a significant increase of bacterial richness in the migraine group. The β-diversity analysis showed significant differences between the two groups indicating gut dysbiosis in patients with migraine. Thirty-seven metabolic pathways were increased in the migraine group, which includes changes in tryptophan and phenylalanine metabolism. The presence of metabolic dysbiosis was confirmed by the increased level of indican in urine. Increased levels of plasmatic occludin and IgA indicated the presence of intestinal permeability and mucosal immune activation. The plasmatic LPS levels showed a low intestinal inflammation in patients with migraine. Pediatric patients with migraine present GM profiles different from healthy subjects, associated with metabolic pathways important in migraine.

B-cell Interleukin 1 Receptor 1 (IL1R1) modulates the female adipose tissue immune microenvironment during aging.

Myeloid cell production of interleukin-1β (IL-1β) drives inflammaging in visceral adipose tissue (vWAT) and contributes to the expansion of interleukin-1 receptor 1 (Il1r1) positive aged adipose B-cells (AABs). AABs promote metabolic dysfunction and inflammation under inflammatory challenges. However, it is unclear whether IL-1β contributes to AAB-associated inflammation during aging. Using a B-cell specific knockout of Il1r1 (BKO mice), we characterized old vWAT in the absence of IL-1β - B-cell signaling. In addition to sex-specific metabolic improvements in females, we identified a reduction in the proportion of B-cells and a sex-specific increase in the B1:B2 B-cell ratio in BKO vWAT. Using single cell RNA-sequencing of vWAT immune cells, we observed that BKO differentially affected inflammatory signaling in vWAT immune cells. These data suggest that IL-1β - B-cell signaling supports the inflammatory response in multiple cell types and provides insight into the complex microenvironment in aged vWAT.

Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α–HO–1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.

Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction.

The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.

Associations of dietary total, heme, non-heme iron intake with diabetes, CVD, and all-cause mortality in men and women with diabetes

BackgroundIron metabolism disorders significantly increase the risk of diabetes and its related complications by inducing oxidative stress, inflammation, insulin resistance, and disturbances in glucose and lipid metabolism. However, whether dietary iron intake can influence progression of diabetes remains unclear. The present study aims to investigate the relationship between total iron, heme iron, and non-heme iron intake and diabetes, CVD, and all-cause mortality among men and women with diabetes in the U.S. population. MethodsA total of 4416 adults with diabetes(2415 men and 2001 women) from the NHANES 2003–2014 were enrolled. Dietary information was collected by 24-h dietary recall during two nonconsecutive days. Dietary total iron intake was measured based on the dietary survey. Dietary heme iron intake was calculated based on its proportion in dietary total iron intake from each food. non-heme iron is the difference between total iron and heme iron. Diabetes, CVD, and all-cause mortality status were identified as main outcomes. Cox models and RCS analysis were performed to estimate the hazard ratios and 95%CIs. ResultsFor men, the participants with a higher dietary heme iron intake were associated with higher risks of CVD (HRheme iron = 1.61,95%CI:1.03–2.51) and all-cause mortality (HRheme iron = 1.42,95%CI:1.10–1.83). For women, participants in the highest quartile of dietary total/heme/non-heme iron intake had a higher diabetes mortality risk ((HRtotal iron = 2.33,95%CI:1.24–4.38; HRheme iron = 1.87,95%CI:1.00–3.49; HRnon-heme iron = 2.28,95%CI:1.19–4.39), compared to those in the lowest quartile. Additionally, the dose–response curve for the relationship between dietary non-heme iron intake and CVD mortality followed a reverse J-shape in women with diabetes. ConclusionsHigher dietary heme iron intake was associated with an increased CVD mortality risk in both men and women with diabetes. Additionally, higher dietary total, heme, and non-heme iron intake was linked to an increased risk of diabetes mortality among women with diabetes. Therefore, women with diabetes should pay more attention on the overconsumption of any type of dietary iron.

Effect of standard feeding with a high-protein diet on arterial blood gases in patients admitted to the intensive care units: A study protocol for a double-blinded, randomized controlled clinical trial

Critically ill patients admitted to the intensive care units (ICUs) often face numerous challenges, including severe metabolic stress, systemic inflammation, and compromised immune function. Studies have suggested that critically ill patients frequently experience a negative nitrogen balance due to a hypercatabolic state, leading to impaired organ function and muscle wasting, which can cause severe muscle weakness and physical disability for years after discharge. Arterial blood gases (ABG) reflect patients' oxygenation and acid-base status and are crucial indicators of respiratory and metabolic function in critically ill individuals. We aim to address this by conducting a double-blinded, randomized controlled clinical trial to compare the effects of standard feeding with a high-protein diet on ABG in ICU patients. In this double-blinded, randomized controlled clinical trial, we will use block randomization of 80 patients aged between 18 to 65 years old and Patients expected to be hospitalized in the ICU for at least 3 days from Kosar Hospital, Kurdistan, Iran. The intervention group (n=40) will receive a protein diet (consisting of 18.7% protein, 45% carbohydrates, and 35% fat per 1000cc). A control group (n=40) will receive a standard diet (14.4% protein, 54% carbohydrates, and 32.4% fat per 1000cc) for the same duration in addition to usual care. The caloric requirements of each patient will be determined by a nutritionist based on their nutritional status, height, weight, age, and initial diagnosis, utilizing the Harris-Benedict formula. The parameters of ABG, including PO2, PCO2, SAO2, HCO3, BE, and pH, will be assessed. By optimizing protein intake through a high-protein diet, we aim to improve the nutritional status of patients and enhance their overall clinical outcomes. This reassures us of the potential benefits of our study.

Tinglu Yixin granule inhibited fibroblast-myofibroblast transdifferentiation to ameliorate myocardial fibrosis in diabetic mice

Ethnopharmacological relevanceMyocardial fibrosis is one of the pathological characteristics of advanced diabetic cardiomyopathy (DCM) and serves as the strong evidence of poor prognosis. Among them, the transdifferentiation of cardiac fibroblasts (CFs) may play a crucial role in the development of myocardial fibrosis in DCM. Tinglu Yixin granule (TLYXG) has been clinically used for many years and can significantly improve cardiac function of patients with DCM. However, the effect of TLYXG on myocardial fibrosis in DCM remains unknown, and the underlying mechanisms of its efficacy have yet to be fully understood. Aim of the studyThis study aimed to investigate the impact and underlying mechanism of TLYXG on myocardial fibrosis in diabetes mice. Materials and methodsThe bioactive compounds in TLYXG were identified using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The potential mechanism of TLYXG in treating DCM was predicted using network pharmacology combined with molecular docking and protein-protein docking. The mice model of type 2 diabetes were established by intraperitoneal injection of streptozotocin (STZ) and the high-fat diet (HFD). Indicators of pancreatic islet function, lipids, oxidative stress, and inflammatory factors were tested using kits. Cardiac function was assessed in diabetic mice using echocardiography. Histologic staining was performed to evaluate myocardial hypertrophy and fibrosis. Mechanistically, the hypothesis was tested through rescue experiments. The expression levels of transient receptor potential channel 6 (TRPC6), transforming growth factor-β1 (TGF-β1), collagen I (COL-I) and alpha-smooth muscle actin (α-SMA), along with the mRNA and phosphorylation levels of SMAD family member 3 (Smad3) and protein 38 mitogen-activated protein kinase (p38 MAPK), were assessed using quantitative RT-qPCR, western blot, immunohistochemistry, and immunofluorescence. Neonatal lactating mice were used to extract primary CFs for vitro experiments. Scratch and transwell assays were conducted to assess CFs migration and invasion abilities. Western blot and immunofluorescence were used to evaluate the expression levels of CFs transdifferentiation markers COL-I and α-SMA. ResultsA total of 168 active ingredients were detected in TLYXG based on UPLC-MS and databases. Network pharmacology indicated that TLYXG could improve DCM through inflammatory mediator regulation of TRP channels, TGF-beta signaling pathway, and MAPK signaling pathway. ELISA results showed that TLYXG could ameliorate metabolic levels, inflammation, and oxidative stress in diabetic mice. Echocardiography suggested that TLYXG improved cardiac systolic and diastolic dysfunction in diabetic mice. Histological analysis revealed that TLYXG alleviated myocardial fibrosis in diabetes mice. Additionally, molecular docking analysis indicated strong binding activity between the main active ingredients of TLYXG and TRPC6 of the TRP family. At the molecular level, TLYXG reduced the mRNA and protein expression levels of TRPC6 and TGF-β1 and inhibited the mRNA and phosphorylation levels of Smad3 and p38 MAPK. Furthermore, TLYXG inhibited CFs migration and invasion, and reduced the expression levels of the CFs transdifferentiation markers COL-I and α-SMA. ConclusionTLYXG inhibited the proliferation, migration, invasion and transdifferentiation of CFs by suppressing TGF-β1/Smad3/p38 MAPK signaling through down-regulation of TRPC6, thereby ameliorating myocardial fibrosis in diabetes mice.

Metabolic Syndrome, Inflammation, Oxidative Stress, and Vitamin D Levels in Children and Adolescents with Obesity.

Metabolic syndrome (MetS) is associated with systemic inflammation, oxidative stress, and hypovitaminosis D. Our aim was to determine whether vitamin D mediates inflammation and oxidative stress, assessed through selected biomarkers, in children with obesity and/or MetS. Eighty children with normal weight, overweight, or obesity were analyzed for serum vitamin D, C-reactive protein, leukocytes, adiponectin, monocyte chemoattractant protein-1, myeloperoxidase, interferon-inducible T-cell alpha chemoattractant (I-TAC/CXCL11), superoxide dismutase-1, fasting lipid and glucose levels, ultrasound-measured abdominal fat thickness, waist circumference, body mass index and blood pressure. Children with obesity or overweight had lower vitamin D levels, increased blood pressure, visceral and subcutaneous fat thickness, and higher leukocytes, C-reactive protein, and myeloperoxidase levels. Those with MetS also had lower adiponectin levels. Vitamin D levels are negatively correlated with body mass index, waist circumference, and visceral and subcutaneous fat thickness. Correlation, mediation, and regression analyses showed no link between vitamin D and inflammatory/oxidative stress variables. The novel biomarker I-TAC did not correlate with obesity or vitamin D status. Our results indicate that vitamin D does not significantly mediate inflammation or oxidative stress in children and adolescents with obesity and/or MetS. Selected inflammation/oxidative stress biomarkers appear to be altered primarily due to obesity rather than vitamin D status.

Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform

With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue.

Metabolic Shift and Hyperosmolarity Underlie Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is both a poorly understood and devastating disease. Here, we analyze the physico-chemical forces at stake, including osmolarity, redox shift, and pressure due to inflammation. Hyperosmolarity plays a key role in diseases of the anterior segment of the eye such as glaucoma, cataracts or dry eyes, and corneal ulceration. However, its role in macular degeneration has been largely overlooked. Hyperosmolarity is responsible for metabolic shifts such as aerobic glycolysis which increases lactate secretion by Muller cells. Increased osmolarity will also cause neoangiogenesis and cell death. Because of its unique energetic demands, the macula is very sensitive to metabolic shifts. As a proof of concept, subretinal injection of drugs increasing hyperosmolarity such as polyethylene glycol causes neoangiogenesis and drusen-like structures in rodents. The link between AMD and hyperosmolarity is reinforced by the fact that treatments aiming to restore mitochondrial activity, such as lipoic acid and/or methylene blue, have been experimentally shown to be effective. We suggest that metabolic shift, inflammation, and hyperosmolarity are hallmarks in the pathogenesis and treatment of AMD.