Prevalence of clinical characteristics of lipodystrophy in the US adult population in a healthcare claims database.

BACKGROUND: Lipodystrophy is characterized by progressive loss of adipose tissue and consequential metabolic abnormalities. With new treatments emerging for lipodystrophy, there is a growing need to understand the prevalence of specific comorbidities that may be commonly associated with lipodystrophy to contextualize the natural history of lipodystrophy without any disease modifying therapy. OBJECTIVE: To examine the risk of specific clinical characteristics in people living with lipodystrophy (LD) in 2018-2019 compared with the general US population, among the commercially insured US population. METHODS: A retrospective cohort study was conducted using the 2018-2019 Clinformatics® Data Mart database. An adult LD cohort (age ≥ 18 years) with at least ≥ 1 inpatient or ≥ 2 outpatient LD diagnoses was created. The LD cohort included non-HIV-associated LD (non-HIV-LD) and HIV-associated LD (HIV-LD) subgroups and compared against age- and sex-matched control groups with a 1:4 ratio from the general population with neither an LD or an HIV diagnosis using odds ratios (ORs) with 95% confidence intervals. RESULTS: We identified 546 individuals with non-HIV-LD (mean age, 60.3 ± 14.9 years; female, 67.6%) and 334 individuals with HIV-LD (mean age, 59.2 ± 8.3 years; female, 15.0%) in 2018-2019. Compared with the general population, individuals with non-HIV-LD had higher risks (odds ratio [95% confidence interval]) for hyperlipidemia (3.32 [2.71-4.09]), hypertension (3.58 [2.89-4.44]), diabetes mellitus (4.72 [3.85-5.79]), kidney disease (2.78 [2.19-3.53]), liver fibrosis or cirrhosis (4.06 [1.66-9.95]), cancer (2.20 [1.59-3.01]), and serious infections resulting in hospitalization (3.00 [2.19-4.10]). Compared with individuals with HIV, those with HIV-LD have higher odds of hypertension (1.47 [1.13-1.92]), hyperlipidemia (2.46 [1.86-3.28]), and diabetes (1.37 [1.04-1.79]). CONCLUSIONS: LD imposes a substantial burden on affected individuals due to a high prevalence of metabolic comorbidities and other complications as compared with the general non-LD population. Future longitudinal follow-up studies investigating the causality between LD and observed comorbidities are warranted.

Precision Phenotyping of Heart Failure in People with HIV: Early Insights and Challenges.

PURPOSE OF REVIEW: People with HIV have an elevated risk of developing heart failure even with optimally controlled disease. In this review, we outline the various mechanisms through which HIV infection may directly and indirectly contribute to heart failure pathology and highlight the emerging relationship between HIV, chronic inflammation, and cardiometabolic disease. RECENT FINDINGS: HIV infection leads to chronic inflammation, immune dysregulation, and metabolic imbalances even in those with well controlled disease. These dysregulations occur through several diverse mechanisms which may lead to manifestations of different phenotypes of heart failure in people with HIV. While it has long been known that people with HIV are at risk of developing heart failure, recent studies have suggested numerous complex mechanisms involving chronic inflammation, immune dysregulation, and metabolic derangement through which this may be mediated. Further comprehensive studies are needed to elucidate the precise relationship between these mechanisms and the development of different subtypes of heart failure in people with HIV.

Comprehensive Analysis of Gut Microbiota Composition and Functional Metabolism in Children with Autism Spectrum Disorder and Neurotypical Children: Implications for Sex-Based Differences and Metabolic Dysregulation.

This study aimed to investigate the gut microbiota composition in children with autism spectrum disorder (ASD) compared to neurotypical (NT) children, with a focus on identifying potential differences in gut bacteria between these groups. The microbiota was analyzed through the massive sequencing of region V3-V4 of the 16S RNA gene, utilizing DNA extracted from stool samples of participants. Our findings revealed no significant differences in the dominant bacterial phyla (Firmicutes, Bacteroidota, Actinobacteria, Proteobacteria, Verrucomicrobiota) between the ASD and NT groups. However, at the genus level, notable disparities were observed in the abundance of Blautia, Prevotella, Clostridium XI, and Clostridium XVIII, all of which have been previously associated with ASD. Furthermore, a sex-based analysis unveiled additional discrepancies in gut microbiota composition. Specifically, three genera (Megamonas, Oscilibacter, Acidaminococcus) exhibited variations between male and female groups in both ASD and NT cohorts. Particularly noteworthy was the exclusive presence of Megamonas in females with ASD. Analysis of predicted metabolic pathways suggested an enrichment of pathways related to amine and polyamine degradation, as well as amino acid degradation in the ASD group. Conversely, pathways implicated in carbohydrate biosynthesis, degradation, and fermentation were found to be underrepresented. Despite the limitations of our study, including a relatively small sample size (30 ASD and 31 NT children) and the utilization of predicted metabolic pathways derived from 16S RNA gene analysis rather than metagenome sequencing, our findings contribute to the growing body of evidence suggesting a potential association between gut microbiota composition and ASD. Future research endeavors should focus on validating these findings with larger sample sizes and exploring the functional significance of these microbial differences in ASD. Additionally, there is a critical need for further investigations to elucidate sex differences in gut microbiota composition and their potential implications for ASD pathology and treatment.

Metabolic Dysregulation and Its Role in Postoperative Pain among Knee Osteoarthritis Patients.

Knee osteoarthritis (KOA) is characterized by low-grade inflammation, loss of articular cartilage, subchondral bone remodeling, synovitis, osteophyte formation, and pain. Strong, continuous pain may indicate the need for joint replacement in patients with end-stage OA, although postoperative pain (POP) of at least a two-month duration persists in 10-40% of patients with OA. STUDY PURPOSE: The inflammation observed in joint tissues is linked to pain caused by the production of proinflammatory cytokines. Since the biosynthesis of cytokines requires energy, their production is supported by extensive metabolic conversions of carbohydrates and fatty acids, which could lead to a disruption in cellular homeostasis. Therefore, this study aimed to investigate the association between POP development and disturbances in energy metabolic conversions, focusing on carbohydrate and fatty acid metabolism. METHODS: Peripheral blood samples were collected from 26 healthy subjects and 50 patients with end-stage OA before joint replacement surgery. All implants were validated by orthopedic surgeons, and patients with OA demonstrated no inherent abnormalities to cause pain from other reasons than OA disease, such as malalignment, aseptic loosening, or excessive bleeding. Pain levels were assessed before surgery using the visual analogue scale (VAS) and neuropathic pain questionnaires, DN4 and PainDETECT. Functional activity was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Three and six months after surgery, pain indices according to a VAS of 30 mm or higher were considered. Total RNA isolated from whole blood was analyzed using quantitative real-time RT-PCR (qRT-PCR) for the expression of genes related to carbohydrate and fatty acid metabolism. Protein levels of the examined genes were measured using an ELISA in the peripheral blood mononuclear cells (PBMCs). We used qRT-PCR because it is the most sensitive and reliable method for gene expression analysis, while an ELISA was used to confirm our qRT-PCR results. KEY FINDINGS: Among the study cohort, 17 patients who reported POP demonstrated significantly higher (p < 0.05) expressions of the genes PKM2, LDH, SDH, UCP2, CPT1A, and ACLY compared to pain-free patients with KOA. Receiver-operating characteristic (ROC) curve analyses confirmed the association between these gene expressions and pain development post-arthroplasty. A principle component analysis identified the prognostic values of ACLY, CPT1A, AMPK, SDHB, Caspase 3, and IL-1ß gene expressions for POP development in the examined subjects. CONCLUSION: These findings suggest that the disturbances in energy metabolism, as observed in the PBMCs of patients with end-stage KOA before arthroplasty, may contribute to POP development. An understanding of these metabolic processes could provide insights into the pathogenesis of KOA. Additionally, our findings can be used in a clinical setting to predict POP development in end-stage patients with KOA before arthroplasty.

Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122.

Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.

Widely targeted quantitative lipidomics and prognostic model reveal plasma lipid predictors for nasopharyngeal carcinoma.

BACKGROUND: Dysregulation of lipid metabolism is closely associated with cancer progression. The study aimed to establish a prognostic model to predict distant metastasis-free survival (DMFS) in patients with nasopharyngeal carcinoma (NPC), based on lipidomics. METHODS: The plasma lipid profiles of 179 patients with locoregionally advanced NPC (LANPC) were measured and quantified using widely targeted quantitative lipidomics. Then, patients were randomly split into the training (125 patients, 69.8%) and validation (54 patients, 30.2%) sets. To identify distant metastasis-associated lipids, univariate Cox regression was applied to the training set (P < 0.05). A deep survival method called DeepSurv was employed to develop a proposed model based on significant lipid species (P < 0.01) and clinical biomarkers to predict DMFS. Concordance index and receiver operating curve analyses were performed to assess model effectiveness. The study also explored the potential role of lipid alterations in the prognosis of NPC. RESULTS: Forty lipids were recognized as distant metastasis-associated (P < 0.05) by univariate Cox regression. The concordance indices of the proposed model were 0.764 (95% confidence interval (CI), 0.682-0.846) and 0.760 (95% CI, 0.649-0.871) in the training and validation sets, respectively. High-risk patients had poorer 5-year DMFS compared with low-risk patients (Hazard ratio, 26.18; 95% CI, 3.52-194.80; P < 0.0001). Moreover, the six lipids were significantly correlated with immunity- and inflammation-associated biomarkers and were mainly enriched in metabolic pathways. CONCLUSIONS: Widely targeted quantitative lipidomics reveals plasma lipid predictors for LANPC, the prognostic model based on that demonstrated superior performance in predicting metastasis in LANPC patients.

High-intensity interval training improves metabolic syndrome in women with breast cancer receiving Anthracyclines.

INTRODUCTION: Anthracycline chemotherapy is a frequent treatment for breast cancer, whereas it can increase risk of physiologic side-effects, such as metabolic syndrome (MetS). Exercise has been used as a non-pharmacological strategy to decrease MetS. Specifically, high-intensity interval training (HIIT) has been shown to improve MetS in patients with diabetes or cardiac rehabilitation patients; however, the effects of HIIT on MetS and associated biomarkers in patients with breast cancer receiving anthracycline chemotherapy have not been previously explored. Therefore, we purposed to determine the effects of HIIT on MetS in breast cancer patients undergoing anthracycline chemotherapy. METHODS: In total, 30 patients with breast cancer were recruited prior to initiating treatment and randomized into HIIT (n = 15) or control (n = 15). The HIIT group attended supervised cycling sessions 3 days/week for 8 weeks. MetS was assessed by waist circumference, blood pressure, fasting levels of high-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose. Circulating levels of MetS-related biomarkers were also measured (total cholesterol, insulin, HbA1c, leptin, adiponectin, and c-reactive protein). RESULTS: After 8 weeks, MetS z-score was significantly improved in the HIIT group compared with controls (-7.60, 95% CI: -9.08 to -6.13, p < 0.001). MetS variables (HDL-C, glucose, and triglycerides) and circulating levels of MetS-related biomarkers were significantly improved in the HIIT group compared with controls (p < 0.001). Non-significant differences were found in body composition outcomes at the end of the study. CONCLUSIONS: HIIT may be an effective strategy to improve MetS in breast cancer patients undergoing anthracycline chemotherapy. Furthermore, changes in MetS were independent of changes in body composition.

The Anti-Diabetic Potential of Baicalin: Evidence from Rodent Studies.

Baicalin is a biologically active flavonoid compound that benefits the organism in various pathological conditions. Rodent studies have shown that this compound effectively alleviates diabetes-related disturbances in models of type 1 and type 2 diabetes. Baicalin supplementation limited hyperglycemia and improved insulin sensitivity. The anti-diabetic effects of baicalin covered the main insulin-sensitive tissues, i.e., the skeletal muscle, the adipose tissue, and the liver. In the muscle tissue, baicalin limited lipid accumulation and improved glucose transport. Baicalin therapy was associated with diminished adipose tissue content and increased mitochondrial biogenesis. Hepatic lipid accumulation and glucose output were also decreased as a result of baicalin supplementation. The molecular mechanism of the anti-diabetic action of this compound is pleiotropic and is associated with changes in the expression/action of pivotal enzymes and signaling molecules. Baicalin positively affected, among others, the tissue insulin receptor, glucose transporter, AMP-activated protein kinase, protein kinase B, carnitine palmitoyltransferase, acetyl-CoA carboxylase, and fatty acid synthase. Moreover, this compound ameliorated diabetes-related oxidative and inflammatory stress and reduced epigenetic modifications. Importantly, baicalin supplementation at the effective doses did not induce any side effects. Results of rodent studies imply that baicalin may be tested as an anti-diabetic agent in humans.

A Transcriptome Array-Based Approach to Link SGLT-2 and Intrarenal Complement C5 Synthesis in Diabetic Nephropathy.

Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log2SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for "metabolism" and "biological oxidations". These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis.

Prognostic and Predictive Utility of GPD1L in Human Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship observed with HCC, the precise role and underlying function of GPD1L in HCC remain poorly understood. Here, we aimed to investigate the prognostic significance, molecular characteristics, and predictive potential of GPD1L overexpression in HCC. Analysis of independent datasets revealed a significant correlation between high GPD1L expression and poor survival in HCC patients. Spatial and single cell transcriptome datasets confirmed elevated GDP1L expression in tumour tissue compared to adjacent normal tissue. GPD1L exhibited increased expression and promoter demethylation with advancing tumour stage, confirming positive selection during tumorigeneses. GPD1L overexpression was associated with metabolic dysregulation and enrichment of gene sets related to cell cycle control, epithelial-mesenchymal transition, and E2F targets. Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC.

IGF-1 Stimulates Glycolytic ATP Production in MCF-7L Cells.

The Insulin-like Growth Factor (IGF) system in breast cancer progression has been a matter of interest for decades, but targeting this system did not result in a successful clinical strategy. The system's complexity and homology of its two receptors-insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-1R)-are possible causes. The IGF system maintains cell proliferation and also regulates metabolism, making it a pathway to explore. To understand the metabolic phenotype of breast cancer cells, we quantified their real-time ATP production rate upon acute stimulation with ligands-insulin-like growth factor 1 (1GF-1) and insulin. MCF-7L cells express both IGF-1R and IR, while tamoxifen-resistant MCF-7L (MCF-7L TamR) cells have downregulated IGF-1R with unchanged IR levels. Treating MCF-7L cells with 5 nM IGF-1 increased the glycolytic ATP production rate, while 10 nM insulin did not affect metabolism when compared with the control. Neither treatment altered ATP production in MCF-7L TamR cells. This study provides evidence of the relationship between metabolic dysfunction, cancer, and the IGF axis. In these cells, IGF-1R, and not IR, regulates ATP production.

Uneven metabolic and lipidomic profiles in recovered COVID-19 patients as investigated by plasma NMR metabolomics.

COVID-19 is a systemic infectious disease that may affect many organs, accompanied by a measurable metabolic dysregulation. The disease is also associated with significant mortality, particularly among the elderly, patients with comorbidities, and solid organ transplant recipients. Yet, the largest segment of the patient population is asymptomatic, and most other patients develop mild to moderate symptoms after SARS-CoV-2 infection. Here, we have used NMR metabolomics to characterize plasma samples from a cohort of the abovementioned group of COVID-19 patients (n = 69), between 3 and 10 months after diagnosis, and compared them with a set of reference samples from individuals never infected by the virus (n = 71). Our results indicate that half of the patient population show abnormal metabolism including porphyrin levels and altered lipoprotein profiles six months after the infection, while the other half show little molecular record of the disease. Remarkably, most of these patients are asymptomatic or mild COVID-19 patients, and we hypothesize that this is due to a metabolic reflection of the immune response stress.

Metabolic abnormalities and survival among patients with non-metastatic breast cancer.

BACKGROUND: Research on the impact of metabolic abnormalities on breast cancer prognosis is limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In this population-based cohort, time-updated laboratory values were adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides) and breast cancer survival. METHODS: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL-C, LDL-C, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, diabetes, dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, tamoxifen, and aromatase inhibitors). RESULTS: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over a median follow-up of 8.6 years, 2,876 patients died; 1,080 of breast cancer. Patients with low HDL-C (≤ 45 vs. > 45 mg/dL) had higher breast cancer-specific mortality (HR, 1.77; 95% CI, 1.53-2.05), as did those with elevated fasting glucose (> 99 vs. 60-99 mg/dL) (HR, 1.19; 95% CI, 1.03-1.37). Elevated levels of triglycerides and LDL-C were not associated with breast cancer-specific mortality. CONCLUSIONS: High fasting glucose and low HDL-C evaluated over time after cancer diagnosis were associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Future studies should address whether pharmacologic or lifestyle treatment of glucose and lipids after breast cancer diagnosis can optimize survival outcomes.

Characterisation of the Mouse Cerebellar Proteome in the GFAP-IL6 Model of Chronic Neuroinflammation.

GFAP-IL6 transgenic mice are characterised by astroglial and microglial activation predominantly in the cerebellum, hallmarks of many neuroinflammatory conditions. However, information available regarding the proteome profile associated with IL-6 overexpression in the mouse brain is limited. This study investigated the cerebellum proteome using a top-down proteomics approach using 2-dimensional gel electrophoresis followed by liquid chromatography-coupled tandem mass spectrometry and correlated these data with motor deficits using the elevated beam walking and accelerod tests. In a detailed proteomic analysis, a total of 67 differentially expressed proteoforms including 47 cytosolic and 20 membrane-bound proteoforms were identified. Bioinformatics and literature mining analyses revealed that these proteins were associated with three distinct classes: metabolic and neurodegenerative processes as well as protein aggregation. The GFAP-IL6 mice exhibited impaired motor skills in the elevated beam walking test measured by their average scores of 'number of footslips' and 'time to traverse' values. Correlation of the proteoforms' expression levels with the motor test scores showed a significant positive correlation to peroxiredoxin-6 and negative correlation to alpha-internexin and mitochondrial cristae subunit Mic19. These findings suggest that the observed changes in the proteoform levels caused by IL-6 overexpression might contribute to the motor function deficits.

The evolving landscape of N6-methyladenosine modification in the tumor microenvironment.

The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. The TME can be described in terms of hypoxia, metabolic dysregulation, immune escape, and chronic inflammation. RNA methylation, an epigenetic modification, has recently been found to have a pivotal role in shaping the TME. The N6-methylation of adenosine (m6A) modification is the most common type of RNA methylation that occurs in the N6-position of adenosine, which is the primary internal modification of eukaryotic mRNA. Compelling evidence has demonstrated that m6A regulates transcriptional and protein expression through splicing, translation, degradation, and export, thereby mediating the biological processes of cancer cells and/or stromal cells and characterizing the TME. The TME also has a crucial role in the complicated regulatory network of m6A modifications and, subsequently, influences tumor initiation, progression, and therapy responses. In this review, we describe the features of the TME and how the m6A modification modulates and interacts with it. We also focus on various factors and pathways involved in m6A methylation. Finally, we discuss potential therapeutic strategies and prognostic biomarkers with respect to the TME and m6A modification.

Hepatic mir-122-3p, mir-140-5p and mir-148b-5p expressions are correlated with cytokeratin-18 serum levels in MAFLD.

INTRODUCTION AND OBJECTIVES: Metabolic-associated fatty liver disease (MAFLD) is defined by steatosis in more than 5% of hepatocytes without other liver diseases. Patients with this disease can progress to multiple stages like liver fibrosis, cirrhosis, and hepatocellular carcinoma. miRNAs are single-stranded molecules that regulate metabolic homeostasis; their differential expression postulates them as potential circulating biomarkers for MAFLD. Previous research reported that hsa-miR-140-5p, hsa-miR-148-5p, and hsa-miR-122-3p have a differential expression in patients with MAFLD. This study aimed to investigate the correlation between liver hsa-miR-140-5p, hsa-miR-148-5p, and hsa-miR-122-3p and serum biomarkers CK-18, APOB, IL-6, IL-32, and TNF-α in patients with MAFLD compared with control patients. MATERIALS AND METHODS: A cross-sectional study was carried out with 16 patients of both sexes, aged between 18-60 years, to determine the association between the levels of hsa-miR-140-5p, hsa-miR-148-5p, and hsa-miR-122-3p with MAFLD in liver biopsies of patients who underwent laparoscopic cholecystectomy. RESULTS: Twelve patients presented MAFLD, four without hepatic steatosis. Circulating levels of CK-18 showed a significant difference in patients with MAFLD, and a strong correlation was found between hsa-miR-122-3p, hsa-miR-140-5p, and hsa-miR-148b-5p versus the CAP value. CONCLUSION: There is a correlation between elevated tissue expression of hsa-miR-122-3p, hsa-miR-140-5p, and hsa-miR-148b-3p with plasma levels of CK-18 in patients with simple steatosis compared with patients without the disease.

Identification of a Novel Theranostic Signature of Metabolic and Immune-Inflammatory Dysregulation in Myocardial Infarction, and the Potential Therapeutic Properties of Ovatodiolide, a Diterpenoid Derivative.

Myocardial infarction (MI) is a multifactorial global disease, recognized as one of the leading causes of cardiovascular morbidity and mortality. Timely and correct diagnoses and effective treatments could significantly reduce incidence of complications and improve patient prognoses. In this study, seven unconventional differentially expressed genes (DEGs) (MAN2A2, TNFRSF12A, SPP1, CSNK1D, PLAUR, PFKFB3, and CXCL16, collectively termed the MTSCPPC signature) were identified through integrating DEGs from six MI microarray datasets. The pathological and theranostic roles of the MTSCPPC signature in MI were subsequently analyzed. We evaluated interactions of the MTSCPPC signature with ovatodiolide, a bioactive compound isolated from Anisomeles indica (L.) Kuntze, using in silico molecular docking tools and compared it to specific inhibitors of the members of the MTSCPPC signature. Single-cell transcriptomic analysis of the public databases revealed high expression levels of the MTSCPPC signature in immune cells of adult human hearts during an MI event. The MTSCPPC signature was significantly associated with the cytokine-cytokine receptor interactions, chemokine signaling, immune and inflammatory responses, and metabolic dysregulation in MI. Analysis of a micro (mi)RNA regulatory network of the MTSCPPC signature suggested post-transcriptional activation and the roles of miRNAs in the pathology of MI. Our molecular docking analysis suggested a higher potential for ovatodiolide to target MAN2A2, CSNK1D, and TNFRSF12A. Collectively, the results derived from the present study further advance our understanding of the complex regulatory mechanisms of MI and provide a potential MI theranostic signature with ovatodiolide as a therapeutic candidate.

Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge.

CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.

Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm.

Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance.

Dynamic control over feedback regulatory mechanisms improves NADPH flux and xylitol biosynthesis in engineered E. coli.

We report improved NADPH flux and xylitol biosynthesis in engineered E. coli. Xylitol is produced from xylose via an NADPH dependent reductase. We utilize 2-stage dynamic metabolic control to compare two approaches to optimize xylitol biosynthesis, a stoichiometric approach, wherein competitive fluxes are decreased, and a regulatory approach wherein the levels of key regulatory metabolites are reduced. The stoichiometric and regulatory approaches lead to a 20-fold and 90-fold improvement in xylitol production, respectively. Strains with reduced levels of enoyl-ACP reductase and glucose-6-phosphate dehydrogenase, led to altered metabolite pools resulting in the activation of the membrane bound transhydrogenase and an NADPH generation pathway, consisting of pyruvate ferredoxin oxidoreductase coupled with NADPH dependent ferredoxin reductase, leading to increased NADPH fluxes, despite a reduction in NADPH pools. These strains produced titers of 200 g/L of xylitol from xylose at 86% of theoretical yield in instrumented bioreactors. We expect dynamic control over the regulation of the membrane bound transhydrogenase as well as NADPH production through pyruvate ferredoxin oxidoreductase to broadly enable improved NADPH dependent bioconversions or production via NADPH dependent metabolic pathways.