Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

Decoding the nexus:branched-chain amino acids and their connection with sleep,circadian rhythms,and cardiometabolic health

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.

Lipid droplets in the nervous system:involvement in cell metabolic homeostasis

Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

FibroScan-aspartate transaminase:A superior non-invasive model for diagnosing high-risk metabolic dysfunction-associated steatohepatitis

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)with hepatic histological NAFLD activity score≥4 and fibrosis stage F≥2 is regarded as“at risk”non-alcoholic steatohepatitis(NASH).Based on an international consensus,NAFLD and NASH were renamed as metabolic dysfunction-associated steatotic liver disease(MASLD)and metabolic dysfunction-associated steatohepatitis(MASH),respectively;hence,we introduced the term“high-risk MASH”.Diagnostic values of seven non-invasive models,including FibroScan-aspartate transaminase(FAST),fibrosis-4(FIB-4),aspartate transaminase to platelet ratio index(APRI),etc.for high-risk MASH have rarely been studied and compared in MASLD.AIM To assess the clinical value of seven non-invasive models as alternatives to liver biopsy for diagnosing high-risk MASH.METHODS A retrospective analysis was conducted on 309 patients diagnosed with NAFLD via liver biopsy at Beijing Ditan Hospital,between January 2012 and December 2020.After screening for MASLD and the exclusion criteria,279 patients wereincluded and categorized into high-risk and non-high-risk MASH groups.Utilizing threshold values of each model,sensitivity,specificity,positive predictive value(PPV),and negative predictive values(NPV),were calculated.Receiver operating characteristic curves were constructed to evaluate their diagnostic efficacy based on the area under the curve(AUROC).RESULTS MASLD diagnostic criteria were met by 99.4%patients with NAFLD.The MASLD population was analyzed in two cohorts:Overall population(279 patients)and the subgroup(117 patients)who underwent liver transient elastography(FibroScan).In the overall population,FIB-4 showed better diagnostic efficacy and higher PPV,with sensitivity,specificity,PPV,NPV,and AUROC of 26.9%,95.2%,73.5%,72.2%,and 0.75.APRI,Forns index,and aspartate transaminase to alanine transaminase ratio(ARR)showed moderate diagnostic efficacy,whereas S index and gamma-glutamyl transpeptidase to platelet ratio(GPR)were relatively weaker.In the subgroup,FAST had the highest diagnostic efficacy,its sensitivity,specificity,PPV,NPV,and AUROC were 44.2%,92.3%,82.1%,67.4%,and 0.82.The FIB-4 AUROC was 0.76.S index and GPR exhibited almost no diagnostic value for high-risk MASH.CONCLUSION FAST and FIB-4 could replace liver biopsy as more effectively diagnostic methods for high-risk MASH compared to APRI,Forns index,ARR,S index,and GPR;FAST is superior to FIB-4.

Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease:Clinical implications

In this editorial,we comment on the article by Chen et al recently published in 2024.We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase(ALT)would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease(MAFLD).This is important given the increasing prevalence of MAFLD and obesity globally.Currently,a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT.The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered,particularly as their study found that 83.12%of their study population with a diagnosis of MAFLD had a normal ALT.The main advantages of screening would be to identify patients and provide intervention early,the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis.However,there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered.Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity,although studies have not yet shown a significant improvement in fibrosis regression.It would also require a huge amount of resource if a reduced ALT level alone was used as criteria;it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk.Currently,there is not a good argument to recommend wide-spread screening with a reduced ALT level as this is unlikely to be cost-effective.This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories.Although studies previously have suggested a more pragmatic approach in screening those over the age of 60,this is likely to change with the increasing incidence of obesity within the younger age groups.The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

Update in lean metabolic dysfunction-associated steatotic liver disease

BACKGROUND A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease(MAFLD).They are now defined as metabolic dysfunction-associated steatotic liver disease(MASLD),which includes cardiometabolic criteria in adults.This condition,extensively studied in obese or overweight patients,constitutes around 30%of the population,with a steady increase worldwide.Lean patients account for approximately 10%-15%of the MASLD population.However,the pathogenesis is complex and is not well understood.AIM To systematically review the literature on the diagnosis,pathogenesis,characteristics,and prognosis in lean MASLD patients and provide an interpretation of these new criteria.METHODS We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023,specifically focusing on lean NAFLD,MAFLD,or MASLD patients.We include original articles with patients aged 18 years or older,with a lean body mass index categorized according to the World Health Organization criteria,using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population.RESULTS We include 85 studies in our analysis.Our findings revealed that,for lean NAFLD patients,the prevalence rate varied widely,ranging from 3.8%to 34.1%.The precise pathogenesis mechanism remained elusive,with associations found in genetic variants,epigenetic modifications,and adaptative metabolic response.Common risk factors included metabolic syndrome,hypertension,and type 2 diabetes mellitus,but their prevalence varied based on the comparison group involving lean patients.Regarding non-invasive tools,Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients.Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles,with some medications showing efficacy to a lesser extent.However,lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart.CONCLUSION MASLD is a complex disease comprising epigenetic,genetic,and metabolic factors in its pathogenesis.Results vary across populations,gender,and age.Limited data exists on clinical practice guidelines for lean patients.Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

Effects of different doses of glucose and fructose on central metabolic pathways and intercellular wireless communication networks in humans

Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases.To observe the effects of different doses of glucose and fructose on human metabolism and cellular communication,volunteers were given low,medium,and high doses of glucose and fructose.Serum cytokines,glucose,lactate,nicotinamide adenine dinucleotide(NADH)and metabolic enzymes were assayed,and central carbon metabolic pathway networks and cytokine communication networks were constructed.The results showed that the glucose and fructose groups basically maintained the trend of decreasing catabolism and increasing anabolism with increasing dose.Compared with glucose,low-dose fructose decreased catabolism and increased anabolism,significantly enhanced the expression of the inflammatory cytokine interferon-γ(IFN-γ),macrophage-derived chemokine(MDC),induced protein-10(IP-10),and eotaxin,and significantly reduced the activity of isocitrate dehydrogenase(ICDH)and pyruvate dehydrogenase complexes(PDHC).Both medium and high doses of fructose increase catabolism and anabolism,and there are more cytokines and enzymes with significant changes.Furthermore,multiple cytokines and enzymes show strong relevance to metabolic regulation by altering the transcription and expression of enzymes in central carbon metabolic pathways.Therefore,excessive intake of fructose should be reduced to avoid excessive inflammatory responses,allergic reactions and autoimmune diseases.

Tanshinone IIA ameliorates energy metabolism dysfunction of pulmonary fibrosis using 13C metabolic flux analysis

Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.

Disparate outcomes in Hispanic patients with metabolic dysfunctionassociated steatotic liver disease/steatohepatitis and type 2 diabetes: Large cohort study

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)and metabolic dysfunction-associated steatohepatitis(MASH)are a growing health burden across a significant portion of the global patient population.However,these conditions seem to have disparate rates and outcomes between different ethnic populations.The combination of MASLD/MASH and type 2 diabetes increases the risk of hepatocellular carcinoma(HCC),and Hispanic patients experience the greatest burden,particularly those in South Texas.AIM To compare outcomes between Hispanic and non-Hispanic patients in the United States,while further focusing on the Hispanic population within Southeast Texas to determine whether the documented disparity in outcomes is a function of geographical circumstance or if there is a more widespread reason that all clinicians must account for in prognostic consideration.METHODS This cohort analysis was conducted with data obtained from TriNetX,LLC(“TriNetX”),a global federated health research network that provides access to deidentified medical records from healthcare organizations worldwide.Two cohort networks were used:University of Texas Medical Branch(UTMB)hospital and the United States national database collective to determine whether disparities were related to geographic regions,like Southeast Texas.RESULTS This study findings revealed Hispanics/Latinos have a statistically significant higher occurrence of HCC,type 2 diabetes mellitus,and liver fibrosis/cirrhosis in both the United States and the UTMB Hispanic/Latino groups.Allcause mortality in Hispanics/Latinos was lower within the United States group and not statistically elevated in the UTMB cohort.CONCLUSION This would appear to support that Hispanic patients in Southeast Texas are not uniquely affected compared to the national Hispanic population.

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease:Opportunities and challenges

Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health burden and com-plex pathogenesis of MASLD,a multifaceted and innovative therapeutic approach is needed.Incretin receptor agonists,which were initially developed for diabetes management,have emerged as promising candidates for MASLD treatment.This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists:glucagon-like peptide-1 receptor agonists,glucose-dependent insulinotropic polypeptide receptor agonists,and glucagon receptor agonists.Incretins and glucagon directly or indirectly impact various organs,including the liver,brain,pancreas,gastro-intestinal tract,and adipose tissue.Thus,these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis.Importantly,this study provides a summary of clinical trials analyzing the effect-iveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function,hepatic steatosis,and intrahepatic inflammation.There are emerging challenges associated with the use of these medications in the real world,particularly adverse events,drug-drug interactions,and barriers to access,which are discussed in detail.Additionally,this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Predictive value of serum alanine aminotransferase for fatty liver associated with metabolic dysfunction

In this editorial,we offer commentary on the article published by Chen et al in a recent issue of the World Journal of Gastroenterology(2024;30:1346-1357).The study highlights a noteworthy association between persistently elevated,yet highnormal levels of alanine transaminase(ALT)and an escalated cumulative risk of developing metabolic dysfunction-associated fatty liver disease(MAFLD).MAFLD has emerged as a globally prevalent chronic liver condition,whose incidence is steadily rising in parallel with improvements in living standards.Left unchecked,MAFLD can progress from hepatic steatosis to liver fibrosis,cirrhosis,and even hepatocellular carcinoma,underscoring the importance of early screening and diagnosis.ALT is widely recognized as a reliable biomarker for assessing the extent of hepatocellular damage.While ALT levels demonstrate a significant correlation with the severity of fatty liver disease,they lack specificity.The article by Chen et al contributes to our understanding of the development of MAFLD by investigating the long-term implications of high-normal ALT levels.Their findings suggest that sustained elevation within the normal range is linked to an increased likelihood of developing MAFLD,emphasizing the need for closer monitoring and potential intervention in such cases.

Immune remodulation in pediatric inherited metabolic liver diseases

Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

Prevalence and risk factors associated with metabolic dysfunctionassociated steatohepatitis in patients with Helicobacter pylori infection: A population-based study

BACKGROUND Helicobacter pylori(H.pylori)is associated with the development of gastrointestinal disorders ranging from gastritis to gastric cancer.The evidence of the association between metabolic dysfunction-associated steatohepatitis(MASH)and H.pylori infection in the literature is scarce.Therefore,we aim to evaluate the risk of developing MASH in patients who have had a diagnosis of H.pylori infection independently of any confounding variables.AIM To evaluate the risk of developing MASH in patients who have had a diagnosis of H.pylori infection.METHODS This study used a validated multicenter research database of over 360 hospitals across 26 healthcare systems across the United States from 1999 to 2022.Multivariate regression analysis assessed the risk of developing MASH,adjusting for confounders including H.pylori infection,obesity,type 2 diabetes,hypertension,dyslipidemia,and male gender.A two-sided P value<0.05 was considered as statistically significant,and all statistical analyses were performed using R version 4.0.2(R Foundation for Statistical Computing,Vienna,Austria,2008).RESULTS A total of 79476132 individuals were screened in the database and 69232620 were selected in the final analysis after accounting for inclusion and exclusion criteria.Smokers(14.30%),patients with hyperlipidemia(70.35%),hypertension(73.86%),diabetes mellitus type 2(56.46%),and obese patients(58.15%)were more common in patients with MASH compared to control.Using a multivariate regression analysis,the risk of MASH was increased in diabetics[odds ratio(OR):3.55;95%CI:3.48-3.62],obese(OR:5.93;95%CI:5.81-6.04),males(OR:1.49;95%CI:1.46-1.52),individuals with hyperlipidemia(OR:2.43;95%CI:2.38-2.49)and H.pylori infection(OR:2.51;95%CI:2.31-2.73).CONCLUSION This is the largest population-based study in the United States illustrating an increased prevalence and odds of developing MASH in patients with H.pylori infection after adjusting for risk factors.

Ornithine aspartate effects on bacterial composition and metabolic pathways in a rat model of steatotic liver disease

BACKGROUND Metabolic-dysfunction associated steatotic liver disease(MASLD)is a hepatic manifestation of metabolic syndrome.Studies suggest ornithine aspartate(LOLA)as drug therapy.AIM To analyze the influence of LOLA intake on gut microbiota using a nutritional model of MASLD.METHODS Adult male Sprague Dawley rats were randomized into three groups:Control(10 rats fed with a standard diet),MASLD(10 rats fed with a high-fat and choline-deficient diet),and LOLA(10 rats receiving 200 mg/kg/d LOLA,after the 16th week receiving high-fat and choline-deficient diet).After 28 wk of the experiment,animals were euthanized,and feces present in the intestine were collected.Following fecal DNA extraction,the V4 region of the 16S rRNA gene was amplified followed by sequencing in an Ion S5™system.RESULTS Alpha and beta diversity metrics were comparable between MASLD and LOLA.3 OTUs were differentially abundant between MASLD and LOLA,which belong to the species Helicobacter rodentium,Parabacteroides goldsteinii,and Parabacteroides distasonis.The functional prediction provided two different metabolic profiles between MASLD and LOLA.The 9 pathways differentially abundant in MASLD are related to a change in energy source,adenosine/purine nucleotides degradation as well as guanosine and adenosine deoxyribonucleotides biosynthesis.The 14 pathways differentially abundant in LOLA are associated with four major metabolic functions primarily influenced by L-aspartate,including tricarboxylic acid cycle pathways,purine/guanosine nucleotides biosynthesis,pyrimidine ribonucleotides biosynthesis and salvage as well as lipid IVA biosynthesis.CONCLUSION Although LOLA had no influence on alpha and beta diversity in this nutritional model of MASLD,it was associated with changes in specific gut microbes and their related metabolic pathways.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China

BACKGROUND Within the normal range,elevated alanine aminotransferase(ALT)levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease(MAFLD).AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively.METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected.The incidence rate,cumulative times,and equally and unequally weighted cumulative effects of excess high-normal ALT levels(ehALT)were measured.Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD.RESULTS A total of 83.13%of participants with MAFLD had normal ALT levels.The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group.Compared with those in the low-normal ALT group,the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651[95%confidence interval(CI):1.199-2.273]and 1.535(95%CI:1.119-2.106)in the third quartile and 1.616(95%CI:1.162-2.246)and 1.580(95%CI:1.155-2.162)in the fourth quartile,respectively.CONCLUSION Most participants with MAFLD had normal ALT levels.Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Omics-based biomarkers as useful tools in metabolic dysfunctionassociated steatotic liver disease clinical practice:How far are we?

Unmet needs exist in metabolic dysfunction-associated steatotic liver disease(MASLD)risk stratification.Our ability to identify patients with MASLD with advanced fibrosis and at higher risk for adverse outcomes is still limited.Incorporating novel biomarkers could represent a meaningful improvement to current risk predictors.With this aim,omics technologies have revolutionized the process of MASLD biomarker discovery over the past decades.While the research in this field is thriving,much of the publication has been haphazard,often using single-omics data and specimen sets of convenience,with many identified candidate biomarkers but lacking clinical validation and utility.If we incorporate these biomarkers to direct patients’management,it should be considered that the roadmap for translating a newly discovered omics-based signature to an actual,analytically valid test useful in MASLD clinical practice is rigorous and,therefore,not easily accomplished.This article presents an overview of this area’s current state,the conceivable opportunities and challenges of omics-based laboratory diagnostics,and a roadmap for improving MASLD biomarker research.