Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid ß-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid ß-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-ß targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.

Staphylococcus simulans infections in a patient following high supracondylar osteotomy to treat osteoarthritis: a case report.

Staphylococcus simulans (S. simulans) is a coagulase-negative staphylococcus that is commonly found in animal pathogens. S. simulans rarely causes infections in clinical practice due to its low pathogenic ability and opportunistic pathogen, which results in few relevant clinical reports. In this paper, the authors primarily report a patient infected with S. simulans after a high supracondylar osteotomy and the S. simulans was identified by the means of the next-generation sequencing technology. This case report provides new evidence for the further research of S. simulans and paves the way for its clinical therapy.

Protection against fibrosis by a bacterial consortium in metabolic dysfunction-associated steatohepatitis and the role of amino acid metabolism.

The gut microbiota drives progression to liver fibrosis, the main determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH). In this study, we aimed to identify bacterial species associated with protection against liver fibrosis in a high-risk population, and test their potential to protect against liver fibrosis in vivo. Based on stool shotgun metagenomic sequencing of 340 subjects from a population cohort disproportionally affected by MASH, we identified bacterial species from the Bacteroidales and Clostridiales orders associated with reduced risk of liver fibrosis. A bacterial consortium was subsequently tested in a mouse model of MASH, which demonstrated protective effects against liver fibrosis. Six of the eight inoculated bacteria were detected in mouse stool and liver. Intrahepatic presence of bacteria was further confirmed by bacterial culture of mouse liver tissue. Changes in liver histological parameters, gut functional profiles, and amino acid profiles were additionally assessed. Comparison between fibrosis-associated human metagenome and bacteria-induced metagenome changes in mice identified microbial functions likely to mediate the protective effect against liver fibrosis. Amino acid profiling confirmed an increase in cysteine synthase activity, associated with reduced fibrosis. Other microbiota-induced changes in amino acids associated with reduced fibrosis included increased gut asparaginase activity and decreased hepatic tryptophan-to-kynurenine conversion. This human-to-mouse study identified bacterial species and their effects on amino acid metabolism as innovative strategies to protect against liver fibrosis in MASH.

Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.

Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer. Previously, we and others have identified that SMARCA4 -mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). Despite initial excitements, therapeutics targeting metabolic pathways such as OXPHOS have largely been disappointing due to rapid adaptation of cancer cells to inhibition of single metabolic enzymes or pathways, suggesting novel combination strategies to overcome adaptive responses are urgently needed. Here, we performed a functional genomics screen using CRISPR-Cas9 library targeting genes with available FDA approved therapeutics and identified ROCK1/2 as a top hit that sensitizes cancer cells to OXPHOS inhibition. We validate these results by orthogonal genetic and pharmacologic approaches by demonstrating that KD025 (Belumosudil), an FDA approved ROCK inhibitor, has highly synergistic anti-cancer activity in vitro and in vivo in combination with OXPHOS inhibition. Mechanistically, we showed that this combination induced a rapid, profound energetic stress and cell cycle arrest that was in part due to ROCK inhibition-mediated suppression of the adaptive increase in glycolysis normally seen by OXPHOS inhibition. Furthermore, we applied global phosphoproteomics and kinase-motif enrichment analysis to uncover a dynamic regulatory kinome upon combination of OXPHOS and ROCK inhibition. Importantly, we found converging phosphorylation-dependent regulatory cross-talk by AMPK and ROCK kinases on key RHO GTPase signaling/ROCK-dependent substrates such as PPP1R12A, NUMA1 and PKMYT1 that are known regulators of cell cycle progression. Taken together, our study identified ROCK kinases as critical mediators of metabolic adaptation of cancer cells to OXPHOS inhibition and provides a strong rationale for pursuing ROCK inhibitors as novel combination partners to OXPHOS inhibitors in cancer treatment.

Current status of molecular rice breeding for durable and broad-spectrum resistance to major diseases and insect pests.

In the past century, there have been great achievements in identifying resistance (R) genes and quantitative trait loci (QTLs) as well as revealing the corresponding molecular mechanisms for resistance in rice to major diseases and insect pests. The introgression of R genes to develop resistant rice cultivars has become the most effective and eco-friendly method to control pathogens/insects at present. However, little attention has been paid to durable and broad-spectrum resistance, which determines the real applicability of R genes. Here, we summarize all the R genes and QTLs conferring durable and broad-spectrum resistance in rice to fungal blast, bacterial leaf blight (BLB), and the brown planthopper (BPH) in molecular breeding. We discuss the molecular mechanisms and feasible methods of improving durable and broad-spectrum resistance to blast, BLB, and BPH. We will particularly focus on pyramiding multiple R genes or QTLs as the most useful method to improve durability and broaden the disease/insect spectrum in practical breeding regardless of its uncertainty. We believe that this review provides useful information for scientists and breeders in rice breeding for multiple stress resistance in the future.

Polycaprolactone/gelatin/ZIF-8 nanofiber membrane for advanced guided tissue regeneration in periodontal therapy.

The periodontal tissue regeneration strategy based on guided tissue regeneration (GTR) membranes is an effective therapy for periodontal defects. Traditional GTR membranes, however, primarily serve as physical barriers and lack antimicrobial and osteogenic functions. Herein, we developed a multifunctional nanofiber membrane with zeolitic imidazolate framework-8 nanoparticles (ZIF-8 NPs) loaded in a hydrophilic gelatin layer. The release of Zn2+ from the ZIF-8 NPs effectively promoted bone tissue repair and simultaneously enabled GTR membranes with >99 % antibacterial efficacies against Escherichia coli and Staphylococcus aureus. Additionally, the incorporation of gelatin enhances cellular adhesion and growth. Furthermore, in vivo studies revealed significant bone regeneration, with increased trabecular number and reduced separation. Owing to its multiple functions, excellent biocompatibility and desirable mechanical properties, this membrane has considerable potential in the field of periodontal therapy.

Bacteria-responsive functional electrospun membrane: simultaneous on-site visual monitoring and inhibition of bacterial infection.

Skin infections are a major threat to human health. Early diagnosis of bacterial infections is of great significance for implementing protective measures on the skin. Therefore, in this study, we designed an electrospun membrane (PPBT) for visual monitoring of colonized bacteria and responsive antibacterial ability. Specifically, the acidity of the microenvironment caused by bacterial metabolism was applied to drive the color change of bromothymol blue (BTB) on the PPBT membrane from green to yellow, thereby facilitating the early warning of infection and timely treatment. Within 4 h, different concentrations of Staphylococcus aureus (∼105 CFU mL-1), Escherichia coli (∼105 CFU mL-1), Pseudomonas aeruginosa (∼105 CFU mL-1) and Candida albicans (∼104 CFU mL-1) were visually monitored. Moreover, as the local acidity was enhanced via microbial metabolism, ZIF-8 nanoparticles loaded with TCS (TCS@ZIF-8) on the PPBT membrane could release TCS in an acid-responsive manner. At the same time, ROS were generated under 405 nm irradiation to achieve synergistic antibacterial ability. Experiments confirmed that the PPBT membrane has ideal and controllable antibacterial features based on acid responsive release and a synergistic photocatalytic antibacterial mechanism after monitoring. Therefore, the PPBT membrane developed in this work provides a feasible solution for bacterial monitoring and inactivation devices. More importantly, it can be beneficial for meeting the needs of clinical diagnosis and timely treatment of bacterial infection.

Mechanistic insights into metabolic function of dynamin-related protein 1.

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, DRP1 deficiency induced the retention of nascent lipid droplets in ER, leading to perturbed overall lipid dynamics in the KO mice. Collectively, dysregulation of the dynamics of mitochondria, ER, and lipid droplets contributes to whole-body metabolic disorders, as evidenced by perturbations in energy metabolites. Our findings demonstrate that DRP1 plays diverse and critical roles in regulating energy metabolism within adipose tissue during the progression of obesity.

Bacteroides ovatus alleviates dysbiotic microbiota-induced graft-versus-host disease.

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus.

Case report: A rare case of hereditary hemochromatosis caused by a mutation in the HAMP gene in Fuyang, China.

Hemochromatosis, also known as siderosis, is a disease caused by excessive iron deposition in human organs and tissues, resulting from iron metabolism disorders. It is clinically characterized by skin pigmentation (bronze color), liver cirrhosis, diabetes, weakness, and fatigue. Additional symptoms may include arthritis, hypothyroidism, heart failure, and sexual hypofunction. Clinical manifestations can vary from person to person, with a few patients showing no clinical manifestations, which makes the diagnosis difficult for clinicians. In this case report, we described hereditary hemochromatosis related to a mutation in the HAMP gene in Fuyang City, China, as a reference for clinicians. Hereditary hemochromatosis is rarely reported in China. Clinicians in China have relatively insufficient knowledge of this disease, which leads to frequent misdiagnosis. In this case report, we describe hereditary hemochromatosis related to HAMP gene mutation in Fuyang City, China, for the clinician's reference.

Tobacco crop rotation enhances the stability and complexity of microbial networks.

Introduction: The effects of continuous cropping and rotation cropping, two important tobacco cultivation practices, on soil microbial communities at different stages remain unclear. Different planting patterns have been shown to influence soil physical and chemical properties, which in turn can affect the composition and diversity of soil microbial communities. Methods: In order to investigate the impact of different planting methods on soil microbial community structure, we selected two representative planting methods: continuous cropping (tobacco) and rotational cropping (tobacco-maize). These methods were chosen as the focal points of our research to explore the potential effects on soil microbial communities. High-throughput sequencing technology was employed to investigate the structure of soil microbial communities, as well as their relationships with soil environmental factors, by utilizing the 16S rRNA, ITS, and 18S genes. Furthermore, the interaction among microorganisms was explored through the application of the Random Matrix Theory (RMT) molecular ecological network approach. Results: There was no significant difference in α diversity, but significant difference in ß diversity based on Jaccard distance test. Compared to continuous cropping, crop rotation significantly increased the abundance of beneficial prokaryotes Verrucomicrobia and Rhodanobacter. These findings indicate that crop rotation promotes the enrichment of Verrucomicrobia and Rhodanobacter in the soil microbial community. AP and NH4-N had a greater effect on the community structure of prokaryotes and fungi in tobacco soil, while only AP had a greater effect on the community structure of protist. Molecular ecological network analysis showed that the network robustness and Cohesion of rotation were significantly higher than that of continuous cropping, indicating that the complexity and stability of molecular ecological networks were higher in the rotational, and the microbial communities cooperated more effectively, and the community structure was more stable. Discussion: From this point of view, rotational cropping is more conducive to changing the composition of soil microbial community, enhancing the stability of microbial network structure, and enhancing the potential ecological functions in soil.

A new Urbacodon (Theropoda, Troodontidae) from the Upper Cretaceous Iren Dabasu Formation, China: Implications for troodontid phylogeny and tooth biology.

Tooth attachment and replacement play significant roles in the feeding ecology of polyphyodont vertebrates, yet these aspects have remained largely unexplored in non-avialan paravians including troodontids. Here, we describe a new troodontid species, Urbacodon norelli sp.n., recovered from the Upper Cretaceous Iren Dabasu Formation of Inner Mongolia, China, based on an incomplete right dentary and 12 associated replacement teeth. Urbacodon norelli is distinguished from all other known troodontids, including its relative U. itemirensis from Uzbekistan, by several features: the presence of paired dentary symphyseal foramina, the presence of a relatively steep anterior margin of the dentary, the absence of a dentary chin, the presence of a common groove hosting the anterior 12 dentary teeth, and the presence of relatively larger dentary teeth. Phylogenetic analysis places both species of Urbacodon as sister taxa to Zanabazar junior, confirming their status as later-diverging troodontids. Radiographs revealed an alternating tooth replacement pattern in U. norelli, with a maximum Zahnreihen-spacing estimated to be 3. During tooth replacement, the anteriorly inclined interdental septa, which wedge between anterior dentary teeth, underwent frequent remodelling as the developing tooth moved upwards, particularly anterolabially. This rapid turnover left insufficient time for an interdental plate to form, resulting in the absence of such structures in this specimen. The frequent remodelling of periodontal tissues accompanying tooth replacement is likely to account for the absence of interdental plates. The discovery of this new troodontid expands our understanding of paravian theropods from the Upper Cretaceous Iren Dabasu Formation and provides valuable insights into troodontid tooth biology.

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Discovery of cinnamamide/ester triazole hybrids as potential treatment for Alzheimer's disease.

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.

Translation, cross-cultural adaptation, and psychometric validation of the Malay version of the Assessment of Quality of Life-6 Dimensions (Malay-AQoL-6D) instrument among Malaysians living with chronic heart failure.

BACKGROUND: This study aimed to translate and culturally adapt the Assessment of Quality of Life (AQoL)-6D into Malay (Malay-AQoL-6D), and assesses the instrument's acceptability, reliability, and validity among Malaysians living with chronic heart failure (HF). METHODS: The translation and cross-cultural adaptation process adhered to international guidelines. The Malay-AQoL-6D underwent content and face validity assessments via expert review, and pretesting among healthy individuals and patients with chronic conditions. Subsequent psychometric validation utilised clinico-sociodemographic data and paired AQoL-6D and EQ-5D-5L data from a health-related quality-of-life (HRQoL) survey involving Malay-speaking patients with HF, which encompassed assessments of Malay-AQoL-6D acceptability, internal consistency and test-retest reliability, as well as its construct, concurrent, convergent and divergent, and known-group validity. RESULTS: The Malay-AQoL-6D was deemed acceptable among clinicians and local patients, achieving a 90.8% completion rate among 314 patients surveyed. The instrument demonstrated strong content validity (item-level content validity index [CVI]: 0.83-1.00, average CVI: 0.98), internal consistency (Cronbach's alpha: 0.72-0.89; MacDonald's omega: 0.82-0.90, excluding the Senses dimension), and test-retest reliability (average intraclass correlation coefficients: 0.79-0.95). Confirmatory factor analysis confirmed the instrument's two-level, six-factor structure (Satorra-Bentler [SB]-scaled χ2(df: 164): 283.67, p-value < 0.001; root mean square error of approximation [RMSEA]: 0.051; comparative fix index [CFI]: 0.945, Tucker-Lewis index [TLI]: 0.937; standardised root mean-squared error [SRMR]: 0.058). The Malay-AQoL-6D's concurrent validity was evident through its good agreement with EQ-5D-5L. Multiple hypothesis tests further affirmed its construct and known-group validity. The Malay-AQoL-6D's psychometric properties remained consistent across different missing data techniques. CONCLUSION: The findings suggest that Malay-AQoL-6D could be a culturally acceptable, reliable, and valid HRQoL measure for quantifying HRQoL among the local HF population. Future studies are necessary to further validate the instrument against other measures and confirm the instrument's test-retest reliability and responsiveness, which are possible with the availability of the Malay-AQoL-6D.

Corrigendum: Dynamic evolution of left ventricular strain and microvascular perfusion assessed by speckle tracking echocardiography and myocardial contrast echocardiography in diabetic rats: effect of dapagliflozin.

[This corrects the article DOI: 10.3389/fcvm.2023.1109946.].

Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.

Lynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, including MSH2, and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-Cre Msh2 flox/flox , abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown. Beginning at eight months of age, 30% of Msh2KO mice exhibited endometrial atypical hyperplasia (AH), a precancerous lesion. At 12 to 16 months of age, 47% of Msh2KO mice exhibited either AH or ECs with histologic features similar to human LS-related ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a transcriptomic signature for mitochondrial dysfunction. Studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: marked mitochondrial content reduction, along with pronounced disruptions to the integrity of retained mitochondria. Human LS-related ECs also exhibited mitochondrial content reduction compared with non-LS-related ECs. Functional studies revealed metabolic reprogramming of MSH2-deficient EC cells in vitro , including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. We are the first to identify mitochondrial dysfunction and metabolic disruption as a consequence of MSH2 deficiency-related EC. Mitochondrial and metabolic aberrations should be evaluated as novel biomarkers for endometrial carcinogenesis or risk stratification and could serve as targets for cancer interception in women with LS. Significance: This is the first study to report mitochondrial dysfunction contributing to MSH2-deficient endometrial cancer development, identifying a noncanonical pathway for MSH2 deficient carcinogenesis, which also imparts vulnerability to metabolic targeting.

High-elevation-induced decrease in soil pH weakens ecosystem multifunctionality by influencing soil microbiomes.

Plant environmental stress response has become a global research hotspot, yet there is a lack of clear understanding regarding the mechanisms that maintain microbial diversity and their ecosystem services under environmental stress. In our research, we examined the effects of moderate elevation on the rhizosphere soil characteristics, microbial community composition, and ecosystem multifunctionality (EMF) within agricultural systems. Our findings revealed a notable negative correlation between EMF and elevation, indicating a decline in multifunctionality at higher elevations. Additionally, our analysis across bacterial and protistan communities showed a general decrease in microbial richness with increasing elevation. Using random forest models, pH was identified as the key environmental stressor influencing microbial communities. Furthermore, we found that microbial community diversity is negatively correlated with stability by mediating complexity. Interestingly, while pH was found to affect the complexity within bacterial networks, it did not significantly impact the ecosystem stability along the elevation gradients. Using a Binary-State Speciation and Extinction (BiSSE) model to explore the evolutionary dynamics, we found that Generalists had higher speciation rates and lower extinction rates compared to specialists, resulting in a skewed distribution towards higher net diversification for generalists under increasing environmental stress. Moreover, structural equation modeling (SEM) analysis highlighted a negative correlation between environmental stress and community diversity, but showed a positive correlation between environmental stress and degree of cooperation & competition. These interactions under environmental stress indirectly increased community stability and decreased multifunctionality. Our comprehensive study offers valuable insights into the intricate relationship among environmental factors, microbial communities, and ecosystem functions, especially in the context of varying elevation gradients. These findings contribute significantly to our understanding of how environmental stressors affect microbial diversity and ecosystem services, providing a foundation for future ecological research and management strategies in similar contexts.

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss. METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

Examining health-related quality of life in ambulatory adult patients with chronic heart failure: insights from Malaysia using EQ-5D-5L.

PURPOSE: Health-related quality-of-life (HRQoL) data for the chronic heart failure (HF) population in Malaysia are lacking. Using EQ-5D-5L, this study intended to describe their HRQoL, identify predictors of worse HRQoL, and derive EQ-5D-5L index scores for use in economic evaluations. METHODS: A cross-sectional survey was conducted between April and September 2023 to collect EQ-5D-5L, sociodemographic, and clinical data from outpatients with HF across seven public specialist hospitals in Malaysia. Multivariable logistic and linear regression models were used to identify independent predictors of reported problems in the EQ-5D-5L dimensions, and predictors of index scores and EQ-VAS, respectively. RESULTS: EQ-5D-5L data from 424 outpatients of multi-ethnic background (mean age: 57.1 years, 23.8% female, mean left ventricular ejection fraction: 35.7%, 89.7% NYHA class I-II) were collected using either Malay, English, or Chinese, achieving a 99.8% completion rate. Nearly half of the respondents reported issues in the Mobility, Usual Activities, and Pain/Discomfort dimensions. Mean EQ-5D-5L index was 0.820, lower than the general population, and significantly lower with NYHA class III-IV (0.747) versus NYHA class I (0.846) and NYHA class II (0.805). Besides NYHA class, independent predictors of worse HRQoL included Indian ethnicity, living alone, lower education, unemployment due to ill-health, and proxy-reported HRQoL, largely aligning with existing literature. CONCLUSION: Community-dwelling Malaysians with HF reported poorer HRQoL compared to the general population. The observed disparities in HRQoL among HF patients may be linked to specific patient characteristics, suggesting potential areas for targeted interventions. HRQoL assessment using EQ-5D-5L proves feasible and should be considered for routine implementation in local clinics.