Although glass-based long-persistent luminescence (LPL) materials offer superior transparency and integration capability compared with conventional phosphors, their emission has been predominantly res Show more
Although glass-based long-persistent luminescence (LPL) materials offer superior transparency and integration capability compared with conventional phosphors, their emission has been predominantly restricted to the blue-green region, leaving warm-color LPL largely unexplored. In this work, Mn Show less
This study integrates fluorescence resonance energy transfer (FRET) and small-angle X-ray scattering (SAXS) to elucidate, in real time, how triacylglycerol (TAG) self-assembly dynamics in human milk r Show more
This study integrates fluorescence resonance energy transfer (FRET) and small-angle X-ray scattering (SAXS) to elucidate, in real time, how triacylglycerol (TAG) self-assembly dynamics in human milk regulate digestion and absorption. Among three major human milk TAGs-1-oleoyl-2-palmitoyl-3-linoleoyl-glycerol (OPL), 1,3-dioleoyl-2-palmitoyl-glycerol (OPO), and 1,3-dilinoleoyl-2-palmitoyl-glycerol (LPL)-OPL showed ∼20% faster lipolysis and more rapid micelle formation (I Show less
Intramuscular fat (IMF) is a key determinant of meat quality, influencing tenderness, juiciness, and flavor. Previous studies have reported that the deposition of IMF is controlled by various factors. Show more
Intramuscular fat (IMF) is a key determinant of meat quality, influencing tenderness, juiciness, and flavor. Previous studies have reported that the deposition of IMF is controlled by various factors. However, there is a shortage of research exploring the variations in IMF deposition across age groups from a microbial perspective. This study evaluated the differences in IMF deposition between yearling (1-year-old) and mature (4-year-old) Longdong Cashmere goats and analyzed its association with gut microbiota. The results revealed that the IMF content in shoulder meat and blood lipid levels increased with age (p < 0.05). Conversely, the contents of lipoprotein lipase (LPL) in the liver and duodenum significantly decreased with age. Microbial diversity differed between the two age groups, with specific microbiota identified from the gut of goats involved in the lipid metabolism pathway. The concentrations of valeric and isovaleric acids in the rumen, as well as acetic, propionic and isovaleric acids in the colon, were higher in yearling goats than in mature goats (p < 0.05). Spearman correlation analysis of IMF deposition indicators with gut microbiota revealed that, within the rumen, the abundances of CAG-791 and Sodaliphilus were positively correlated with IMF content in shoulder meat and TG levels, while exhibiting a negative correlation with the contents of valeric acids. Furthermore, the abundance of Clostridium_R showed a positive association with IMF content in shoulder meat and with the abundances of CAG-791and Sodaliphilus. In contrast, the abundance of Bact₁₁ was negatively correlated with IMF content in shoulder meat, TG levels, and the abundances of CAG-791, Sodaliphilus and Clostridium_R. Within the abomasum, the abundances of UMGS and Hylemonella₅₈₂₃₀₈ were correlated with IMF content in the shoulder meat, as well as serum LDL and VLDL levels. This study provides significant insights into the age-dependent gut microbiota associated with intramuscular fat deposition in goats and identifies several potential gut microbiota for further research on their impacts on IMF deposition. Show less
Backfat thickness, a key selection trait in pig-breeding programmes, has traditionally been measured as a homogeneous layer. However, backfat is anatomically structured into three distinct layers, and Show more
Backfat thickness, a key selection trait in pig-breeding programmes, has traditionally been measured as a homogeneous layer. However, backfat is anatomically structured into three distinct layers, and each layer likely contributes differently to carcass quality. In addition, previous studies have shown that the deposition of the third layer of backfat is phenotypically correlated with intramuscular fat (IMF). Therefore, targeted selection for specific backfat layers, particularly the third layer, represents a potential strategy to increase IMF content while maintaining a high lean meat percentage. However, the genetic architecture of these distinct porcine backfat layers remains poorly understood. The aim of this study was to estimate the genetic parameters and identify key candidate genes underlying the three backfat layers. We collected B-mode ultrasound images from 561 Landrace pigs to measure individual layer thickness, followed by DNA extraction, genotyping, genetic parameter estimation, and a genome-wide association study (GWAS). Our measurements showed that the first layer of backfat (FBF) is the thickest, followed by the second (SBF) and the third (TBF) layers. Genetic parameter estimation yielded heritability estimates of 0.37, 0.42, 0.38, 0.34, 0.32, 0.24, and 0.21 for total backfat (BF), FBF, FBF/BF, SBF, SBF/BF, TBF, and TBF/BF, respectively. Through integrated analysis of GWAS, Bayesian fine-mapping, and gene annotation, we identified 15 non-redundant candidate genes associated with different backfat layers. These included two genes (SOAT1 and ACBD6) shared by BF and SBF, LPL for BF and FBF, and CAND1 for TBF and TBF/BF. Additionally, SERPINA12 and SERPINA6 were associated with BF; PRKAG1 and PRDM16 with FBF; EPRS1 and SLC39A10 with FBF/BF; PTGES and CRAT with SBF; and ACLY, CAVIN1, and PDZRN3 with SBF/BF. Our results indicate that each layer is governed by a distinct set of genes, which advances our understanding of the genetic basis of backfat layers in pigs. Show less
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify t Show more
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children. Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted. The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain ( The heterozygous mutations Show less
Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy associated with adverse maternal and fetal outcomes, highlighting the urgent need for novel, genetically supporte Show more
Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy associated with adverse maternal and fetal outcomes, highlighting the urgent need for novel, genetically supported drug targets due to suboptimal glycemic control and safety concerns with existing therapies. This study integrated cis-expression quantitative trait loci (cis-eQTL) of druggable genes with genome-wide association data to identify putative causal genes for GDM through two-sample Mendelian randomization (MR), with significant associations further validated using multi-tissue summary data-based Mendelian randomization (SMR), colocalization analysis, cis-protein quantitative trait loci (cis-pQTL) MR, and single-cell RNA sequencing (scRNA-seq) to confirm tissue- and cell type specific expression. MR analysis identified 15 genes significantly associated with GDM risk after Bonferroni correction, with SMR and colocalization analyses confirming robust associations for five key genes: higher expression of NRBP1, LPL, and BTN3A2 was causally linked to reduced GDM risk, while elevated GSTM1 and GRINA levels were associated with increased risk. ScRNA-seq revealed distinct expression patterns in placental cell types, with NRBP1 and GRINA highly expressed in trophoblasts and certain immune cell populations. Phenome-wide association studies revealed no significant pleiotropic effects, and pharmacological drug-target databases identified several compounds with potential regulatory interactions. This multi-omics study successfully identifies several genetically supported, druggable targets for GDM, providing a robust foundation for developing mechanism-based therapeutics and precision prevention strategies in pregnancy metabolism. Show less
Tail fat deposition constitutes a distinctive adaptive phenotype in sheep. The Large-tailed Han (LTH) and Small-tailed Han (STH) breeds display pronounced divergence in tail fat storage, offering an i Show more
Tail fat deposition constitutes a distinctive adaptive phenotype in sheep. The Large-tailed Han (LTH) and Small-tailed Han (STH) breeds display pronounced divergence in tail fat storage, offering an ideal model for elucidating lipid metabolism regulation. Integrated sRNA-Seq and RNA-Seq analysis identified 521 differentially expressed genes and 144 miRNAs, which were significantly enriched in lipid metabolism pathways, including fatty acid metabolism and PPAR signaling. Key candidate genes ( Show less
One important element impacting meat quality is fat metabolism, which mainly affects meat features through intramuscular fat deposition. Chinese native yellow-feathered broilers and white-feathered br Show more
One important element impacting meat quality is fat metabolism, which mainly affects meat features through intramuscular fat deposition. Chinese native yellow-feathered broilers and white-feathered broilers differ significantly in intramuscular fat concentration. This study used transcriptomic and metabolomic sequencing technologies to identify a total of 173 differentially expressed genes and 259 differential metabolites in the pectoral muscles of Chahua Chicken No. 2 and Cobb broiler in order to explore the genetic mechanisms by which lipid metabolism influences meat quality in Chinese indigenous yellow-feathered and white-feathered broilers. These included differentially expressed genes like FABP1, LPL, ELOVL7, SLC27A1, MOGAT1, and ULK2, which were enriched in pathways relevant to lipid metabolism and showed strong associations with γ-linolenic acid and palmitaldehyde, two distinct metabolites. In order to develop local chicken germplasm resources and breed superior indigenous chicken varieties, these candidate genes could serve as the genetic foundation for the variations in meat quality and lipid metabolism between Chinese native yellow-feathered and white-feathered broilers. Show less
For the advancements of photoresponsive materials with tunable properties, the usage of multidimensional signals is desired. Using the polarization of the light in addition to the wavelength represent Show more
For the advancements of photoresponsive materials with tunable properties, the usage of multidimensional signals is desired. Using the polarization of the light in addition to the wavelength represents a further parameter to control the materials properties. Here, the first-time dynamic and reversible manipulation of the guest-host properties of a nanoporous material by linearly polarized light (LPL) is reported. The material is based on a metal-organic framework (MOF) with photoresponsive azobenzene side groups covalently connected to the MOF structure. The azobenzene moieties are reversibly reoriented by LPL, making the MOF structure and, thus, the pores anisotropic. As a result, the mobility of the guest molecules in the pores of the initially isotropic material becomes anisotropic, which can be dynamically controlled by the light polarization. The experiments by impedance spectroscopy are supported by molecular dynamics (MD) simulations. The study shows that the light polarization can be a further parameter to modify the material properties, allowing a more complex and more refined level of control for smart materials. Show less
Excessive fat deposition compromises the health of companion animals and the carcass quality of food-producing livestock. Follicle-stimulating hormone (FSH) has been demonstrated to play a critical re Show more
Excessive fat deposition compromises the health of companion animals and the carcass quality of food-producing livestock. Follicle-stimulating hormone (FSH) has been demonstrated to play a critical regulatory role in fat deposition, with its function dependent on binding to its cognate receptor (FSHR) in target organs. In this study, female Sprague-Dawley (SD) rats were immunized with subunit vaccines targeting FSHβ and FSHR, respectively, and obesity was induced by a high-fat diet (HFD) to investigate the effects of these vaccines on adipose deposition in female mammals. The results revealed that active immunization against FSHβ and FSHR effectively suppressed HFD-induced obesity and the elevated serum triglyceride levels. Histological observations found that FSHβ and FSHR immunity decreased adipocyte hypertrophy and increased the cross-sectional area of skeletal muscle fibers caused by HFD, partially ameliorated HFD-associated hepatic sinusoidal spaces and vacuolated steatosis in the cytoplasm. RT-qPCR results indicated that FSHβ and FSHR immunization inhibited lipid synthesis by downregulating adipogenic-related genes, including C/ebpα, Creb, Pparγ, Lpl, and Perilipin. These findings suggest that both vaccines can mitigate HFD-induced adipose deposition in rats, with the FSHR vaccine exhibiting more pronounced effects. This study provides a novel strategy to mitigate pet health deterioration caused by excessive obesity and the decline in carcass quality of food-producing livestock. Show less
This study induced diabetic nephropathy (DN) in rats, analyzing perirenal adipose tissue (PRAT) via whole transcriptome sequencing to identify key mRNAs in DN pathogenesis. Type-2 diabetes was induced Show more
This study induced diabetic nephropathy (DN) in rats, analyzing perirenal adipose tissue (PRAT) via whole transcriptome sequencing to identify key mRNAs in DN pathogenesis. Type-2 diabetes was induced in SD rats, evaluating metabolic and renal indicators. Whole transcriptome sequencing identified differentially expressed RNAs in PRAT. CeRNA networks, PPI networks, and ingenuity pathway analysis (IPA) revealed key mRNAs linked to physiological indicators in DN. This study explores correlations between mRNAs and health parameters, shedding light on the complex interplay in type-2-diabetes mellitus (T2DM)-induced nephropathy. SD rats with type-2 diabetes exhibited insulin resistance, elevated blood glucose, disrupted lipid metabolism, and renal dysfunction. PRAT weight was higher in T2DM rats, and immunohistochemistry revealed distinct renal injury. Transcriptome sequencing identified 476 DE-mRNAs, 79 DE-miRNAs, 200 DE-lncRNAs, and 10 DE-circRNAs. The lncRNA-miRNA-mRNA network comprised 159 lncRNAs, 62 miRNAs, and 138 mRNAs, whereas the circRNA-miRNA-mRNA network included 76 mRNAs, 27 miRNAs, and 10 circRNAs. Key mRNAs (Lpl, Elovl6, Dgat2, Acaca, and Acly) were associated with 10 classical pathways according to IPA. Notably, all key mRNAs showed a negative correlation with blood urea nitrogen (BUN), serum creatinine, proteinuria, LDL-C, triglycerides (TG), and total cholesterol (TC), and a positive correlation with urine creatinine and HDL-C. Our study successfully established a T2DM model in SD rats and identified five key mRNAs, elucidating the role of PRAT in DN. These findings lay a scientific foundation for future investigations into DN. Show less
Previous studies have reported that IGF-1 single nucleotide polymorphism is associated with milk fat traits, but they are limited to trait association analysis. We previously identified a synonymous m Show more
Previous studies have reported that IGF-1 single nucleotide polymorphism is associated with milk fat traits, but they are limited to trait association analysis. We previously identified a synonymous mutation c.258 A > G (rs322131043) in IGF-1, which influenced IGF-1 expression and caused differences in metabolism. This study aims to reveal a new regulatory function of IGF-1 c.258 A > G on milk fat metabolism. Livers transcriptomics was used to identify differentially expressed genes between wild type mice (WT) and IGF-1 c.258 A > G mice (Homozygous mutation, Ho). Subsequently, lipid phenotyping, followed by metabolomics of mammary glands was conducted to verify transcriptomic findings. Finally, the potential mechanisms underlying IGF-1 c.258 A > G-induced changes in milk fat metabolism were explored though integrated transcriptomics-metabolomics analysis and Western blot validation. IGF-1 c.258 A > G changed the expression of genes related to lipid metabolism in livers of 8-week-old mice, including a 10-fold lipoprotein lipase (LPL) expression (P < 0.01) and 80-90 % downregulation of acyl-CoA thioesterase 3 (Acot3), enoyl-Coenzyme A delta isomerase 3 (Eci3), fatty acid synthase (FASN), and sterol regulatory element binding protein1 (SREBP1) expression (P < 0.01). The milk fat content of Ho dams on the second day of lactation (L2D) was decreased 50 % than that of WT dams (P < 0.05), although there was no significant difference in adipose tissue of 8-week-old WT/Ho mice. The levels of triglycerides, sphingolipids and their related fatty acyl chains (10:0, 26:0, 14:2, 20:4, 11:3, 19:0) in mammary glands of L2D Ho dams were reduced 10-50 % observed by lipid metabolomics. And combined with transcriptomics and Western blot, the data suggested that a 2.5-fold upregulation of LPL expression (P < 0.05) may contribute to the milk fat metabolism changes mediated by the IGF-1 c.258 A > G. This study revealed new function of IGF-1 c.258 A > G on milk fat metabolism, thereby informing the development of targeted genetic breeding on milk fat trait. Show less
Microtubule and actin crosslinking factor 1 (MACF1) plays a critical role in cytoskeletal regulation. Pathogenic variants in We identified two Chinese patients with Our findings broaden the phenotypic Show more
Microtubule and actin crosslinking factor 1 (MACF1) plays a critical role in cytoskeletal regulation. Pathogenic variants in We identified two Chinese patients with Our findings broaden the phenotypic spectrum of The online version contains supplementary material available at 10.1186/s40246-026-00917-y. Show less
The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reac Show more
The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. Show less
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited treatment options and frequent drug resistance. Novel therapeutic targets are urgently needed. We performed a druggabl Show more
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with limited treatment options and frequent drug resistance. Novel therapeutic targets are urgently needed. We performed a druggable genome-wide Mendelian randomization (MR) analysis using blood cis-expression quantitative trait locus (eQTL) and HS genome-wide association study (GWAS) data. Colocalization, transcriptomic validation, single-cell RNA sequencing, and cell-cell communication analyses were integrated to explore gene function and cell-type specificity. We identified eight genes that showed significant associations with HS through MR analysis. Colocalization analysis further prioritized PSMA4 and MAST3 as the most promising druggable targets for HS. Specifically, PSMA4 (single nucleotide polymorphisms [SNPs] = 10; inverse-variance weighted [IVW] OR = 1.912, 95% CI: 1.492-2.450, Show less
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variant Show more
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variants have been implicated, the cumulative impact of genetic variation within relevant biological pathways remains unexplored. We evaluated single nucleotide polymorphisms across 18 pathways previously identified as relevant to mucositis in 278 pediatric patients with acute lymphoblastic leukemia from six academic health centers across Canada. Pathway enrichment was assessed using the Joint Association of Genetic variants tool, and a predictive model was developed using XGBoost, a supervised machine learning algorithm based on gradient-boosted decision trees. Pathway enrichment identified significant associations in IL6 (P = 0.04) and WNT/β-catenin (P = 0.048) signaling pathways. The predictive model (area under the curve [AUC] = 0.76) highlighted single nucleotide polymorphisms associated with inflammation- and mucosa-related genes, including PRKCD, IL17B, MAST3, and CAPN9, with both risk and protective effects. Model performance dropped by 0.15 in AUC (from 0.76 to 0.61) after removing single nucleotide polymorphism features, underscoring their predictive value. This pathway-informed approach identifies genetic contributors to methotrexate-induced mucositis and supports polygenic risk prediction. Our findings provide a foundation for individualized toxicity risk profiling and suggest potential therapeutic targets to mitigate treatment-limiting mucositis in pediatric oncology. Show less
Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variants (SVs). Current clinical workflows to detect such alterations rely on a multimodal ap Show more
Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variants (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs (n = 5/5) detected through routine clinical testing. This approach also identified crSVs that resulted in the classification of a leukemia genetic subtype for four additional patients (n = 4/12), such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, that were missed by routine clinical approaches. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs. Show less
In this retrospective study, a total of 3468 adolescent and adult AML patients were screened, and 181 patients harboring The incidence of Our study revealed the heterogeneous outcomes of
PICALM∶∶MLLT10 fusion gene-positive precursor B-cell acute lymphoblastic leukemia(pro-B-ALL)is clinically rare.This article reports the case of a 29-year-old female patient who presented a mediastinal Show more
PICALM∶∶MLLT10 fusion gene-positive precursor B-cell acute lymphoblastic leukemia(pro-B-ALL)is clinically rare.This article reports the case of a 29-year-old female patient who presented a mediastinal mass.Diagnostic investigations confirmed PICALM∶∶MLLT10 fusion gene-positive pro-B-ALL.The patient sequentially received radiotherapy and multiple lines of chemotherapy but developed short-term drug resistance and lineage change,progressing to mixed-phenotype acute leukemia.A review of relevant literature was conducted to analyze its pathogenesis and molecular characteristics,aiming to provide references for clinical diagnosis and treatment. Show less
Ting Fang, Xinyu Yang, Xiaoqing Deng+5 more · 2026 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Excessive fructose intake is strongly associated with metabolic diseases, with the carbohydrate response element-binding protein (ChREBP) playing a key role in its metabolism, particularly in renal tu Show more
Excessive fructose intake is strongly associated with metabolic diseases, with the carbohydrate response element-binding protein (ChREBP) playing a key role in its metabolism, particularly in renal tubules. However, the role of its active form, ChREBP-β, was previously unclear. In this study, ChREBP-β overexpression and ChREBP knockout mouse models were utilized to investigate the effects of excessive fructose intake in vivo. In addition, primary renal tubular epithelial cells from mice and human kidney-2 (HK2) cells were applied for further validation in vitro. We found that ChREBP-β leads to increased transcription to mediate endoplasmic reticulum stress and mitochondrial dysfunction, which ultimately impairs renal function. Our findings underscore the critical role of ChREBP-β in fructose-related renal disorders. Show less
Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whet Show more
Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regulates hepatic DNL remains unclear. In this study, we investigated whether low-dose galactose supplementation attenuates glucose- or fructose-induced DNL activation and protects against fatty liver diseases driven by DNL overactivation, such as alcohol-associated liver disease (ALD). In this study, we used integrated hepatocyte and mouse models to assess hepatic DNL and related signaling under high-glucose or high-fructose conditions, with or without low-dose galactose. Pharmacological and genetic interventions targeting the Leloir and hexosamine biosynthetic pathways (HBP) defined underlying mechanisms. For in vivo validation, male C57BL/6 mice were fed an isocaloric control or ethanol-containing diet for 4 wk. We found that glucose engages the HBP-mTORC1-SREBP-1c axis to stimulate hepatic DNL, whereas fructose acts predominantly through carbohydrate-responsive element-binding protein (ChREBP). Low-dose galactose selectively suppressed glucose-induced hepatic fat accumulation, concomitant with the inhibition of the HBP-mTORC1-SERBP-1c pathway. These effects required an intact Leloir pathway for galactose metabolism and were not observed with fructose. In alcohol-fed mice, hepatic HBP-mTORC1-SREBP-1c signaling was markedly upregulated, contributing to steatosis and liver injury. Replacing even a small fraction of dietary glucose with galactose normalized these alterations, attenuating hepatic lipid accumulation and injury without altering systemic glucose levels. In conclusion, glucose-induced hepatic lipogenesis involves the HBP-mTORC1-SREBP-1c pathway, which is also activated during chronic alcohol exposure. Low-dose galactose, obtainable from dairy sources, attenuates this pathway, thereby limiting excessive lipogenesis and protecting against early-stage ALD. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become highly prevalent worldwide, largely as a consequence of the global obesity epidemic. This research endeavors to elucidate th Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become highly prevalent worldwide, largely as a consequence of the global obesity epidemic. This research endeavors to elucidate the role and molecular mechanisms of hepatic glycogen synthase (GS) in MASLD progression. Published transcriptomic data reveal a downward trend in GYS2 gene expression in patients with obesity, MASLD, and metabolic dysfunction-associated steatohepatitis. In mouse models of MASLD, GYS2 gene or protein expression was downregulated, consistent with the human data. Here, GS-deficient mice fed with a normal diet displayed hepatic lipid accumulation and liver injury, whereas hepatic steatosis progression and inflammation were aggravated in mice fed with a high-fat diet. Loss of hepatic GS stimulated fatty acid de novo synthesis through carbohydrate-response element-binding protein and AKT-mTOR1-sterol regulatory element-binding protein 1 axis pathways. In GS-deficient mice, lipid accumulation in the hepatocytes significantly decreased when carbohydrate-response element-binding protein and sterol regulatory element-binding protein 1 levels were suppressed to levels comparable to those of cytotoxic T lymphocyte hepatocytes. Forced expression of hepatic GS by adeno-associated virus in db/db mice ameliorated lipid accumulation in male mice. Our findings provide proof of concept whereby targeting glycogen metabolism in hepatocytes may offer potential therapeutic avenues to treat MASLD. Show less
Plin4 is transcriptionally regulated by peroxisome proliferator-activated receptor gamma and is primarily expressed in white adipose tissue (WAT). We found that expression of Plin4 is elevated in the Show more
Plin4 is transcriptionally regulated by peroxisome proliferator-activated receptor gamma and is primarily expressed in white adipose tissue (WAT). We found that expression of Plin4 is elevated in the liver upon prolonged feeding with an obesogenic diet containing saturated fat, fructose, and cholesterol (Western diet). To investigate the functional role of Plin4 in energy metabolism, we generated Plin4 Show less
Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expressi Show more
Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear. To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7 First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM. Show less
Sevoflurane, a widely used volatile anesthetic, has raised concerns regarding its potential developmental toxicity, particularly due to its extensive application in non-obstetric surgeries and fetal i Show more
Sevoflurane, a widely used volatile anesthetic, has raised concerns regarding its potential developmental toxicity, particularly due to its extensive application in non-obstetric surgeries and fetal intervention procedures during pregnancy. However, its effects on heart development and function remain unclear. Using zebrafish larvae as a model, we investigated the effects of prolonged sevoflurane exposure (0.04-0.08%) from 10 to 72 h post-fertilization (hpf). Under these conditions, treated larvae exhibited dose-dependent developmental abnormalities, including reduced body length, pericardial edema, and impaired heart tube looping. Cardiac function analysis revealed significant decreases in ejection fraction, stroke volume, heart rate, and cardiac output, indicating impaired cardiac contractility and pumping efficiency. These functional impairments were accompanied by structural changes including ventricular wall thinning and chamber dilation, along with upregulation of cardiac stress markers (nppa, nppb) - characteristic features of dilated cardiomyopathy (DCM). Molecular analysis demonstrated downregulation of sarcomeric (tnnt2a, mybpc3) and calcium-handling (atp2a2a, slc8a1a) genes, suggesting disruption of sarcomere integrity and calcium homeostasis. Additionally, sevoflurane exposure elevated inflammatory cytokines (il-6, tnf-α, il-1β) and promoted leukocyte infiltration into cardiac tissue. RNA sequencing analysis implicated dysregulation of Apelin signaling pathway, with reduced prkaa2 (AMPKα2) expression and phosphorylation observed in both zebrafish and H9C2 cardiomyocytes. Critically, pharmacological activation of AMPK using A-769662 effectively mitigated sevoflurane-induced cardiotoxicity, identifying AMPKα2 as a potential therapeutic target. Collectively, these findings delineate the molecular mechanisms underlying sevoflurane-induced developmental cardiotoxicity following prolonged exposure in zebrafish and suggest that targeting AMPKα2 signaling merits investigation as a potential strategy to mitigate anesthetic-related cardiac developmental risks. Show less
MYBPC3 mutations are the leading cause of hypertrophic cardiomyopathy. Here, to study the pathogenesis of hypertrophic cardiomyopathy, we created a MYBPC3 knockout (KO) model using human induced pluri Show more
MYBPC3 mutations are the leading cause of hypertrophic cardiomyopathy. Here, to study the pathogenesis of hypertrophic cardiomyopathy, we created a MYBPC3 knockout (KO) model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). MYBPC3-deleted hiPSC-CMs revealed the characteristics of heart failure, which exhibited increased contractility at 30 days but decreased at 40 days. Furthermore, at 40 days, it also shows abnormal calcium handling, increased ROS levels, and mitochondrial damage. Further RNA sequencing revealed that the oxidative stress pathway was aberrant, in addition to alterations linked to hypertrophic cardiomyopathy. Moreover, after adding melatonin to hiPSC-CMs at 30 days, MYBPC3-deleted hiPSC-CMs showed restored calcium handling capacity, decreased ROS levels, and improved myocardial contractility. In summary, reducing ROS can improve the phenotype of hypertrophic cardiomyopathy. Show less
This study aimed to systematically elucidate the antihyperlipidemic mechanism of paeoniflorin, and we adopted an integrated multi-omics strategy to screen the key molecular targets and regulatory path Show more
This study aimed to systematically elucidate the antihyperlipidemic mechanism of paeoniflorin, and we adopted an integrated multi-omics strategy to screen the key molecular targets and regulatory pathways involved in its action, followed by experimental validation to verify the potential regulatory effects of paeoniflorin on the screened targets and metabolic processes. Rats with high-fat diet-induced hyperlipidemia received paeoniflorin treatment. Liver histopathology was evaluated using hematoxylin-eosin and Oil Red O staining. Serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bile acids, activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen were measured using a biochemical analyzer. Integrated multi-omics analyses were performed to investigate paeoniflorin's lipid-lowering mechanism. Critical pathways and targets identified were validated using Western blotting. Paeoniflorin alleviated pathological liver damage in hyperlipidemic rats and improved blood lipid levels, coagulation function, and liver function markers. Multi-omics analyses verified that paeoniflorin downregulated the expression of TREM-1, TLR4, NF-κB, TNF-α, and IL-1β, thereby alleviating hepatic inflammation. Paeoniflorin also upregulated the expression of low-density lipoprotein receptors (LDLR), liver X receptor alpha (LXRα), and ATP-binding cassette subfamily G member 1 (ABCG1), while downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, contributing to balanced cholesterol metabolism. Paeoniflorin normalized glycerophospholipid and branched-chain amino acid metabolism, which correlated with reduced inflammation and improved cholesterol metabolism. Paeoniflorin ameliorates hyperlipidemia through multitarget mechanisms, potentially by suppressing the TREM-1-TLR4-NF-κB signaling pathway to reduce inflammation and by regulating cholesterol metabolism via the PCSK9-LDLR and LXRα-ABCG1 pathways. Show less