Hierarchical superstructure aerogels for in situ biofluid metabolomics.

High-throughput biofluid metabolomics analysis for screening life-threatening diseases is urgently needed. However, the high salt content of biofluid samples, which introduces severe interference, can greatly limit the analysis throughput. Here, a new 3-D interconnected hierarchical superstructure, namely a "plasmonic gold-on-silica (Au/SiO2) double-layered aerogel", integrating distinctive features of an upper plasmonic gold aerogel with a lower inert silica aerogel was successfully developed to achieve in situ separation and storage of inorganic salts in the silica aerogel, parallel enrichment of metabolites on the surface of the functionalized gold aerogel, and direct desorption/ionization of enriched metabolites by the photo-excited gold aerogel for rapid, sensitive, and comprehensive metabolomics analysis of human serum/urine samples. By integrating all these unique advantages into the hierarchical aerogel, multifunctional properties were introduced in the SALDI substrate to enable its effective utilization in clinical metabolomics for the discovery of reliable metabolic biomarkers to achieve unambiguous differentiation of early and advanced-stage lung cancer patients from healthy individuals. This study provides insight into the design and application of superstructured nanomaterials for in situ separation, storage, and photoexcitation of multi-components in complex biofluid samples for sensitive analysis.

Association of Combined Healthy Lifestyle Factors With Incident Dementia in Participants With and Without Multimorbidity: A Large Population-Based Prospective Cohort Study.

BACKGROUND: The effect of a healthy lifestyle on dementia associated with multimorbidity is not well understood. Our objective is to examine whether the adoption of a healthy lifestyle could potentially reduce the elevated risk of dementia in individuals with and without multimorbidity. METHODS: We utilized data from the UK Biobank cohort. A comprehensive healthy lifestyle score, ranging from 0 to 6, was generated. Cox proportional hazards models were used to examine the associations between multimorbidity, the healthy lifestyle score, and the incidence risk of dementia. RESULTS: Over a median follow-up period of 12.5 years, 5 852 all-cause dementia were recorded. Multimorbidity including cardiovascular, metabolic, neuropsychiatric, and inflammation-related diseases was associated with a higher risk of subsequent dementia. Each additional chronic disease was associated with a hazard ratio (HR) of 1.38 (95% CI: 1.33, 1.44). Compared to individuals without multimorbidity and a healthy lifestyle score of 5-6, patients with multimorbidity and a lifestyle score of 0-1 had a significantly higher risk of dementia (HR: 3.13; 95% CI: 2.64, 3.72), but the risk was markedly attenuated among those with multimorbidity and a lifestyle score of 5-6. Among patients with 3 or more diseases, the HR for dementia was 0.53 (95%CI: 0.42, 0.68) when comparing a lifestyle score of 5-6 to 0-1. And we observed more pronounced association between them among people younger than 60 years old. CONCLUSIONS: Adherence to a combination of healthy lifestyle factors, especially at a young age, was associated with a significantly lower risk of dementia among participants with multimorbidity.

Interventions for psychiatric disorders among university students: An umbrella review of systematic reviews and meta-analyses.

Background: Mental disorders are considered to be the main reason for the increase of the disease burden. College students seem to be more vulnerable to the adverse effects of stress, which makes them more at risk of suffering from mental disorders. This umbrella review aimed to evaluate the credibility of published evidence regarding the effects of interventions on mental disorders among university students. Methods: To identify systematic reviews and meta-analyses investigating the effects of interventions on mental disorders in the university student population, extensive searches were carried out in databases including PubMed, Embase, and the Cochrane Database, spanning from inception to July 21, 2023. Subsequently, a thorough reanalysis of crucial parameters such as summary effect estimates, 95 % confidence intervals, heterogeneity I2 statistic, 95 % prediction intervals, small-study effects, and excess significance bias was performed for each meta-analysis found. Results: Nineteen articles involving 74 meta-analyses were included. Our grading of the current evidence showed that interventions based on exercise, Cognitive-behavioural Intervention (CBI), mindfulness-based interventions (MBI), and other interventions like mood and anxiety interventions (MAI) were effective whereas exercise intervention had the highest effect size for both depression and anxiety among university students. However, the credibility of the evidence was weak for most studies. Besides, suggestive evidence was observed for the positive effects of CBI on sleep disturbance(SMD: -0.603, 95 % CI: -0.916, -0.290; P-random effects<0.01) and MAI on anxiety (Hedges'g = -0.198, 95 % CI: -0.302, -0.094; P-random effects<0.01). Conclusion: Based on our findings, it appears that exercise interventions, CBI, and MAI have the potential to alleviate symptoms related to mental disorders. Despite the overall weak credibility of the evidence and the strength of the associations, these interventions offer a promising avenue for further exploration and research in the future. More high-quality randomized controlled trials should be taken into account to verify the effects of these interventions on various mental disorders.

µ-PESI-based MS profiling combined with untargeted metabolomics analysis for rapid identification of red wine geographical origin.

BACKGROUND: The commercial value of red wine is strongly linked to its geographical origin. Given the large global market, there is great demand for high-throughput screening methods to authenticate the geographical source of red wine. However, only limited techniques have been established up to now. RESULTS: Herein, a sensitive and robust method, namely probe electrospray ionization mass spectrometry (µ-PESI-MS), was established to achieve rapid analysis at approximately 1.2 min per sample without any pretreatment. A scotch near the needle tip provides a fixed micro-volume for each analysis to achieve satisfactory ion signal reproducibility (RSD < 26.7%). In combination with a machine learning algorithm, 16 characteristic ions were discovered from thousands of detected ions and were utilized for differentiating red wine origin. Among them, the relative abundances of two characteristic metabolites (trigonelline and proline) correlated with geographical conditions (sun exposure and water stress) were identified, providing the rationale for differentiation of the geographical origin. CONCLUSION: The proposed µ-PESI-MS-based method demonstrates a promising high-throughput determination capability in red wine traceability.

Efficacy and safety of hepatitis B vaccine: an umbrella review of meta-analyses.

BACKGROUND: There is a lack of synthesis of literature to determine hepatitis B vaccine (HepB) strategies for hepatitis B virus (HBV) supported by quality evidence. We aimed to explore the efficacy and safety of HepB strategies among people with different characteristics. RESEARCH DESIGN AND METHODS: PubMed, Cochrane Library, Embase, and Web of Science were searched for meta-analyses comparing the efficacy and safety of HepB up to July 2023. RESULTS: Twenty-one meta-analyses comparing 83 associations were included, with 16 high quality, 4 moderate, and 1 low quality assessed by AMSTAR 2. Highly suggestive evidence supports HepB booster and HepB with 1018 adjuvant (HBsAg-1018) for improved seroprotection, and targeted and universal HepB vaccination reduced HBV infection Suggestive evidence indicated that targeted vaccination decreased the rate of hepatitis B surface antibody positivity and booster doses increased seroprotection in people aged 10-20. Weak evidence suggests potential local/systemic reaction risk with nucleotide analogs or HBsAg-1018. Convincing evidence shows HLA-DPB1*04:01 and DPB1*04:02 increased, while DPB1*05:01 decreased, hepatitis B antibody response. Obesity may reduce HepB seroprotection, as highly suggested. CONCLUSION: Targeted vaccination could effectively reduce HBV infection, and adjuvant and booster vaccinations enhance seroprotection without significant reaction. Factors such as obesity and genetic polymorphisms may affect the efficacy.

FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.

Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.

Potential active compounds and common mechanisms of Evodia rutaecarpa for Alzheimer's disease comorbid pain by network pharmacology analysis.

Evodia rutaecarpa (Evodia) is a Chinese herbal medicine with analgesic and anti-neurodegenerative properties. However, whether Evodia compounds can be applied for the comorbid pain of Alzheimer's disease (AD) and the underlying mechanisms remain unclear. Herein, 137 common targets of Evodia between AD and pain were predicted from drug and disease target databases. Subsequently, protein-protein interaction (PPI) network, protein function module construction, and bioinformatics analyses were used to analyze the potential relationship among targets, pathways, and diseases. Evodia could simultaneously treat AD comorbid pain through multi-target, multi-component, and multi-pathway mechanisms, and inflammation was an important common phenotype of AD and pain. The relationship between important transcription factors such as RELA, NF-κB1, SP1, STAT3, and JUN on IL-17, TNF, and MAPK signaling pathways might be potential mechanisms of Evodia. Additionally, 10 candidate compounds were predicted, and evodiamine might be the effective active ingredient of Evodia in treating AD or pain. In summary, this study provided a reference for subsequent research and a novel understanding and direction for the clinical use of evodiamine to treat AD patients with comorbid pain.

FAM210A mediates an inter-organelle crosstalk essential for protein synthesis and muscle growth in mouse.

Mitochondria are not only essential for energy production in eukaryocytes but also a key regulator of intracellular signaling. Here, we report an unappreciated role of mitochondria in regulating cytosolic protein translation in skeletal muscle cells (myofibers). We show that the expression of mitochondrial protein FAM210A (Family With Sequence Similarity 210 Member A) is positively associated with muscle mass in mice and humans. Muscle-specific Myl1Cre-driven Fam210a knockout (Fam210aMKO) in mice reduces mitochondrial density and function, leading to progressive muscle atrophy and premature death. Metabolomic and biochemical analyses reveal that Fam210aMKO reverses the oxidative TCA cycle towards the reductive direction, resulting in acetyl-CoA accumulation and hyperacetylation of cytosolic proteins. Specifically, hyperacetylation of several ribosomal proteins leads to disassembly of ribosomes and translational defects. Transplantation of Fam210aMKO mitochondria into wildtype myoblasts is sufficient to elevate protein acetylation in recipient cells. These findings reveal a novel crosstalk between the mitochondrion and ribosome mediated by FAM210A.

PRMT5 links lipid metabolism to contractile function of skeletal muscles.

Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels of Prmt5, we generated skeletal muscle-specific Prmt5 knockout (Prmt5MKO ) mice. We observe reduced muscle mass, oxidative capacity, force production, and exercise performance in Prmt5MKO mice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and accelerated degradation. Specifically, PRMT5 deletion reduces dimethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Moreover, Prmt5MKO impairs the repressive H4R3 symmetric dimethylation at the Pnpla2 promoter, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, skeletal muscle-specific double knockout of Pnpla2 and Prmt5 normalizes muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.

Multimodal high-resolution nano-DESI MSI and immunofluorescence imaging reveal molecular signatures of skeletal muscle fiber types.

The skeletal muscle is a highly heterogeneous tissue comprised of different fiber types with varying contractile and metabolic properties. The complexity in the analysis of skeletal muscle fibers associated with their small size (30-50 µm) and mosaic-like distribution across the tissue tnecessitates the use of high-resolution imaging to differentiate between fiber types. Herein, we use a multimodal approach to characterize the chemical composition of skeletal fibers in a limb muscle, the gastrocnemius. Specifically, we combine high-resolution nanospray desorption electrospray ionization (nano-DESI) mass spectrometry imaging (MSI) with immunofluorescence (IF)-based fiber type identification. Computational image registration and segmentation approaches are used to integrate the information obtained with both techniques. Our results indicate that the transition between oxidative and glycolytic fibers is associated with shallow chemical gradients (<2.5 fold change in signals). Interestingly, we did not find any fiber type-specific molecule. We hypothesize that these findings might be linked to muscle plasticity thereby facilitating a switch in the metabolic properties of fibers in response to different conditions such as exercise and diet, among others. Despite the shallow chemical gradients, cardiolipins (CLs), acylcarnitines (CAR), monoglycerides (MGs), fatty acids, highly polyunsaturated phospholipids, and oxidized phospholipids, were identified as molecular signatures of oxidative metabolism. In contrast, histidine-related compounds were found as molecular signatures of glycolytic fibers. Additionally, the presence of highly polyunsaturated acyl chains in phospholipids was found in oxidative fibers whereas more saturated acyl chains in phospholipids were found in glycolytic fibers which suggests an effect of the membrane fluidity on the metabolic properties of skeletal myofibers.

Integration of Non-targeted Proteomics Mass Spectrometry with Machine Learning for Screening Cooked Beef Adulterated Samples.

The degradation of ingredients in heat-processed meat products makes their authentication challenging. In this study, protein profiles of raw beef, chicken, duck, pork, and binary simulated adulterated beef samples (chicken-beef, duck-beef, and pork-beef) and their heat-processed samples were obtained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Heat-stable characteristic proteins were found by screening the overlapping characteristic protein ion peaks of the raw and corresponding heat-processed samples, which were discovered by partial least-squares discriminant analysis. Based on the 36 heat-stable characteristic proteins, qualitative classification for the raw and heat-processed meats was achieved by extreme gradient boosting. Moreover, quantitative analysis via partial least squares regression was applied to determine the adulteration ratio of the simulated adulterated beef samples. The validity of the approach was confirmed by a blind test with the mean accuracy of 97.4%. The limit of detection and limit of quantification of this method were determined to be 5 and 8%, respectively, showing its practical aspect for the beef authentication.

The prognostic value of NLRP1/NLRP3 and its relationship with immune infiltration in human gastric cancer.

BACKGROUND: Inflammasomes are related to tumorigenesis and immune-regulation. Here, we investigated the prognostic value of the NLR family pyrin domain containing (NLRP) 1/NLRP3 inflammasome and its potential mechanisms in immune-regulation in gastric cancer (GC). METHODS: We analyzed the differential expression of NLRP1/NLRP3 between tumor and normal tissues using the Oncomine and Tumor Immune Estimate Resource (TIMER) databases. Immunohistochemistry and western blotting were used to detect NLRP1/NLRP3 protein expression in GC tissues. Correlations between NLRP1/NLRP3 expression levels and patient survival were analyzed using Kaplan-Meier survival curves. The relationships of NLRP1/NLRP3 expression and tumor-infiltrating immune cells/marker genes were assessed using the TIMER database. NLRP1/NLRP3 and immune checkpoint gene correlations were verified by single-gene co-expression analyses, and tumor immune-related pathways involving NLRP1/NLRP3 were analyzed using gene set enrichment analysis (GSEA). RESULTS: Elevated NLRP1/NLRP3 expression was significantly correlated with lymph node metastasis, poor survival, immune-infiltrating cell abundances, and immune cell markers. NLRP3 showed stronger correlations with immune infiltration and the prognosis of gastric cancer. NLRP1 and NLRP3 might be involved in the same tumor immune-related pathways. Thus, high NLRP1/NLRP3 expression promotes immune cell infiltration and poor prognosis in GC. NLRP1/NLRP3, particularly NLRP3, may have important roles in immune infiltration and may serve as a prognostic biomarker for GC. CONCLUSIONS: NLRP1/NLRP3, particularly NLRP3, may have important roles in immune infiltration and may serve as a prognostic biomarker for GC.

Comparison of Different Varieties on Quality Characteristics and Microbial Activity of Fresh-Cut Pineapple during Storage.

This study compared the quality and storage characteristics of four pineapple varieties to select those displaying adequate storage resistance and those suitable for freshly cut processing. Four varieties of pineapple, namely Tainong No.16, Tainong No.17, Tainong No.11, and Bali, were used to analyze the quality differences in freshly cut pineapple during storage by measuring the quality, physiological indicators, and total microbial count. The results indicated that the nutritional quality and storability of freshly cut pineapples differed significantly among the varieties. During refrigeration at 4 °C, Tainong No.11 and Bali displayed the shortest storage period of 4 d, while Tainong No.17 and Tainong No.16 presented storage periods of 5 d and 6 d, respectively. A sensory evaluation indicated that the Tainong No.16 variety was superior in terms of consumer preference, while the Bali slices were generally rated lower than the other cultivars. Additionally, the sensory properties, weight loss, firmness, and ascorbic acid (AA) content of Tainong No.16 changed the least during storage, with values of 60.75%, 6.48%, 75.15%, and 20.44%, respectively. Overall, the quality order of the four varieties of freshly cut pineapples during storage was: Tainong No.16 > Tainong No.17 > Tainong No.11 > Bali. Moreover, two-way ANOVA showed that the main effect of variety and storage time on the storage quality of fresh-cut pineapple was significant (p < 0.05). The interaction effect of variety and storage time on other quality characteristics of fresh-cut pineapple was significant (p < 0.05) except for Titratable acid (TA) and AA. In conclusion, Tainong No.16 displayed higher storage potential than the other varieties. The results of this work provide application possibilities to promote the successful processing of pineapple cultivars as freshly cut produce.

Chchd10 is dispensable for myogenesis but critical for adipose browning.

The Chchd10 gene encodes a coiled-coil-helix-coiled-coil-helix-domain containing protein predicted to function in the mitochondrion and nucleus. Mutations of Chchd10 are associated with ALS, dementia and myopathy in humans and animal models, but how knockout of Chchd10 (Chchd10KO) affects various tissues especially skeletal muscle and adipose tissues remains unclear. Here we show that Chchd10 expression increases as myoblasts and preadipocytes differentiate. During myogenesis, CHCHD10 interacts with TAR DNA binding protein 43 (TDP-43) in regenerating myofibers in vivo and in newly differentiated myotubes ex vivo. Surprisingly, Chchd10KO mice had normal skeletal muscle development, growth and regeneration, with moderate defects in grip strength and motor performance. Chchd10KO similarly had no effects on development of brown and white adipose tissues (WAT). However, Chchd10KO mice had blunted response to acute cold and attenuated cold-induced browning of WAT, with markedly reduced UCP1 levels. Together, these results demonstrate that Chchd10 is dispensable for normal myogenesis and adipogenesis but is required for normal motility and cold-induced, mitochondrion-dependent browning of adipocytes. The data also suggest that human CHCHD10 mutations cause myopathy through a gain-of-function mechanism.

Lipid droplet dynamics regulate adult muscle stem cell fate.

The lipid droplet (LD) is a central hub for fatty acid metabolism in cells. Here we define the dynamics and explore the role of LDs in skeletal muscle satellite cells (SCs), a stem cell population responsible for muscle regeneration. In newly divided SCs, LDs are unequally distributed in sister cells exhibiting asymmetric cell fates, as the LDLow cell self-renews while the LDHigh cell commits to differentiation. When transplanted into regenerating muscles, LDLow cells outperform LDHigh cells in self-renewal and regeneration in vivo. Pharmacological inhibition of LD biogenesis or genetic inhibition of LD catabolism through knockout of Pnpla2 (encoding ATGL, the rate-limiting enzyme for lipolysis) disrupts cell fate homeostasis and impairs the regenerative capacity of SCs. Dysfunction of Pnpla2-null SCs is associated with energy insufficiency and oxidative stress that can be partially rescued by antioxidant (N-acetylcysteine) treatment. These results establish a direct link between LD dynamics and stem cell fate determination.

Oestrogen promotes lipids transportation through oestrogen receptor α in hepatic steatosis of geese in vitro.

Evidence has shown that oestrogen suppresses lipids deposition in the liver of mammals. However, the molecular mechanism of oestrogen action in hepatic steatosis of geese liver has yet to be determined. This study aimed to investigate the effect of oestrogen on lipid homeostasis at different states of geese hepatocytes in vitro. The results showed that an in vitro model of hepatic steatosis was induced by 1.5 mM sodium oleate via detecting the viability of hepatocytes and content of lipids. When the normal hepatocytes were administrated with different concentrations of oestrogen (E2 ), the expression levels of diacylglycerol acyltransferase 2 (DGAT2), microsomal triglyceride transfer protein (MTTP) and oestrogen receptors (ERs, alpha and beta) were up-regulated only at high concentrations of E2 , whereas the lipid content was not a significant difference. In goose hepatocytes of hepatic steatosis, however, the expression levels of MTTP, apolipoprotein B (apoB) and ERα/ß significantly increased at 10-7 or 10-6  M E2 . Meanwhile, the lipids content significantly increased at 10-9 and 10-8  M E2 and decreased at 80 µM E2 . Further heatmap analysis showed that ERα was clustered with apoB and MTTP in either normal hepatocytes or that of hepatic steatosis. Taken together, E2  might bind to ERα to up-regulate the expression levels of apoB and MTTP, promoting the transportation of lipids and alleviating lipids overload in hepatic steatosis of geese in vitro.

LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes.

Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non-shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mitochondrial outer membrane protein, LETM1-domain containing 1 (LETMD1), in BAT. We generated a knockout (Letmd1KO ) mouse model and analyzed BAT morphology, function and gene expression under various physiological conditions. While the Letmd1KO mice are born normally and have normal morphology and body weight, they lose multilocular brown adipocytes completely and have diminished mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression in the intrascapular BAT, associated with elevated reactive oxidative stress. In consequence, the Letmd1KO mice fail to maintain body temperature in response to acute cold exposure without food and become hypothermic within 4 h. Although the cold-exposed Letmd1KO mice can maintain body temperature in the presence of food, they cannot upregulate expression of uncoupling protein 1 (UCP1) and convert white to beige adipocytes, nor can they respond to adrenergic stimulation. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes.

Imaging and Analysis of Isomeric Unsaturated Lipids through Online Photochemical Derivatization of Carbon-Carbon Double Bonds*.

Unraveling the complexity of the lipidome requires the development of novel approaches for the structural characterization of lipid species with isomer-level discrimination. Herein, we introduce an online photochemical approach for lipid isomer identification through selective derivatization of double bonds by reaction with singlet oxygen. Lipid hydroperoxide products are generated promptly after laser irradiation. Fragmentation of these species in a mass spectrometer produces diagnostic fragments revealing the C=C locations in the unreacted lipids. This approach uses an inexpensive light source and photosensitizer making it easy to incorporate into any lipidomics workflow. We demonstrate the utility of this approach for the shotgun profiling of C=C locations in different lipid classes present in tissue extracts using electrospray ionization (ESI) and ambient imaging of lipid species differing only by the location of C=C bonds using nanospray desorption electrospray ionization (nano-DESI).

PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is caused by a mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting, loss of mobility, and, ultimately, cardiorespiratory failure and premature death. Currently there is no cure for DMD. Herein, we report that skeletal muscle-specific knockout (KO) of the phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidence. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and it improves grip strength and exercise performance in mdx mice. Pten KO also reduces fibrosis and inflammation, and it ameliorates muscle pathology in mdx mice. Unbiased RNA sequencing reveals that Pten KO upregulates extracellular matrix and basement membrane components positively correlated with wound healing and suppresses negative regulators of wound healing and lipid biosynthesis, thus improving the integrity of muscle basement membrane at the ultrastructural level. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our findings provide evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

Role of stearyl-coenzyme A desaturase 1 in mediating the effects of palmitic acid on endoplasmic reticulum stress, inflammation, and apoptosis in goose primary hepatocytes.

OBJECTIVE: Unlike mammals, goose fatty liver shows a strong tolerance to fatty acids without obvious injury. Stearyl-coenzyme A desaturase 1 (SCD1) serves crucial role in desaturation of saturated fatty acids (SAFs), but its role in the SAFs tolerance of goose hepatocytes has not been reported. This study was conducted to explore the role of SCD1 in regulating palmitic acid (PA) tolerance of goose primary hepatocytes. METHODS: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide was examined to reflect the effect of PA on hepatocytes viability, and quantitative polymerase chain reaction was used to detect the mRNA levels of several genes related to endoplasmic reticulum (ER) stress, inflammation, and apoptosis, and the role of SCD1 in PA tolerance of goose hepatocytes was explored using RNA interfere. RESULTS: Our results indicated that goose hepatocytes exhibited a higher tolerant capacity to PA than human hepatic cell line (LO2 cells). In goose primary hepatocytes, the mRNA levels of fatty acid desaturation-related genes (SCD1 and fatty acid desaturase 2) and fatty acid elongate enzyme-related gene (elongase of very long chain fatty acids 6) were significantly upregulated with 0.6 mM PA treatment. However, in LO2 cells, expression of ER stressrelated genes (x box-binding protein, binding immunoglobulin protein, and activating transcription factor 6), inflammatory response-related genes (interleukin-6 [IL-6], interleukin- 1ß [IL-1ß], and interferon-γ) and apoptosis-related genes (bcl-2-associated X protein, b-cell lymphoma 2, Caspase-3, and Caspase-9) was significantly enhanced with 0.6 mM PA treatment. Additionally, small interfering RNA (siRNA) mediated downregulation of SCD1 significantly reduced the PA tolerance of goose primary hepatocytes under the treatment of 0.6 mM PA; meanwhile, the mRNA levels of inflammatory-related genes (IL-6 and IL-1ß) and several key genes involved in the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT), forkhead box O1 (FoxO1), mammalian target of rapamycin and AMPK pathways (AKT1, AKT2, FoxO1, and sirtuin 1), as well as the protein expression of cytochrome C and the apoptosis rate were upregulated. CONCLUSION: In conclusion, our data suggested that SCD1 was involved in enhancing the PA tolerance of goose primary hepatocytes by regulating inflammation- and apoptosisrelated genes expression.