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Purpose: Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating cardiovascular and renal disorders, its impacts and mechanisms on NAFLD are poorly understood. This research aimed to examine the metabolic regulatory mechanism through which empagliflozin protects against NAFLD. Methods: Equal grouping of twenty-seven male C57BL/6J mice into those fed a normal diet (NCD), those fed a high-fat diet (HFD), and those fed an HFD with empagliflozin (Empa) was approached. HE, oil red O staining, and Masson staining were utilized for evaluating the pathological damage to the liver and the mice's liver and body weights. Lipids, blood glucose, and inflammation index were compared across the three groups. Liquid chromatography/mass spectrometry (LC-MS) has been employed for identifying liver metabolomics. Results: The findings suggested that empagliflozin mitigated the inflammatory and oxidative stress response associated with the buildup of lipids caused by HFD. Differentially expressed metabolites (DEMs) were identified by metabonomics analysis as present in both the HFD/NCD and Empa/HFD groups. These DEMs were primarily found in lipids and organic acids like lysophosphatidylcholine (lysoPC), lecithin (PC), triglyceride (TG), palmitic acid, and L-isoleucine. Among the enriched pathways that were shown to be important were those involved in the metabolism of histidine, arachidonic acid, the control of lipolysis in adipocytes, and insulin resistance. There was a strong correlation between inflammation and oxidative stress in most of the metabolites. The inflammation and oxidative stress unbalance were ameliorated by empagliflozin. Conclusion: NAFLD mice model showed considerable improvement in metabolic abnormalities and liver protection after treatment with empagliflozin. The process may include the overexpression of L-isoleucine and the downregulation of lysoPC, PC, TG, and palmitic acid to reduce liver harm caused by lipotoxicity.

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Objective: Based on the 4D label-free phosphoproteomic technique, we examined the differences in cognitive function and hippocampal phosphorylated protein expression in high-fat diet-induced obese mice after the intervention of semaglutide and empagliflozin, as well as the effects of both on protein activity and function in obese mice's hippocampal tissues and the signaling pathways involved. Methods: Thirty-two C57BL/6JC male mice were assigned to two groups randomly: A control group (group C, 10% of energy is from fat, n = 8) and a high-fat diet group (group H, 60% of energy is from fat, n = 24). The high-fat diet-induced obese mice were screened after 12 weeks of feeding based on the criterion that the bodyweight of mice in fat rich diet group was greater than or equal to 20% of the average body weight of the mice in the blank control group. Group H separate into group H (n = 8), group Semaglutide (group S, n = 8), and group empagliflozin (group E, n = 8). For a total of 12 weeks, group S received 30 nmol/kg/d bodyweight of semaglutide intraperitoneally, group E received 10 mg/kg/d bodyweight of empagliflozin via gavage, and groups C and H received equal amounts of saline by intraperitoneal injection and gavage. At the end of treatment, the mice were appraised for cognitive function employing the Morris water maze (MWM), and serum fasting glucose, lipids, and inflammatory parameters were measured. The 4D label-free phosphoproteomics method was employed to screen the differential phosphoproteins and loci in hippocampal tissues of mice in different treatment groups, and bioinformatics was used to analyze the biological processes, signaling pathways, and related protein-protein interaction (PPI) network analysis of these differentially phosphorylated proteins. Results: In comparison to normal controls, The escape latency of obese mice induced by high-fat diet was prolonged, the percentage of swimming time in the target quadrant was reduced, and the number of times of crossing the platform was reduced, whereas semaglutide and empagliflozin treatment reduced escape latency, increase the percentage of swim time in the target quadrant and increase the frequency of passing through the platform area, although there is little difference in the effect of the two drugs. The phosphoproteomic results showed 20,493 unique phosphorylated peptides, representing 21,239 phosphorylation sites and 4,290 phosphorylated proteins. Further analysis revealed that the proteins corresponding to these differentially phosphorylated sites are jointly distributed in signaling pathways such as dopaminergic synapses and axon guidance, and are involved in biological processes such as neuronal projection development, synaptic plasticity, and axonogenesis. Notably, the key factors voltage-dependent L-type calcium channel subunit alpha-1D (CACNA1D), voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A), and voltage-dependent N-type calcium channel subunit alpha-1B (CACNA1B) were all found to be involved in the dopaminergic synapse pathway, and their expression was upregulated by semaglutide and empagliflozin. Conclusion: We found for the first time that a high-fat diet decreased CACNA1D, CACNA1A, and CACNA1B protein serine phosphorylation, which may affect neuronal development, synaptic plasticity, and cognitive function in mice. Notably, semaglutide and empagliflozin increased the phosphorylation of these proteins.

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Purpose: The aim of this study was to evaluate changes in body weight, liver weight, blood glucose, liver injury markers, pro-inflammatory factors and oxidative stress marker levels in obese mice with HFD induced NAFLD after semaglutide use. Patients and methods: The 24 C57BL6J mice were randomly divided into three groups (NCD, HFD and Sema) for the assessment of metabolic status, inflammatory factor and oxidative stress marker levels, liver histopathology in mice. Liver metabolomics was determined by liquid chromatography/mass spectrometry (LC-MS) method. Results: The mice body weight, liver weight, blood glucose, TG, TCHO, LDL and pro-inflammatory factors were significantly reduced after semaglutide. Meanwhile, semaglutide increased the SOD level. Semaglutide treatment significantly improved the pathological changes such as hepatocyte steatosis, balloon degeneration and lymphoid foci by HE. It also significantly reduced lipid droplet by Oil Red O. The mitochondria were swollen, the volume increased, the cristae were partially broken and reduced, the intramembrane matrix was partially dissolved, and the mitophagy structure was visible in the visual field. There were 6 metabolites down-regulated and 2 metabolites significantly up-regulated after semaglutide treatment. Conclusions: Semaglutide can reduce blood glucose level and liver fat accumulation and play an anti-inflammatory role in advanced NAFLD that due to the effects of HFD.

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Purpose: Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury. Methods: Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples. Results: Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD+) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury. Conclusion: Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD+ and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.

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Background: Obesity is a chronic metabolic disease caused by a combination of genetic and environmental factors. To determine whether semaglutide could improve aortic injury in obese C57BL/6J mice, and further explore its molecular mechanism of action using proteomics. Methods: 24 C57BL/6J male mice were randomly divided into normal diet group (NCD group), high-fat diet group (HFD group) and high-fat diet + semaglutide group (Sema group, semaglutide (30 nmol/kg/d) for 12 weeks). The serum samples were collected from mice to detect blood glucose, insulin and blood lipid concentrations. Aortic stiffness was detected by Doppler pulse wave velocity (PWV). Changes in vascular structure were detected by HE, masson, EVG staining and electron microscopy. The aorta-related protein expression profiles were detected by proteomic techniques, and proteins with potential molecular mechanisms were identified. Results: Semaglutide could reduce body weight, the concentrations of blood glucose, total cholesterol (TC), triglycerides (TG), lipoprotein cholesterol (LDL-C), and reduce the aortic PWV and ameliorate vascular damage in obese mice. The results of proteomic analysis showed there were 537 up-regulated differentially expressed proteins (DEPs) and 322 down-regulated DEPs in NCD/HFD group, 251 up-regulated DEPs and 237 down-regulated proteins in HFD/Sema group. There were a total of 25 meaningful overlapping DEPs in the NCD/HFD and HFD/Sema groups. GO enrichment analysis of overlapping DEPs found that these differential proteins were mainly located in the signaling pathways of the extracellular matrix. The most obvious changes of extracellular matrix associated proteins in the three experimental groups were Coll5a1, Lama4, Sparc. Conclusion: Semaglutide may protect vascular structure and improve endothelial permeability by reducing the levels of Coll5a1, Lama4, Sparc in extracellular matrix, so as to improve vascular function and achieve vascular protection.

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Using proteomic techniques the impact of the sodium-glucose transport protein 2 inhibitor empagliflozin on cardiac protein expression in a mouse model was assessed under normal and high-fat diet (HFD) conditions. We examined the effect of obesity on serological markers and heart function in obese mice treated with or without empagliflozin and used proteomic techniques to investigate alterations in cardiac protein expression. Using bioinformatic techniques, data were screened for differentially expressed proteins (DEPs) implicated in the putative mechanism of empagliflozin's cardioprotective effects. In C57BL/6 mice, HFD increased body weight, blood lipid, and glucose levels and was associated with structural damage to the heart. Empagliflozin reduces body weight, improves glucose and lipid metabolism, alleviates obesity-induced cardiac ventricular wall thickening, and lowers cardiac tissue collagen. The expression of several proteins was altered in the heart, mainly related to lipid metabolism. Following empagliflozin treatment, the expression of several lipid metabolism-related proteins was considerably reduced. Further examination of DEPs revealed that following empagliflozin treatment, the expressions of Apoe, Apoc1, Saa2, Apoa2, and Pon1 altered dramatically, suggesting that these proteins may be the main proteins that empagliflozin uses to treat obesity-induced aberrant lipid metabolism. Empagliflozin may protect the heart by altering the expression of genes including Apoe, Apoc1, Saa2, Apoa2, and Pon1, which are all involved in lipid metabolism disturbance in obesity.

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Potassium-ion batteries (PIBs) are emerging as a powerful alternative to lithium-ion battery systems in large-scale energy storage owing to plentiful resources. Nevertheless, pursuing high-yield anode materials with high initial Coulombic efficiency (ICE) and superior rate capability is still one of the most critical challenges in practical application. Herein, an integrated electrode (PC-x) derived from a petroleum coke precursor (carbon residue rate as high as 89%) is regulated from microstructural engineering to binder optimization devoting to high ICE and efficient potassium storage. Excitingly, with a strong assist from a sodium carboxymethyl cellulose (CMC) binder, the PC-900 anode displays an ultrahigh ICE of 80.5%, one of the highest values reported for PIB carbon anodes. Simultaneously, the PC-900 anode submits a high capacity (304.3 mAh g-1), superb rate (138.2 mAh g-1 at 10C), and excellent stability. Furthermore, the full cell exhibits an outstanding rate and cycling performance (210.7 mAh g-1 at 0.5C), confirming its large-scale application prospects. The ultrahigh ICE and excellent performance are mainly attributable to the beneficial microstructures (low surface area, functional group content, and larger interlayer spacing) created by microstructural engineering. Meanwhile, binder optimization also plays a crucial role in reducing the irreversible capacity and interface impedance, further improving the ICE and rate capability. Importantly, mechanism analysis confirms two-stage K+ storage behavior: reversible adsorption at edges and defects (>0.25 V) and intercalation into crystalline layers (<0.25 V). This work provides an efficient and easily scalable electrode design strategy for future practical applications of PIBs.

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Purpose: This study aimed to investigate the effect of Semaglutide on skeletal muscle and its metabolomics. Methods: A total of 18 male C57BL/6 mice were randomly divided into normal control (NC) group, high-fat diet (HFD) group and HFD+Semaglutide group, and were given standard diet, HFD diet, HFD diet plus Semaglutide, respectively. The body weight, gastrocnemius weight, serum lipid, blood glucose and inflammatory index levels of mice in each group were observed and compared, and the morphological and structural changes of gastrocnemius were also analyzed. Meanwhile, gastrocnemius metabolite changes were analyzed by untargeted metabolomics. Results: After Semaglutide treatment, the food intake and body weight of mice were evidently decreased, while the relative gastrocnemius weight ratio were conversely increased. Meanwhile, the levels of TG, CHO, LDL, HDL, TNF-α, IL-6, IL-1ß and HOMA-IR were all observed to decrease remarkably after Semaglutide intervention. Histological analysis showed that Semaglutide significantly improved the pathological changes of gastrocnemius, manifested as increased type I/type II muscle fiber ratio, total muscle fiber area, muscle fiber density, sarcomere length, mitochondrial number and mitochondrial area. Furthermore, metabolic changes of gastrocnemius after Semaglutide intervention were analyzed, and 141 kinds of differential metabolites were screened out, mainly embodied in lipids and organic acids, and enriched in 9 metabolic pathways including a variety of amino acids. Conclusion: Semaglutide can significantly reduce the body weight and the accumulation of intramuscular fat, promote muscle protein synthesis, increase the relative proportion of skeletal muscle, and improve muscle function of obese mice, possibly by altering the metabolism of muscle lipids and organic acids.

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With an increasing prevalence of obesity related kidney disease, exploring the mechanisms of therapeutic method is of critical importance. Empagliflozin is a new antidiabetic agent with broad clinical application prospect in cardiovascular and renal diseases. However, a metabonomics-based renoprotective mechanism of empagliflozin in obesity remains unclear. Our results showed that empagliflozin significantly alleviated the deposition of lipid droplet, glomerular and tubular injury. The innovation lied in detection of empagliflozin-targeted differential metabolites in kidneys. Compared with normal control mice, obese mice showed higher levels of All-trans-heptaprenyl diphosphate, Biliverdin, Galabiose, Galabiosylceramide (d18:1/16:0), Inosine, Methylisocitric acid, Uric acid, Xanthosine, O-glutarylcarnitine, PG(20:3(8Z,11Z,14Z)/0:0), PG(20:4(5Z,8Z,11Z,14Z)/0:0), PE(O-16:0/0:0), PG(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/0:0), and lower level of Adenosine. Empagliflozin regulated these metabolites in the opposite direction. Associated metabolic pathways were Phospholipids metabolism, Purine metabolism, and Biliverdin metabolism. Most of metabolites were associated with inflammatory response and oxidative stress. Empagliflozin improved the oxidative stress and inflammation imbalance. Our study revealed the metabonomics-based renoprotective mechanism of empagliflozin in obese mice for the first time. Empagliflozin may be a promising tool to delay the progression of obesity-related kidney disease.

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Non-cardiomyocytes (nonCMs) play an important part in cardiac fibrosis pathophysiology, but the underlying molecular pathways are unknown. Semaglutide has cardioprotective properties, but it is still unclear whether it helps with cardiac fibrosis and what the processes are. The goal of this study is to use single cell transcriptomics approaches to investigate the molecular mechanism of semaglutide's cardioprotective action in obese mice. We found 15 non-CMs, with fibroblasts making up the majority of them. We found eight DEGs that altered significantly following semaglutide treatment by screening for differentially expressed genes (DEGs). DEGs were shown to have biological activities primarily related to extracellular matrix and collagen synthesis and distribution, with Serpinh1 and Pcolce expression being the most dramatically altered. Serpinh1 and Pcolce were mostly found in fibroblasts, which play a key role in the fibrosis of the heart. Furthermore, we discovered that semaglutide lowered cardiac collagen content and alleviated obesity-induced ventricular wall hypertrophy. As a result, our findings show that Serpinh1 and Pcolce, which are expressed by fibroblasts, may play a role in the development of obese cardiac fibrosis. By reducing Serpinh1 and Pcolce expression and delaying cardiac fibrosis, semaglutide may have a cardioprotective effect.

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Background: This study is aimed at exploring the key genes and the possible mechanism of heart damage caused by obesity. Methods: We analyzed the GSE98226 dataset. Firstly, differentially expressed genes (DEGs) were identified in heart tissues of obese and normal mice. Then, we analyzed DEGs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Thirdly, we constructed a protein-protein interaction (PPI) network and key modules and searched hub genes. Finally, we observed the pathological changes associated with obesity through histopathology. Results: A total of 763 DEGs were discovered, including 629 upregulated and 134 downregulated genes. GO enrichment analysis showed that these DEGs were mainly related to the regulation of transcription, DNA-templated, nucleic acid binding, and metal ion binding. KEGG pathway analysis revealed that the DEGs were enriched in long-term depression, gap junction, and sphingolipid signaling pathways. Finally, we identified UTP14A, DKC1, DDX10, PinX1, and ESF1 as the hub genes. Histopathologic analysis showed that obesity increased the number of collagen fibers and decreased the number of microvessels and proliferation of the endothelium and increased endothelial cell damage which further leads to dysfunction of cardiac microcirculation. Conclusion: UTP14A, DKC1, DDX10, PinX1, and ESF1 have been identified as hub genes in obesity-induced pathological changes in the heart and may be involved in obesity-induced cardiac injury by affecting cardiac microcirculatory function.

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Obesity is a risk factor for cardiovascular disease, leading to ventricular dysfunction and cardiac fibrosis, in which non-cardiomyocytes (nonCMs) play an important role. Early detection and treatment of heart illness may help to limit its progression. We screened for key markers of obesity-induced cardiac fibrosis using single-cell transcriptomics techniques. To begin, an obese mouse model was constructed using a high-fat diet. From a pathogenic perspective, pathological alterations in the obesity-induced heart were found. Differentially expressed genes (DEGs) were identified and functional enrichment analysis was performed. Then, to look for hub genes, key modules of DEGs were built. Finally, the cellular location of the hub genes was investigated. In mice, a high-fat diet raised body weight, messed up myocardial shape, and increased cardiac collagen content. NonCMs transcriptome data revealed 15 different cell types, including fibroblasts, immunological cells, and endothelial cells. There were a total of 33 DEGs found, with 22 up-regulated genes and 11 down-regulated genes. DEGs have a high connection with collagen and extracellular matrix (ECM), according to functional enrichment analysis. Col1a1 and Col1a2 scored well in module analysis and hub gene screening, and were chosen as hub genes. Col1a1 and Col1a2 were shown to be mostly expressed by fibroblasts after localization study. As a result, we believe Col1a1 and Col1a2 may be important markers of obesity-induced cardiac fibrosis, in which fibroblasts play a critical role.

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Objective: To investigate the association between body mass index (BMI) and clinicopathologic parameters in patients with idiopathic membranous nephropathy (IMN). Methods: This study was retrospective and included patients with biopsy-proven IMN from 2018 to 2021 in Hebei General Hospital. Patients were categorized into two groups based on BMI. Clinical and histopathologic data were analyzed at the time of renal biopsy. Pathological data included immunofluorescence staining, glomerulosclerosis (GS, 0-2), mesangial cell proliferation (MCP, 0-1), tubular atrophy (TA, 0-1), interstitial fibrosis (IF, 0-1), vascular wall thickness (VWT, 0-1) and a combination score (GMTIV) graded from 0 to 5. Results: Our study revealed that the obese group had a higher prevalence of hypertension and diabetes than the overweight/normal weight group (P=0.001, P=0.002). Systolic blood pressure (P=0.005), diastolic blood pressure (P<0.001), haemoglobin (P=0.006), triglycerides (P<0.001), serum uric acid (P=0.05), 24 h urine proteinuria concentration (UP) (P=0.012), MCP (P=0.042), IF (P=0.033), and GMITV (P=0.033) score were higher in obese group compared to the other group, while the high-density lipoprotein-cholesterol (P=0.034) and immunoglobulin A deposition score (P=0.005) were lower. Factors significantly associated with UP were the ratio of lymphocyte count to white blood cell count, serum pre-albumin, immunoglobulin G, microscopic hematuria, anti-phospholipase A2 receptor (anti-PLA2R), C3 deposit on multivariable analysis (adjusted R 2=0.343). Binary logistic regression analysis illustrated that MCP was correlated to BMI (OR=2.528, P=0.036). Ordinal logistic regression analysis demonstrated that GMTIV was associated with BMI (OR=1.114, P=0.010) and C3 deposit (OR=1.655, P=0.001). Conclusion: High BMI was associated with MCP and GMTIV score in IMN patients. Obesity may play an essential role in mesangial lesions of IMN. This study emphasized the relation between BMI and histological parameters under the universal usage of anti-PLA2R antibodies for diagnosis and prognosis in IMN.

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As the leading anode material for sodium-ion batteries (SIBs), hard carbon (HC) still faces the puzzle of low initial Coulombic efficiency (ICE) in achieving commercialization. From the perspective of precursors, the low ICE has been attributed to the large specific surface area and porosity produced by the rapid decomposition of polymers during the carbonization. Therefore, increasing the cross-linking degree of precursors will be an effective shortcut to improve the ICE. Herein, a facile pre-oxidation tactic was successfully employed to tailor the cross-linking degree of phenolic resin precursors to precisely control the specific surface area of the obtained HC. As the pre-oxidation time is increased, the optimal HC with the lowest specific surface area shows an ICE elevated by 22.2% (from 62.5 to 84.7%) compared to the original pre-oxidation HC and delivers a high reversible capacity of 334.3 mAh g-1 at 20 mA g-1. Besides, the pre-oxidation also introduces abundant carbonyl groups, which increase the disorder degree of HC and supply abundant adsorption sites of Na+, thus enhancing the rate performance. When matched with a layered O3-NaNi1/3Fe1/3Mn1/3O2 cathode, the full cell achieves an energy density of ca. 256.2 Wh kg-1 with superior rate performance. This work sheds light on the positive effect of pre-oxidation in elevating the ICE of HC and provides effective guidance to achieve a high ICE for other HC materials.