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Diabetic cardiomyopathy (DCM) is an important complication resulting in heart failure and death of diabetic patients. However, there is no effective drug for treatments. This study investigated the effect of D-pinitol (DP) on cardiac injury using diabetic mice and glycosylation injury of cardiomyocytes and its molecular mechanisms. We established the streptozotocin-induced SAMR1 and SAMP8 mice and DP (150 mg/kg/day) intragastrically and advanced glycation end-products (AGEs)-induced H9C2 cells. H9C2 cells were transfected with optineurin (OPTN) siRNA and overexpression plasmids. The metabolic disorder indices, cardiac dysfunction, histopathology, immunofluorescence, western blot, and immunoprecipitation were investigated. Our results showed that DP reduced the blood glucose and AGEs, and increased the expression of heart OPTN in diabetic mice and H9C2 cells, thereby inhibiting the endoplasmic reticulum stress (GRP78, CHOP) and glycophagy (STBD1, GABARAPL1), and alleviating the myocardial apoptosis and fibrosis of DCM. The expression of filamin A as an interaction protein of OPTN downregulated by AGEs decreased OPTN abundance. Moreover, OPTN siRNA increased the expression of GRP78, CHOP, STBD1, and GABARAPL1 and inhibited the expression of GAA via GSK3ß phosphorylation and FoxO1. DP may be helpful to treat the onset of DCM. Targeting OPTN with DP could be translated into clinical application in the fighting against DCM.
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Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Inositol/análogos & derivados , Humanos , Camundongos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Chaperona BiP do Retículo Endoplasmático , Miócitos Cardíacos , Estresse do Retículo Endoplasmático , Transdução de Sinais , Apoptose , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacologiaRESUMO
Freshwater environmental antibiotic pollution is becoming more severe because of the irregular use of sulfonamide antibiotics. Sulfamethoxazole (SMZ) is a kind of antibiotic that can cause harm to the urinary systems of organisms. However, the toxic impacts of environment-related concentrations of antibiotics in fish have not been thoroughly studied. Lycopene (LYC) has the property of alleviating antibiotic toxicity by diminishing oxidative stress and inflammation. This investigation is intended to examine the instrument of the mitigative part of LYC on SMZ-caused renal inflammatory injury in grass carp. Grass carp were born with SMZ (0. 3 µg L-1) and LYC (10 mg/kg body weight) for 30 days. Serum was used to measure creatinine (CREA) and urea nitrogen (BUN) contents; what is more, kidneys were used to measure histological structure, oxidative stress indicators, relative expressions of cytokines, and inflammatory factors. We found that SMZ exposure significantly increased oxidative stress, characterized by decreased catalase activity (CAT) and superoxide dismutase (SOD). In addition, inflammation-related factors: interleukin (IL-18, IL-6, and IL-1ß), an apoptotic speck-containing protein with a card (ASC), NOD-like receptor protein3 (NLRP3), cysteinyl aspartate specific proteinase-1 (caspase-1), tumor necrosis factor-α (TNF-α), and nuclear factor-activated B cells (NF-κB) expression increased significantly contrasted with those control group. Inflammatory reactions and ultrastructural changes accompany. LYC administration alleviated the changes mentioned above. In conclusion, In conclusion, these results suggest a protective effect of LYC dietary supplements against kidney damage caused by SMZ. LYC is expected to prevent and treat oxidative stress and chronic inflammation caused by antibiotics as a critical component in the fish breeding diet.
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Carpas , Animais , Antibacterianos , Carpas/metabolismo , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/veterinária , Rim/metabolismo , Licopeno/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas NLR , SulfametoxazolRESUMO
Cypermethrin (CMN) is a man-made insecticide, and its abuse has led to potential adverse effects, particularly in sensitive populations such as aquatic organisms. The present study was focused on the toxic phenotype and detoxification mechanism in grass carp (Ctenopharyngodon idella) after treatment with waterborne CMN (0.651 µg/L) for 6 weeks in vivo or 6.392 µM for 24 h in vitro. In vivo, we describe the toxic phenotype of the liver of grass carp in terms of pathological changes, serum transaminase levels, oxidative stress indexes, and apoptosis rates. RNA-Seq analysis (2 × 3 cDNA libraries) suggested a compromise of proteasome and oxidative phosphorylation signaling pathways under CMN exposure. Thus, these two pathways were chosen for the in vitro study, which suggested that the CMN intoxication-induced proteasome pathway caused hepatotoxicity in the liver cell line of grass carp (L8824 cells). Moreover, pretreatment with MG132, a proteasome inhibitor, displayed protection against the toxic effects of CMN by enhancing antioxidative and anti-inflammatory capability by directly inhibiting the proteasomal degradation of nuclear factor erythroid-2 related factor (Nrf2) and IκB-α, thus turning on the transcription of downstream genes of Nrf2 and NF-κB, respectively. Taken together, these results suggest proteasome activity as a reason for CMN-induced hepatotoxicity.
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Carpas , Doença Hepática Induzida por Substâncias e Drogas , Animais , Carpas/metabolismo , Dieta , Proteínas de Peixes/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma , Piretrinas , Espécies Reativas de Oxigênio/metabolismoRESUMO
The progression of diabetic cardiomyopathy is related to cardiomyocyte dysfunction and apoptosis. Our previous studies showed that asporin (ASPN) was significantly increased in the myocardium of db/db mice through proteomics, and grape seed procyanidin B2 (GSPB2) significantly inhibited the expression of ASPN in the heart of db/db mice. We report here that ASPN played a critical role in glycated low-density lipoproteins (gly-LDL) induced-cardiomyocyte apoptosis. We found that gly-LDL upregulated ASPN expression. ASPN increased H9C2 cardiomyocyte apoptosis with down-regulation of Bcl-2, upregulation of transforming growth factor-ß1, Bax, collagen III, fibronectin, and phosphorylation of smad2 and smad3. However, GSPB2 treatment reversed ASPN-induced impairments in H9C2 cardiomyocytes. These results provide evidence for the cardioprotective action of GSPB2 against ASPN injury, and thus suggest a new target for fighting against diabetic cardiomyopathy.
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The electrochemical oxygen reduction reaction (ORR) has received great attention due to its importance in fuel cells and metal-air batteries. Here, we present a simple approach to prepare non-noble metal catalyst-Co3O4 nanocrystals (NCs). The particle size and shape were simply controlled by different types and concentrations of metal precursor. Furthermore, different sizes and shapes of Co3O4 NCs are explored as electrocatalysts for ORR, and it has been observed that particles with a similar shape, and smaller particle size led to greater catalytic current densities because of the greater surface area. For particles with a comparable size, the shape or crystalline structure governed the activity of the electrocatalytic reactions. Most importantly, the 9 nm-Co3O4 were demonstrated to act as low-cost catalysts for the ORR with a similar performance to that of Pt catalysts.
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In this article, novel types of Bi2S3-Au heterostructures are fabricated through rationally controlling the growth atmosphere. Under argon, Au nanoparticles are preferentially deposited onto the tips of Bi2S3 nanorods to form Bi2S3-Au dumbbell heterostructures. In contrast, because of the etching effect by amine, Au nanoparticles are randomly anchored onto the surface of nanorods to form Bi2S3-Au nanocorns in the presence of oxygen. Furthermore, the size of gold nanoparticles can be controlled through adjusting the concentration of reaction precursors. Bi2S3-Au dumbbells show superior activity for the photodegradation of organic pollutants and an enhanced photoresponse compared to the Bi2S3-Au nanocorns. The significantly improved photocatalytic performance of Bi2S3-Au dumbbells is ascribed to the more efficient charge separation compared to that of Bi2S3-Au nanocorns. These heterostructures composed of environmentally friendly elements are expected to be promising for applications in the field of clean energy.
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Moderate efficiency and the utilization of noble metal cocatalysts are the key factors that restrict the large-scale application of photocatalytic hydrogen production. To develop more efficient photocatalysts based on earth abundant elements, either a new material strategy or a fundamental understanding of the semiconductor/cocatalyst interfaces is highly desirable. In this paper, we studied the feasibility of in situ formation of defect-rich cocatalysts on graphene-based photocatalysts. A facile biomolecule-assisted strategy was used to self-assmble Cd1-xZnxS/MoS2/graphene hollow spheres. The defect-mediated cocatalyst and synergetic charge transfer around heterostructured interfaces exhibit a significant impact on the visible-light-driven photocatalytic activity of multicomponent solid solutions. With engineered interfacial defects, Cd0.8Zn0.2S/MoS2/graphene hollow spheres exhibited a 63-fold improved H2 production rate, which was even 2 and 3.8 times higher than those of CdS/MoS2/graphene hollow spheres and Cd0.8Zn0.2S/Pt. Therefore, our research provides a promising approach for the rational design of high-efficiency and low-cost photocatalysts for solar fuel production.
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Elevated level of glycated low-density lipoproteins (glyLDL) is believed to contribute to endothelial dysfunction, which is involved in the pathogenesis and acceleration of diabetic vascular diseases. Grape seed procyanidin B2 (GSPB2) has been reported to possess protective effects against endothelial dysfunction. However, the underlying mechanism remains unclear. Prohibitin (PHB) is a multifunctional protein implicated in cellular survival and apoptosis. In this study, we showed that glyLDL treatment decreased protein level of PHB, reduced viability, and increased apoptosis in human umbilical vein endothelial cells (HUVEC). PHB overexpression or GSPB2 significantly attenuated apoptosis induced by glyLDL. Moreover, PHB siRNA increased HUVEC apoptosis, along with defective mitochondria and increased levels of cytosol cytochrome c concentration, caspase-3 activity, Bax/Bcl-2 ratio, and phosphorylated Akt, whereas PHB overexpression or GSPB2 restored these changes. Our study identified PHB as an important player responsible for HUVEC apoptosis induced by glyLDL. GSPB2 protected against HUVEC apoptosis at least in part through upregulating PHB. Targeting PHB could be significant in fighting against diabetic vascular complications.
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Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/farmacologia , Extrato de Sementes de Uva/química , Proantocianidinas/farmacologia , Proteínas Repressoras/metabolismo , Biflavonoides/isolamento & purificação , Catequina/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipoproteínas LDL/metabolismo , Mitocôndrias/patologia , Fosforilação/efeitos dos fármacos , Proantocianidinas/isolamento & purificação , Proibitinas , RNA Interferente Pequeno/administração & dosagemRESUMO
Diabetic nephropathy, as a severe microvascular complication of diabetic mellitus, has become the leading cause of end-stage renal diseases. However, no effective therapeutic strategy has been developed to prevent renal damage progression to end stage renal disease. Hence, the present study evaluated the protective effects of grape seed procyanidin B2 (GSPB2) and explored its molecular targets underlying diabetic nephropathy by a comprehensive quantitative proteomic analysis in db/db mice. Here, we found that oral administration of GSPB2 significantly attenuated the renal dysfunction and pathological changes in db/db mice. Proteome analysis by isobaric tags for relative and absolute quantification (iTRAQ) identified 53 down-regulated and 60 up-regulated proteins after treatment with GSPB2 in db/db mice. Western blot analysis confirmed that milk fat globule EGF-8 (MFG-E8) was significantly up-regulated in diabetic kidney. MFG-E8 silencing by transfection of MFG-E8 shRNA improved renal histological lesions by inhibiting phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), Akt and glycogen synthase kinase-3beta (GSK-3ß) in kidneys of db/db mice. In contrast, over-expression of MFG-E8 by injection of recombinant MFG-E8 resulted in the opposite effects. GSPB2 treatment significantly decreased protein levels of MFG-E8, phospho-ERK1/2, phospho-Akt, and phospho-GSK-3ß in the kidneys of db/db mice. These findings yield insights into the pathogenesis of diabetic nephropathy, revealing MFG-E8 as a new therapeutic target and indicating GSPB2 as a prospective therapy by down-regulation of MFG-E8, along with ERK1/2, Akt and GSK-3ß signaling pathway.
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Antígenos de Superfície/biossíntese , Biflavonoides/farmacologia , Catequina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas do Leite/biossíntese , Proantocianidinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Antígenos de Superfície/genética , Biflavonoides/química , Catequina/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Extrato de Sementes de Uva/química , Extrato de Sementes de Uva/farmacocinética , Rim/metabolismo , Rim/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Proteínas do Leite/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proantocianidinas/química , Proteômica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima/genéticaRESUMO
Diabetic cardiomyopathy is one of the major complications of diabetes mellitus. Oxidative stress appears to play a substantial role in cardiomyopathy. Grape seed procyanidin B2 (GSPB2) has been known as an anti-oxidant in treating diabetes mellitus; however, little is known about its effects and underlying mechanisms on diabetic cardiomyopathy. The present study is to explore the molecular targets of GSPB2 responsible for the anti-oxidative effects in db/db mice by quantitative proteomics. GSPB2 (30 mg/kg body weight/day) were intragastric administrated to db/db mice for 10 weeks. Proteomics of the heart tissue extracts by isobaric tags for relative and absolute quantification analysis was obtained from db/db mice. Our study provides important evidence that GSPB2 protect against cardiomyopathy in diabetes mellitus, which are believed to result from regulating the expression of key proteins involving cardiac fibrosis and proliferation. GSPB2 could be expected to become novel clinical application in fighting against diabetic cardiomyopathy.
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Antioxidantes/administração & dosagem , Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Cardiomiopatias Diabéticas/tratamento farmacológico , Proantocianidinas/administração & dosagem , Proteômica , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Estudos de Avaliação como Assunto , Extrato de Sementes de Uva/química , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/químicaRESUMO
BACKGROUND: Sarcopenia is a common geriatric condition closely associated with cardiovascular diseases and other health issues. This study aims to investigate the causal relationship between sarcopenia-related traits and electrocardiogram(ECG) indices. METHODS: We conducted a comprehensive analysis utilizing summary data from genome-wide association studies (GWAS) associated with sarcopenia-related traits, including hand grip strength, lean body mass, and walking pace. ECG indices included PR interval, PP interval, ST duration, QRS duration and T wave duration. The primary analytical method employed was the inverse variance-weighted method (IVW). RESULTS: According to our study findings, we identified a significant association between sarcopenia-related traits and ECG indices. Specifically, we observed a positive correlation between increased muscle mass and certain ECG indices. For instance, increased limb muscle mass (including left arm, right arm, left leg, and right leg) was associated with prolonged PR interval and QRS duration. This suggests that enhancing muscle mass may impact the timing of cardiac electrical activity. Additionally, increased whole-body fat-free mass showed similar associations with cardiac electrical activity. CONCLUSION: Sarcopenia-related traits have a unidirectional causal relationship with ECG indices, indicating that sarcopenia affects cardiac electrical activity.
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Eletrocardiografia , Estudo de Associação Genômica Ampla , Força da Mão , Análise da Randomização Mendeliana , Sarcopenia , Humanos , Sarcopenia/genética , Sarcopenia/epidemiologia , Força da Mão/fisiologia , Idoso , Masculino , FemininoRESUMO
d-Pinitol (DP) is primarily found in Vigna sinensis, which has been shown to have hypoglycemic and protective effects on target organs. However, the mechanism of DP in treating diabetic sarcopenia (DS) is still unclear. To explore the underlying mechanism of DS and the protective targets of DP by high-throughput analysis of 16S rRNA gene, metabolome, and the proteome. Streptozotocin-induced SAMP8 mice were intragastrically administrated DP (150 mg/kg) for 8 weeks. Fecal 16S rRNA gene sequencing and gastrocnemius muscle metabolomic and proteomic analyses were completed to investigate the gut-muscle axis interactions. DP significantly alleviated the muscle atrophy in diabetic mice. Dysfunction of the gut microbiota was observed in the DS mice. DP significantly reduced the Parabacteroides, Akkermansia, and Enterobacteriaceae, while it increased Lachnospiraceae_NK4A136. Metabolome and proteome revealed that 261 metabolites and 626 proteins were significantly changed in the gastrocnemius muscle of diabetic mice. Among these, DP treatment restored 44 metabolites and 17 proteins to normal levels. Functional signaling pathways of DP-treated diabetic mice included nucleotide metabolism, ß-alanine, histidine metabolism, ABC transporters, and the calcium signaling pathway. We systematically explored the molecular mechanism of DS and the protective effect of DP, providing new insights that may advance the treatment of sarcopenia.
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Microbioma Gastrointestinal , Inositol , Metaboloma , Proteoma , Sarcopenia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Sarcopenia/metabolismo , Sarcopenia/tratamento farmacológico , Masculino , Proteoma/metabolismo , Metaboloma/efeitos dos fármacos , Inositol/farmacologia , Inositol/análogos & derivados , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Humanos , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/metabolismo , Bactérias/efeitos dos fármacosRESUMO
Hyperuricemia (HUA) is a metabolic disease and contributes to renal injury (RI). Vine grape tea polyphenols (VGTP) have been widely used to treat HUA and RI. However, the potential mechanism of VGTP activity remains unclear. To explore the underlying mechanism of VGTP treatment for HUA-induced RI based on network pharmacology that is confirmed by an in vivo study. All ingredients of VGTP were retrieved using a Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Comparative Toxicogenomics Database systems. The related targets of HUA and RI were obtained from GeneCards and National Center for Biotechnology Information (NCBI) databases. Some ingredients and targets were selected for molecular docking verification. One hour after administering potassium oxonate (300 mg/kg), VGTP (50, 100, and 200 mg/kg/d) was orally administered to HUA mice for 4 weeks. Histopathology and western blotting were performed in renal tissue. Our results showed that VGTP significantly reduced blood urea nitrogen, creatinine, uric acid, and significantly improved the RI and fibrosis of HUA mice. There were 54 active ingredients and 62 targets of HUA-induced RI. Further studies showed that VGTP decreased the expression of Bax, cleaved caspase 3, transforming growth factor-ß (TGF-ß1), CHOP, p-STAT3, and P53, and increased Bcl-2 expression in renal tissue. The related signaling pathways have apoptosis, TGF-ß1, P53 and STAT, and endoplasmic reticulum stress (ERS). In this study, VGTP exerted antihyperuricemic and anti fibrosis effects by regulating the apoptosis and ERS signaling pathways. VGTP is expected to become a drug for combating HUA and RI.
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Hiperuricemia , Vitis , Animais , Camundongos , Hiperuricemia/tratamento farmacológico , Farmacologia em Rede , Fator de Crescimento Transformador beta1 , Simulação de Acoplamento Molecular , Proteína Supressora de Tumor p53 , RimRESUMO
Rice false smut (RFS) caused by Ustilaginoidea virens is widely distributed in major rice-producing regions. Previous studies have shown that treating RFS with chelerythrine can decrease the germination of fungus spores by 86.7% and induce fungal cell apoptosis. In the present study, the effects of chelerythrine on the metabolism of U. virens explored using metabolomics and analyses of differentially accumulated metabolites and altered metabolic pathways. The top 15 metabolites in random forest analysis were significantly different between groups. In positive ion mode, purine, phenylalanine metabolism, phenylalanine, tyrosine, tryptophan biosynthesis, pyrimidine metabolism, and nitrogen metabolism were dominant. Alanine, aspartate, glutamate metabolism, and phenylalanine metabolism were enriched in negative ion mode. Differentially expressed genes and altered metabolic pathways of U. virens were effected by chelerythrine. The findings support future research on the prevention and treatment of RFS by chelerythrine and provide a theoretical basis for targeted drug delivery.
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BACKGROUND: Diabetic sarcopenia is a disease-related skeletal muscle disorder that causes progressive symptoms. The complete understanding of its pathogenesis is yet to be unravelled, which makes it difficult to develop effective therapeutic strategies. This study investigates how MFG-E8 affects mitophagy and the protective role of D-pinitol (DP) in diabetic sarcopenia. METHODS: In vivo, streptozotocin-induced diabetic SAM-R1 (STZ-R1) and SAM-P8 (STZ-P8) mice (16-week-old) were used, and STZ-P8 mice were administrated of DP (150 mg/kg per day) for 6 weeks. Gastrocnemius muscles were harvested for histological analysis including transmission electron microscopy. Proteins were evaluated via immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) assay. In vitro, advanced glycation end products (AGEs) induced diabetic and D-galactose (DG) induced senescent C2C12 models were established and received DP, MFG-E8 plasmid (Mover)/siRNA (MsiRNA), or 3-MA/Torin-1 intervention. Proteins were evaluated by IF and WB assay. Immunoprecipitation (IP) and co-immunoprecipitation (CO-IP) were used for hunting the interacted proteins of MFG-E8. RESULTS: In vivo, sarcopenia, mitophagy deficiency, and up-regulated MFG-E8 were confirmed in the STZ-P8 group. DP exerted protective effects on sarcopenia and mitophagy (DP + STZ-P8 vs. STZ-P8; all P < 0.01), such as increased lean mass (8.47 ± 0.81 g vs. 7.08 ± 1.64 g), grip strength (208.62 ± 39.45 g vs. 160.87 ± 26.95 g), rotarod tests (109.7 ± 11.81 s vs. 59.3 ± 20.97 s), muscle cross-sectional area (CSA) (1912.17 ± 535.61 µm2 vs. 1557.19 ± 588.38 µm2), autophagosomes (0.07 ± 0.02 per µm2 vs. 0.02 ± 0.01 per µm2), and cytolysosome (0.07 ± 0.03 per µm2 vs. 0.03 ± 0.01 per µm2). DP down-regulated MFG-E8 in both serum (DP + STZ-P8: 253.19 ± 34.75 pg/mL vs. STZ-P8: 404.69 ± 78.97 pg/mL; P < 0.001) and gastrocnemius muscle (WB assay. DP + STZ-P8: 0.39 ± 0.04 vs. STZ-P8: 0.55 ± 0.08; P < 0.01). DP also up-regulated PINK1, Parkin and LC3B-II/I ratio, and down-regulated P62 in gastrocnemius muscles (all P < 0.01). In vitro, mitophagy deficiency and MFG-E8 up-regulation were confirmed in diabetic and senescent models (all P < 0.05). DP and MsiRNA down-regulated MFG-E8 and P62, and up-regulated PINK1, Parkin and LC3B-II/I ratio to promote mitophagy as Torin-1 does (all P < 0.05). HSPA1L was confirmed as an interacted protein of MFG-E8 in IP and CO-IP assay. Mover down-regulated the expression of Parkin via the HSPA1L-Parkin pathway, leading to mitophagy inhibition. MsiRNA up-regulated the expression of PINK1 via SGK1, FOXO1, and STAT3 phosphorylation pathways, leading to mitophagy stimulation. CONCLUSIONS: MFG-E8 is a crucial target protein of DP and plays a distinct role in mitophagy regulation. DP down-regulates the expression of MFG-E8, reduces mitophagy deficiency, and alleviates the symptoms of diabetic sarcopenia, which could be considered a novel therapeutic strategy for diabetic sarcopenia.
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Mitofagia , Sarcopenia , Ubiquitina-Proteína Ligases , Animais , Mitofagia/efeitos dos fármacos , Camundongos , Sarcopenia/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Diabetes Mellitus Experimental/complicações , Inositol/farmacologia , Inositol/uso terapêutico , Inositol/metabolismo , Masculino , Antígenos de Superfície/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Modelos Animais de Doenças , Transdução de SinaisRESUMO
Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, which is an active component of the gum resin of Boswellia serrata. AKBA has been used as an adjuvant medication for treatment of inflammatory diseases. In this study, we aimed to evaluate the efficacy of AKBA as a chemopreventive agent against intestinal adenomatous polyposis in the adenomatous polyposis coli multiple intestinal neoplasia (APC(Min/+) ) mouse model. APC(Min/+) mice were administered AKBA by p.o. gavage for 8 consecutive weeks. The mice were sacrificed and the number, size and histopathology of intestinal polyps were examined by light microscopy. AKBA decreased polyp numbers by 48.9% in the small intestine and 60.4% in the colon. An even greater AKBA effect was observed in preventing the malignant progression of these polyps. The number of large (>3 cm) colonic polyposis was reduced by 77.8%. Histopathologic analysis demonstrated a significant reduction in the number of dysplastic cells and in the degree of dysplasia in each polyp after AKBA treatment. There was no evidence of high grade dysplasia or intramucosal carcinoma in any of the polyps examined within the treated group. More interestingly, interdigitated normal appearing intestinal villi were observed in the polyps of the treated group. During the course of the study, AKBA was well tolerated by the mice with no obvious signs of toxicity. Results from immunohistochemical staining, Western blotting and enzyme-linked immunosorbent assay indicated that the chemopreventive effect of AKBA was attributed to a collection of activities including antiproliferation, apoptosis induction, antiangiogenesis and anti-inflammation. AKBA was found to exert its chemopreventive action through the inhibition of the Wnt/ß-catenin and NF-κB/cyclooxygenase-2 signaling pathways. Our findings suggest that AKBA could be a promising regimen in chemoprevention against intestinal tumorigenesis.
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Adenoma/prevenção & controle , Proteína da Polipose Adenomatosa do Colo/fisiologia , Polipose Adenomatosa do Colo/prevenção & controle , Apoptose/efeitos dos fármacos , Polipose Intestinal/prevenção & controle , Neovascularização Patológica/prevenção & controle , Triterpenos/uso terapêutico , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Western Blotting , Boswellia/química , Proliferação de Células , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Técnicas Imunoenzimáticas , Mediadores da Inflamação/metabolismo , Polipose Intestinal/genética , Polipose Intestinal/patologia , Leucotrieno B4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais , beta Catenina/metabolismoRESUMO
PURPOSE: Diabetic retinopathy (DR) is a leading cause of vision loss in working-age people. To retard the development and progression of retina lesions, effective therapeutic strategies directed toward key molecular targets are desired. Phlorizin is effective in treating diabetic complications, but little is known about functional protein changes that may mediate its actions. The aim of this study was to identify retinal proteomic alterations in db/db mice treated with phlorizin. METHODS: We used C57BLKS/J db/db mice as a type 2 diabetic animal model, while C57BLKS/J db/m mice were selected as the control. Phlorizin (20 mg/kg bodyweight /d) was administrated to db/db mice for ten weeks. Serum fasting blood glucose and advanced glycation end products were determined. Meanwhile, retina cell apoptosis was determined with terminal transferase dUTP nick end labeling. Isobaric tags for relative and absolute quantification and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to identify and profile retinal proteins among control, untreated diabetic, and phlorizin-treated db/db mice. The expression of glial fibrillary acidic protein was measured in retinas using western blotting analysis. RESULTS: Phlorizin treatment significantly reduced fasting blood glucose and levels of advanced glycation end products (p<0.05) and remarkably inhibited retina cell apoptosis and the expression of glial fibrillary acidic protein in the retinas of db/db mice. In addition, we identified 1,636 proteins from retina tissue in total, of which 348 proteins were differentially expressed in db/db mice compared with the controls. Only 60 proteins in the retinas of the db/db mice were found to be differentially changed following phlorizin treatment, including 33 proteins that were downregulated and 27 proteins that were upregulated. Most of these differentially changed proteins were involved in oxidative stress, apoptosis, energy metabolism, and signaling transduction. CONCLUSIONS: Our study revealed the expression of proteins differentially changed after phlorizin therapy. These proteins are most likely to participate in the development and recovery of DR. Our findings help expand understanding of the mechanism underlying the onset and progression of DR, and provide novel targets for evaluating the effects of phlorizin therapy.
Assuntos
Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Marcação por Isótopo/métodos , Florizina/uso terapêutico , Proteômica/métodos , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Western Blotting , Peso Corporal/efeitos dos fármacos , Biologia Computacional , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Proteínas do Olho/metabolismo , Jejum/sangue , Proteína Glial Fibrilar Ácida/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Florizina/farmacologia , Degeneração Retiniana/sangue , Degeneração Retiniana/patologia , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismoRESUMO
Benign prostatic hyperplasia is caused by kidney deficiency and impaired qi transformation of the urinary bladder and is manifested by the stagnation of essence chamber. Based on jingjin (muscle region of meridian, sinew/fascia) theory and taking the visceral membrane as the principal, acupuncture is delivered at sinew/fascia to promote qi circulation, resolve stasis and open the orifice. Guided by CT, the needle is inserted at Zhongji (CV 3), the front-mu point of the urinary bladder, and then goes to the prostatic capsule, meaning "the disease of zang organ is treated by needling the front-mu point". In treatment of benign prostatic hyperplasia, this acupuncture therapy stimulates the different layers of fascia, by which, the defensive qi on the exterior is regulated and "essence orifice" in the interior is adjusted so that the urination can be promoted.
Assuntos
Terapia por Acupuntura , Meridianos , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/terapia , Próstata , Bexiga UrináriaRESUMO
To summarize and analyze the clinical application characteristics of Qugu (CV 2) in ancient and modern literature based on data mining technology. The Chinese Medical Code (the 5th edition) was taken as the retrieval source of ancient literature, while the CNKI, Wanfang, and VIP databases were taken as the retrieval source of modern literature. The indications of Qugu (CV 2) used alone or with compatible acupoints, compatible acupoints, acupuncture-moxibustion manipulation, etc., were systematically sorted out. As a result, a total of 140 articles of ancient literature were included. The common indications of Qugu (CV 2) used alone were urinary retention, profuse vaginal discharge and hernia. The common indications of Qugu (CV 2) used with compatible acupoints were profuse vaginal discharge, stranguria and hernia. Sixty-four acupoints were concurrently used with Qugu (CV 2), Qugu (CV 2) was mainly compatible with acupoints of conception vessel, bladder meridian and liver meridian, and the high-frequency acupoints included Zhongji (CV 3), Guanyuan (CV 4) and Sanyinjiao (SP 6); five-shu points were the most used special acupoints, and moxibustion therapy was often used. A total of 73 modern articles were included. The common indications of Qugu (CV 2) used alone were urinary retention, erectile dysfunction and chronic prostatitis; the common indications of Qugu (CV 2) used with compatible scupoints were urinary retention, erectile dysfunction and prostatic hyperplasia. Thirty-six acupoints were concurrently used with Qugu (CV 2), Qugu (CV 2) was mainly compatible with acupoints of conception vessel, kidney meridian and spleen meridian, and the high-frequency acupoints included Zhongji (CV 3), Guanyuan (CV 4) and Zusanli (ST 36); front-mu points were the most used special acupoints, and acupuncture therapy was often used. Qugu (CV 2) treats a wide range of diseases in ancient times, the distant treatment effectiveness of acupoints is emphasized; and it mainly treats local diseases in modern times, the nearby treatment effectiveness of acupoints is emphasized.
Assuntos
Terapia por Acupuntura , Disfunção Erétil , Literatura Moderna , Meridianos , Moxibustão , Retenção Urinária , Descarga Vaginal , Feminino , Masculino , Humanos , Pontos de AcupunturaRESUMO
Introduction: Diabetic sarcopenia (DS) is characterized by muscle atrophy, slower nerve conduction, reduced maximum tension generated by skeletal muscle contraction, and slower contraction rate. Hence, DS can cause limb movement degeneration, slow movement, reduced balance, reduced metabolic rate, falls, fractures, etc. Moreover, the relevant early biological metabolites and their pathophysiological mechanism have yet to be characterized. Method: The current cross-sectional study employed serum metabolomics analysis to screen potential noninvasive biomarkers in patients with diabetic sarcopenia. A total of 280 diabetic patients were enrolled in the study (n = 39 sarcopenia [DS], n = 241 without sarcopenia [DM]). Ten patients were randomly selected from both groups. Non-targeted metabolomic analysis was performed by ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. Results: A total of 632 differential metabolites were identified, including 82 that were significantly differentially abundant (P < 0.05, VIP > 1, FC > 1.2 or FC < 0.8). Compared with the DM group, the contents of pentadecanoic acid, 5'-methylthioadenosine (5'-MTA), N,N-dimethylarginine (asymmetric dimethylarginine, ADMA), and glutamine in the DS group were significantly increased, while that of isoxanthohumol was decreased. Discussion: Based on receiver operating characteristic curve analysis, pentadecanoic acid, 5'-MTA, ADMA, and glutamine may serve as potential biomarkers of DS. Moreover, ATP-binding cassette (ABC) transporters and the mammalian target of the rapamycin signaling pathway were found to potentially have important regulatory roles in the occurrence and development of DS (P < 0.05). Collectively, the differential metabolites identified in this study provide new insights into the underlying pathophysiology of DS and serve as a basis for therapeutic interventions.