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1.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500559

RESUMO

Endothelial dysfunction plays key roles in the pathological process of contrast media (CM)-induced acute kidney injury (CI-AKI) in patients undergoing vascular angiography or intervention treatment. Previously, we have demonstrated that an apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, inhibits oxidative stress and improves endothelial dysfunction caused by CM through the AMPK/PKC pathway. However, it is unclear whether CM induce metabolic impairments in endothelial cells and whether D-4F ameliorates these metabolic impairments. In this work, we evaluated vitalities of human umbilical vein endothelial cells (HUVECs) treated with iodixanol and D-4F and performed nuclear magnetic resonance (NMR)-based metabolomic analysis to assess iodixanol-induced metabolic impairments in HUVECs, and to address the metabolic mechanisms underlying the protective effects of D-4F for ameliorating these metabolic impairments. Our results showed that iodixanol treatment distinctly impaired the vitality of HUVECs, and greatly disordered the metabolic pathways related to energy production and oxidative stress. Iodixanol activated glucose metabolism and the TCA cycle but inhibited choline metabolism and glutathione metabolism. Significantly, D-4F pretreatment could improve the iodixanol-impaired vitality of HUVECs and ameliorate the iodixanol-induced impairments in several metabolic pathways including glycolysis, TCA cycle and choline metabolism in HUVECs. Moreover, D-4F upregulated the glutathione level and hence enhanced antioxidative capacity and increased the levels of tyrosine and nicotinamide adenine dinucleotide in HUVECs. These results provided the mechanistic understanding of CM-induced endothelial impairments and the protective effects of D-4F for improving endothelial cell dysfunction. This work is beneficial to further exploring D-4F as a potential pharmacological agent for preventing CM-induced endothelial impairment and acute kidney injury.


Assuntos
Apolipoproteína A-I/metabolismo , Meios de Contraste/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Peptídeos/metabolismo , Doenças Vasculares/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Células Cultivadas , Humanos , Redes e Vias Metabólicas/fisiologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
2.
Skelet Muscle ; 11(1): 17, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229732

RESUMO

BACKGROUND: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia. METHODS: The CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. RESULTS: The CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. Both the CT26 and LLC cachexia mice showed increased plasma exosome densities which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis, and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. CONCLUSIONS: Amiloride ameliorates cachectic muscle wasting and alleviates cancer cachexia progression through inhibiting tumor-derived exosome release. Our results are beneficial to understanding the underlying molecular mechanisms, shedding light on the potentials of amiloride in cachexia therapy.

3.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201416

RESUMO

Hypoxia is associated with clinical diseases. Extreme hypoxia leads to multiple organs failure. However, the different effects of hypoxia on brain and visceral organs still need to be clarified, and moreover, characteristics in vulnerable organs suffering from hypoxia remain elusive. In the present study, we first aimed to figure out the hypoxic sensitivity of organs. Adult male mice were exposed to 6% O2 or 8% O2 for 6 h. Control mice were raised under normoxic conditions. In vivo and in vitro imaging of anti-HIF-1α-NMs-cy5.5 nanocomposites showed that the expression level of hypoxia-inducible factor (HIF-1α) was the highest in the liver, followed by kidney and brain. HIF-1α was detected in the hepatocytes of liver, distal convoluted tubules of kidney and neurons of cerebral cortex. The liver, kidney and brain showed distinct metabolic profiles but an identical change in glutamate. Compared with kidney and brain, the liver had more characteristic metabolites and more disturbed metabolic pathways related to glutaminolysis and glycolysis. The level of O-phosphocholine, GTP, NAD and aspartate were upregulated in hypoxic mice brain, which displayed significant positive correlations with the locomotor activity in control mice, but not in hypoxic mice with impaired locomotor activities. Taken together, the liver, kidney and brain are the three main organs of the body that are strongly respond to acute hypoxia, and the liver exhibited the highest hypoxic sensitivity. The metabolic disorders appear to underlie the physiological function changes.


Assuntos
Encéfalo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Rim/metabolismo , Fígado/metabolismo , Animais , Comportamento Animal , Western Blotting , Carbocianinas/química , Carbocianinas/farmacocinética , Hipóxia/fisiopatologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Imagem Molecular , Nanocompostos/química
4.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805924

RESUMO

α-Ketoglutarate (AKG) is attracting much attention from researchers owing to its beneficial effects on anti-aging and cancer suppression, and, more recently, in nutritional supplements. Given that glucose is the main source of energy to maintain normal physiological functions of skeletal muscle, the effects of AKG supplementation for improving muscle performance are closely related to the glucose level in skeletal muscle. The differences of AKG-induced effects in skeletal muscle between two states of normal energy and energy deficiency are unclear. Furthermore, AKG-induced metabolic changes in skeletal muscles in different energy states also remain elusive. Here, we assessed the effects of AKG supplementation on mouse C2C12 myoblast cells cultured both in normal medium (Nor cells) and in low-glucose medium (Low cells), which were used to mimic two states of normal energy and energy deficiency, respectively. We further performed NMR-based metabolomic analysis to address AKG-induced metabolic changes in Nor and Low cells. AKG supplementation significantly promoted the proliferation and differentiation of cells in the two energy states through glutamine metabolism, oxidative stress, and energy metabolism. Under normal culture conditions, AKG up-regulated the intracellular glutamine level, changed the cellular energy status, and maintained the antioxidant capacity of cells. Under low-glucose culture condition, AKG served as a metabolic substrate to reduce the glutamine-dependence of cells, remarkably enhanced the antioxidant capacity of cells and significantly elevated the intracellular ATP level, thereby ensuring the normal growth and metabolism of cells in the state of energy deficiency. Our results provide a mechanistic understanding of the effects of AKG supplements on myoblasts in both normal energy and energy deficiency states. This work may be beneficial to the exploitation of AKG applications in clinical treatments and nutritional supplementations.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Ácidos Cetoglutáricos/farmacologia , Espectroscopia de Ressonância Magnética , Metabolômica , Mioblastos Esqueléticos/metabolismo , Animais , Linhagem Celular , Camundongos
5.
J Ethnopharmacol ; 261: 112978, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-32442586

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Huiyang Shengji formula (HSF) is a compound Chinese herbal medicine prescription, and has long been used for treating chronic non-healing wounds. AIM OF THE STUDY: The purpose of this study was to provide new insight into molecular mechanisms of healing effects of the HSF treatments. MATERIALS AND METHODS: We established a rat diabetic skin ulcer (DSU) model, and assessed healing effects of four HSF treatments on DSUs by calculating wound healing rates and immunohistochemical detection of the expressions of angiogenesis-related factors in the model rats (Mod) relative to normal rats (Nor), including Huiyang extract (HE), Shengji extract (SE), Huiyang Shengji extract (HSE) and HSE associated with acupuncture (Ac-HSE). We then performed NMR-based metabolomic analyses on skin tissues of the Nor, Mod, HSE-treated, Ac-HSE-treated rats to address metabolic mechanisms underlying these effects. RESULTS: These treatments up-regulated expressions of two angiogenesis-related factors VEGF and CD31, and improved efficacy of healing DSUs, in which HSE and Ac-HSE exhibited the most significant effects. Compared with Mod, HSE and Ac-HSE groups shared four characteristic metabolites (lactate, histidine, succinate and acetate) and four significantly altered metabolic pathways with Nor. Both HSE and Ac-HSE treatments could partly reverse the metabolically disordered pathological state of DSUs to the normal state. They might improve wound healing through promoting glucose metabolism, BCAAs metabolism, and enhancing antioxidant capacity and angiogenesis in DSU tissues. Ac-HSE significantly enhanced wound healing rates compared to HSE, potentially owing to significant capacities of enhancing anti-oxidation and angiogenesis and interfering three more metabolic pathways. CONCLUSIONS: This work provides a mechanistic understanding of the healing effects of the HSE and Ac-HSE treatments on DSUs, is of benefit to improvements of the HSF treatments for clinically healing chronic non-healing wounds.


Assuntos
Terapia por Acupuntura , Angiopatias Diabéticas/terapia , Medicamentos de Ervas Chinesas/farmacologia , Espectroscopia de Ressonância Magnética , Metabolômica , Úlcera Cutânea/terapia , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/terapia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais , Pele/lesões , Pele/metabolismo , Pele/patologia , Úlcera Cutânea/metabolismo , Úlcera Cutânea/patologia , Estreptozocina , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
6.
Cancer Sci ; 111(9): 3195-3209, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32369664

RESUMO

Gastric cancer (GC) is one of the deadliest cancers worldwide, and the progression of gastric carcinogenesis (GCG) covers multiple complicated pathological stages. Molecular mechanisms of GCG are still unclear. Here, we undertook NMR-based metabolomic analysis of aqueous metabolites extracted from gastric tissues in an established rat model of GCG. We showed that the metabolic profiles were clearly distinguished among 5 histologically classified groups: control, gastritis, low-grade gastric dysplasia, high-grade gastric dysplasia (HGD), and GC. Furthermore, we carried out metabolic pathway analysis based on identified significant metabolites and revealed significantly disturbed metabolic pathways closely associated with the 4 pathological stages, including oxidation stress, choline phosphorylation, amino acid metabolism, Krebs cycle, and glycolysis. Three metabolic pathways were continually disturbed during the progression of GCG, including taurine and hypotaurine metabolism, glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism. Both the Krebs cycle and glycine, serine, and threonine metabolism were profoundly impaired in both the HGD and GC stages, potentially due to abnormal energy supply for tumor cell proliferation and growth. Furthermore, valine, leucine, and isoleucine biosynthesis and glycolysis were significantly disturbed in the GC stage for higher energy requirement of the rapid growth of tumor cells. Additionally, we identified potential gastric tissue biomarkers for metabolically discriminating the 4 pathological stages, which also showed good discriminant capabilities for their serum counterparts. This work sheds light on the molecular mechanisms of GCG and is of benefit to the exploration of potential biomarkers for clinically diagnosing and monitoring the progression of GCG.


Assuntos
Transformação Celular Neoplásica/metabolismo , Espectroscopia de Ressonância Magnética , Metabolômica , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Metabolismo Energético , Humanos , Espectroscopia de Ressonância Magnética/métodos , Redes e Vias Metabólicas , Metaboloma , Metabolômica/métodos , Ratos , Neoplasias Gástricas/diagnóstico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Aging (Albany NY) ; 12(4): 3626-3646, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32074082

RESUMO

Cellular senescence is a physiological process reacting to stimuli, in which cells enter a state of irreversible growth arrest in response to adverse consequences associated with metabolic disorders. Molecular mechanisms underlying the progression of cellular senescence remain unclear. Here, we established a replicative senescence model of human umbilical vein endothelial cells (HUVEC) from passage 3 (P3) to 18 (P18), and performed biochemical characterizations and NMR-based metabolomic analyses. The cellular senescence degree advanced as the cells were sequentially passaged in vitro, and cellular metabolic profiles were gradually altered. Totally, 8, 16, 21 and 19 significant metabolites were primarily changed in the P6, P10, P14 and P18 cells compared with the P3 cells, respectively. These metabolites were mainly involved in 14 significantly altered metabolic pathways. Furthermore, we observed taurine retarded oxidative damage resulting from senescence. In the case of energy deficiency, HUVECs metabolized neutral amino acids to replenish energy, thus increased glutamine, aspartate and asparagine at the early stages of cellular senescence but decreased them at the later stages. Our results indicate that cellular replicative senescence is closely associated with promoted oxidative stress, impaired energy metabolism and blocked protein synthesis. This work may provide mechanistic understanding of the progression of cellular senescence.


Assuntos
Aminoácidos/metabolismo , Senescência Celular/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Metaboloma , Humanos , Espectroscopia de Ressonância Magnética , Metabolômica , Estresse Oxidativo/fisiologia
8.
Appl Microbiol Biotechnol ; 104(1): 277-289, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31728583

RESUMO

The most wide-spread "hostile" environmental factor for marine microorganisms is low temperature, which is usually accompanied by high hydrostatic pressure (HHP). Metabolic mechanisms of marine microorganisms adapting to prolonged low temperature under HHP remain to be clarified. To reveal the underlying metabolic mechanisms, we performed NMR-based metabolomic analysis of aqueous extracts derived from a psychrotolerant Microbacterium sediminis YLB-01, which was isolated from deep-sea sediment and possess great biotechnology potentials. The YLB-01 cells were firstly cultivated at the optimal condition (28 °C, 0.1 MPa) for either 18 h (logarithmic phase) or 24 h (stationary phase), then continually cultivated at either 28 °C or 4 °C under HHP (30 MPa) for 7 days. The cells cultivated at low temperature, which experienced cold stress, were distinctly distinguished from those at normal temperature. Cold stress primarily induced metabolic changes in amino acid metabolism and carbohydrate metabolism. Furthermore, the logarithmic and stationary phase cells cultivated at low temperature exhibited distinct metabolic discrimination, which was mostly reflected in the significantly disturbed carbohydrate metabolism. The logarithmic phase cells displayed suppressed TCA cycle, while the stationary phase cells showed decreased pyruvate and increased lactate. In addition, we performed transcriptome analysis for the stationary phase cells to support the metabolomic analysis. Our results suggest that the cold adaptation of the psychrotroph YLB-01 is closely associated with profoundly altered amino acid metabolism and carbohydrate metabolism. Our work provides a mechanistic understanding of the metabolic adaptation of marine psychrotrophs to prolonged low temperature under HHP.


Assuntos
Actinobacteria/metabolismo , Adaptação Fisiológica , Temperatura Baixa , Pressão Hidrostática , Metabolômica , Actinobacteria/genética , Actinobacteria/crescimento & desenvolvimento , Aminoácidos/metabolismo , Organismos Aquáticos/genética , Organismos Aquáticos/metabolismo , Metabolismo dos Carboidratos , Ciclo do Ácido Cítrico , Resposta ao Choque Frio , Perfilação da Expressão Gênica , Sedimentos Geológicos/microbiologia
9.
Front Pharmacol ; 10: 817, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379582

RESUMO

Apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, exhibits anti-atherogenic effects similar to high-density lipoprotein (HDL). However, it remains elusive whether D-4F and HDL share similar molecular mechanisms underlying anti-atherogenic effects and endothelial cell protections. We here compared the metabolic changes in endothelial cells induced by D-4F and HDL against oxidized low-density lipoprotein (ox-LDL), which may be of benefit to understanding the protective mechanisms of HDL and D-4F. Functional assays, including wound healing, transwell migration, and tube formation, were used to evaluate the pro-angiogenic effects of HDL and D-4F. NMR-based metabolomic analysis was employed to explore the protective mechanisms underlying HDL and D-4F. Partial least-squares discriminant analysis (PLS-DA) was performed to assess metabolic profiles, and orthogonal PLS-DA (OPLS-DA) was carried out to identify characteristic metabolites. Moreover, significantly altered metabolic pathways were also analyzed. We found that ox-LDL impaired the migration and tube formation of endothelial cells. Metabolomic analysis showed that ox-LDL triggered oxidative stress, impaired glycolysis, and enhanced glycerophospholipid metabolism. Both HDL and D-4F improved the migration and angiogenesis of endothelial cells, alleviated oxidative stress, and ameliorated disordered glycolysis impaired by ox-LDL. Strikingly, HDL partially attenuated the disturbed glycerophospholipid metabolism, whereas D-4F did not show this effect. In summary, although D-4F shared the similar protective effects with HDL on the migration and angiogenesis of endothelial cells, it could not deduce the molecular mechanisms of HDL completely. Nevertheless, D-4F possesses the potentiality to be exploited as clinically applicable agent for endothelial cell protection and cardiovascular disease treatment.

10.
J Proteome Res ; 18(4): 1880-1892, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30888184

RESUMO

Cachexia is a complex metabolic derangement syndrome that affects approximately 50-80% of cancer patients. So far, few works have been reported to provide a global overview of gastric cancer cachexia (GCC)-related metabolic changes. We established a GCC murine model by orthotopicly implanting BGC823 cell line and conducted NMR-based metabolomic analysis of gastric tissues, sera, and gastrocnemius. The model with typical cachexia symptoms, confirmed by significant weight loss and muscle atrophy, showed distinctly distinguished metabolic profiles of tumors, sera, and gastrocnemius from sham mice. We identified 20 differential metabolites in tumors, 13 in sera, and 14 in gastrocnemius. Tumor extracts displayed increased pyruvate and lactate, and decreased hypoxanthine, inosine, and inosinate, indicating significantly altered glucose and nucleic acid metabolisms. Cachectic mice exhibited up-regulated serum lactate and glycerol, and down-regulated glucose, which were closely related to hyperlipidemia and hypoglycemia. Furthermore, gastrocnemius transcriptomic and metabolomic data revealed that GCC induced perturbed pathways mainly concentrated on carbohydrate and amino acid metabolism. Specifically, cachectic gastrocnemius exhibited increased α-ketoglutarate and decreased glucose. In vitro study indicated that α-ketoglutarate could prompt myoblasts proliferation and reduce glucose deficiency-induced myotubes atrophy. Overall, this work provides a global metabolic overview to understand the metabolic alterations associated with GCC-induced muscle atrophy.


Assuntos
Caquexia/metabolismo , Metaboloma/fisiologia , Músculo Esquelético/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacologia , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Músculo Esquelético/química , Neoplasias Gástricas/química
11.
J Pharm Biomed Anal ; 167: 100-113, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763881

RESUMO

Dyslipidemia is known as a common clinical disease that affects the health of millions of people around the world. The treatment of dyslipidemia with traditional Chinese medicine (TCM) is generally based on the accurate identification of disease syndromes. TCM syndromes are judged by traditional four-diagnosis method, which is subjective and fuzzy. Additionally, the judgment of TCM syndromes highly depend on doctors' own clinical experience. In this present study, we used nuclear magnetic resonance (NMR)-based serum metabolomics patterns to figure out the metabolic characteristics of different syndromes in patients with dyslipidemia. In total, we enrolled 60 patients with dyslipidemia (30 cases with Spleen and Kidney Yang Deficiency syndrome (SKYD) and 30 cases with Phlegm-Dampness Retention syndrome (PDR)) and 20 healthy controls. Based on NMR technique, the serum metabolomics patterns of patients with different syndromes and healthy controls were analyzed, in the hope of screening the different metabolites among different syndromes and the differential metabolic pathway, as well as exploring the changes of metabolic network among different syndromes of dyslipidemia. The results suggested that the serum metabolomics patterns based on NMR was used to identify serum metabolites in patients with dyslipidemia of SKYD and PDR as well as healthy controls. Besides, it was found that the metabolic patterns of these three groups can be distinguished well and the different metabolites between different syndromes can be screened. From the point of view of metabolites, the metabolic characteristics of the patients with PDR were mainly the accumulation of noxious metabolites, while the metabolic characteristics of the patients with SKYD were mainly the lack of metabolites with protective function. From the point of view of metabolic mode, there were different metabolic patterns in patients with different syndromes of dyslipidemia in liver metabolism, oxidation, inflammatory reaction as well as energy metabolism, which reflects the difference of syndromes from different angles. The differences in metabolic outcomes among patients with different syndromes of dyslipidemia had a close association with to the effects of multiple signaling pathways. This study identified the characteristics of serum metabolic model of patients with different syndromes of dyslipidemia and the potential differential metabolites and characteristic metabolic characteristics of syndromes in order to understand the biological characteristics of patients with dyslipidemia of SKYD and PDR.


Assuntos
Dislipidemias/sangue , Redes e Vias Metabólicas , Metabolômica/métodos , Adulto , Idoso , Estudos de Casos e Controles , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Dislipidemias/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , Síndrome , Triglicerídeos/sangue
12.
Skelet Muscle ; 9(1): 3, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635036

RESUMO

BACKGROUND: Cachexia is a complex metabolic disorder and muscle atrophy syndrome, impacting 80% patients with advanced cancers. Malignant glioma is considered to be one of the deadliest human cancers, accounting for about 60% of all primary brain tumors. However, cachexia symptoms induced by glioma have received little attention. This work aims to explore skeletal muscle atrophy in orthotopic glioma murine models. METHODS: BALB/c nude mice were orthotopicly implanted with normal glial (HEB) and glioma (WHO II CHG5 and WHO IV U87) cells. Cachexia symptoms of mice were depicted by phenotypic, histopathologic, physiological, and biochemical analyses. Muscle atrophy-related proteins were examined by western blot, and the involved signaling pathways were analyzed. NMR-based metabolomic analysis was applied to profile metabolic derangements in the skeletal muscle, including multivariate statistical analysis, characteristic metabolite identification, and metabolic pathway analysis. RESULTS: Compared with controls, mice implanted with glioma cells exhibit typical cachexia symptoms, indicating a high correlation with the malignant grades of glioma. U87 mice develop cachexia much earlier and more severe than CHG5 mice. The glioma-bearing mice showed significantly decreased skeletal muscle mass and strength, which were associated with suppressed AKT, activated AMPK, FOXO, Atrogin1, and LC3. Interestingly, expressions of MuRF1, MyoD1, and eIF3f were not significantly changed. Consistently, metabolomic analyses elucidate pronounced metabolic derangements in cachectic gastrocnemius relative to controls. Glucose, glycerol, and 3-hydroxybutyrate were remarkably downregulated, whereas glutamate, arginine, leucine, and isoleucine were upregulated in cachectic gastrocnemius. Furthermore, U87 mice showed more characteristic metabolites and more disturbed metabolic pathways including glucose and lipid metabolism, protein catabolism, anabolism, and citric acid cycle anaplerotic. CONCLUSIONS: This study demonstrates for the first time that the orthotopic glioma murine model developed here exhibits high fidelity of cachexia manifestations in two malignant grades of glioma. Signaling pathway analysis in combination with metabolomic analysis provides significant insights into the complex pathophysiology of glioma cachexia and expands understanding of the molecular mechanisms underlying muscle atrophy.


Assuntos
Neoplasias Encefálicas/complicações , Caquexia/metabolismo , Glioma/complicações , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Animais , Atrofia , Caquexia/etiologia , Caquexia/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Masculino , Metaboloma , Camundongos Endogâmicos BALB C , Camundongos Nus , Músculo Esquelético/patologia , Transdução de Sinais
13.
Cell Physiol Biochem ; 46(4): 1668-1682, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29694977

RESUMO

BACKGROUND/AIMS: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. METHODS: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. RESULTS: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. CONCLUSION: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future.


Assuntos
Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/patologia , Mitocôndrias/metabolismo , Animais , Córtex Cerebelar/metabolismo , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Análise Discriminante , Modelos Animais de Doenças , Hipocampo/metabolismo , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Metaboloma , Metabolômica , Análise de Componente Principal , Ratos , Ratos Sprague-Dawley , Estreptozocina/toxicidade
14.
Free Radic Res ; 52(5): 544-555, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29526117

RESUMO

Although previous studies have reported the protective effect of glucagon-like peptide-1 (GLP-1) in diabetes nephropathy, the molecular mechanism such as nephroprotection remains elusive. In this study, we explored the molecular mechanism of exendin-4 as an GLP-1 receptor agonist for the treatment of tert-butyl hydroperoxide (t-BHP)-induced injury in mouse glomerulus mesangial cells (SV40 MES 13 cells) via an NMR-based metabonomic analysis. We found that exendin-4 protected mesangial cells from t-BHP-mediated toxicity, decreased the percentage of t-BHP-treated cells undergoing apoptosis, and restored glucose consumption in the t-BHP-treated group. A supervised partial least-squares discriminant analysis (PLS-DA) revealed that the metabolic profiles could be distinguished between the control, t-BHP-treated, and exendin-4-pretreated groups. Our findings indicate that exendin-4 pretreatment can cause distinct changes in energy, glycerol phospholipid, and amino acid metabolism. Our study provides novel insight into the metabolic mechanism of exendin-4-mediated nephroprotective effects.


Assuntos
Hipoglicemiantes/farmacologia , Células Mesangiais/efeitos dos fármacos , Peptídeos/farmacologia , Substâncias Protetoras/farmacologia , Peçonhas/farmacologia , terc-Butil Hidroperóxido/antagonistas & inibidores , Aminoácidos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Exenatida , Glucose/metabolismo , Glicerofosfolipídeos/metabolismo , Espectroscopia de Ressonância Magnética , Células Mesangiais/citologia , Células Mesangiais/metabolismo , Metabolômica/métodos , Camundongos , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Análise de Componente Principal , terc-Butil Hidroperóxido/farmacologia
15.
Zhen Ci Yan Jiu ; 43(3): 152-62, 2018 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-29560630

RESUMO

OBJECTIVE: We have repeatedly demonstrated that electroacupuncture (EA) of "Neiguan"(PC 6) can improve myocardial ischemia in rats. The present study was designed to investigate the metabolomic profile of peripheral blood se-rum and myocardium involving EA-induced improvement of myocardial ischemia-reperfusion injury (MIRI) in rats by using nuclear magnetic resonance spectroscopy. METHODS: Thirty male SD rats were equally randomized into blank control, model and EA groups. Rats of the control group were only banded for 20 min, once a day for 7 days. The MIRI model was established by occlusion of the anterior descending branch of the left coronary artery for 40 min, followed by reperfusion for 60 min, and rats of the model group were banded as those in the control group. EA (10 Hz/50 Hz, 1 mA) was applied to bilateral PC 6 for 20 min, once daily for 7 days. The blood samples and left ventricular myocardial tissues were collected for assaying the profiles of differential metabolites using 1H nuclear magnetic resonance (1H NMR) spectroscopy and multivariate statistical analysis such as the principal components analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) with SIMCA-P software 12.0. RESULTS: A total of 19 differential metabolites (17 down-regulated, 2 up-regulated) in the serum and 14 differential metabolites (13 down-regulated and 1 up-regulated) in the ischemic left myocardium were identified after MIRI. Of the 19 serum differential metabolites, amino acids (leucine, isoleucine, valine,alanine, lysine, glycine, glutamine), 3-hydroxy butyric acid (3-HB), lactic acid, acetate, N-acetyl glycoprotein (NAc), acetone, acetoacetate, succinate, polyunsaturated fatty acids (PUFA), creatine, glycerophosphocholine (GPC) were down-regulated; while low density lipoprotein (LDL), LDL/very low density lipoprotein(LDL/VLDL)and glucose obviously up-regulated. Of the 14 myocardial differential metabolites, amino acids (alanine, lysine, glutamate, glutamine, aspartate, taurine, glycine, threonine), GPC, creatine, lactic acid, adenosine monophosphate (AMP), nicotinamide adenine dinucleotide (NAD+) were significantly decreased, and glucose was up-regulated. Following EA treatment, most of the decreased serum differential metabolites except acetone, acetoacetate and PUFA, and the increased serum LDL, LDL/VLDL and glucose recovered, basically close to the control level; and the decreased myocardial creatine, GPC and NAD+ were also apparently up-regulated and the increased myocardial glucose was down-regulated. But, myocardial threonine and AMP still presented a decreasing state. Although the pattern of myocardial differential metabolites of the EA group had a trend to be close to the control group, the significant difference still existed, while the metabolic pattern of serum metabolites in the EA group was close to that of the control group. CONCLUSION: EA stimulation of PC 6 can regulate serum or/and myocardial metabolites as amino acids, carbohydrates, lipids, etc. in MIRI rats, of which both serum and myocardial creatine, GPC and glucose may be jointly confer a favorable potential for EA-induced improvement of MIRI.


Assuntos
Eletroacupuntura , Isquemia Miocárdica , Traumatismo por Reperfusão , Pontos de Acupuntura , Animais , Espectroscopia de Ressonância Magnética , Masculino , Miocárdio , Ratos , Ratos Sprague-Dawley
16.
J Cell Mol Med ; 21(12): 3810-3820, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28767201

RESUMO

D-4F, an apolipoprotein A-I (apoA-I) mimetic peptide, possesses distinctly anti-atherogenic effects. However, the biological functions and mechanisms of D-4F on the hyperplasia of vascular smooth muscle cells (VSMCs) remain unclear. This study aimed to determine its roles in the proliferation and migration of VSMCs. In vitro, D-4F inhibited VSMC proliferation and migration induced by ox-LDL in a dose-dependent manner. D-4F up-regulated heme oxygenase-1 (HO-1) expression in VSMCs, and the PI3K/Akt/AMP-activated protein kinase (AMPK) pathway was involved in these processes. HO-1 down-regulation with siRNA or inhibition with zinc protoporphyrin (Znpp) impaired the protective effects of D-4F on the oxidative stress and the proliferation and migration of VSMCs. Moreover, down-regulation of ATP-binding cassette transporter A1 (ABCA1) abolished the activation of Akt and AMPK, the up-regulation of HO-1 and the anti-oxidative effects of D-4F. In vivo, D-4F restrained neointimal formation and oxidative stress of carotid arteries in balloon-injured Sprague Dawley rats. And inhibition of HO-1 with Znpp decreased the inhibitory effects of D-4F on neointimal formation and ROS production in arteries. In conclusion, D-4F inhibited VSMC proliferation and migration in vitro and neointimal formation in vivo through HO-1 up-regulation, which provided a novel prophylactic and therapeutic strategy for anti-restenosis of arteries.


Assuntos
Apolipoproteína A-I/farmacologia , Aterosclerose/prevenção & controle , Heme Oxigenase-1/genética , Músculo Liso Vascular/efeitos dos fármacos , Neointima/prevenção & controle , Substâncias Protetoras/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Heme Oxigenase-1/metabolismo , Lipoproteínas LDL/antagonistas & inibidores , Lipoproteínas LDL/farmacologia , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Neointima/genética , Neointima/metabolismo , Neointima/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
17.
Acta Biochim Biophys Sin (Shanghai) ; 49(7): 617-627, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28475656

RESUMO

Creatine (Cr) supplementation has drawn much attention from researchers owing to its widespread efficacy in sports, and more recently, in therapeutic fields. However, the underlying molecular mechanisms remain elusive. Here, we performed nuclear magnetic resonance-based metabolomic analysis to address the metabolic profile of aqueous extracts from the mouse myoblast cell line C2C12 exposed to 2 mM Cr for 24 h (the Cr-treated group). Results showed that Cr supplementation facilitated the proliferation of C2C12 myoblasts. Both pattern recognition and hierarchical cluster analyses demonstrated that the metabolic profiles of the Cr-treated and control groups were distinctly different. We identified 13 characteristic metabolites significantly responsible for the discrimination of metabolic profiles between the two groups, through orthogonal projection to latent structures discriminant analysis and independent samples t-test. We further verified the discrimination performances of these metabolites by conducting univariate receiver operating characteristic curve analysis. Compared with the control group, the Cr-treated group exhibited increased levels of Cr, phosphocreatine (PCr), glutathione (GSH), and glucose, but decreased levels of leucine, valine, isoleucine, phenylalanine, methionine, choline, O-phosphocholine, sn-glycero-3-phosphocholine, and glycerol. Our results demonstrated that Cr supplementation upregulated PCr and glucose, promoted trichloroacetic acid cycle anaplerotic flux and GSH-mediated antioxidant capacity, and stabilized lipid membranes through suppressing glycerophospholipid metabolism. Our work provides new clues to the molecular mechanisms underlying the pleiotropic effects of Cr in muscle cells.


Assuntos
Creatina/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Metabolômica , Mioblastos/efeitos dos fármacos , Animais , Células Cultivadas , Suplementos Nutricionais , Glutationa/metabolismo , Camundongos , Mioblastos/metabolismo , Curva ROC
18.
J Mol Cell Cardiol ; 105: 77-88, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28274624

RESUMO

Apolipoprotein A-I (apoA-I) mimetic peptide exerts many anti-atherogenic properties. However, the underlying mechanisms related to the endothelial protective effects remain elusive. In this study, the apoA-I mimetic peptide, D-4F, was used. Proliferation assay, wound healing, and transwell migration experiments showed that D-4F improved the impaired endothelial proliferation and migration resulting from ox-LDL. Endothelial adhesion molecules expression and monocyte adhesion assay demonstrated that D-4F inhibited endothelial inflammation. Caspase-3 activation and TUNEL stain indicated that D-4F reduced endothelial cell apoptosis. A pivotal anti-oxidant enzyme, heme oxygenase-1 (HO-1) was upregulated by D-4F. The Akt/AMPK/eNOS pathways were involved in the expression of HO-1 induced by D-4F. Moreover, the anti-oxidation, pro-proliferation, and pro-migration capacities of D-4F were diminished by the inhibitors of both eNOS (L-NAME) and HO-1 (Znpp). Additionally, downregulation of ATP-binding cassette transporter A1 (ABCA1) by siRNA abolished the activation of Akt, AMPK and eNOS, and reduced the upregulation of HO-1 triggered by D-4F. Furthermore, D-4F promoted the reendothelialization of injured intima in carotid artery injury model of C57BL/6J mice in vivo. In summary, these findings suggested that D-4F might be a powerful candidate in the protection of endothelial cells and the prevention of cardiovascular disease (CVD).


Assuntos
Apolipoproteína A-I/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Heme Oxigenase-1/metabolismo , Lipoproteínas LDL/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Adesão Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Oxirredução/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regeneração , Cicatrização
19.
J Clin Endocrinol Metab ; 101(11): 4357-4366, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27533309

RESUMO

CONTEXT: MicroRNA (miR)-146b is overexpressed in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal invasion, advanced tumor stage, and poor prognosis. However, the underlying mechanism of miR-146b in relation to its oncogenic behavior in PTC and its putative targets remain unknown. OBJECTIVE: The purpose was to investigate IL-1 receptor-associated kinase 1 (IRAK1) as the potential miR-146b target gene and its involvement in PTC. DESIGN: We used genome-wide microarray, computational analysis, and 3' UTR reporter gene assays to identify IRAK1 as a miR-146b target gene. In vitro gain/loss-of-function experiments were further performed to determine the effects of IRAK1 on proliferation, colony formation, and wound-healing in PTC cancer cell lines. Expression levels of miR-146b and IRAK1 of 50 cases of PTC and its adjacent normal thyroid specimens were assessed via qRT-PCR. RESULTS: Microarray expression profile revealed that the mRNA level of IRAK1 gene was down-regulated by miR-146b. The 3' UTR of IRAK1 mRNA was found to be a molecular target of miR-146b posttranscriptional repression in BCPAP cells by reporter gene assays. MiR-146b promoted the migration and proliferation of PTC cells by down-regulating IRAK1 expression, whereas restoration of IRAK1 expression reversed this effect. In addition, the expression of IRAK1 mRNA was significantly lower in PTC clinical tissue samples than normal adjacent thyroid specimens and showed a strong inverse correlation with the expression of miR-146b in PTC specimens. CONCLUSION: Our results demonstrated that IRAK1 is a direct target of miR-146b and has functional roles to inhibit various aggressive PTC cell activities. In conjunction with current therapeutic regimens, targeting the miR-146b-IRAK1 axis may provide a potential approach for PTC management.


Assuntos
Carcinoma/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Regiões 3' não Traduzidas , Carcinoma Papilar , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , MicroRNAs/genética , Câncer Papilífero da Tireoide
20.
Oncotarget ; 7(37): 60053-60073, 2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27527852

RESUMO

Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression.


Assuntos
Gastrite/metabolismo , Glicólise , Neoplasias Gástricas/metabolismo , Animais , Carcinogênese , Colina/metabolismo , Modelos Animais de Doenças , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Redes e Vias Metabólicas , Metabolômica , Estresse Oxidativo , Ratos , Ratos Wistar
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