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BACKGROUND: Periostin is an extracellular matrix protein that plays a critical role in cell fate determination and tissue remodeling, but the underlying role and mechanism of periostin in diabetic cardiomyopathy (DCM) are far from clear. Thus, we aimed to clarify the mechanistic participation of periostin in DCM. METHODS: The expression of periostin was examined in DCM patients, diabetic mice and high glucose (HG)-exposed cardiac fibroblasts (CF). Gain- and loss-of-function experiments assessed the potential role of periostin in DCM pathogenesis. RNA sequencing was used to investigate the underlying mechanisms of periostin in DCM. RESULTS: A mouse cytokine antibody array showed that the protein expression of periostin was most significantly upregulated in diabetic mouse heart, and this increase was also observed in patients with DCM or HG-incubated CF. Periostin-deficient mice were protected from diabetes-induced cardiac dysfunction and myocardial damage, while overexpression of periostin held the opposite effects. Hyperglycemia stimulated the expression of periostin in a TGF-ß/Smad-dependent manner. RNA sequencing results showed that periostin upregulated the expression of nucleosome assembly protein 1-like 2 (NAP1L2) which recruited SIRT3 to deacetylate H3K27ac on the promoters of the branched-chain amino acid (BCAA) catabolism-related enzymes BCAT2 and PP2Cm, resulting in BCAA catabolism impairment. Additionally, CF-derived periostin induced hypertrophy, oxidative injury and inflammation in primary cardiomyocytes. Finally, we identified that glucosyringic acid (GA) specifically targeted and inhibited periostin to ameliorate DCM. CONCLUSION: Overall, manipulating periostin expression may function as a promising strategy in the treatment of DCM.
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Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Sirtuína 3 , Humanos , Camundongos , Animais , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Sirtuína 3/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Miócitos Cardíacos/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos de Cadeia Ramificada/farmacologia , Fibroblastos/metabolismoRESUMO
Light olefins are abundantly manufactured in the petroleum industry and thus represent ideal starting materials for modern chemical synthesis. Selective and divergent transformations of feedstock light olefins to value-added chemicals are highly sought-after but remain challenging. Herein we report an exceptionally regioselective carbonickelation of light alkenes followed by in situ trapping with three types of nucleophiles, namely a reductant, base, or Grignard reagent. This protocol enables efficient 1,2-hydrofunctionalization, dicarbofunctionalization, and branched-selective Heck-type cross-coupling of light alkenes with aryl and alkenyl reagents to streamline access to diverse alkyl arenes and complex alkenes. Harnessing bulky N-heterocyclic carbene ligands with acenaphthyl backbones for nickel catalysts is crucial to attain high reactivity and selectivity. This strategy provides a rare, modular, and divergent platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes.
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Monosaccharides play important roles in biological processes. Sensitive and accurate analyses of monosaccharides remain challenging because of their high hydrophilicities and poor ionization efficiencies. Here, we developed a paired derivatization approach with H/D-labeled hydroxylamines for simultaneous quantification of 12 monosaccharides by liquid chromatography tandem mass spectrometry (LC-MS/MS). O-(4-Methoxybenzyl)hydroxylamine hydrochloride (4-MOBHA·HCl) showed higher derivatization efficiency for monosaccharides compared to six other hydroxylamine analogues. The derivatization of monosaccharides was readily achieved in an aqueous solution. Furthermore, the deuterium-labeled isotope reagent, d3-4-MOBHA·HCl, was newly synthesized to stably label monosaccharides to improve its accuracy and precision in complex matrix analysis. As a result, 12 monosaccharides were rapidly detected by LC-MS/MS within 16 min with significant improvements in chromatographic separation and retention time. The detection sensitivity increased by 83 to 1600-fold with limits of quantitation ranging from 0.25 to 3.00 fmol. With the paired derivatization strategy, the monosaccharides could be accurately quantified with good linearity (R2 > 0.99) and satisfactory accuracy (recoveries: 85-110%). Using this method, we achieved sensitive and accurate quantification of the monosaccharide composition of herbal polysaccharides and the change in monosaccharide levels in human cell lines under physiopathological conditions. More importantly, the developed method was able to differentiate between the levels of the monosaccharides in fecal samples of human ulcerative colitis (UC) patients and UC mice compared to their respective controls. The differential monosaccharides determined in human feces provided a good diagnostic performance in distinguishing the UC patients from healthy individuals, showing potential for clinical application.
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Monossacarídeos , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Humanos , Hidroxilamina , Hidroxilaminas , Indicadores e Reagentes , Camundongos , Monossacarídeos/análise , Espectrometria de Massas em Tandem/métodosRESUMO
Due to their high prevalence and incidence, diabetes and atherosclerosis are increasingly becoming global public health concerns. Atherosclerosis is one of the leading causes of morbidity and disability in type 1 and/or type 2 diabetes patients. Atherosclerosis risk in diabetic patients is obviously higher than that of non-diabetic individuals. Diabetes-related glycolipid metabolism disorder has been shown to play a central role in atherosclerosis development and progression. Hyperglycemia and dyslipidemia increase the risks for atherosclerosis and plaque necrosis through multiple signaling pathways, such as a prolonged increase in reactive oxygen species (ROS) and inflammatory factors in cardiovascular cells. Notwithstanding the great advances in the understanding of the pathologies of diabetes-accelerated atherosclerosis, the current medical treatments for diabetic atherosclerosis hold undesirable side effects. Therefore, there is an urgent demand to identify novel therapeutic targets or alternative strategies to prevent or treat diabetic atherosclerosis. Burgeoning evidence suggests that plant and herbal medicines are closely linked with healthy benefits for diabetic complications, including diabetic atherosclerosis. In this review, we will overview the utilization of plant and herbal medicines for the treatment of diabetes-accelerated atherosclerosis. Furthermore, the underlying mechanisms of the ethnopharmacological therapeutic potentials against diabetic atherosclerosis are gathered and reviewed. It is foreseeable that the natural constituents from medicinal plants might be a new hope for the treatment of diabetes-accelerated atherosclerosis.
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Aterosclerose , Diabetes Mellitus Tipo 2 , Dislipidemias , Plantas Medicinais , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , HumanosRESUMO
The transition-metal-catalyzed C-N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as -50 °C), enantioselective Ni-catalyzed C-N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2 -symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.
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BACKGROUND: To find a succedaneum of present methods for slaughtering tilapia, we have demonstrated the influence of nitric oxide (NO) (saturated NO solution) through euthanasia before slaughter on the animal welfare and muscle color of tilapia. The results suggested that NO euthanasia significantly improved the animal welfare and muscle color. Besides, the investigation of NO postmortem treatment on the muscle color and color stability of tilapia fillets suggested that NO postmortem treatment not only improved the muscle color and color stability but also prolonged the shelf-life of tilapia fillets during the refrigerated storage. OBJECTIVE: To further investigate the effect of NO euthanasia on the quality of tilapia fillets and to estimate the safety of NO treatments (NO euthanasia and NO postmortem treatment) for the application of NO treatments in industrial manufacturing of tilapia and possibly of other fish species. METHODS: NO euthanasia was adopted in this study following a simulated fish processing line. HbNO and MbNO values were measured to clarify the mechanism and process of NO euthanasia. The blood parameters, muscle pH, rigor index, drip loss and total volatile basic nitrogen (TVB-N) values were measured to evaluate the quality of the fillets obtained from NO euthanized tilapia. Besides, the nitrate (NO3-) levels in the muscles after the refrigerated storage were detected to estimate the food safety of both NO euthanasia and NO postmortem treatment. RESULTS: Fillets obtained from the tilapia euthanized by NO showed a later reduction of muscle pH, a later onset of rigor mortis postmortem and less drip loss during the refrigerated storage than control. NO euthanasia caused less TVB-N than control and prolonged the shelf life of tilapia fillets. Moreover, the NO3- levels in the muscles of both NO euthanasia and NO postmortem treatment after the refrigerated storage were below the maximum permitted limit. CONCLUSION: Both the NO euthanasia and NO postmortem treatment are suitable for improving the quality of tilapia fillets and reducing the food safety threats, which may be valuable for industrial manufacturing of tilapia and may be applicable for other fish species.
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Ciclídeos , Conservação de Alimentos , Óxido Nítrico/farmacologia , Alimentos Marinhos/normas , Animais , Pesqueiros , Melhoria de QualidadeRESUMO
BACKGROUND: Nitric oxide (NO) has been recognized as pivotal for color and color stability of meat products and has an evident effect on inhibiting microbial growth in processed meat. The use of indirect NO (nitrate/nitrite) in industrial meat curing has potential deleterious effects and great concerns have been expressed over residual nitrite in meat after curing. To find a succedaneum, we have demonstrated the influence of direct NO (saturated NO solution) through euthanasia before slaughter on the fillets color of tilapia and the results suggested that direct NO treatment prior to slaughter is a good procedure to improve the color of tilapia fillets. OBJECTIVE: To further investigate the effect of direct NO on the muscle color and shelf-life of fillets from tilapia, this study was conducted to investigate the muscle color and color stability of tilapia fillets postmortem treated with saturated NO solution and their shelf-life during refrigerated storage. METHODS: Tilapia fillets were immersed in a saturated NO solution for 13 min, vacuum-packed and stored at refrigerated temperature for 15 days. Visual observations, color values and absorption maxima were used to evaluate the muscle color and color stability of tilapia fillets. Total volatile basic nitrogen (TVB-N) values were used to evaluate the shelf-life of tilapia fillets during refrigerated storage. RESULTS: By visual observation, NO treated tilapia fillets showed a brighter red color as compered to control samples after NO-treatment and during the whole storage. The redness (a*) values of NO treated tilapia fillets were significantly increased (P < 0.05) after NO-treatment, continuously increased (P < 0.05) during the earlier 9 days of the storage and remained roughly unchanged during the rest days of the storage. While the a* values of control samples decreased progressively during the storage. NO-treatment effectively improved the muscle color and color stability of tilapia fillets. The peak wavelengths of extract from the muscles of NO treated tilapia fillets increased from 418 nm to 421 nm at 15 d of the storage, while that of control decreased from 418 nm to 410 nm, indicated that color improvement in NO-treated tilapia fillets is mainly due to the formation of MbNO. Moreover, NO-treatment resulted in less TVB-N values than control (16.06 and 21.93 mg of N/100 g at the end of the storage, respectively), prolonging the shelf-life of tilapia fillets. CONCLUSION: The results suggested that postmortem treatment with NO is a good procedure not only for improving the muscle color and color stability but also for prolonging the shelf-life of tilapia fillets during the storage, which is valuable for industrial manufacturing of tilapia and possibly for other fish species.
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Ciclídeos , Cor , Manipulação de Alimentos , Carne , Músculos/efeitos dos fármacos , Óxido Nítrico/farmacologia , Alimentos Marinhos , AnimaisRESUMO
The physicochemical properties of Lipu taro starch (LTS), cassava starch (CS) and wheat starch (WS) were analyzed. These starches exhibited a comparable starch content (86 %). However, LTS had a significantly lower amylose content (15.93 %) compared to CS (26.62 %) and WS (33.53 %). Moreover, LTS demonstrated an irregular polygonal cubic morphology with a smaller particle size of 2.55 µm while possessed an A-type crystal structure with high crystallinity at 25.07 %. In contrast, CS and WS had larger particle sizes of 13.33 µm and 16.68 µm, respectively, with lower crystallinities of 22.52 % and 20.33 %. Due to these physicochemical properties, LTS exhibited superior emulsification properties with a higher emulsifying activity index of 8.63 m2/g and an emulsion stability index of 69.18 min, whereas CS and WS had values of 2.35 m2/g and 25.15 min, and 0.37 m2/g and 11.48 min, respectively. LTS also demonstrated enhanced thermal stability, characterized by higher gelatinization temperature (indicated by To, Tp, Tc, and ΔT) and reduced paste viscosity (indicated by PV, TV, FV, SBV, and BDV) compared to CS. However, the mechanical strength of the gel made from LTS (indicated by hardness, adhesiveness, springiness, gumminess, and chewiness) was comparatively inferior to those from CS and WS.
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Colocasia , Amido , Amido/química , Colocasia/química , Amilose/química , Tamanho da Partícula , ViscosidadeRESUMO
BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.
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Ácidos Cafeicos , Cardiomiopatias , Sepse , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Tubulina (Proteína)/metabolismo , Reprogramação Metabólica , Macrófagos/metabolismo , Succinatos/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Sepse/complicações , Sepse/tratamento farmacológico , Ácido Succínico/efeitos adversos , Lipopolissacarídeos/efeitos adversosRESUMO
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/diagnóstico , Prognóstico , Biomarcadores Tumorais/genética , RNA não Traduzido/genética , RNA Longo não Codificante/genética , Animais , MicroRNAs/genéticaRESUMO
Significance: Diabetes and its related complications are becoming an increasing public health problem that affects hundreds of millions of people globally. Increased disability and mortality rate of diabetic individuals are closely associated with various life-threatening complications, such as atherosclerosis, nephropathy, retinopathy, and cardiomyopathy. Recent Advances: Conventional treatments for diabetes are still limited because of undesirable side effects, including obesity, hypoglycemia, and hepatic and renal toxicity. Studies have shown that hydrogen sulfide (H2S) plays a critical role in the modulation of glycolipid metabolism, pancreatic ß cell functions, and diabetic complications. Critical Issues: Preservation of endogenous H2S systems and supplementation of H2S donors are effective in attenuating diabetes-induced complications, thus representing a new avenue to treat diabetes and its associated complications. Future Directions: This review systematically recapitulates and discusses the most recent updates regarding the therapeutic effects of H2S on diabetes and its various complications, with an emphasis on the molecular mechanisms that underlie H2S-mediated protection against diabetic complications. Furthermore, current clinical trials of H2S in diabetic populations are highlighted, and the challenges and solutions to the clinical transformation of H2S-derived therapies in diabetes are proposed. Finally, future research directions of the pharmacological actions of H2S in diabetes and its related complications are summarized. Antioxid. Redox Signal. 38, 18-44.
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Complicações do Diabetes , Diabetes Mellitus , Sulfeto de Hidrogênio , Humanos , Sulfeto de Hidrogênio/metabolismo , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Diabetes Mellitus/tratamento farmacológico , Fígado/metabolismoRESUMO
The arylation of sterically hindered amines represents one of the long-standing challenges in synthetic chemistry. Herein, we report a highly efficient Ni-catalysed arylation of sterically hindered primary and secondary amines with aryl chlorides or phenol derivatives enabled by an unsymmetric N-heterocyclic carbene (NHC) ligand. The protocol provides general, efficient, and scalable access to various sterically demanding anilines in excellent yields under mild conditions. A wide range of functional groups and heterocycles are compatible (>50 examples), including those present in biologically relevant molecules. Computational studies suggest that the unsymmetric bulky and flexible NHC ligand was critical to balance the oxidative addition and reductive elimination elementary steps, thus promoting this challenging transformation.
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BACKGROUND: Na+/K+-ATPase (NKA), an ion pumping enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However, the role of NKA in hepatic lipid homeostasis has yet to be fully characterized. METHODS: The activity of NKA and NKAα1 expression were determined in steatotic cells, mice and patients. The roles of NKAα1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKAα1 in mice. RESULTS: Herein, we demonstrated that the expression and activity of α1 subunit of NKA (NKAα1) were lowered in the livers of nonalcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-induced obese mice, and genetically obese (ob/ob, db/db) mice, as well as oleic acid-induced hepatocytes. Hepatic deficiency of NKAα1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKAα1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKAα1 upregulated sirtuin 1 (SIRT1) via interacting with ubiquitin specific peptidase 22 (USP22), a deubiquitinating enzyme for the stabilization and deubiquitination of SIRT1, thus activating the downstream autophagy signaling. Blockade of the SIRT1/autophagy signaling pathway eliminated the protective effects of NKAα1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (897DVEDSYGQQWTYEQR911) of NKAα1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKAα1 and inducing its activation. CONCLUSIONS: Collectively, this study renews the functions of NKAα1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKAα1.
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Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Camundongos Obesos , Sirtuína 1/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatócitos/metabolismo , Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BLRESUMO
Rehmannia glutinosa produces many pharmacological natural components, including ferulic acid (FA) which is also an important precursor of some medicinal ingredients, so it is very significant to explore FA biosynthesis for enhancing the production of FA and its derivations. This study aimed to determine and reconstitute the R. glutinosa FA biosynthetic pathway from phenylalanine (Phe) metabolism in Saccharomyces cerevisiae as a safe host for the biosynthesis of plant-derived products. Although plant caffeic acid O-methyltransferases (COMTs) are thought to be a vital catalytic enzyme in FA biosynthesis pathways, to date, none of the RgCOMTs in R. glutinosa has been characterized. This study identified an RgCOMT and revealed its protein enzymatic activity for FA production in vitro. The RgCOMT overexpression in R. glutinosa significantly increased FA yield, suggesting that its molecular function is involved in FA biosynthesis. Heterologous expression of the RgCOMT and reported R. glutinosa genes, RgPAL2 (encoding phenylalanine ammonia-lyase [PAL] protein), RgC4H (cinnamate 4-hydroxylase [C4H]), and RgC3H (p-coumarate-3-hydroxylase [C3H]), in S. cerevisiae confirmed their catalytic abilities in the reaction steps for the FA biosynthesis. Importantly, in this study, these genes were introduced into S. cerevisiae and coexpressed to reconstitute the R. glutinosa FA biosynthetic pathway from Phe metabolism, thus obtaining an engineered strain that produced an FA titer of 148.34 mg L-1 . This study identified the functional activity of RgCOMT and clarified the R. glutinosa FA biosynthesis pathway in S. cerevisiae, paving the way for the efficient production of FA and its derivatives.
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Vias Biossintéticas , Rehmannia , Vias Biossintéticas/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Rehmannia/genética , Rehmannia/metabolismo , Metiltransferases/metabolismoRESUMO
INTRODUCTION: Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined. OBJECTIVES: We aimed to elucidate the potential roles of Metrnl in DCM. METHODS: Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM. RESULTS: We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation. CONCLUSION: Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Animais , Camundongos , Ratos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Autofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Miócitos Cardíacos , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/farmacologiaRESUMO
As a chronic and progressive disorder, hypertension remains to be a serious public health problem around the world. Among the different types of hypertension, pulmonary arterial hypertension (PAH) is a devastating disease associated with pulmonary arteriole remodeling, right ventricular failure and death. The contemporary management of systemic hypertension and PAH has substantially grown since more therapeutic targets and/or agents have been developed. Evolving treatment strategies targeting the vascular remodeling lead to improving outcomes in patients with hypertension, nevertheless, significant advancement opportunities for developing better antihypertensive drugs remain. Carbon monoxide (CO), an active endogenous gasotransmitter along with hydrogen sulfide (H2S) and nitric oxide (NO), is primarily generated by heme oxygenase (HO). Cumulative evidence suggests that CO is considered as an important signaling molecule under both physiological and pathological conditions. Studies have shown that CO confers a number of biological and pharmacological properties, especially its involvement in the pathological process and treatment of hypertension-related vascular remodeling. This review will critically outline the roles of CO in hypertension-associated vascular remodeling and discuss the underlying mechanisms for the protective effects of CO against hypertension and vascular remodeling. In addition, we will propose the challenges and perspectives of CO in hypertensive vascular remodeling. It is expected that a comprehensive understanding of CO in the vasculature might be essential to translate CO to be a novel pharmacological agent for hypertension-induced vascular remodeling.
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Monóxido de Carbono , Hipertensão , Monóxido de Carbono/metabolismo , Monóxido de Carbono/farmacologia , Monóxido de Carbono/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação VascularRESUMO
Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47phox luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47phox and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47phox stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE-/- mice, but not in ApoE-/- mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47phox in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes.
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Aterosclerose , Produtos Biológicos , Diabetes Mellitus , Animais , Camundongos , Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Diabetes Mellitus/metabolismo , Células Endoteliais/metabolismo , Ginsenosídeos , Glucose/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Luciferases/metabolismo , Lisina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Estreptozocina , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Growing evidence suggests that hypertension is one of the leading causes of cardiovascular morbidity and mortality since uncontrolled high blood pressure increases the risk of myocardial infarction, aortic dissection, hemorrhagic stroke, and chronic kidney disease. Impaired vascular homeostasis plays a critical role in the development of hypertension-induced vascular remodeling. Abnormal behaviors of vascular cells are not only a pathological hallmark of hypertensive vascular remodeling, but also an important pathological basis for maintaining reduced vascular compliance in hypertension. Targeting vascular remodeling represents a novel therapeutic approach in hypertension and its cardiovascular complications. Phytochemicals are emerging as candidates with therapeutic effects on numerous pathologies, including hypertension. An increasing number of studies have found that curcumin, a polyphenolic compound derived from dietary spice turmeric, holds a broad spectrum of pharmacological actions, such as antiplatelet, anticancer, anti-inflammatory, antioxidant, and antiangiogenic effects. Curcumin has been shown to prevent or treat vascular remodeling in hypertensive rodents by modulating various signaling pathways. In the present review, we attempt to focus on the current findings and molecular mechanisms of curcumin in the treatment of hypertensive vascular remodeling. In particular, adverse and inconsistent effects of curcumin, as well as some favorable pharmacokinetics or pharmacodynamics profiles in arterial hypertension will be discussed. Moreover, the recent progress in the preparation of nano-curcumins and their therapeutic potential in hypertension will be briefly recapped. The future research directions and challenges of curcumin in hypertension-related vascular remodeling are also proposed. It is foreseeable that curcumin is likely to be a therapeutic agent for hypertension and vascular remodeling going forwards.
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OBJECTIVE: To study the strategy and process of out-hospital emergency care of acute cardiovascular events. METHODS: One hundred and eighty-three patients in the Second Affiliated Hospital of Baotou Medical College were prospectively studied. The patients were divided into two groups according to the different ways of out-hospital care, one group consisted of patients who received first-aid care after calling "120" (94 cases), another was self-aid group consisting of patients sent to hospital by relatives (89 cases). The proportion of persons with higher than high school education and better knowledge for emergency care of patients with heart disease in first-aid group was higher than self-aid group (50.0% vs. 29.2%, 83.0% vs. 60.7%, both P<0.05). When the patients were brought to the emergency room, they were all treated according to our standard procedure and then registered. All patients were followed up at the end of first and third month after illness. RESULTS: Cardiovascular events were mainly myocardial infarction (61.7%) among 183 patients. There were statistically significant differences between two groups in self-aid response time, first disposal time and out-hospital rescuing time [(32.3+/-5.6) minutes vs. (89.6+/- 8.4) minutes, (47.3+/-7.3) minutes vs. (149.8+/-13.5) minutes, (61.7+/-8.3) minutes vs. [(149.8+/- 13.5) minutes, all P<0.01], but no difference was found in in-hospital rescuing time [(29.9+/-5.3) minutes vs. (31.1+/-4.5) minutes, P>0.05]. Morbidity rate was lower in first-aid group than self-aid group in 1st and 3rd month, respectively (2.1% vs. 9.0%, 4.2% vs. 12.4%, both P<0.05). CONCLUSION: Excellent emergency system and procedure can shorten initial disposal time and out-hospital rescuing time, thus improve patients' prognosis. The education level and health knowledge of patients and their relatives directly affect their mode of arriving hospital and prognosis.
Assuntos
Serviços Médicos de Emergência , Infarto do Miocárdio/terapia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
The effectiveness of pectin coatings enriched with clove essential oil (CEO), as new edible coatings were investigated to preserve bream (Megalobrama ambycephala) fillets during refrigeration over a period of 15â¯days. All samples were analyzed for physicochemical (pH, PV, TBA and TVB-N), microbiological (Total viable count, Psychrophilic bacteria, Lactic acid bacteria, Enterobacteriaceae, Pseudomonas spp., H2S producing bacteria) and organoleptic attributes. The results revealed that the CEO incorporation reduced the extent of lipid oxidation, as judged by PV, TBA and TVB-N, thus extending the shelf life of bream fillets by at least 15â¯days. Moreover, the application of pectin coatings with CEO improved the weight loss, water holding capacity, textural and color attributes of the bream samples significantly compared to untreated sample. Pectin coating along with CEO was effective in inhibiting bacterial growth especially in gram-negative bacteria, while the growth of lactic acid bacteria remained constant for most of the storage period. The effect on the microorganisms during storage was in accordance with biochemical indexes of the quality, representing the viability of these coatings for bream preservation. Thus, the coatings developed in present study could inhibit the development of lipid oxidation during cold storage, representing an option as a seafood preservative.