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Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1ß, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.
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Adipócitos Marrons , Biogênese de Organelas , Animais , Camundongos , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Homeostase , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Termogênese/fisiologiaRESUMO
The role of Dy-S coordination in a single-molecule magnet (SMM) is investigated via an ab initio study in a group of mononuclear structures. The SMM performance of this group is well interpreted via a concise criterion consisting of long quantum tunneling of magnetization (QTM) time τQTM and high effective barrier for magnetic reversal Ueff. The best SMMs in the selected group, i.e., 1Dy (CCDC refcode: PUKFAF) and 2Dy (CCDC refcode: NIKSEJ), are just those holding the longest τQTM and the highest Ueff simultaneously. Further analysis based on the crystal field model and ab initio magneto-structural exploration indicates that the influence of Dy-S coordination on the SMM performance of 1Dy is weaker than that of axial Dy-O coordination. Thus, Dy-S coordination is more likely to play an auxiliary role rather than a dominant one. However, if placed at the suitable equatorial position, Dy-S coordination could provide important support for good SMM performance. Consequently, starting from 1Dy, we built two new structures where Dy-S coordination only exists at the equatorial position and two axial positions are occupied by strong Dy-O/Dy-F coordination. Compared to 1Dy and 2Dy, these new ones are predicted to have significantly longer τQTM and higher Ueff, as well as a nearly doubled blocking temperature TB. Thus, they are probable candidates of SMM having clearly improved performance.
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The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri.
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Compostos de Espiro , Animais , Compostos de Espiro/farmacologia , Compostos de Espiro/metabolismo , Acaricidas/farmacologia , Propionatos/farmacologia , Propionatos/metabolismo , Tetranychidae/efeitos dos fármacos , Tetranychidae/genética , Tetranychidae/metabolismo , Simulação de Acoplamento Molecular , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Resistência a Medicamentos/genética , 4-Butirolactona/análogos & derivadosRESUMO
Uncontrolled gluconeogenesis results in elevated hepatic glucose production in type 2 diabetes (T2D). The small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is known to catalyze deSUMOylation of target proteins, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic gluconeogenesis and the occurrence of T2D remain unknown. Herein, we established SENP2 hepatic knockout mice and found that SENP2 deficiency could protect against high-fat diet-induced hyperglycemia. Pyruvate- or glucagon-induced elevation in blood glucose was attenuated by disruption of SENP2 expression, whereas overexpression of SENP2 in the liver facilitated high-fat diet-induced hyperglycemia. Using an in vitro assay, we showed that SENP2 regulated hepatic glucose production. Mechanistically, the effects of SENP2 on gluconeogenesis were found to be mediated by the cellular fuel sensor kinase, 5'-AMP-activated protein kinase alpha (AMPKα), which is a negative regulator of gluconeogenesis. SENP2 interacted with and deSUMOylated AMPKα, thereby promoting its ubiquitination and reducing its protein stability. Inhibition of AMPKα kinase activity dramatically reversed impaired hepatic gluconeogenesis and reduced blood glucose levels in SENP2-deficient mice. Our study highlights the novel role of hepatic SENP2 in regulating gluconeogenesis and furthers our understanding of the pathogenesis of T2D.
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Proteínas Quinases Ativadas por AMP , Cisteína Endopeptidases , Diabetes Mellitus Tipo 2 , Hiperglicemia , Sumoilação , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese , Glucose/metabolismo , Hiperglicemia/metabolismo , Fígado/metabolismo , Camundongos , Peptídeo Hidrolases/metabolismoRESUMO
Single-molecule magnets (SMMs) have great potential in becoming revolutionary materials for micro-electronic devices. As one type of SMM and holding the performance record, lanthanide single-ion magnets (Ln-SIMs) stand at the forefront of the family. Lowering the coordination number (CN) is an important strategy to improve the performance of Ln-SIMs. Here, we report a theoretical study on a typical group of low-CN Ln-SIMs, i.e., tetracoordinated structures. Our results are consistent with those of experiments and they identify the same three best Ln-SIMs via a concise criterion, i.e., the co-existence of long τQTM and high Ueff. Compared to the record-holding dysprosocenium systems, the best SIMs here possess τQTM values that are shorter by several orders of magnitude and Ueff values that are lower by â¼1000 Kelvin (K). These are important reasons for the fact that the tetracoordinated Ln-SIMs are clearly inferior to dysprosocenium. A simple but intuitive crystal-field analysis leads to several routes to improve the performance of a given Ln-SIM, including compression of the axial bond length, widening the axial bond angle, elongation of the equatorial bond length and usage of weaker equatorial donor ligands. Although these routes are not brand-new, the most efficient option and the degree of improvement resulting from it are not known in advance. Consequently, a theoretical magneto-structural study, covering various routes, is carried out for the best Ln-SIM here and the most efficient route is shown to be widening the axial â O-Dy-O angle. The most optimistic case, having a â O-Dy-O of 180°, could have a τQTM (up to 103 s) and Ueff (â¼2400 K) close to those of the record-holders. Subsequently, a blocking temperature (TB) of 64 K is predicted to be possible for it. A more practical case, with â O-Dy-O being 160°, could have a τQTM of up to 400 s, Ueff of around 2200 K and the possibility of a TB of 57 K. Although having an inherent precision limit, these predictions provide a guide to performance improvement, starting from an existing system.
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Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta-analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, -3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL-1ß, IL-10, TNF-α, TGF-ß, vascular endothelial growth factor (VEGF), hydroxyproline and alpha-smooth muscle actin (α-SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition.
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BACKGROUND AND AIMS: NAFLD, characterized by aberrant triglyceride accumulation in liver, affects the metabolic remodeling of hepatic and nonhepatic tissues by secreting altered hepatokines. Small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is responsible for de-SUMOylation of target protein, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic metabolism remains unclear. APPROACH AND RESULTS: We found that SENP2 was the most dramatically increased SENP in the fatty liver and that its level was modulated by fed/fasted conditions. To define the role of hepatic SENP2 in metabolic regulation, we generated liver-specific SENP2 knockout (Senp2-LKO) mice. Senp2-LKO mice exhibited resistance to high-fat diet-induced hepatic steatosis and obesity. RNA-sequencing analysis showed that Senp2 deficiency up-regulated genes involved in fatty acid oxidation and down-regulated genes in lipogenesis in the liver. Additionally, ablation of hepatic SENP2 activated thermogenesis of adipose tissues. Improved energy homeostasis of both the liver and adipose tissues by SENP2 disruption prompted us to detect the hepatokines, with FGF21 identified as a key factor markedly elevated in Senp2-LKO mice that maintained metabolic homeostasis. Loss of FGF21 obviously reversed the positive effects of SENP2 deficiency on metabolism. Mechanistically, by screening transcriptional factors of FGF21, peroxisome proliferator-activated receptor alpha (PPARα) was defined as the mediator for SENP2 and FGF21. SENP2 interacted with PPARα and deSUMOylated it, thereby promoting ubiquitylation and subsequent degradation of PPARα, which in turn inhibited FGF21 expression and fatty acid oxidation. Consistently, SENP2 overexpression in liver facilitated development of metabolic disorders. CONCLUSIONS: Our finding demonstrated a key role of hepatic SENP2 in governing metabolic balance by regulating liver-adipose tissue crosstalk, linking the SUMOylation process to metabolic regulation.
Assuntos
Tecido Adiposo/metabolismo , Cisteína Endopeptidases/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , PPAR alfa/metabolismo , Animais , Cisteína Endopeptidases/metabolismo , Dieta Hiperlipídica , Metabolismo Energético/genética , Ácidos Graxos/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Lipogênese/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/genética , Obesidade/metabolismo , Sumoilação , Termogênese/genética , UbiquitinaçãoAssuntos
Ipomoea batatas , Phytoplasma , China , DNA Ribossômico , Phytoplasma/genética , RNA Ribossômico 16SRESUMO
A novel facultatively anaerobic, Gram-stain-negative bacterium, designated strain HT7-2(T), was isolated from Ulva prolifera collected from the intertidal zone of Qingdao sea area, China, during its bloom. Cells were rod-shaped (1.9-3.5×0.4-0.6 µm), non-sporulating and motile by gliding. Strain HT7-2(T) was able to grow at 4-50 °C (optimum 40-42 °C), pH 5.5-8.5 (optimum pH 7.0), 0-8â% (w/v) NaCl (optimum 2-3â%) and 0.5-10â% (w/v) sea salts (optimum 2.5â%). The genomic DNA G+C content was 38.8 mol%. The phylogenetic analysis based on 16S rRNA gene sequences revealed that strain HT7-2(T) belonged to the genus Maribacter with sequence similarity values of 94.5-96.6â%, and was most closely related to Maribacter aestuarii GY20(T) (96.6%). Chemotaxonomic analysis showed that the main isoprenoid quinone was MK-6 and the major fatty acids were iso-C15:0 and unknown equivalent chain-length 13.565. The polar lipids of strain HT7-2(T) consisted of one phosphatidylethanolamine, four unidentified lipids and one unidentified aminolipid. On the basis of the phenotypic, phylogenetic and chemotaxonomic characteristics, strain HT7-2(T) (â=CGMCC 1.12207(T)â=JCM 18466(T)) is concluded to represent a novel species of the genus Maribacter, for which the name Maribacter thermophilus sp. nov. is proposed. An emended description of the genus Maribacter is also proposed.
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Eutrofização , Flavobacteriaceae/classificação , Filogenia , Ulva/microbiologia , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Flavobacteriaceae/genética , Flavobacteriaceae/isolamento & purificação , Dados de Sequência Molecular , Fosfatidiletanolaminas/química , RNA Ribossômico 16S/genética , Água do Mar/microbiologia , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMO
INTRODUCTION: With an incidence rate as high as 46%-58%, hypoglycemia is a common complication of glycemic management among those suffering from type 2 diabetes mellitus(T2DM). According to preclinical research, hypoglycemia episodes may impair cognition by harming neurons. However, there is still controversy regarding the clinical evidence for the relationship between hypoglycemic events and the likelihood of cognitive impairment. Furthermore, little research has been done on the dose-response association between hypoglycemia incidents and the possibility of cognitive impairment. To address these knowledge gaps, the present research intends to update the comprehension of the association among hypoglycemic events and the risk of cognitive impairment and to clarify the correlation between dose and response by incorporating the most recent investigations. METHOD AND ANALYSIS: This work has developed a protocol for a systematic review and meta-analysis that will examine, via a well-organized assessment of several databases, the relationship between the incidence of hypoglycemia and the probability of cognitive impairment. Observational studies investigating the connection between hypoglycemia episodes and cognitive impairment will be included. The databases that will be searched are PubMed, Web of Science, the Chinese Biomedical Literature Database (CBM), Cochrane Library, Embase, the China National Knowledge (CNKI), Wan Fang, the Chinese Science and Technology Periodical Database (VIP), and Du Xiu. Literature from the establishment of each database to December 2023 will be included in the search. Two researchers will independently screen the studies that satisfy the requirements for both inclusion and exclusion. A third researcher will be asked to mediate any disputes. The methodological caliber of the studies included will be assessed utilizing the Newcastle-Ottawa Scale (NOS) or the Joanna Briggs Institute (JBI) critical appraisal method. With regard to GRADE, which stands for Grading of Recommendations, Assessment, Development, and Evaluation, the quality of the evidence will be evaluated. ROBIS Tool will be used to evaluate the risk of bias in the development of the systematic review. If the data is accessible, meta-analysis and dose-response curve analysis will be employed by Stata software. However, if the data does not allow for such analysis, a descriptive review will be performed. DISCUSSION AND CONCLUSION: Hypoglycemic episodes may raise the likelihood of cognitive impairment, according to earlier investigations. This study will update the relevant evidence and explore the dose-response connection between hypoglycemic episodes and cognitive impairment. The results of this review will have significant effects on decision-making by individuals with diabetes, healthcare providers, and government policy institutions. TRIAL REGISTRATION: Prospero registration number: CRD42023432352.
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Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Hipoglicemia , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/complicações , Disfunção Cognitiva/etiologia , Metanálise como Assunto , Revisões Sistemáticas como Assunto , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêuticoRESUMO
Overexpression of carboxyl/cholinesterase (CCE) genes has been reported to be associated with many cases of pesticide resistance in arthropods. However, it has been rarely documented that CCE genes participate in spirodiclofen resistance in Panonychus citri. In previous research, we found that spirodiclofen resistance is related to increased P450 and CCE enzyme activities in P. citri. In this study, we identified two CCE genes, PcCCE3 and PcCCE5, which were significantly upregulated in spirodiclofen-resistant strain and after exposure to spirodiclofen. RNA interference of PcCCE3 and PcCCE5 increased the spirodiclofen susceptibility in P. citri. In vitro metabolism indicated that PcCCE3 and PcCCE5 could interact with spirodiclofen, but metabolites were detected only in the PcCCE3 treatment. Our results indicated that PcCCE3 participates in spirodiclofen resistance through direct metabolism, and PcCCE5 may be involved in the spirodiclofen resistance by passive binding and sequestration, which provides new insights into spirodiclofen resistance in P. citri.
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Proteínas de Artrópodes , Compostos de Espiro , Animais , Compostos de Espiro/farmacologia , Compostos de Espiro/metabolismo , Compostos de Espiro/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Proteínas de Artrópodes/química , Resistência a Medicamentos/genética , Carboxilesterase/genética , Carboxilesterase/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacologiaRESUMO
OBJECTIVE: Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. METHODS: We examined the differentiation of immortalized brown adipocytes and primary brown adipocytes when NR2F6 were deleted, and explored the mechanism through which NR2F6 regulated adipogenesis using ChIP-qPCR in vitro. Male wild type (WT) and Pdgfra-Cre-mediated deletion of Nr2f6 in preadipocytes (NR2F6-PKO) mice were fed with high fat diet (HFD) for 12 weeks, and adiposity, glucose intolerance, insulin resistance and inflammation were assessed. RESULTS: NR2F6 exhibited abundant expression in BAT, while its expression was minimal in white adipose tissue (WAT). Within BAT, NR2F6 was highly expressed in preadipocytes, experienced a transient increase in the early stage of brown adipocyte differentiation, and significantly decreased in the mature adipocytes. Depletion of NR2F6 in preadipocytes inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of BAT, but without affecting WAT development. NR2F6 transcriptionally regulated PPARγ expression to promote adipogenic process in brown adipocytes. Loss of NR2F6 in preadipocytes led to increased susceptibility to diet-induced metabolic disorders. CONCLUSIONS: Our findings unveiled NR2F6 as a novel key regulator of brown adipogenesis, potentially opening up new avenues for maintaining metabolic homeostasis by targeting NR2F6.
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Adipócitos Marrons , Tecido Adiposo Marrom , Animais , Masculino , Camundongos , Adipócitos Marrons/metabolismo , Adipogenia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , HomeostaseRESUMO
Obesity, particularly increased visceral fat, positively correlates with various metabolic challenges, including atherosclerosis, but the mechanism is not fully understood. The aim of this study is to determine the role of visceral-fat-derived exosomes (Exo) in endothelial cells and atherosclerosis. We show that obesity changes the miRNA profile of visceral adipose exosomes in mice. Importantly, exosomal miR-27b-3p efficiently enters into the vascular endothelial cells and activates the NF-κB pathway by downregulating PPARα. Mechanistically, miR-27b-3p binds directly to the CDS region of PPARα mRNA, thereby promoting mRNA degradation and suppressing translation. In ApoE-deficient mice, administration of miR-27b-3p mimic increases inflammation and atherogenesis, while overexpression of PPARα protects against atherosclerosis. Thus, obesity-induced exosomal miR-27b-3p promotes endothelial inflammation and facilitates atherogenesis by PPARα suppression. We reveal an exosomal pathway by which obesity aggravates atherosclerosis and proposed therapeutic strategies for atherosclerosis in people with obesity.
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Aterosclerose , Exossomos , MicroRNAs , Camundongos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Células Endoteliais/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Adipócitos/metabolismo , Inflamação/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Obesidade/metabolismo , Exossomos/metabolismoRESUMO
Background: Perivascular adipose tissue (PVAT), an active endocrine organ, exerts direct effect on vascular tone through paracrine. Activation of PVAT metabolism plays an inhibitory role in atherosclerosis via secreting relaxing factors. The present studies were designed to investigate the role of PVAT metabolism in regulation of hypertension. Materials and methods: Apolipoprotein E (ApoE) knockout mice with BMP4 knockout in adipose tissue or brown adipose tissue (aP2-DKO or UCP1-DKO, respectively) were used for exploring the role of impaired PVAT metabolism in hypertension. Vascular function was assessed using wire myography. The potential regulatory factor of vascular function was explored using qPCR and ELISA and further confirmed in perivascular fat cell line. Results: Knockout of BMP4 either in adipose tissue or specifically in BAT aggravates high-fat diet (HFD, 40% fat)-induced hypertension and endothelial dysfunction in ApoE-/- mice. In the meanwhile, deficiency of BMP4 also aggravates Ang II (angiotensin II) -induced hypertension and vascular remodeling in ApoE-/- mice. Moreover, deficiency of BMP4 inhibits NO release and induces ROS production. In vitro system, aortic rings pretreated with PVAT extracts from BMP4-DKO mice showed increased vasoconstriction and reduced endothelial-dependent relaxation compared with the controls. We further demonstrated that PVAT of BMP4-DKO mice expressed higher level of angiotensinogen (AGT) and Ang II compared with the controls. Conclusion: Impaired PVAT metabolism aggravates hypertension, and this effect is dependent on the activation of local renin-angiotensin-aldosterone system (RAAS). The results of this study first demonstrate the regulatory role of PVAT metabolism in hypertension.
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Brown and beige adipocytes dissipate energy in a nonshivering thermogenesis manner, exerting beneficial effects on metabolic homeostasis. CHCHD10 is a nuclear-encoded mitochondrial protein involved in cristae organization; however, its role in thermogenic adipocytes remains unknown. We identify CHCHD10 as a novel regulator for adipocyte thermogenesis. CHCHD10 is dramatically upregulated during thermogenic adipocyte activation by PPARγ-PGC1α and positively correlated with UCP1 expression in adipose tissues from humans and mice. We generated adipocyte-specific Chchd10 knockout mice (Chchd10-AKO) and found that depleting CHCHD10 leads to impaired UCP1-dependent thermogenesis and energy expenditure in the fasting state, with no effect in the fed state. Lipolysis in adipocytes is disrupted by CHCHD10 deficiency, while augmented lipolysis through ATGL overexpression recovers adipocyte thermogenesis in Chchd10-AKO mice. Consistently, overexpression of Chchd10 activates thermogenic adipocytes. Mechanistically, CHCHD10 deficiency results in the disorganization of mitochondrial cristae, leading to impairment of oxidative phosphorylation complex assembly in mitochondria, which in turn inhibits ATP generation. Decreased ATP results in downregulation of lipolysis by reducing nascent protein synthesis of ATGL, thereby suppressing adipocyte thermogenesis. As a result, Chchd10-AKO mice are prone to develop high-fat diet-induced metabolic disorders. Together, our findings reveal an essential role of CHCHD10 in regulating lipolysis and the thermogenic program in adipocytes.
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Adipócitos Bege , Adipócitos Marrons , Lipólise , Proteínas Mitocondriais , Termogênese , Trifosfato de Adenosina/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Animais , Humanos , Lipólise/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning on left-cardiac function, contents of serum TNF-α and IL-6 and expression of myocardial farnesoid X receptor(FXR), small heterodimer partner (SHP), apoptosis inducing factor (AIF) and heat shock proteins 70 (HSP70) genes in myocardial ischemia-reperfusion injury (MIRI) rats, so as to explore its mechanisms underlying improvement of ischemic myocardial injury. METHODS: Forty male Wistar rats were randomly divided into normal control, sham operation, MIRI model and EA pretreatment groups, with 10 rats in each group. Rats of the sham operation group received exposure of the thorax and heart. The MIRI model was established by occlusion of the anterior descending branch of the left coronary artery (LAD). EA (2 Hz/100 Hz and 1 mA) was applied to bilateral "Neiguan" (PC6), "Zusanli" (ST36) and "Guanyuan" (CV4) for 20 min, once a day for 7 days. The left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP)and maximal rates of rise and fall of left ventricular pressure (±dp/dtmax) were detected, the contents of serum TNF-α and IL-6 were detected by using enzyme-linked immunosorbent assay (ELISA), and the expression of FXR, SHP, AIF and HSP70 apoptotic genes in the myocardial tissue were measured by fluorescent quantitative RT-PCR. RESULTS: Compared with the normal control group, the LVEDP, contents of serum TNF-α and IL-6, and the expression levels of myocardial FXR, SHP, AIF and HSP70 mRNAs were significantly increased (P<0.05), while LVSP and ±dp/dtmax levels were obviously decreased in the model group (P<0.05). In comparison with the model group, MIRI-induced increases of LVEDP, TNF-α and IL-6 contents, and FXR, SHP and AIF mRNA expression and decreases of ±dp/dtmax and LVSP levels were reversed(P<0.05), except HSP70 mRNA expression with significantly increased (P<0.05) in the EA pretreatment group. CONCLUSION: EA pretreatment can protect the left ventricular function of the ischemic heart in MIRI rats, which may be related to its effects in reliving peripheral inflammation and regulating the expression levels of apoptosis-related factors FXR, SHP, AIF and HSP70 in the myocardium.
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Eletroacupuntura , Traumatismo por Reperfusão Miocárdica , Pontos de Acupuntura , Animais , Apoptose/genética , Masculino , Células Musculares , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/terapia , Ratos , Ratos WistarRESUMO
Inhibition of protein fibrillation process with nanomaterials is a promising strategy to combat neurodegenerative diseases. Copper-based nanomaterials have been seldom utilized in fibrillation inhibiting research due to Copper ions are generally considered as accelerators of fibrosis. Here, we proposed ultra-small Zn doped Cu2S (Zn:Cu2S) QDs as inhibitors of human insulin (HI) fibrosis. ThT, DLS, CD and TEM confirm that Zn:Cu2S QDs effectively inhibited insulin fibrosis in a dose-dependent manner with lag phase time extended (beyond 13-time by Zn:Cu2S QDs of 1 mg·mL-1), final fibril formation and the conversion from α-helix to ß-sheet reduced. Additionally, thermodynamics analyzed results reveal that the HI fluorescence quenching process is static quenching dominated, and the Zn:Cu2S QDs inhibit HI fibrosis mainly through specific electrostatic interaction with oligomers. The positively charged amino acid residues of oligomers bind to the negatively charged Zn:Cu2S QDs, which prevents the self-assembly of the oligomers from growing into mature fibers to enhance the stability of the protein. Unlike free Copper ions, the as-prepared QDs show an excellent inhibition in HI fibrillation, breaking through the bottleneck of copper-based materials in inhibiting protein fibrosis and providing a potential strategy to inhibit protein fibrosis in-situ by biosynthesizing copper-based fibrosis inhibitors.
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Insulina/química , Multimerização Proteica , Pontos Quânticos/química , Cobre/química , Humanos , Eletricidade Estática , Sulfetos/química , Zinco/químicaRESUMO
The ever-increasing space exploration enterprise calls for novel and high-quality radiation-resistant materials, among which nonlinear optical materials and devices are particularly scarce. Two-dimensional (2D) materials have shown promising potential, but the radiation effects on their nonlinear optical properties remain largely elusive. We previously fabricated 2D bismuthene for mode-locking sub-ns laser; herein, their space adaption was evaluated under a simulated space radiation environment. The as-synthesized thin layers of bismuthene exhibited strong third-order nonlinear optical responses extending into the near-infrared region. Remarkably, when exposed to 60Co γ-rays and electron irradiation, the bismuthene showed only slight degradation in saturable absorption behaviors that were critical for mode-locking in space. Ultrafast spectroscopy was applied to address the radiation effects and damage mechanisms that are difficult to understand by routine techniques. This work offers a new bottom-up approach for preparing 2D bismuthene, and the elucidation of its fundamental excited-state dynamics after radiation also provides a guideline to optimize the material for eventual space applications.
RESUMO
OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning on cell apoptosis and the content of mitochondrial reactive oxygen species (ROS) in rats with myocardial ischemia/reperfusion injury (MIRI), so as to explore their mechanisms underlying improvement of MIRI. METHODS: Eighty male Wistar rats were randomly divided into control, sham, ischemia reperfusion (IR) and EA groups, with 20 rats in each group. Rats of the control, sham and IR groups were just banded on the boards for 30 min, once daily for 7 days. Before modeling, EA (2 Hz, 1 mA) was applied to "Neiguan" (PC6), "Zusanli" (ST36), "Guanyuan"(CV4) for 20 min, once daily for 7 successive days in the EA group. The MIRI model was established by occlusion of the left anterior descending branch of the left coronary artery for 20 min, followed by reperfusion for 30 min. Ventricular arrhythmia (VA) score was used to evaluate arrhythmia. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of CK-MB. DHE staining was used to detect the content of reactive oxygen species (ROS). The gene expression levels of cytochrome C (Cyt-C), Caspase-9 and Caspase-3 were detected by real-time fluorescent quantitative PCR. RESULTS: Compared with the sham group, VA score, serum CK-MB content, ROS content in heart tissue and Cyt-C, Caspase-9 and Caspase-3 gene expression were significantly up-regulated in the MIRI group (all P<0.01). Following the intervention, the increased VA score, serum CK-MB content, ROS content in heart tissue, Cyt-C, Caspase-9 and Caspase-3 gene expression were all reversed in the EA group compared with the MIRI group (all P<0.01). CONCLUSION: The protective effect of EA preconditioning on MIRI may be based on the regulation of ROS mediated-apoptosis pathway.
Assuntos
Eletroacupuntura , Traumatismo por Reperfusão Miocárdica , Pontos de Acupuntura , Animais , Apoptose , Masculino , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/terapia , Ratos , Ratos Wistar , Espécies Reativas de OxigênioRESUMO
Amyloid fibrillation of protein is associated with a great variety of pathologic conditions. The aggregation of protein is a complicated process with multisteps, whereas most of the inhibitors with elaborately designed structures can show an inhibition effect only on the nucleation stages of protein fibrillation. Herein, oxidized carbon dots (CDs) were achieved to study the relationship between the surface properties of CDs and their inhibition effect on human insulin (HI) fibrillation. More oxygen-containing function groups can be obtained after oxidation reaction of CDs, such as -OH and -COOH. The results show that 10-1 CDs (the mass ratios of CD/KMnO4 is 10:1), with the highest carboxyl group content, possess the best inhibition ability. All the nucleation, growth, and final phases can be retarded by 10-1 CDs, which have been studied in detail by fluorescence spectra. However, CDs without oxidation can show only a weak inhibition effect on the nucleation stage. The 10-1 CDs is demonstrated to binding with HI monomers much stronger than that of CDs by isothermal titration calorimetry (ITC). Moreover, molecular dynamics simulations (MD) studies indicate that CDs with more carboxyl groups can show stronger affinities with native or unfolded HI monomers, which may be mainly derived from the active binding sites of histidine residues (His5 and His10) on B-chain through electrostatic interaction. Because the unfolding of B-chain in HI is prior to that of A-chain in our MD simulations, the later aggregation of HI can be inhibited effectively by the stronger binding forces between 10 and 1 CDs and the B-chain of HI.