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Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg-1 RNAi C. elegans or C. elegans with UPRmt-related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ-induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ-induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH-1, and serotonin synthesis and neurosecretion were required for PAE-mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ-related diseases including HD, which is dependent on autophagy and cell-non-autonomous UPRmt activation.
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Magnolol is a naturally occurring polyphenolic compound in many edible plants, which has various biological effects including anti-aging and alleviating neurodegenerative diseases. However, the underlying mechanism on longevity is uncertain. In this study, we investigated the effect of magnolol on the lifespan of Caenorhabditis elegans and explored the mechanism. The results showed that magnolol treatment significantly extended the lifespan of nematode and alleviated senescence-related decline in the nematode model. Meanwhile, magnolol enhanced stress resistance to heat shock, hydrogen peroxide (H2O2), mercuric potassium chloride (MeHgCl) and paraquat (PQ) in nematode. In addition, magnolol reduced reactive oxygen species and malondialdehyde (MDA) levels, and increased superoxide dismutase and catalase (CAT) activities in nematodes. Magnolol also up-regulated gene expression of sod-3, hsp16.2, ctl-3, daf-16, skn-1, hsf-1, sir2.1, etc., down-regulated gene expression of daf-2, and promoted intranuclear translocation of daf-16 in nematodes. The lifespan-extending effect of magnolol were reversed in insulin/IGF signaling (IIS) pathway-related mutant lines, including daf-2, age-1, daf-16, skn-1, hsf-1 and sir-2.1, suggesting that IIS signaling is involved in the modulation of longevity by magnolol. Furthermore, magnolol improved the age-related neurodegeneration in PD and AD C. elegans models. These results indicate that magnolol may enhance lifespan and health span through IIS and sir-2.1 pathways. Thus, the current findings implicate magnolol as a potential candidate to ameliorate the symptoms of aging.
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Compostos de Bifenilo , Proteínas de Caenorhabditis elegans , Lignanas , Longevidade , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Peróxido de Hidrogênio/metabolismo , Antioxidantes/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Insulina/metabolismo , Estresse Oxidativo , Fatores de Transcrição Forkhead/metabolismoRESUMO
Mulberrin, a naturally occurring flavone found in mulberry and Romulus Mori, exhibits diverse biological functions. Here, we showed that mulberrin extended both the lifespan and healthspan in C. elegans. Moreover, mulberrin increased the worms' resistance to toxicants and activated the expression of detoxification genes. The longevity-promoting effect of mulberrin was attenuated in nuclear hormone receptor (NHR) homologous nhr-8 and daf-12 mutants, indicating that the lifespan extending effects of mulberrin in C. elegans may depend on nuclear hormone receptors NHR-8/DAF-12. Further analyses revealed the potential associations between the longevity effects of mulberrin and the insulin/insulin-like growth factor signaling (IIS) and adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways. Together, our findings suggest that mulberrin may prolong lifespan and healthspan by activating detoxification functions mediated by nuclear receptors.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Longevidade , Receptores Citoplasmáticos e Nucleares , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Longevidade/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inativação Metabólica , Flavonas/farmacologia , Insulina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , MutaçãoRESUMO
Stress granules (SGs) are membraneless organelles formed by eukaryotic cells in response to stress to promote cell survival through their pleiotropic cytoprotective effects. SGs recruit a variety of components to enhance their physiological function, and play a critical role in the propagation of pathological proteins, a key factor in neurodegeneration. Recent advances indicate that SG dynamic disorders exacerbate neuronal susceptibility to stress in neurodegenerative diseases (NDs) including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) and Parkinson's disease (PD). Here, we outline the biological functions of SGs, highlight SG dynamic disorders in NDs, and emphasize therapeutic approaches for enhancing SG dynamics to provide new insights into ND intervention.
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Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis are leading causes of cirrhosis with rising morbidity and mortality worldwide. Currently, there is no appropriate treatment for NASH and hepatic fibrosis. Many studies have shown that oxidative stress is a main factor inducing NASH. Nomilin (NML) and obacunone (OBA) are limonoid compounds naturally occurring in citrus fruits with various biological properties. However, whether OBA and NML have beneficial effects on NASH remains unclear. Here, we demonstrated that OBA and NML inhibited hepatic tissue necrosis, inflammatory infiltration and liver fibrosis progression in methionine and choline-deficient (MCD) diet, carbon tetrachloride (CCl4 )-treated and bile duct ligation (BDL) NASH and hepatic fibrosis mouse models. Mechanistic studies showed that NML and OBA enhanced anti-oxidative effects, including reduction of malondialdehyde (MDA) level, increase of catalase (CAT) activity and the gene expression of glutathione S-transferases (GSTs) and Nrf2-keap1 signaling. Additional, NML and OBA inhibited the expression of inflammatory gene interleukin 6 (Il-6), and regulated the bile acid metabolism genes Cyp3a11, Cyp7a1, multidrug resistance-associated protein 3 (Mrp3). Overall, these findings indicate that NML and OBA may alleviate NASH and liver fibrosis in mice via enhancing antioxidant and anti-inflammation capacity. Our study proposed that NML and OBA may be potential strategies for NASH treatment.
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Limoninas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Antioxidantes/metabolismo , Limoninas/farmacologia , Limoninas/metabolismo , Limoninas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Estresse Oxidativo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismo , Metionina , Dieta , Camundongos Endogâmicos C57BL , FígadoRESUMO
Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals' lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.
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Proteínas de Caenorhabditis elegans , Longevidade , Masculino , Humanos , Animais , Camundongos , Longevidade/genética , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Receptor de Pregnano X , Fatores de Transcrição Forkhead , Mamíferos/metabolismoRESUMO
Strength is a crucial performance indicator for evaluating the durability of pervious concrete (PC). However, there are few models for estimating the remaining strength of in-service PC in sulfate and dry-wet cycle circumstances. Even though there are already direct detection methods for strength, nondestructive testing methods are still worth additional research. This paper aims to give a calculation model for the residual strength of PC under corrosion conditions based on ultrasonic methods, which is economical and convenient for engineering applications. The apparent morphological, compressive strength, and ultrasonic velocity of PC against sulfate and dry-wet cycle attack were examined. The results highlight that the primary cause of the macroscopic mechanical deterioration is the worsening in interface strength. Furthermore, the compressive strength and ultrasonic wave velocity of PC followed the same trends during sulfate and dry-wet cycles, increasing first and subsequently decreasing. Additionally, using the curve-fitting approach, an empirical model of strength deterioration based on ultrasonic velocity was developed and validated utilizing experimental data, demonstrating that the proposed model could more accurately define the strength progression. The results can provide an effective calculation method for monitoring the residual strength of PC pavement engineering in a corrosive environment.
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Sulfatos , Ultrassom , Ondas Ultrassônicas , Óxidos de Enxofre , Força CompressivaRESUMO
Hepatic fibrosis is a late stage process of many chronic liver diseases. Blocking the fibrosis process will be beneficial to the treatment and recovery of the diseases. Mangiferin has many pharmacological activities. Recently, it has been reported that mangiferin may relieve tissue fibrosis, including renal, myocardial, pulmonary fibrosis via anti-inflammatory and anti-oxidative effects in animal models. Here, we investigate the effects of mangiferin on CCl4-induced liver fibrosis and the underlying mechanism in mice. Thirty-two male C57BL/6 mice were randomly divided into 4 groups (n = 8 in each group), injected with carbon tetrachloride (10% CCl4) for 8 weeks, and oral administrated with mangiferin (50 mg/kg or 100 mg/kg) from the fifth week. The serum levels of ALT, AST were analyzed to evaluate liver function. H&E, Masson's trichrome and Sirius red staining were used to assess liver morphology and the degree of liver fibrosis. Quantitative RT-PCR and Western blot were used to assay the gene expression and protein levels. The results showed that mangiferin alleviated the serum levels of AST, ALT, ALP, TBA and TBIL, reduced liver lesions, prevented hepatic parenchymal necrosis, and ameliorated collagen accumulation in the liver of CCl4-treated mice. Meanwhile, mangiferin inhibited the expression of inflammatory genes IL-6 and IL-1ß, fibrogenic genes α-SMA, TGF-ß and MMP-2 and bile acid metabolism genes ABCB4, ABCB11, SULT2A1 in the liver of CCl4-treated mice. Furthermore, mangiferin reduced collagen accumulation and HSCs activation, inhibited the p-IκB and p-p65 protein levels. Our results suggest that mangiferin could alleviate liver fibrosis in CCl4-treated mice through inhibiting NF-κB signaling, and mango consuming may have beneficial effects to hepatic fibrosis.
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Cirrose Hepática , Fígado , Camundongos , Masculino , Animais , Camundongos Endogâmicos C57BL , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Fígado/patologia , Fibrose , Tetracloreto de Carbono/toxicidade , Colágeno/farmacologiaRESUMO
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the striatum, leading to dopamine (DA) deficiency in the striatum and typical motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine (HOR) is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer, a widely consumed beverage. This study was aimed to identify HOR as a dopamine D2 receptor (DRD2) agonist in living cells, and investigate the alleviative effect and mechanism of HOR on PD-like motor deficits in mice and nematodes. Our results firstly showed that HOR is an agonist of DRD2, but not DRD1, in living cells. Moreover, HOR could improve the locomotor dysfunction, gait, and postural imbalance in MPTP- or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway in C. elegans. Our results suggested that HOR could activate DRD2 to attenuate the PD-like motor deficits, and provide scientific evidence for the safety and reliability of HOR as a dietary supplement.
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Doenças Neurodegenerativas , Doença de Parkinson , Camundongos , Animais , Dopamina/metabolismo , Caenorhabditis elegans/metabolismo , Reprodutibilidade dos Testes , Doença de Parkinson/tratamento farmacológico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Neurônios Dopaminérgicos , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Natural dual farnesyl X receptor (FXR)/G protein-coupled bile acid receptor 1 (TGR5) activators have received little attention in the management of metabolic diseases. Deoxyschizandrin (DS), a natural lignan, occurs in S. chinensis fruit and has potent hepatoprotective effects, whereas its protective roles and mechanisms against obesity and non-alcoholic fatty liver disease (NAFLD) are largely elusive. Here, we identified DS as a dual FXR/TGR5 agonist using luciferase reporter and cyclic adenosine monophosphate (cAMP) assays. DS was orally or intracerebroventricularly administrated to high-fat diet-induced obesity (DIO) mice, and methionine and choline-deficient L-amino acid diet (MCD diet)-induced non-alcoholic steatohepatitis to evaluate its protective effects. Exogenous leptin treatment was employed to investigate the sensitization effect of DS on leptin. The molecular mechanism of DS was explored by Western blot, quantitative real-time PCR analysis, and ELISA. The results showed that DS activated FXR/TGR5 signaling and effectively reduced NAFLD in DIO and MCD diet-fed mice. DS countered obesity in DIO mice by promoting anorexia and energy expenditure and reversing leptin resistance, involving both peripheral and central TGR5 activation and leptin sensitization. Our findings indicate that DS may be a novel therapeutic approach for alleviating obesity and NAFLD through regulating FXR and TGR5 activities and leptin signaling.
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Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Leptina/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ácidos e Sais Biliares/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/farmacologia , Proteínas de Ligação ao GTP/uso terapêutico , Camundongos Endogâmicos C57BL , FígadoRESUMO
The Yellow River Basin is an energy-rich area. The low-carbon development of the Yellow River Basin is one of the ways to achieve ecological protection and high-quality development. Based on panel data from 2007 to 2019, the dynamic and static carbon emission efficiencies of 98 cities in the Yellow River Basin were calculated using the Undesirable Super Slacks-based model and the Global Malmquist-Luengerber index method, respectively, and the spatial effects of influencing factors were analyzed using the spatial Dubin model. Main conclusions are as follows: (1) The carbon emission efficiency of cities in the Yellow River Basin is different, and only a small numbers of cities have reached the effective state. (2) The main factor for the increase in the overall carbon emission efficiency of the whole Basin is technological progress, and the main factors for the improvement of carbon emission efficiency of different cities are various. (3) The direct effects of economic development level and industrial structure upgrading are significantly positive, the direct effects of technological development level, energy intensity, and opening up are significantly negative, and the indirect effects of population density are positive. The conclusions are of great significance for promoting low-carbon development, ecological protection and high-quality development in the Yellow River Basin.
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Carbono , Rios , Cidades , Desenvolvimento Econômico , Indústrias , China , EficiênciaRESUMO
BACKGROUND: Motor symptoms of Parkinson's disease (PD) are characterized by bradykinesia, resting tremor, rigidity, slow movement, impaired gait and postural instability, resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Atractylon is a natural furan compound in Atractylodes rhizomes, exhibiting anticancer, anti-inflammation, antiviral and gastroprotective activities, and so on. However, it is still unknown whether atractylon is beneficial to motor dysfunctions of PD. METHODS: GPCR-targeted piggyBac-TANGO compound screening system, cAMP assay, and immunostaining of p-CREB and BDNF were used to identify dopamine 2 receptor (DRD2) activation. The effects of atractylon on motor deficits and gait disturbances, as well as tyrosine hydroxylase (TH) in the SNpc were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. RESULTS: Atractylon treatment increased the eGFP expression in dose-dependent manner in piggyBac-TANGO assay, decreased cAMP production, and enhanced the levels of p-CREB and BDNF in DRD2 highly expresseding SY-SY5Y cells. In MPTP-induced mice, atractylon improved the slow movement, diminished voluntary locomotion, and abnormal gait parameters, such as duration, cadence, average speed, step cycle, stride length, and so on. Moreover, atractylon rescued the TH positive cells in SNpc and TH positive nerve fibers in striatum. CONCLUSIONS: Atractylon could effectively activate DRD2, attenuate motor deficits and gait disorders, and protect dopaminergic neurons in MPTP-induced PD mice. Our findings stretch out the therapeutic potential of atractylon for motor symptoms of PD.
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Agonistas de Dopamina , Transtornos Parkinsonianos , Sesquiterpenos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Corpo Estriado , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Sesquiterpenos/farmacologia , Substância Negra , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Small GTPase Rab8a is involved in fat-specific protein 27 (Fsp27) mediated lipid droplet accumulation in adipocytes. By screening inhibitors of Rab8a GTPase from a natural compound library, berbamine (BBM), a marketing drug for treatment of leukopenia in China, was identified to inhibit the activity of Rab8a GTPase and block the differentiation of 3T3-L1 adipocytes. Animal study showed that BBM could reduce body weight, improved glucose and lipid metabolic homeostasis in high-fat diet-induced obesity (DIO) C57BL/6 mice and db/db mice. Additional, BBM increased energy expenditure and inhibited food intake in mice but not in lean mice. Moreover, intracerebroventricular injection (i.c.v.) of BBM inhibited feeding behavior and increased c-Fos expression in paraventricular nucleus of the hypothalamus (PVH) of mice. Our data suggest that BBM may improve obesity through the inhibition of Rab8a GTPase activity and the activation of anorexigenic energy-sensing neuron in PVH.
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Hipotálamo , Núcleo Hipotalâmico Paraventricular , Animais , Benzilisoquinolinas , Peso Corporal , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Nomilin is one of the major limonoids, which are plant secondary metabolites also known as tetranortriterpenoids. Nomilin is found mostly in common edible citrus fruits including lemons, limes, oranges, grapefruits, mandarins, along with traditional Chinese medicines derived from citrus fruits, such as tangerine seed, tangerine peel, fructus aurantii immaturus, etc. A number of studies have demonstrated that nomilin and its analogues exhibit a variety of biological and pharmacological activities. These include anti-cancer, immune-modulatory, anti-inflammatory, anti-obesity, anti-viral, anti-osteoclastogenic, anti-oxidant, and neuro-protective effects. Thus, nomilin and its analogues have emerged as a potential therapy for human diseases. The purpose of this review is to chronicle the evolution of nomilin research from examining its history, structure, occurrence, to its pharmacological and disease-preventing properties as well as its potential utilization in medicine and food science.
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Benzoxepinas , Citrus , Limoninas , Humanos , Limoninas/química , Citrus/química , Frutas/metabolismo , Benzoxepinas/farmacologia , Benzoxepinas/metabolismoRESUMO
Tangeretin is a polymethoxylated flavonoid naturally occurred in citrus fruits with many pharmacological activities, such as anti-inflammatory, antiproliferative, and neuroprotective properties. A previous study reported that tangeretin-enriched orange extract could prolong the lifespan in Caenorhabditis elegans. However, the antiaging effect of tangeretin remains uncertain. In this study, we used the model organism C. elegans to conduct a lifespan test, observed the aging-related functional changes of nematodes, the fluorescence changes of stress-related proteins (DAF-16 and HSP-16.2) and its response to stress assay, and monitored the effect of tangeretin on the mRNA expression levels. The results showed that tangeretin supplementation (30 and 100 µM) extended the mean lifespan, slowed aging-related functional declines, and increased the resistance against heat-shock stress. Furthermore, tangeretin upregulated the mRNA expression of daf-16, hsp-16.2, and hsp-16.49, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2, while it had no effect on the lifespan of daf-2, age-1, and daf-16 mutants. The current findings suggest that tangeretin can significantly extend the lifespan and enhance heat stress tolerance in an insulin/insulin-like growth factor signaling dependent manner.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Flavonas , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Longevidade/genética , Transdução de SinaisRESUMO
Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc) are selectively activated in T1D. Activation of LepRArc neurons, Arc GABAergic (GABAArc) neurons, or arcuate AgRP neurons, is able to reverse the leptin's rescuing effect. Conversely, inhibition of GABAArc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin's rescuing effects. Finally, T1D LepRArc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepRArc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepRArc neurons through reversing energy deprivation.
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Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hiperglicemia/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Receptores para Leptina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Glicemia/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/sangue , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Infusões Intraventriculares , Leptina/administração & dosagem , Masculino , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Receptores para Leptina/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Ubiquitin-specific peptidase (USP)18 belongs to the USP family, and is involved in cleaving and removing ubiquitin or ubiquitin-like molecules from their target molecules. Recently, increasing evidence has suggested that USP18 is constitutively expressed in different types of human tumors, and ectopic expression or downregulation of USP18 expression may contribute to tumorigenesis. However, the role of USP18 in uterine cervical cancer (UCC) remains unclear. Thus, the present study aimed to investigate USP18 expression in a human tissue microarray constructed using UCC and non-cancer cervical tissues, and to determine the potential role and molecular mechanism by which USP18 is implicated in the tumor biology of human UCC HeLa cells. Microarray analysis demonstrated that USP18 protein expression was downregulated in tumor tissues compared with in normal tissues. In addition, in vitro analysis revealed that USP18-knockdown markedly promoted the proliferation, colony formation, migration and aggressiveness of HeLa cells. Mechanistic analysis demonstrated that USP18-knockdown increased the levels of Bcl-2, STAT3 and phosphorylated-ERK in HeLa cells. Notably, USP18 silencing-induced malignant phenotypes were interrupted following exogenous administration of the ERK1/2 inhibitor PD98059. Overall, the results of the present study suggested that USP18 may be a potent inhibitor involved in UCC tumor-associated biological behaviors, which are associated with the ERK signaling pathway.
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Farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has emerged as a potential therapy for nonalcoholic fatty liver disease (NAFLD). However, the side effects of OCA may limit its application in clinics. We identified previously that isotschimgine (ITG) is a non-steroidal FXR selective agonist and has potent therapeutic effects on NAFLD in mice. Here, we aimed to evaluate the therapeutic effects of ITG on nonalcoholic steatohepatitis (NASH) and fibrosis in mice. We used methionine and choline deficient (MCD) diet-induced NASH mice, bile duct ligation (BDL), and carbon tetrachloride (CCl4 )-treated hepatic fibrosis mice to investigate the effects of ITG on NASH, fibrosis, and cholestatic liver injury. Our results showed that ITG improved steatosis and inflammation in the liver of MCD diet-fed mice, as well as alleviated fibrosis and inflammation in the liver of CCl4 -treated mice. Furthermore, ITG attenuated serum bile acid levels, and reduced vacuolization, inflammatory infiltration, hepatic parenchymal necrosis, and collagen accumulation in the liver of BDL mice. Mechanistically, ITG increased the expression of FXR target genes. These data suggest that ITG is an FXR agonist and may be developed as a novel therapy for NASH, hepatic fibrosis, or primary biliary cholangitis.
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Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Éteres Fenílicos/farmacologia , Animais , Tetracloreto de Carbono , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Dieta , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver and associates with obesity, hyperlipidemia, and insulin resistance. NAFLD could lead to nonalcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and even cancers. The development of therapy for NAFLD has been proven difficult. Emerging evidence suggests that liver X receptor (LXR) antagonist is a potential treatment for fatty liver disease. However, concerns about the cholesterol-increasing effects make it questionable for the development of LXR antagonists. Here, the overweight monkeys were fed with LXRß-selective antagonist sophoricoside or LXRα/ß dual-antagonist morin for 3 months. The morphology of punctured liver tissues was examined by H&E staining. The liver, heart, and kidney damage indices were analyzed using plasma. The blood index was assayed using complete blood samples. We show that LXRß-selective antagonist sophoricoside and LXRα/ß dual-antagonist morin alleviated lipid accumulation in the liver in overweight monkeys. The compounds resulted in higher plasma TC or LDL-c contents, increased white blood cell and lymphocyte count, and decreased neutrophile granulocyte count in the monkeys. The compounds did not alter plasma glucose, apolipoprotein A (ApoA), ApoB, ApoE, lipoprotein (a) (LPA), nonesterified fatty acid (NEFA), aspartate transaminases (AST), creatinine (CREA), urea nitrogen (UN), and creatine kinase (CK) levels. Our data suggest that LXRß-selective and LXRα/ß dual antagonism may lead to hypercholesterolemia in nonhuman primates, which calls into question the development of LXR antagonist as a therapy for NAFLD.
Assuntos
Benzopiranos/farmacologia , Colesterol/metabolismo , Flavonoides/farmacologia , Receptores X do Fígado/antagonistas & inibidores , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Benzopiranos/administração & dosagem , Benzopiranos/química , Colesterol/sangue , Feminino , Flavonoides/administração & dosagem , Flavonoides/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Macaca mulatta , Masculino , Estrutura Molecular , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/químicaRESUMO
Owing to their high performance and earth abundance, copper sulfides (Cu2-x S) have attracted wide attention as a promising medium-temperature thermoelectric material. Nanostructure and grain-boundary engineering are explored to tune the electrical transport and phonon scattering of Cu2-x S based on the liquid-like copper ion. Here multiscale architecture-engineered Cu2-x S are fabricated by a room-temperature wet chemical synthesis combining mechanical mixing and spark plasma sintering. The observed electrical conductivity in the multiscale architecture-engineered Cu2-x S is four times as much as that of the Cu2-x S sample at 800 K, which is attributed to the potential energy filtering effect at the new grain boundaries. Moreover, the multiscale architecture in the sintered Cu2-x S increases phonon scattering and results in a reduced lattice thermal conductivity of 0.2 W·m-1·K-1 and figure of merit (zT) of 1.0 at 800 K. Such a zT value is one of the record values in copper sulfide produced by chemical synthesis. These results suggest that the introduction of nanostructure and formation of new interface are effective strategies for the enhancement of thermoelectric material properties. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s12598-020-01698-6) contains supplementary material, which is available to authorized users.