RESUMO
Endometrial cancer (EC) is a common gynecological malignancy, and advanced-stage or recurrent EC is associated with a high mortality rate owing to the ineffectiveness of currently available treatments. FK506-binding protein 38 (FKBP38) is a member of the immunophilin family and inhibits melanoma and breast cancer cell metastasis. However, the functions of FKBP38 and its potential mechanism in EC remain unclear. Herein, we analyzed the expression levels of FKBP38 in EC cells and found that the FKBP38 expression was high in Ishikawa cells, and low in AN3CA cells, traditionally considered a low grade and a high grade cell line, respectively, in pathology classification. Moreover, FKBP38 inhibited cell proliferation, migration and invasion in EC cells, FKBP38 knockdown significantly promoted tumor growth of Ishikawa cells in a subcutaneous xenograft model and increased the number of lung metastases of Hec-1-A cells in a metastatic mouse model. Furthermore, FKBP38 suppressed several target proteins of epithelial-to-mesenchymal transition (EMT) and reduced the phosphorylation of ribosomal S6 protein (S6), eukaryotic initiation factor 4E-binding protein 1 (4EBP-1), indicating the potent inhibition of the mammalian target of rapamycin (mTOR) pathway. Meanwhile, the inhibition of mTOR neutralized the elevation of EC cell proliferation, migration and invasion after FKBP38 knockdown. In summary, FKBP38 would exert a tumor-suppressing role by modulating the mTOR pathway. Our results indicate that FKBP38 may be considered as a factor of EC metastasis and a new target for EC therapeutic intervention.
Assuntos
Neoplasias do Endométrio , Proteínas de Ligação a Tacrolimo , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Endométrio/metabolismo , Mamíferos/metabolismo , Transdução de Sinais/fisiologia , Proteínas de Ligação a Tacrolimo/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Obesity is one of the major risk factors for cancer. Clinical studies have demonstrated that circulating levels of adiponectin are inversely correlated, not only with the extent of adiposity, but also with the incidence of several types of cancer, particularly endometrial cancer (EC). However, thus far, adiponectin remains a correlative factor, without definitive evidence to show a causal effect in EC and the potential mechanism(s) involved. To address this issue, we introduced an Apn-null mutation into Pten haploid-deficient (Pten+/- ) mice. The Pten heterozygous mutation alone led to the development of EC in less than 30% of female mice; however, when combined with the Apn-null mutation, the incidence of endometrial lesions rose to at least two-thirds. Although Apn deficiency did not further potentiate the Akt activation caused by the Pten mutation, it elevated the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44, indicating activation of the MAPK signaling pathway. Treatment of Apn-/- ;Pten+/- mice with a MEK inhibitor blocked the development of EC. Finally, xenografts of a PTEN-proficient human EC cell line grew faster in Apn-deficient mice, whereas an adiponectin receptor agonist reduced xenograft growth of a PTEN-deficient human EC cell line. Thus, reduction of adiponectin activity promotes EC development, at least in the context of Pten mutation, by activating MAPK. © 2022 The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias do Endométrio , Erros Inatos do Metabolismo , Adiponectina/deficiência , Adiponectina/genética , Adiponectina/farmacologia , Animais , Neoplasias do Endométrio/patologia , Feminino , Humanos , Camundongos , Proteínas Quinases Ativadas por Mitógeno , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Obesity contributes to the progression of various chronic diseases, and shortens life expectancy. With abundant mitochondria, brown adipose tissue (BAT) dissipates energy through heat to limit weight gain and metabolic dysfunction in obesity. Our previous studies have shown that aurantio-obtusin (AO), a bioactive ingredient in Chinese traditional medicine Cassiae semen significantly improves hepatic lipid metabolism in a steatotic mouse model. In the current study we investigated the effects of AO on lipid metabolism in the BAT of diet-induced obesity mice and in oleic acid and palmitic acid (OAPA)-stimulated primary mature BAT adipocytes. Obese mice were established by feeding a HFHS diet for 4 weeks, and then administered AO (10 mg/kg, i.g.) for another 4 weeks. We showed that AO administration significantly increased the weight of BAT and accelerated energy expenditure to protect the weight increase in the obese mice. Using RNA sequencing and molecular biology analysis we found that AO significantly enhanced mitochondrial metabolism and UCP1 expression by activating PPARα both in vivo and in vitro in the primary BAT adipocytes. Interestingly, AO administration did not improve metabolic dysfunction in the liver and white adipose tissue of obese mice after interscapular BAT excision. We demonstrated that low temperature, a trigger of BAT thermogenesis, was not a decisive factor for AO to stimulate the growth and activation of BATs. This study uncovers a regulatory network of AO in activating BAT-dependent lipid consumption and brings up a new avenue for the pharmaceutical intervention in obesity and related comorbidities.
Assuntos
Tecido Adiposo Marrom , PPAR alfa , Camundongos , Animais , Tecido Adiposo Marrom/metabolismo , PPAR alfa/metabolismo , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Mitocôndrias/metabolismo , Metabolismo Energético , Tecido Adiposo Branco/metabolismo , Termogênese , Camundongos Endogâmicos C57BLRESUMO
This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose-dependently inhibited the expression of ECM-related proteins induced by transforming growth factor ß1 (TGF-ß1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-ß signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.
Assuntos
Nefropatias , Inibidores da Fosfodiesterase 5 , Animais , Humanos , Masculino , Camundongos , Ratos , Proteínas da Matriz Extracelular , Fibrose , Rim , Inibidor 1 de Ativador de PlasminogênioRESUMO
BACKGROUND: Adiponectin is an adipocyte-secreted cytokine that enhances insulin sensitivity and attenuates inflammation. Although circulating adiponectin level is often inversely associated with several malignancies, its role in the development of nasopharyngeal carcinoma (NPC) remains unclear. Here, we investigated the clinical association between circulating adiponectin level and NPC, and examined the impact of adiponectin, as well as the underlying mechanisms, on NPC growth both in vitro and in vivo. METHODS: The association between circulating adiponectin level and the risk of developing NPC was assessed in two different cohorts, including a hospital-based case-control study with 152 cases and 132 controls, and a nested case-control study with 71 cases and 142 controls within a community-based NPC screening cohort. Tumor xenograft model, cell proliferation and cycle assays were applied to confirm the effects of adiponectin on NPC growth in cultured cells and in xenograft models. We also investigated the underlying signaling mechanisms with various specific pharmacological inhibitors and biochemistry analysis. RESULTS: High adiponectin levels were associated with a monotonic decreased trend of NPC risk among males in both the hospital-based case-control study and a nested case-control study. In vitro, recombinant human full-length adiponectin significantly inhibited NPC cell growth and arrested cell cycle, which were dependent on AMPK signaling pathway. The growth of xenograft of NPC tumor was sharply accelerated in the nude mice carrying genetic adiponectin deficiency. An adiponectin receptor agonist, AdipoRon, displayed strong anti-tumor activity in human xenograft models. CONCLUSIONS: These findings demonstrated for the first time that circulating adiponectin is not only inversely associated with NPC, but also controls the development of NPC via AMPK signaling pathway. Stimulation of adiponectin function may become a novel therapeutic modality for NPC.
Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias Nasofaríngeas , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Animais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. A new approach to treating TNBC is required to improve patient survival. Phosphodiesterase-4 (PDE4) is an enzyme that is predominantly involved in the modulation of intracellular signaling mediated by cAMP. Although the efficacy of PDE4 inhibitors in several human inflammatory diseases is well documented, their clinical utility has been limited by side effects, including nausea and emesis. Recently, PDE4 has been used as a potential therapeutic target for different cancer types. In the present study, we investigated the anticancer effects of a novel PDE4 inhibitor ZL-n-91 on TNBC and the underlying mechanism. We showed that ZL-n-91 inhibited the proliferation of TNBC cells, induced cell apoptosis, and caused cell cycle arrest. Western blot analysis showed that ZL-n-91 increased Bax level and reduced Bcl-2 expression. Furthermore, downregulation of the cell cycle-related proteins, such as CDK2, CDK4, cyclin D1, PCNA, p-RB, and ZL-n-91, significantly inhibited the transcription of DNA repair genes and triggered an intracellular DNA damage response. Moreover, ZL-n-91 prevented the growth of the transplanted MDA-MB-231 tumor xenograft in nude mice and increased the γ-H2AX expression. These data demonstrate the anticancer effects of ZL-n-91 on TNBC cells and suggest its potential use in anticancer therapy.
Assuntos
Inibidores da Fosfodiesterase 4 , Neoplasias de Mama Triplo Negativas , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Isofraxidin is a coumarin compound mainly isolated from several traditional and functional edible plants beneficial for neurodegenerative diseases, including Sarcandra glabra and Apium graveolens, and Siberian Ginseng. OBJECTIVE: This study aimed to assess effects of isofraxidin against memory impairments and cognition deficits in a scopolamine-induced mouse model. MATERIALS & METHODS: Animals were randomly divided into 6 groups, control, vehicle, donepezil (10 mg/kg, p.o.), and isofraxidin (3, 10, and 30 mg/kg, p.o.). Isofraxidin or donepezil was administered for 44 days, once per day. The scopolamine insults (1 mg/kg, i.p.) was given from the 21st day, once per day. Morris water maze test and Y-maze test were used for the behavioral test. After that, brain samples were collected for analysis. RESULTS: Firstly, isofraxidin significantly improved scopolamine-induced behavioral impairments and cognition deficits in Morris water maze and Y-maze test. Then, isofraxidin facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, isofraxidin decreased lipid peroxidation level but enhanced levels of glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, isofraxidin suppressed the expression of inflammatory mediators and cytokines. Further investigations showed that isofraxidin up-regulated expression of brain-derived neurotrophic factor (BDNF), and promoted phosphorylation of tropomyosin-related kinase B (TrkB), cyclic AMP-response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). DISCUSSION & CONCLUSIONS: These results suggested that isofraxidin ameliorated scopolamine-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress and inflammatory response, and modulating BDNF-CREB-ERK pathways.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Escopolamina , Animais , Camundongos , Escopolamina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Acetilcolinesterase/metabolismo , Donepezila/farmacologia , Donepezila/uso terapêutico , Memória , Hipocampo/metabolismo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Aprendizagem em Labirinto , Transdução de Sinais , CogniçãoRESUMO
Autophagy is essential for the maintenance of hepatic homeostasis, and autophagic malfunction has been linked to the pathogenesis of substantial liver diseases. As a popular source of drug discovery, natural products have been used for centuries to effectively prevent the progression of various liver diseases. Emerging evidence has suggested that autophagy regulation is a critical mechanism underlying the therapeutic effects of these natural products. In this review, relevant studies are retrieved from scientific databases published between 2011 and 2022, and a novel scoring system was established to critically evaluate the completeness and scientific significance of the reviewed literature. We observed that numerous natural products were suggested to regulate autophagic flux. Depending on the therapeutic or pathogenic role autophagy plays in different liver diseases, autophagy-regulative natural products exhibit different therapeutic effects. According to our novel scoring system, in a considerable amount of the involved studies, convincing and reasonable evidence to elucidate the regulatory effects and underlying mechanisms of natural-product-mediated autophagy regulation was missing and needed further illustration. We highlight that autophagy-regulative natural products are valuable drug candidates with promising prospects for the treatment of liver diseases and deserve more attention in the future.
Assuntos
Produtos Biológicos , Hepatopatias , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Autofagia , Hepatopatias/tratamento farmacológico , Fígado , Descoberta de DrogasRESUMO
Adiponectin is an adipocytokine with anti-inflammatory and anticancer properties. Our previous study has shown that blood adiponectin levels were inversely correlated to the risk of nasopharyngeal carcinoma (NPC), and that adiponectin could directly suppress the proliferation of NPC cells. However, the effect of adiponectin on NPC metastasis remains unknown. Here, we revealed in clinical studies that serum adiponectin level was inversely correlated with tumor stage, recurrence, and metastasis in NPC patients, and that low serum adiponectin level also correlates with poor metastasis-free survival. Coculture with recombinant adiponectin suppressed the migration and invasion of NPC cells as well as epithelial-mesenchymal transition (EMT). In addition, recombinant adiponectin dampened the activation of NF-κB and STAT3 signaling pathways induced by adipocyte-derived proinflammatory factors such as leptin, IL-6, and TNF-α. Pharmacological activation of adiponectin receptor through its specific agonist, AdipoRon, largely stalled the metastasis of NPC cells. Taken together, these findings demonstrated that adiponectin could not only regulate metabolism and inhibit cancer growth, but also suppress the metastasis of NPC. Pharmacological activation of adiponectin receptor may be a promising therapeutic strategy to stall NPC metastasis and extend patients' survival.
Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/patologia , Adiponectina/metabolismo , Receptores de Adiponectina/metabolismo , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismoRESUMO
Applying pesticides can result in emissions of volatile organic compounds (VOCs), but little is known about VOC emission characteristics and the quantities in particular regions. We investigated the use of pesticides in China based on a large-scale survey of 330 counties in 31 provinces and evaluated the national pesticide VOC emission potentials based on thermogravimetric analysis of 1930 commercial pesticides. The results showed that herbicides were the most extensively used pesticide category in China, accounting for 43.47%; emulsifiable concentrate (EC), suspension concentrate, and wettable powder were the dominant pesticide formulations, with proportions of 26.75%, 17.68%, and 17.31%, respectively. The VOC emission potential coefficient (EP) of the liquid formulations was higher than the solid formulations, and the maximum mean EP was 45.59% for EC and the minimum was 0.76% for WP. Among 437 high-VOC pesticide products used in China, EC accounted for 83.52%, and 16.93% of those contained abamectin. The total VOC emissions derived from commercial pesticides in China were 280 kt (kilotons) in 2018, and 65.35% of the contribution was derived from EC. Shandong, Hunan, and Henan were the three provinces with the highest pesticide VOC emissions (>21 kt/y). The emission rate of VOCs from pesticides was 24.80 t/d in China, which was higher than in San Joaquin Valley, California. These findings suggest that some comprehensive measures (e.g., perfecting pesticide management policy, strict supervision for pesticide production and use, and strengthening pesticide reduction publicity) should be taken to reduce VOC emissions from pesticide applications.
Assuntos
Poluentes Atmosféricos , Ozônio , Praguicidas , Compostos Orgânicos Voláteis , Poluentes Atmosféricos/análise , China , Monitoramento Ambiental , Ozônio/análise , Compostos Orgânicos Voláteis/análiseRESUMO
AIMS/HYPOTHESIS: Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. METHODS: Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. RESULTS: CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism. CONCLUSIONS/INTERPRETATION: This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin's central effect and hypothalamic signalling.
Assuntos
Proteína C-Reativa/genética , Resistência à Doença/genética , Resistência à Insulina/genética , Obesidade/genética , Animais , Peso Corporal/genética , Dieta Hiperlipídica , Metabolismo Energético/genética , Técnicas de Inativação de Genes , Masculino , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos TransgênicosRESUMO
Proteins from food-grade expression systems can be used in food products and medical applications. Herein, we describe a one-step method of constructing an expression vector in Kluyveromyces lactis by combining a URA3-deficient strain and a plasmid vector with no drug-resistant selection. Adjacent DNA elements of the vector were assembled in a targeted manner through a reaction with a special recombinase to form a plasmid vector using a one-step reaction. The unnecessary fragments containing the pUC origin and the ampicillin resistance gene were removed, and the vector was isolated and purified before transformation. A single transformation of the vector can produce a URA3-deficient strain. PCR assay, sequencing, and western blot analysis all indicated that the method of vector construction and target protein expression (mCherry and human serum albumin) were successful. This method may potentially be applied to any species containing the URA3 gene; this system has the potential to become a safe and powerful tool for promoting protein expression in food-safe species.
Assuntos
Kluyveromyces , Vetores Genéticos/genética , Humanos , Kluyveromyces/genética , Plasmídeos/genética , Transformação GenéticaRESUMO
NEW FINDINGS: What is the central question of this study? What is the protective benefit of n-3 polyunsaturated fatty acids (PUFAs) on liver fibrosis and what are the relevant signalling pathways in a transgenic mouse model overexpressing the mfat-1 enzyme? What is the main finding and its importance? n-3 PUFA elevation strongly prevented carbon tetrachloride (CCl4 )-induced hepatic damage and inhibited the activation of hepatic stellate cells. n-3 PUFAs suppressed CCl4 -induced activation of mTOR, elevated Bcl-2 expression, and reduced Bax level, suggesting that n-3 PUFAs can render strong protective effects against liver fibrosis and point to the potential of mfat-1 gene therapy as a treatment modality. ABSTRACT: Liver fibrosis is a reversible wound healing response with excessive accumulation of extracellular matrix proteins. It is a globally prevalent disease with ultimately severe pathological consequences. However, very few current clinical therapeutic options are available. Nutritional addition of n-3 polyunsaturated fatty acids (PUFAs) can delay and lessen the development of liver fibrosis. Herein, this study examined the protective benefit of n-3 PUFAs on liver fibrosis and the relevant signalling pathways using a transgenic mouse model overexpressing the mfat-1 enzyme that converts n-6 to n-3 PUFAs. Male C57BL/6 wild-type and mfat-1 transgenic mice were administered carbon tetrachloride (CCl4 ) or control corn oil by intraperitoneal injection. Blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were subsequently measured. CCl4 -induced hepatic damage and fibrosis were assessed using haematoxylin-eosin and Masson's trichrome staining. Western blot assays were used to detect and quantify fibrosis-related proteins and mechanistic target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) signalling components. The direct effect of docosahexaenoic acid (DHA) on primary hepatic stellate cells (HSCs) was also investigated in a co-culture experiment. n-3 PUFAs, as a result of mfat-1 activity, had a strong protective effect on liver fibrosis. The elevation of ALT and AST induced by CCl4 was significantly lessened in the mfat-1 mice. Histological determination revealed the protective effects of n-3 PUFAs on liver inflammation and collagen deposition. Co-incubation with DHA reduced the expression of profibrogenic factors in the primary HSCs. Moreover, mfat-1 transgenic mice showed significant reduction of proteins that are involved in mTOR and Bcl-2/Bax signalling pathways. Collectively, these results suggest that n-3 PUFA elevation strongly prevents CCl4 -induced hepatic damage by directly inhibiting the activation of HSCs and regulating the basal activity of the mTOR and Bcl-2/Bax signalling pathways. Gene therapy applying mfat-1 and elevating n-3 PUFAs represents a promising treatment strategy to prevent liver fibrosis.
Assuntos
Tetracloreto de Carbono , Ácidos Graxos Ômega-3 , Animais , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
The modulation of attentional load on the perception of auditory and visual information has been widely reported; however, whether attentional load alters audiovisual integration (AVI) has seldom been investigated. Here, to explore the effect of sustained auditory attentional load on AVI and the effects of aging, nineteen older and 20 younger adults performed an AV discrimination task with a rapid serial auditory presentation task competing for attentional resources. The results showed that responses to audiovisual stimuli were significantly faster than those to auditory and visual stimuli (AV > V ≥ A, all p < 0.001), and the younger adults were significantly faster than the older adults under all attentional load conditions (all p < 0.001). The analysis of the race model showed that AVI was decreased and delayed with the addition of auditory sustained attention (no_load > load_1 > load_2 > load_3 > load_4) for both older and younger adults. In addition, AVI was lower and more delayed in older adults than in younger adults in all attentional load conditions. These results suggested that auditory sustained attentional load decreased AVI and that AVI was reduced in older adults.
Assuntos
Atenção/fisiologia , Percepção Auditiva/fisiologia , Percepção Visual/fisiologia , Idoso , Envelhecimento/fisiologia , Discriminação Psicológica , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação/fisiologia , Adulto JovemRESUMO
Epithelial-to-mesenchymal transition (EMT) is postulated to be a prerequisite for the establishment of endometriosis (EMS), a common reproductive disorder in women. Our previous studies have demonstrated the elevated expression of transmembrane glycoprotein CD147 and its prosurvival effect on abnormal cells in endometriosis. Intriguingly, CD147 is known to promote EMT in cancers. However, the involvement of CD147 in EMT during the establishment of endometriosis remains incompletely understood. We found that CD147 promotes EMT in human endometrial adenocarcinoma cell line Ishikawa. We identified a novel CD147-interacting partner, cellular apoptosis susceptibility protein (CAS), which stabilized the interaction between E-cadherin (E-cad) and ß-catenin (ß-cat) by forming the CAS/E-cad/ß-cat complex. Down-regulation of CAS led to the release and nuclear translocation of ß-cat from E-cad, resulting in the overexpression of the EMT-promoting gene SNAIL. Interestingly, overexpression of CD147 impaired the interaction between CAS and E-cad and triggered the release of ß-cat from the CAS/E-cad/ß-cat complex, which in turn led to EMT. Furthermore, CAS was down-regulated in EMS, with elevated levels of CD147 and nuclear ß-cat. These findings suggest a previously undefined role of CAS in regulating EMT and reveal the involvement of a CD147-induced EMT signaling pathway in pathogenic progression of EMS.
Assuntos
Antígenos CD/metabolismo , Basigina/metabolismo , Caderinas/metabolismo , Proteína de Suscetibilidade a Apoptose Celular/metabolismo , Neoplasias do Endométrio/patologia , Endometriose/patologia , Transição Epitelial-Mesenquimal , beta Catenina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Antígenos CD/genética , Basigina/genética , Caderinas/genética , Estudos de Casos e Controles , Membrana Celular , Proteína de Suscetibilidade a Apoptose Celular/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Endometriose/genética , Endometriose/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Células Tumorais Cultivadas , beta Catenina/genéticaRESUMO
Perivascular adipose tissue (PVAT)-derived adiponectin (APN) is a secreted adipokine that protects against hypertension-related cardiovascular injury. However, the regulation of APN expression in hypertension remains to be explored. In this study, we demonstrated that down-regulation of APN was associated with complement activation in the PVAT of desoxycorticosterone acetate (DOCA)-salt hypertensive mice. Complement 3-deficient hypertensive mice were protected from ANP decrease in the PVAT. APN deficiency blockaded the protective effects of complement inhibition against hypertensive vascular injury. Mechanistically, complement 5a (C5a)-induced TNF-α secretion from macrophages is required for inhibiting APN expression in adipocytes. Macrophage depletion reversed C5a agonist peptide-induced TNF-α up-regulation and APN down-regulation in the PVAT of DOCA mice. Moreover, we detected increased macrophage infiltration and C5a expression associated with decreased APN expression in adipose tissue from patients with aldosterone-producing adenoma. These results identify a novel interaction between macrophages and adipocytes in the PVAT, where complement-mediated inhibition of APN acts as a potential risk factor for hypertensive vascular inflammation.-Ruan, C.-C., Ma, Y., Ge, Q., Li, Y., Zhu, L.-M., Zhang, Y., Kong, L.-R., Wu, Q-H., Li, F., Cheng, L., Zhao, A. Z., Zhu, D.-L., Gao, P.-J. Complement-mediated inhibition of adiponectin regulates perivascular inflammation and vascular injury in hypertension.
Assuntos
Adipócitos/metabolismo , Adiponectina/metabolismo , Complemento C3/metabolismo , Complemento C5a/metabolismo , Hipertensão/metabolismo , Remodelação Vascular , Adiponectina/genética , Animais , Regulação para Baixo , Humanos , Hipertensão/patologia , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Defective central leptin signalling and impaired leptin entry into the CNS (central nervous system) represent two important aspects of leptin resistance in obesity. In the present study, we tested whether circulating human CRP (C-reactive protein) not only diminishes signalling of leptin within the CNS, but also impedes this adipokine's access to the CNS. Peripheral infusion of human CRP together with co-infused human leptin was associated with significantly decreased leptin content in the CSF of ob/ob mice. Furthermore, following peripheral infusion of human leptin, the CSF (cerebrospinal fluid) concentration of leptin in transgenic mice overexpressing human CRP was sharply lower than that achieved in similarly infused wild-type mice. Administration of LPS (lipopolysaccharide) to human CRP-transgenic mice dramatically elevated the concentrations of human CRP in the CSF. The i.c.v. (intracerebroventricular) delivery of human CRP into the lateral ventricles of ob/ob mice blocked the satiety and weight-reducing actions of human leptin, but not those of mouse leptin. I.c.v. injection of human CRP abolished hypothalamic signalling by human leptin, and ameliorated the effects of leptin on the expression of NPY (neuropeptide Y), AgRP (Agouti-related protein), POMC (pro-opiomelanocortin) and SOCS-3 (suppressor of cytokine signalling 3). Human CRP can impede the access of leptin to the CNS, and elevation of human CRP within the CNS can have a negative impact on the physiological actions of leptin.
Assuntos
Proteína C-Reativa , Hipotálamo/metabolismo , Leptina , Proteína Relacionada com Agouti/metabolismo , Animais , Proteína C-Reativa/farmacocinética , Proteína C-Reativa/farmacologia , Humanos , Leptina/farmacocinética , Leptina/farmacologia , Masculino , Camundongos , Camundongos Obesos , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/metabolismo , Transporte Proteico , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
This article aims to address the challenge of predicting the salaries of college graduates, a subject of significant practical value in the fields of human resources and career planning. Traditional prediction models often overlook diverse influencing factors and complex data distributions, limiting the accuracy and reliability of their predictions. Against this backdrop, we propose a novel prediction model that integrates maximum likelihood estimation (MLE), Jeffreys priors, Kullback-Leibler risk function, and Gaussian mixture models to optimize LSTM models in deep learning. Compared to existing research, our approach has multiple innovations: First, we successfully improve the model's predictive accuracy through the use of MLE. Second, we reduce the model's complexity and enhance its interpretability by applying Jeffreys priors. Lastly, we employ the Kullback-Leibler risk function for model selection and optimization, while the Gaussian mixture models further refine the capture of complex characteristics of salary distribution. To validate the effectiveness and robustness of our model, we conducted experiments on two different datasets. The results show significant improvements in prediction accuracy, model complexity, and risk performance. This study not only provides an efficient and reliable tool for predicting the salaries of college graduates but also offers robust theoretical and empirical foundations for future research in this field.
RESUMO
Objective: Hepatic fibrosis has been widely considered as a conjoint consequence of almost all chronic liver diseases. Chuanxiong Rhizoma (Chuanxiong in Chinese, CX) is a traditional Chinese herbal product to prevent cerebrovascular, gynecologic and hepatic diseases. Our previous study found that CX extracts significantly reduced collagen contraction force of hepatic stellate cells (HSCs). Here, this study aimed to compare the protection of different CX extracts on bile duct ligation (BDL)-induced liver fibrosis and investigate plausible underlying mechanisms. Methods: The active compounds of CX extracts were identified by high performance liquid chromatography (HPLC). Network pharmacology was used to determine potential targets of CX against hepatic fibrosis. Bile duct hyperplasia and liver fibrosis were evaluated by serologic testing and histopathological evaluation. The expression of targets of interest was determined by quantitative real-time PCR (qPCR) and Western blot. Results: Different CX extracts were identified by tetramethylpyrazine, ferulic acid and senkyunolide A. Based on the network pharmacological analysis, 42 overlap targets were obtained via merging the candidates targets of CX and liver fibrosis. Different aqueous, alkaloid and phthalide extracts of CX (CXAE, CXAL and CXPHL) significantly inhibited diffuse severe bile duct hyperplasia and thus suppressed hepatic fibrosis by decreasing CCCTC binding factor (CTCF)-c-MYC-long non-coding RNA H19 (H19) pathway in the BDL-induced mouse model. Meanwhile, CX extracts, especially CXAL and CXPHL also suppressed CTCF-c-MYC-H19 pathway and inhibited ductular reaction in cholangiocytes stimulated with taurocholate acid (TCA), lithocholic acid (LCA) and transforming growth factor beta (TGF-ß), as illustrated by decreased bile duct proliferation markers. Conclusion: Our data supported that different CX extracts, especially CXAL and CXPHL significantly alleviated hepatic fibrosis and bile duct hyperplasia via inhibiting CTCF-c-MYC-H19 pathway, providing novel insights into the anti-fibrotic mechanism of CX.
RESUMO
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune dysregulation and hepatocyte damage. FKBP38, a member of the immunophilin family, has been implicated in immune regulation and the modulation of intracellular signaling pathways; however, its role in AIH pathogenesis remains poorly understood. In this study, we aimed to investigate the effects of hepatic FKBP38 deletion on AIH using a hepatic FKBP38 knockout (LKO) mouse model created via cre-loxP technology. We compared the survival rates, incidence, and severity of AIH in LKO mice with those in control mice. Our findings revealed that hepatic FKBP38 deletion resulted in an unfavorable prognosis in LKO mice with AIH. Specifically, LKO mice exhibited heightened liver inflammation and extensive hepatocyte damage compared to control mice, with a significant decrease in anti-apoptotic proteins and a marked increase in pro-apoptotic proteins. Additionally, transcriptional and translational levels of pro-inflammatory cytokines and chemokines were significantly increased in LKO mice compared to control mice. Immunoblot analysis showed that MCP-1 expression was significantly elevated in LKO mice. Furthermore, the phosphorylation of p38 was increased in LKO mice with AIH, indicating that FKBP38 deletion promotes liver injury in AIH by upregulating p38 phosphorylation and increasing MCP-1 expression. Immune cell profiling demonstrated elevated populations of T, NK, and B cells, suggesting a dysregulated immune response in LKO mice with AIH. Overall, our findings suggest that FKBP38 disruption exacerbates AIH severity by augmenting the immune response by activating the MCP-1/p38 signaling pathway.