RESUMO
Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50-70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)-high expression of which is a signature specific to the S-III subtype-alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Terapia de Alvo Molecular/tendências , Proteômica , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Processos de Crescimento Celular , Movimento Celular , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estadiamento de Neoplasias , Prognóstico , Esterol O-Aciltransferase/genéticaRESUMO
BACKGROUND: Several observational studies have explored the prevalence and predictors of female sexual dysfunction (FSD) among females with type 1 diabetes. However, no systematic review and meta-analysis of pooled data provide reliable estimates of FSD prevalence among females with type 1 diabetes. AIM: To investigate the global prevalence of FSD, analyze the association between FSD risk and type 1 diabetes, and evaluate the predictors of FSD among females with type 1 diabetes. METHODS: The study search of the present systematic review was conducted through the Wanfang Database, China National Knowledge Infrastructure, PubMed, and Embase from the inception date to February 28, 2023. Heterogeneity among the studies was analyzed with the Q and I2 tests. The sources of heterogeneity were detected through subgroup analyses and meta-regression. OUTCOMES: Outcomes included the pooled prevalence of FSD among females with type 1 diabetes, the association between FSD risk and type 1 diabetes, and the predictors of FSD among females with type 1 diabetes. RESULTS: The pooled prevalence of FSD among females with type 1 diabetes was 38.5% (95% CI, 32.1%-45.0%). The risk of FSD was higher in patients with type 1 diabetes than in healthy controls (odds ratio [OR], 3.77; 95% CI, 2.24-6.35). The significant predictors of FSD among females with type 1 diabetes were depression status (OR, 2.77; 95% CI, 1.29-5.93) and longer diabetes duration (OR, 1.19; 95% CI, 1.06-1.34). CLINICAL IMPLICATIONS: Females with type 1 diabetes had a significantly increased prevalence of FSD, indicating that clinicians should be concerned about FSD among females with type 1 diabetes. STRENGTHS AND LIMITATIONS: The strength of the present study is that it is the first systematic review and meta-analysis to investigate the global prevalence and predictors of FSD among females with type 1 diabetes. The limitation is that the results revealed significant heterogeneity after pooling the articles. CONCLUSIONS: The present systematic review and meta-analysis revealed that the overall prevalence of FSD among females with type 1 diabetes was 38.5%, demonstrating a significant association between FSD risk and type 1 diabetes among females. Furthermore, we found that the significant predictors for FSD among females with type 1 diabetes were depression and a longer duration of diabetes.
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Diabetes Mellitus Tipo 1 , Disfunções Sexuais Fisiológicas , Disfunções Sexuais Psicogênicas , Humanos , Feminino , Disfunções Sexuais Psicogênicas/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Prevalência , Disfunções Sexuais Fisiológicas/epidemiologia , Disfunções Sexuais Fisiológicas/etiologia , Fatores de TempoRESUMO
CONTEXT: Panax ginseng C. A. Meyer (Araliaceae) is a famous Asian medicine. Ginsenoside Rc is a component isolated from Panax ginseng. OBJECTIVE: This study evaluates the effect of ginsenoside Rc on myocardial ischaemic injury. MATERIALS AND METHODS: Male Swiss mice were subcutaneously injected with 50 mg/kg isoproterenol once a day for three days. Ginsenoside Rc (10, 20, or 40 mg/kg) was intragastrically administered 1 h after isoproterenol injection. The mice in the control group were subcutaneously injected with normal saline and intragastrically given 0.5% CMC-Na. CK-MB and troponin T were assayed. Histopathological examination of myocardium was conducted. The expression of Nrf2, GCLC, GCLM and HO-1 in heart tissues was evaluated by Western blot. RESULTS: In myocardial ischaemic mice, ginsenoside Rc reduced the levels of CK-MB (197.1 ± 15.7, 189.9 ± 19.0, 184.0 ± 14.4 vs. 221.6 ± 27.9) and troponin T (10.3 ± 1.7, 9.5 ± 1.3, 8.7 ± 1.7 vs. 13.4 ± 2.4). Ginsenoside Rc attenuated the necrosis and inflammatory cells infiltration in myocardium. Furthermore, ginsenoside Rc not only decreased the contents of MDA, TNF-α but also increased GSH level in the heart tissues. The expression of Nrf2, GCLC, GCLM and HO-1 was significantly increased in the animals treated with ginsenoside Rc. ML385, an Nrf2 inhibitor, blocked partially the ginsenoside Rc-mediated cardioprotective effect. Ginsenoside Rc attenuated myocardial ischaemic injury in mice, which may be, in part, through its antioxidative and anti-inflammatory effects. CONCLUSIONS: This study indicated that ginsenoside Rc might be a novel candidate for treatment of myocardial ischaemia.
Assuntos
Antioxidantes , Panax , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ginsenosídeos , Isoproterenol , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Panax/metabolismo , Troponina TRESUMO
CONTEXT: Panax ginseng C.A. Meyer (Araliaceae) has cardioprotective effects. Ginsenosides are responsible for most of the pharmacological activities of ginseng. OBJECTIVE: This study investigates the effect of ginsenoside Rg2 on myocardial fibrosis in myocardial ischaemia rats. MATERIALS AND METHODS: Male Wistar rats were divided into control, isoproterenol, ginsenoside Rg2 (5, 20 mg/kg) groups (n = 8). The rats were subcutaneously injected with isoproterenol (5 mg/kg) or normal saline (control group) once daily for 7 days. The animals were intragastrically treated with ginsenoside Rg2 or 0.5% CMC-Na (control and isoproterenol groups) daily for 28 days. At day 28, cardiac function, myocardial fibrosis, and TGF-ß1/Smad signalling pathway were evaluated. RESULTS: Compared with myocardial ischaemic rats, ginsenoside Rg2 at doses of 5, 20 mg/kg abated partially the augment of LVEDP (8.9 ± 1.3 vs. 7.5 ± 0.7, 7.2 ± 1.0 mmHg) and the decreases of the LVSP (96.75 ± 13.2 vs. 118.3 ± 19.4, 124.3 ± 21.3 mmHg), the + dp/dt (2142.8 ± 309.3 vs. 2598.6 ± 404.0, 2661.5 ± 445.2 mmHg/s), and the -dp/dt (1996.3 ± 306.3 vs. 2476.6 ± 289.7, 2509.6 ± 353.1 mmHg/s). Ginsenoside Rg2 (9.2 ± 0.9%, 8.5 ± 0.8%) alleviated myocardial fibrosis when compared with the isoproterenol group (10.1 ± 1.0%), which was accompanied by suppressed TGF-ß1/Smad signalling in heart tissues. CONCLUSIONS: Ginsenosides from ginseng possess the property of alleviating myocardial fibrosis, improving cardiac function after myocardial ischaemia. Ginsenosides may be promising agents for improving the outcomes of patients with myocardial ischaemia.
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Cardiotônicos/farmacologia , Ginsenosídeos/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Panax/química , Animais , Cardiotônicos/administração & dosagem , Cardiotônicos/isolamento & purificação , Relação Dose-Resposta a Droga , Fibrose/tratamento farmacológico , Fibrose/patologia , Ginsenosídeos/administração & dosagem , Ginsenosídeos/isolamento & purificação , Isoproterenol/farmacologia , Masculino , Isquemia Miocárdica/fisiopatologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Colorectal carcinoma (CRC) recurrence is often accompanied by metastasis. Most metastasis undergo through epithelial-mesenchymal transition (EMT). Studies showed that retinol X receptor alpha (RXRα) and 20(S)-Protopanaxadiol (PPD) have anti-tumour effects. However, the anti-metastasis effect of 20(S)-PPD and the effect of RXRα on EMT-induced metastasis are few studies on. Therefore, the role of RXRα and 20(S)-PPD in CRC cell metastasis remains to be fully elucidated. RXRα with clinicopathological characteristics and EMT-related expression in clinical samples were examined. Then, RXRα and EMT level in SW480 and SW620 cells, overexpressed and silenced RXRα in SW620 cells and SW480 cells, respectively, were evaluated. Finally, 20(S)-PPD effect on SW620 and SW480 cells was evaluated. The results showed that a lower RXRα expression in cancer tissues, and a moderate negative correlation between RXRα and N stage, and tended to higher level of EMT. SW480 and SW620 cells had the highest and lowest RXRα expression among four CRC cell lines. SW480 had lower EMT level than SW620. Furthermore, 20(S)-PPD increased RXRα and inhibited EMT level in SW620 cell. Finally, 20(S)-PPD cannot restore SW480 cells EMT level to normal when RXRα silencing. These findings suggest that 20(S)-PPD may inhibit EMT process in CRC cells by regulating RXRα expression.
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Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptor X Retinoide alfa/metabolismo , Sapogeninas/farmacologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Receptor X Retinoide alfa/genéticaRESUMO
Parkinson's disease (PD) is characterized by the selective death of dopaminergic neurons. To avoid inconvenience of frequent administration caused by short half life and recurrence of symptoms such as tremor and bradykinesia incurred by drug elimination, a novel long-acting pramipexole transdermal patch has been made. In the present study, we evaluated the neuroprotective effects and underlying mechanisms of pramipexole patch (PPX patch) in a subacute PD mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results showed that PPX patch treatment improved dyskinesia. MPTP-induced reduction of DA as well as its metabolites DOPAC and HVA in the striatum were prevented by PPX patch in a dose-dependent manner. PPX patch also restored the activity of antioxidant enzymes including SOD, GSH-Px and CAT in the striatum while reduced the content of MDA. Furthermore, PPX patch upregulated Nrf2/HO-1 expression. The protective effects of PPX patch was also associated with downregulation of the Bax/Bcl-2 ratio and Apaf-1, inhibition of cytochrome c release and inactivation of caspase-9 and caspase-3. In conclusion, our studies demonstrated that the long-acting pramipexole patch exerts its neuroprotective effects, at least in part, by inhibiting oxidative stress and mitochondrial apoptosis pathway and holds promise as a candidate drug.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacologia , Fármacos Neuroprotetores , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Pramipexol/administração & dosagem , Pramipexol/farmacologia , Adesivo Transdérmico , Administração Cutânea , Animais , Apoptose/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Superóxido Dismutase/metabolismoRESUMO
20(S)-Protopanaxadiol (PPD) is one of the major active metabolites of ginseng. It has been reported that 20(S)-PPD shows a broad spectrum of antitumor effects. Our research study aims were to investigate whether apoptosis of human breast cancer MCF-7 cells could be induced by 20(S)-PPD by targeting the Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway in vitro and in vivo. Cell cycle analysis was performed by Propidium Iodide (PI) staining. To overexpress and knock down the expression of mTOR, pcDNA3.1-mTOR and mTOR small interfering RNA (siRNA) transient transfection assays were used, respectively. Cell viability and apoptosis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test and Annexin V /PI double-staining after transfection. The antitumor effect in vivo was determined by the nude mice xenograft assay. After 24 h of incubation, treatment with 20(S)-PPD could upregulate phosphorylated-Phosphatase and tensin homologue deleted on chromosome 10 (p-PTEN) expression and downregulate PI3K/AKT/mTOR-pathway protein expression. Moreover, G0/G1 cell cycle arrest in MCF-7 cells could be induced by 20(S)-PPD treatment at high concentrations. Furthermore, overexpression or knockdown of mTOR could inhibit or promote the apoptotic effects of 20(S)-PPD. In addition, tumor volumes were partially reduced by 20(S)-PPD at 100 mg/kg in a MCF-7 xenograft model. Immunohistochemical staining indicated a close relationship between the inhibition of tumor growth and the PI3K/AKT/mTOR signal pathway. PI3K/AKT/mTOR pathway-mediated apoptosis may be one of the potential mechanisms of 20(S)-PPD treatment.
Assuntos
Apoptose/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sapogeninas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND AIM: Increasing evidence shows that the calpain regulatory subunit Capn4 can modulate the proliferation and metastasis of cancer cells, and plays an important role in the development of malignant tumors. However, there is no information on the clinical significance of Capn4 in epithelial ovarian carcinoma (EOC) or the molecular mechanisms by which Capn4 promotes the growth and metastasis of EOC. Therefore, the aim of this study was to clarify the role of Capn4 in EOC. METHODS: We evaluated Capn4 and osteopontin (OPN) expression in EOC cell lines and tissues from patients with ovarian cancer by western blotting and immunohistochemical analysis. We then created cell lines with downregulated and upregulated Capn4 expression, using Capn4-targeting small interfering RNA and a pcDNA3.1-Capn4 overexpression vector, respectively, to investigate its function in EOC in vitro. In addition, we investigated the potential mechanism underlying the function of Capn4 by examining the effect of modifying Capn4 expression on Wnt/ß-catenin signaling pathway-related genes by western blotting. RESULTS: Capn4 was overexpressed in clinical EOC tissues compared with that in normal ovarian epithelial tissue, and was associated with poor clinical outcomes. Upon silencing or overexpressing Capn4 in EOC cells, we concluded that Capn4 promotes cell proliferation and migration in vitro. Furthermore, Capn4 promoted EOC metastasis by interacting with the Wnt/ß-catenin signaling pathway to upregulate OPN expression. CONCLUSION: Our study indicates that Capn4 plays a critical role in the progression and metastasis of EOC, and could be a potential therapeutic target for EOC management.
Assuntos
Calpaína/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Osteopontina/metabolismo , Neoplasias Ovarianas/patologia , Via de Sinalização Wnt , beta Catenina/metabolismo , Calpaína/antagonistas & inibidores , Calpaína/genética , Carcinoma Epitelial do Ovário , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/mortalidade , Osteopontina/antagonistas & inibidores , Osteopontina/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Plasmídeos/genética , Plasmídeos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/genéticaRESUMO
[Purpose] To investigate the effect of Tai Chi on cognitive and physical function in the elderly. [Subjects and Methods] A randomized trial design was used. A total 150 subjects were enrolled and were divided into Tai Chi and control groups. Subjects in the Tai Chi group participated Tai Chi for 6 months, and subjects in the control group participated in other non-athletic activities. [Results] There were no differences between the groups in the one leg standing time with eyes open, left grip strength, or the Frontal Assessment Battery at bedside after 3 and 6 months of intervention. The Mini-Mental State Examination scores after 3 and 6 months were higher in the Tai Chi group than in the control group. The right grip strength after 3 months increased more in the Tai Chi group than in the control group. Both the 5-m high walking speed and 10-m normal walking speed were significantly lower after 3 and 6 months of Tai Chi practice. [Conclusion] These results suggest that regular Tai Chi practice may improve cognitive and physical function in the elderly.
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In this study, we examined the cardiovascular protective effects of IL-1ra-Fc-IL-18BP on experimental myocardial infarction in a rat model. An animal model of myocardial infarction (MI) was induced by permanent ligation of the left anterior descending coronary artery (LAD) in SD rats. After surgery sixty male rats and sixty female rats were randomly divided into groups as followed: sham group, MI group, IL-1ra-Fc-IL-18BP 50,100, 200 mg/kg treatment groups, and verapamil 5 mg/kg treatment group. IL-1 ra-Fc-IL-18BP and verapamil were administered to the animals immediately after operation by intravenous injection. Treatment with IL-1ra-Fc-IL-18BP (50, 100 and 200 mg/kg) could remarkably decrease infarct size from 24.82% to 13.43% (p < 0.05), and decrease the activities of serum aspartate aminotransferase (AST), creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) compared with sham group (p < 0.05). Meanwhile, treatment with IL-1ra-Fc-IL-18BP (200 mg/kg) could significantly increase the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), but decreased the content of malondiadehyde (MDA) in serum (p < 0.05). Furthermore, IL-1ra-Fc-IL-18BP marablely reduced the content of calcium (Ca2+) in serum (p < 0.05), and also decreased the levels of serum interleukin-1ß (IL-1ß), tumor necrosis factor (TNF-α) (p < 0.05). Histopathological results demonstrated the same protective effect of IL-1ra-Fc-IL-18BP All these results above indicated that IL-1ra-Fc-IL-18BP has protective effects in myocardial infarction, improves free radicals metabolism, ameliorates myocardial calcium overload and inhibits the release of inflammatory cytokines.
Assuntos
Cardiotônicos/farmacologia , Inflamação/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Animais , Antioxidantes/farmacologia , Cálcio/sangue , Citocinas/biossíntese , Feminino , Inflamação/metabolismo , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To explore the effects of serum from ginsenoside saponins (GSS) on the proliferation, differentiation and mineralization in osteoblasts (OB). METHODS: Serum from GSS with different doses were fed to calvaria bone specimens from rats. The proliferation of osteoblasts and the alkaline phosphatase (ALP) activity of OB were analyzed. After alizarin red S staining, the area of calcium nodule was calculated to observe the result of serum from GSS on OB mineralization. RESULTS: Serum from GSS had notable effects on the proliferation of in vitro cultured OB (P < 0.01) and remarkably stimulated the mineralization of OB (P < 0.05) while its effect on the ALP activity of OB was also marked (P < 0.01). CONCLUSION: Serum from GSS can promote the proliferation and mineralization ability of OB and significantly accelerate the formation of OB.
Assuntos
Diferenciação Celular , Proliferação de Células , Osteoblastos , Animais , Cálcio , Células Cultivadas , Ginsenosídeos , Ratos , Saponinas , CrânioRESUMO
Existing Cross-Domain Few-Shot Learning (CDFSL) methods require access to source domain data to train a model in the pre-training phase. However, due to increasing concerns about data privacy and the desire to reduce data transmission and training costs, it is necessary to develop a CDFSL solution without accessing source data. For this reason, this paper explores a Source-Free CDFSL (SF-CDFSL) problem, in which CDFSL is addressed through the use of existing pretrained models instead of training a model with source data, avoiding accessing source data. However, due to the lack of source data, we face two key challenges: effectively tackling CDFSL with limited labeled target samples, and the impossibility of addressing domain disparities by aligning source and target domain distributions. This paper proposes an Enhanced Information Maximization with Distance-Aware Contrastive Learning (IM-DCL) method to address these challenges. Firstly, we introduce the transductive mechanism for learning the query set. Secondly, information maximization (IM) is explored to map target samples into both individual certainty and global diversity predictions, helping the source model better fit the target data distribution. However, IM fails to learn the decision boundary of the target task. This motivates us to introduce a novel approach called Distance-Aware Contrastive Learning (DCL), in which we consider the entire feature set as both positive and negative sets, akin to Schrödinger's concept of a dual state. Instead of a rigid separation between positive and negative sets, we employ a weighted distance calculation among features to establish a soft classification of the positive and negative sets for the entire feature set. We explore three types of negative weights to enhance the performance of CDFSL. Furthermore, we address issues related to IM by incorporating contrastive constraints between object features and their corresponding positive and negative sets. Evaluations of the 4 datasets in the BSCD-FSL benchmark indicate that the proposed IM-DCL, without accessing the source domain, demonstrates superiority over existing methods, especially in the distant domain task. Additionally, the ablation study and performance analysis confirmed the ability of IM-DCL to handle SF-CDFSL. The code will be made public at https://github.com/xuhuali-mxj/IM-DCL.
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AIM: Animals exhibit physiological changes designed to eliminate the perceived danger, provoking similar symptoms of fever. However, a high-grade fever indicates poor clinical outcomes. Caspase11 (Casp11) is involved in many inflammatory diseases. Whether Casp11 leads to fever remains unclear. In this study, we investigate the role of the preoptic area of the hypothalamus (PO/AH) microglia Casp11 in fever. METHODS: We perform experiments using a rat model of LPS-induced fever. We measure body temperature and explore the functions of peripheral macrophages and PO/AH microglia in fever signaling by ELISA, immunohistochemistry, immunofluorescence, flow cytometry, macrophage depletion, protein blotting, and RNA-seq. Then, the effects of macrophages on microglia in a hyperthermic environment are observed in vitro. Finally, adeno-associated viruses are used to knockdown or overexpress microglia Casp11 in PO/AH to determine the role of Casp11 in fever. RESULTS: We find peripheral macrophages and PO/AH microglia play important roles in the process of fever, which is proved by macrophage and microglia depletion. By RNA-seq analysis, we find Casp11 expression in PO/AH is significantly increased during fever. Co-culture and conditioned-culture simulate the induction of microglia Casp11 activation by macrophages in a non-contact manner. Microglia Casp11 knockdown decreases body temperature, pyrogenic factors, and inflammasome, and vice versa. CONCLUSION: We report that Casp11 drives fever. Mechanistically, peripheral macrophages transmit immune signals via cytokines to microglia in PO/AH, which activate the Casp11 non-canonical inflammasome. Our findings identify a novel player, the microglia Casp11, in the control of fever, providing an explanation for the transmission and amplification of fever immune signaling.
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Febre , Inflamassomos , Microglia , Animais , Masculino , Ratos , Caspases/metabolismo , Caspases/genética , Febre/metabolismo , Inflamassomos/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Área Pré-Óptica/metabolismo , Ratos WistarRESUMO
Purpose: The objective of this study was to create and validate a novel prediction model that incorporated both multi-modal radiomics features and multi-clinical features, with the aim of accurately identifying acute ischemic stroke (AIS) patients who faced a higher risk of poor outcomes. Methods: A cohort of 461 patients diagnosed with AIS from four centers was divided into a training cohort and a validation cohort. Radiomics features were extracted and selected from diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) images to create a radiomic signature. Prediction models were developed using multi-clinical and selected radiomics features from DWI and ADC. Results: A total of 49 radiomics features were selected from DWI and ADC images by the least absolute shrinkage and selection operator (LASSO). Additionally, 20 variables were collected as multi-clinical features. In terms of predicting poor outcomes in validation set, the area under the curve (AUC) was 0.727 for the DWI radiomics model, 0.821 for the ADC radiomics model, 0.825 for the DWI + ADC radiomics model, and 0.808 for the multi-clinical model. Furthermore, a prediction model was built using all selected features, the AUC for predicting poor outcomes increased to 0.86. Conclusion: Radiomics features extracted from DWI and ADC images can serve as valuable biomarkers for predicting poor clinical outcomes in patients with AIS. Furthermore, when these radiomics features were combined with multi-clinical features, the predictive performance was enhanced. The prediction model has the potential to provide guidance for tailoring rehabilitation therapies based on individual patient risks for poor outcomes.
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Juglone is a natural compound which has been isolated from Juglans mandshurica Maxim. Recent studies have shown that juglone had various pharmacological effects such as anti-viral, anti-bacterial and anti-cancer. However, its anti-cancer activity on human prostate cancer LNCaP cell has not been examined. Thus, the current study was designed to elucidate the molecular mechanism of apoptosis induced by juglone in androgen-sensitive prostate cancer LNCaP cells. MTT assay was performed to examine the anti-proliferative effect of juglone. Occurrence of apoptosis was detected by Hoechst 33342 staining and flow cytometry in LNCaP cells treated with juglone for 24h. The result shown that juglone inhibited the growth of LNCaP cells in a dose-dependent manner. Morphological changes of apoptotic body formation after juglone treatment were observed by Hoechst 33342 staining. This apoptotic induction was associated with loss of mitochondrial membrane potential, and caspase-3, -9 activation. Moreover, we found that juglone significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a dose-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and/or without dihydrotestosterone (DHT). Take together, our results demonstrated that juglone might induce the apoptosis in LNCaP cell via down-regulation of AR expression. Therefore, our results indicated that juglone may be a potential candidate of drug for androgen-sensitive prostate cancer.
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Apoptose/efeitos dos fármacos , Juglans/química , Extratos Vegetais/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/biossíntese , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/genéticaRESUMO
In this study, we investigated the cardioprotective effect of Panax quinquefolium 20(S)-protopanaxadiol saponins (PQDS) both in vivo and in vitro. An animal model of acute myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery in Sparague Dawley rats. Neonatal rat cardiomycocytes were used to examine the cytoprotective effect of PQDS against H202 exposure. Pretreatment with PQDS (25 and 50 mg/kg) could significantly improve the heart function, remarkably decrease infarct size from 20.87% to 14.87% (p<0.01), decrease the levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and cardiac troponin T (cTnT) content in serum (p< 0.05). Meanwhile, pretreatment with PQDS (25 and 50 mg/kg) significantly increased the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) in the heart, and decreased the level of malondiadehyde (MDA) in the myocardium (p<0.05). Histopathological results demonstrated the same protective effect of PQDS. Pretreatment with PQDS (200 and 400 microg/ml) prior to H202 exposure could increase cell viability of neonatal rat cardiomycocytes. Pretreatment PQDS (200 and 400 microg/ml) also increased the activity of SOD, decreased level of LDH in the cultured supernatant and the MDA level in cardiomyocytes. These results indicated that PQDS had a cardioprotective effect proven in vivo and in vitro. The mechanisms might be due to its scavenging lipid peroxidation products, increasing endogenous antioxidant defense enzymes.
Assuntos
Cardiotônicos , Panax/química , Sapogeninas/farmacologia , Animais , Animais Recém-Nascidos , Biomarcadores/análise , Células Cultivadas , Oclusão Coronária/complicações , Oclusão Coronária/patologia , Eletrocardiografia/efeitos dos fármacos , Feminino , Testes de Função Cardíaca , Peróxido de Hidrogênio/farmacologia , Indicadores e Reagentes , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Oxidantes/farmacologia , Ratos , Ratos Sprague-Dawley , Sapogeninas/isolamento & purificação , SobrevidaRESUMO
In recent years, numerous epidemiological studies have investigated the prevalence of female sexual dysfunction (FSD) in females with inflammatory bowel disease (IBD). However, a comprehensive systematic review with meta-analysis pooling their findings is lacking. This study aimed to determine the pooled prevalence estimates of FSD and its risk factors among females with IBD based on extensive research in electronic databases (PubMed, Embase, and Web of Science) from inception until April 1, 2023. The overall prevalence of FSD among females with IBD, along with its 95% confidence interval (CI), and subgroup-specific prevalence rates, were summarized. Sources of heterogeneity were identified through subgroup analyses and meta-regression. A total of 13 studies were included in this systematic review and meta-analysis. The pooled global prevalence of FSD among females with IBD was 61.4% (95% CI: 52.8-70.1%). Sensitivity analysis, which involved excluding individual studies, indicated no significant variation in the pooled prevalence, confirming the robustness of our results. Additionally, a significant risk factor for FSD among females with IBD was the quality of life (OR = 0.39, 95% CI: 0.19-0.79). In conclusion, our systematic review and meta-analysis revealed a high prevalence of FSD among females with IBD, which warrants attention from health organizations and clinical practitioners. Importantly, the quality of life was identified as a potential risk factor for FSD in this population. Nonetheless, future prospective cohort studies with a large sample size are warranted to confirm these findings.
RESUMO
Myocardial ischemia-reperfusion (MI/R) injury occurs when coronary blood supply is impaired and then re-established, leading to additional injury to the myocardial tissue, including mitochondria oxidative stress and apoptosis. Ginsenoside Rc is one of the main protopanaxadiol-type saponins, and there has been relatively little research on it. Despite research confirming that ginsenoside Rc regulates mitochondrial functions, its potential benefits against MI/R injury have not been explored. In this study, we examined the protective effects of ginsenoside Rc in MI/R injury, along with its underlying mechanisms, using an in vitro H9c2 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R) and an in vivo rat model of MI/R injury. Prior to this, the H9c2 cells or rats were exposed to ginsenoside Rc with or without SIRT1 small interfering RNA (siRNA) or the selective SIRT1 inhibitor EX527. The results showed that after MI/R (or OGD/R) injury, ginsenoside Rc had a cardioprotective effect; improved cardiac function (or cell survival); reduced myocardial infarct size; decreased levels of creatine kinase-MB, cardiac troponin I, and lactate dehydrogenase (LDH) in the serum (or LDH release into culture medium); reduced cardiomyocyte apoptosis; and attenuated mitochondrial oxidative damage. Ginsenoside Rc pre-treatment also upregulated the anti-apoptotic protein Bcl-2 while downregulating the pro-apoptotic proteins Bax and cleaved caspase-3. Furthermore, the cardioprotective effect of ginsenoside Rc was concomitant with upregulated SIRT1 expression and downregulated Ac-FOXO1 expression. SIRT1 siRNA or SIRT1 inhibitor EX527 abolished the cardioprotective effects of ginsenoside Rc by inhibiting the SIRT1 signaling pathway. In conclusion, our findings demonstrate that ginsenoside Rc ameliorated MI/R injury by reducing mitochondrial oxidative stress and apoptosis, at least in part, by activating SIRT1.
Assuntos
Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Apoptose , Estresse Oxidativo , RNA Interferente Pequeno/metabolismo , Miócitos CardíacosRESUMO
Carbon tetrachloride (CCl4)-induced lipid peroxidation associated with hepatic oxidative stress and cell death is an important mechanism of acute liver injury (ALI). Ginsenoside Rd is considered an active ingredient of ginseng. Evidence suggests that ginsenoside Rd may improve ischaemic stroke, nerve damage, cancer and other diseases involving apoptosis, inflammation, oxidative stress, mitochondrial injury and autophagy. However, the effects of ginsenoside Rd on CCl4-induced ALI and its underlying mechanisms are still unclear. In this study, 0.25% CCl4 was injected intraperitoneally in mice to establish a CCl4-induced ALI model. In the Rd treatment group, Rd (10, 20[Formula: see text]mg/kg) doses were injected intraperitoneally 1[Formula: see text]h before and 23[Formula: see text]h after CCl4 administration. Ferroptosis inducer imidazole ketone erastin (IKE) was injected intraperitoneally 4[Formula: see text]h before CCl4 administration to explore the mechanism. The blood and liver were collected 24[Formula: see text]h after CCl4 administration to investigate the effect and mechanism of ginsenoside Rd on CCl4-induced ALI. Our results showed that ginsenoside Rd inhibited CCl4-induced ALI in mice. Ginsenoside Rd also downregulated CCl4-induced serum and liver iron, 4-hydroxynonenal, and 8-hydroxy-2 deoxyguanosine levels. Furthermore, it upregulated glutathione and glutathione peroxidase 4 levels. In addition, ginsenoside Rd downregulated the expression of cGAS and STING. Subsequently, the ferroptosis inducer imidazole ketone erastin significantly reversed the hepatoprotective effect and influence of ginsenoside Rd with regard to the indicators mentioned above. Our study confirmed that ginsenoside Rd ameliorated CCl4-induced ALI in mice, which was related to the reduction of ferroptosis. Simultaneously, the ginsenoside Rd-mediated inhibition of the cGAS/STING pathway contributed to its antiferroptosis effect. In conclusion, our results suggested that ginsenoside Rd inhibited ferroptosis via the cGAS/STING pathway, thereby protecting mice from CCl4-induced ALI. These results suggested ginsenoside Rd may be used as a potential intervention treatment against CCl4-induced ALI.
Assuntos
Isquemia Encefálica , Doença Hepática Induzida por Substâncias e Drogas , Ferroptose , Acidente Vascular Cerebral , Camundongos , Animais , Isquemia Encefálica/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/farmacologia , Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
Astrocytes and microglia play an orchestrated role following spinal cord injury; however, the molecular mechanisms through which microglia regulate astrocytes after spinal cord injury are not yet fully understood. Herein, microglia were pharmacologically depleted and the effects on the astrocytic response were examined. We further explored the potential mechanisms involving the signal transducers and activators of transcription 3 (STAT3) pathway. For in vivo experiments, we constructed a contusion spinal cord injury model in C57BL/6 mice. To deplete microglia, all mice were treated with colony-stimulating factor 1 receptor inhibitor PLX3397, starting 2 weeks prior to surgery until they were sacrificed. Cell proliferation was examined by 5-ethynyl-2-deoxyuridine (EdU) and three pivotal inflammatory cytokines were detected by a specific Bio-Plex ProTM Reagent Kit. Locomotor function, neuroinflammation, astrocyte activation and phosphorylated STAT3 (pSTAT3, a maker of activation of STAT3 signaling) levels were determined. For in vitro experiments, a microglia and astrocyte coculture system was established, and the small molecule STA21, which blocks STAT3 activation, was applied to investigate whether STAT3 signaling is involved in mediating astrocyte proliferation induced by microglia. PLX3397 administration disrupted glial scar formation, increased inflammatory spillover, induced diffuse tissue damage and impaired functional recovery after spinal cord injury. Microglial depletion markedly reduced EdU+ proliferating cells, especially proliferating astrocytes at 7 days after spinal cord injury. RNA sequencing analysis showed that the JAK/STAT3 pathway was downregulated in mice treated with PLX3397. Double immunofluorescence staining confirmed that PLX3397 significantly decreased STAT3 expression in astrocytes. Importantly, in vitro coculture of astrocytes and microglia showed that microglia-induced astrocyte proliferation was abolished by STA21 administration. These findings suggest that microglial depletion impaired astrocyte proliferation and astrocytic scar formation, and induced inflammatory diffusion partly by inhibiting STAT3 phosphorylation in astrocytes following spinal cord injury.