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ETHNOPHARMACOLOGICAL RELEVANCE: Coix seed, the dry mature seed kernel of the gramineous plant coix (Coix lacryma-jobi L. var. ma-yuen Stapf), is widely consumed as a traditional Chinese medicine and functional food in China and South Korea. We have previously demonstrated the protective effect of coixol, a polyphenolic compound extracted from coix, against Toxoplasma gondii (T. gondii) infection-induced lung injury. However, the protective effect of coixol on hepatic injury induced by T. gondii infection have not yet been elucidated. AIM OF THE STUDY: This study explores the impact of coixol on T. gondii infection-induced liver injury and elucidates the underlying molecular mechanisms. MATERIALS AND METHODS: Female BALB/c mice and Kupffer cells (KCs) were employed to establish an acute T. gondii infection model in vivo and an inflammation model in vitro. The study examined coixol's influence on the T. gondii-derived heat shock protein 70 (T.g.HSP70)/toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway in T. gondii-infected liver macrophages. Furthermore, a co-culture system of KCs and NCTC-1469 hepatocytes was developed to observe the impact of liver macrophages infected with T. gondii on hepatocyte injury. RESULTS: Coixol notably inhibited the proliferation of tachyzoites and the expression of T.g.HSP70 in mouse liver and KCs, and attenuated pathological liver injury. Moreover, coixol decreased the production of high mobility group box 1, tumor necrosis factor-α, and inducible nitric oxide synthase by suppressing the TLR4/NF-κB signaling pathway in vitro and in vivo. Coixol also mitigated KCs-mediated hepatocyte injury. CONCLUSIONS: Coixol protects against liver injury caused by T. gondii infection, potentially by diminishing hepatocyte injury through the suppression of the inflammatory cascade mediated by the T.g.HSP70/TLR4/NF-κB signaling pathway in KCs. These findings offer new perspectives for developing coixol as a lead compound for anti-T. gondii drugs.
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18ß-Glycyrrhetinic acid (GA) is an oleane-type pentacyclic triterpene saponin obtained from glycyrrhizic acid by removing 2 glucuronic acid groups. GA and its analogues are active substances of glycyrrhiza aicd, with similar structure and important pharmacological effects such as anti-inflammatory, anti-diabetes, anti-tumor and anti-fibrosis. Although GA combined compounds are in the clinical trial stages, its application potential is severely restricted by its low bioavailability, water solubility and membrane permeability. In this article, synthetic methods and structure-activity relationships (SARs) of GA derivatives from 2018 to present are reviewed based on pharmacological activity. It is hoped that this review can provide reference for the future development of potential GA preclinical candidate compounds, and furnish ideas for the development of pentacyclic triterpenoid lead compounds.
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INTRODUCTION: Stroke is always associated with a difficult functional recovery process. A brain-computer interface (BCI) is a technology which provides a direct connection between the human brain and external devices. The primary aim of this study was to determine whether training with a BCI-controlled robot can improve functions in patients with subacute stroke. METHODS: Subacute stroke patients aged 32-68 years with a course of 2 weeks to 3 months were randomly assigned to the BCI group or to the sham group for a 4-week course. The primary outcome measures were Loewenstein Occupational Therapy Cognitive Assessment (LOCTA) and Fugl-Meyer Assessment for Lower Extremity (FMA-LE). Secondary outcome measures included Fugl-Meyer Assessment for Balance (FMA-B), Functional Ambulation Category (FAC), Modified Barthel Index (MBI), serum brain-derived neurotrophic factor (BDNF) levels and motor-evoked potential (MEP). RESULTS: A total of 28 patients completed the study. Both groups showed a significant increase in mean LOCTA (sham: P < 0.001, Cohen's d = - 2.972; BCI: P < 0.001, Cohen's d = - 4.266) and FMA-LE (sham: P < 0.001, Cohen's d = - 3.178; BCI: P < 0.001, Cohen's d = - 3.063) scores. The LOCTA scores in the BCI group were 14.89% higher than in the sham group (P = 0.049, Cohen's d = - 0.580). There were no significant differences between the two groups in terms of FMA-B (P = 0.363, Cohen's d = - 0.252), FAC (P = 0.363), or MBI (P = 0.493, Cohen's d = - 0.188) scores. The serum levels of BDNF were significantly higher within the BCI group (P < 0.001, Cohen's d = - 1.167), and the MEP latency decreased by 3.75% and 4.71% in the sham and BCI groups, respectively. CONCLUSION: Training with a BCI-controlled robot combined with traditional physiotherapy promotes cognitive function recovery, and enhances motor functions of the lower extremity in patients with subacute stroke. These patients also showed increased secretion of BDNF. TRIAL REGISTRATION: Chinese clinical trial registry: ChiCTR-INR-17012874.
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BACKGROUND: Maternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. METHODS: We examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. RESULTS: We showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). CONCLUSION: This study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-κB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection.
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BACKGROUND & AIMS: Data on long-term tenofovir alafenamide (TAF) therapy for pregnant women with active chronic hepatitis B (CHB) (immune clearance and reactivation phases, currently and previously diagnosed) and their infants are lacking. METHODS: Pregnant women with active CHB treated with TAF and tenofovir disoproxil fumarate (TDF) were enrolled in this multicenter prospective study, and infants received immunoprophylaxis. The primary outcomes were rates of adverse (safety) events in pregnant women and defects in infants and fetuses. The secondary outcomes were virologic responses in pregnant women, infants' safety, hepatitis B surface antigen (HBsAg) status, and growth conditions. RESULTS: One hundred three and 104 pregnant women were enrolled and 102 and 104 infants were born in the TAF and TDF groups, respectively. In the TAF group, the mean age, gestational age, alanine aminotransferase level, and viral loads at treatment initiation were 29.3 years, 1.3 weeks, 122.2 U/L, and 5.1 log10 IU/mL, respectively. TAF was well-tolerated, and the most common adverse event was nausea (29.1%) during a mean of 2 years of treatment. Notably, 1 (1.0%) TAF-treated pregnant woman underwent induced abortion due to noncausal fetal cleft lip and palate. No infants in either group had birth defects. In the TAF group, the hepatitis B e antigen seroconversion rate was 20.7% at postpartum month 6, infants had normal growth parameters, and no infants were positive for HBsAg at 7 months. The TDF group had comparable safety and effectiveness profiles. CONCLUSIONS: TAF administered throughout or beginning in early pregnancy is generally safe and effective for pregnant women with active CHB and their infants.
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Fenda Labial , Fissura Palatina , Hepatite B Crônica , Hepatite B , Feminino , Humanos , Gravidez , Recém-Nascido , Adulto , Antígenos de Superfície da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Gestantes , Estudos Prospectivos , Fenda Labial/induzido quimicamente , Fenda Labial/tratamento farmacológico , Fissura Palatina/induzido quimicamente , Fissura Palatina/tratamento farmacológico , Tenofovir/efeitos adversos , Adenina/efeitos adversos , China , Antivirais/efeitos adversos , Hepatite B/diagnósticoRESUMO
A. membranaceus is a traditional Chinese medicine that regulates blood sugar levels, suppresses inflammation, protects the liver, and enhances immunity. In addition, A. membranaceus is also widely used in diet therapy and is a well-known health tonic. Formononetin is a natural product isolated from A. membranaceus that has multiple biological functions, including anti-cancer activity. However, the mechanism by which formononetin inhibits tumor growth is not fully understood. In this present study, we demonstrated that formononetin suppresses PD-L1 protein synthesis via reduction of MYC and STAT3 protein expression. Furthermore, formononetin markedly reduced the expression of MYC protein via the RAS/ERK signaling pathway and inhibited STAT3 activation through JAK1/STAT3 pathway. Co-immunoprecipitation experiments illustrated that formononetin suppresses protein expression of PD-L1 by interfering with the interaction between MYC and STAT3. Meanwhile, formononetin promoted PD-L1 protein degradation via TFEB and TFE3-mediated lysosome biogenesis. T cell killing assay revealed that formononetin could enhance the activity of cytotoxic T lymphocytes (CTLs) and restore ability to kill tumor cells in a co-culture system of T cells and tumor cells. In addition, formononetin inhibited cell proliferation, tube formation, cell migration, and promoted tumor cell apoptosis by suppressing PD-L1. Finally, the inhibitory effect of formononetin on tumor growth was confirmed in a murine xenograft model. The present study revealed the anti-tumor potential of formononetin, and the findings should support further research and development of anti-cancer drugs for cervical cancer.
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Antígeno B7-H1/metabolismo , Carcinogênese/efeitos dos fármacos , Isoflavonas/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias do Colo do Útero/fisiopatologia , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Técnicas de Cocultura , Regulação para Baixo , Feminino , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Lisossomos/metabolismo , Biogênese de Organelas , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Linfócitos T/imunologia , Neoplasias do Colo do Útero/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that can cause liver diseases in the host, including hepatitis and hepatomegaly. High mobility group box 1 (HMGB1) is the main inflammatory mediator causing cell injury or necrosis. HMGB1 binds to toll like receptor 4 (TLR4), then activates the nuclear factor-κB (NF-κB) signaling pathway, which promotes the release of inflammatory factors. Our previous studies showed that HMGB1 mediated TLR4/NF-κB signaling pathway plays an important role in liver injury induced by T. gondii infection. Resveratrol (RSV) is a small polyphenol, which has anti-inflammatory, anti-cancer, anti-T. gondii effect. However, the effect of RSV on liver injury caused by T. gondii infection is unclear. This study used the RH strain tachyzoites of T. gondii to infect murine liver line, NCTC-1469 cells to establish an in vitro model and acute infection of mice for the in vivo model to explore the protective effect of RSV on liver injury induced by T. gondii infection. The results showed that RSV inhibited the proliferation of T. gondii in the liver, reduced the alanine aminotransferase/aspartate aminotransferase levels and pathological liver damage. Additionally, RSV inhibited the production of tumor necrosis factor-α, inducible nitric oxide synthase and HMGB1 by interfering with the TLR4/NF-κB signaling pathway. These results indicate that RSV can protect liver injury caused by T. gondii infection by intervening in the HMGB1/TLR4/NF-κB signaling pathway. This study will provide a theoretical basis for RSV treatment of T. gondii infection induced liver injury.
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Hepatite Animal/prevenção & controle , Fígado/efeitos dos fármacos , Resveratrol/farmacologia , Toxoplasmose/complicações , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Proteína HMGB1/metabolismo , Hepatite Animal/imunologia , Hepatite Animal/parasitologia , Hepatite Animal/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/patologia , Humanos , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Camundongos , NF-kappa B/metabolismo , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/metabolismo , Toxoplasmose/tratamento farmacológico , Toxoplasmose/imunologia , Toxoplasmose/parasitologiaRESUMO
The programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is abnormally expressed in cervical cancer cells. Moreover, PD-1/PD-L1 blockade reduces the apoptosis and exhaustion of T cells and inhibits the development of malignant tumors. Usnic acid is a dibenzofuran compound originating from Usnea diffracta Vain and has anti-inflammatory, antifungal, and anticancer activities. However, the molecular mechanism of its antitumor effects has not been fully elucidated. In this work, we first observed that usnic acid decreased the expression of PD-L1 in HeLa cells and enhanced the cytotoxicity of co-cultured T cells toward tumor cells. Usnic acid inhibited PD-L1 protein synthesis by reducing STAT3 and RAS pathways cooperatively. It was subsequently shown that usnic acid induced MiT/TFE nuclear translocation through the suppression of mTOR signaling pathways, and promoted the biogenesis of lysosomes and the translocation of PD-L1 to the lysosomes for proteolysis. Furthermore, usnic acid inhibited cell proliferation, angiogenesis, migration, and invasion, respectively, by downregulating PD-L1, thereby inhibiting tumor growth. Taken together, our results show that usnic acid is an effective inhibitor of PD-L1 and our study provide novel insights into the mechanism of its anticancer targeted therapy.
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Antígeno B7-H1 , Benzofuranos/farmacologia , Proliferação de Células/efeitos dos fármacos , Linfócitos T/imunologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Células HeLa , Humanos , Parmeliaceae/químicaRESUMO
BACKGROUND: Programmed cell death-ligand 1 (PD-L1) is overexpressed in tumor cells, which causes tumor cells to escape T cell killing, and promotes tumor cell survival, cell proliferation, migration, invasion, and angiogenesis. Britannin is a natural product with anticancer pharmacological effects. PURPOSE: In this work, we studied the anticancer potential of britannin and explored whether britannin mediated its effect by inhibiting the expression of PD-L1 in tumor cells. METHODS: In vitro, the mechanisms underlying the inhibition of PD-L1 expression by britannin were investigated by MTT assay, homology modeling and molecular docking, RT-PCR, western blotting, co-immunoprecipitation, and immunofluorescence. The changes in tumor killing activity, cell proliferation, cell cycle, migration, invasion, and angiogenesis were analyzed by T cell killing assays, EdU labeling, colony formation, flow cytometry, wound healing, matrigel transwell invasion, and tube formation, respectively. In vivo, the antitumor activity of britannin was evaluated in the HCT116 cell xenograft model. RESULTS: Britannin reduced the expression of PD-L1 in tumor cells by inhibiting the synthesis of the PD-L1 protein but did not affect the degradation of the PD-L1 protein. Britannin also inhibited HIF-1α expression through the mTOR/P70S6K/4EBP1 pathway and Myc activation through the Ras/RAF/MEK/ERK pathway. Mechanistically, britannin inhibited the expression of PD-L1 by blocking the interaction between HIF-1α and Myc. In addition, britannin could enhance the activity of cytotoxic T lymphocytes and inhibit tumor cell proliferation and angiogenesis by inhibiting PD-L1. Finally, in vivo observations were confirmed by demonstrating the antitumor activity of britannin in a murine xenograft model. CONCLUSION: Britannin inhibits the expression of PD-L1 by blocking the interaction between HIF-1α and Myc. Moreover, britannin stabilizes T cell activity and inhibits proliferation and angiogenesis by inhibiting PD-L1 in cancer. The current work highlights the anti-tumor effect of britannin, providing insights into the development of cancer therapeutics via PD-L1 inhibition.
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Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lactonas/farmacologia , Neovascularização Patológica/tratamento farmacológico , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Sesquiterpenos/farmacologia , Linfócitos T/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Lactonas/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neovascularização Patológica/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/química , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sesquiterpenos/química , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium chrysotoxum Lindl is a cultivation of Dendrobium which belongs to the family of Orchidaceae. D. chrysotoxum Lindl is a traditional Chinese medicine with a wide range of clinical applications including tonic, astringent, analgesic and anti-inflammatory properties as early as the 28th century B.C. Erianin is a representative index component for the quality control of the D. chrysotoxum Lindl, which is included in the Pharmacopoeia of the People's Republic of China (2020 version). AIM OF THE STUDY: To clarify the anti-tumour mechanisms of erianin in vitro and in vivo. MATERIALS AND METHODS: We detected the anti-tumour activity of erianin using in vitro HeLa cell models and in vivo cervical cancer xenograft models. We performed MTT, western blot, RT-PCR, homology modeling, flow cytometry, and immunoprecipitation assays to study the proteins, genes, and pathways related to erianin's anti-tumour activity. LysoTracker Red staining was performed to detect lysosome function. Transwell, wound healing, tube formation, colony formation and EdU labelling assays were performed to determine cell proliferation, migration and invasion abilities, respectively. Cytotoxic T lymphocytes ability was confirmed using HeLa/T-cell co-culture model. RESULTS: Experimental data demonstrated that erianin inhibited PD-L1 expression and induced the lysosomal degradation of PD-L1. Erianin suppressed HIF-1α synthesis through mTOR/p70S6K/4EBP1 pathway, and inhibited RAS/Raf/MEK/MAPK-ERK pathway. Immunoprecipitation experiments demonstrated that erianin reduced the interaction between RAS and HIF-1α. Experiments using a co-cultivation system of T cells and HeLa cells confirmed that erianin restored cytotoxic T lymphocytes ability to kill tumour cells. Erianin inhibited PD-L1-mediated angiogenesis, proliferation, invasion and migration. The anti-proliferative effects of erianin were supported using in vivo xenotransplantation experiments. CONCLUSIONS: Collectively, these results revealed previously unknown properties of erianin and provided a new basis for improving the efficacy of immunotherapy against cervical cancer and other malignant tumours through PD-L1.
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Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Bibenzilas/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Fenol/farmacologia , Linfócitos T Citotóxicos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Bibenzilas/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Lisossomos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neovascularização Patológica/metabolismo , Fenol/uso terapêutico , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/metabolismo , Proteínas ras/metabolismoRESUMO
BACKGROUND: Ginsenoside Rh2 (GRh2) is a characterized component in red ginseng widely used in Korea and China. GRh2 exhibits a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer properties. However, its effects on Toxoplasma gondii (T. gondii) infection have not been clarified yet. METHODS: The effect of GRh2 against T. gondii was assessed under in vitro and in vivo experiments. The BV2 cells were infected with tachyzoites of T. gondii RH strain, and the effects of GRh2 were evaluated by MTT assay, morphological observations, immunofluorescence staining, a trypan blue exclusion assay, reverse transcription PCR, and Western blot analyses. The in vivo experiment was conducted with BALB/c mice inoculated with lethal amounts of tachyzoites with or without GRh2 treatment. RESULTS AND CONCLUSION: The GRh2 treatment significantly inhibited the proliferation of T. gondii under in vitro and in vivo studies. Furthermore, GRh2 blocked the activation of microglia and specifically decreased the release of inflammatory mediators in response to T. gondii infection through TLR4/NF-κB signaling pathway. In mice, GRh2 conferred modest protection from a lethal dose of T. gondii. After the treatment, the proliferation of tachyzoites in the peritoneal cavity of infected mice markedly decreased. Moreover, GRh2 also significantly decreased the T. gondii burden in mouse brain tissues. These findings indicate that GRh2 exhibits an anti-T. gondii effect and inhibits the microglial activation through TLR4/NF-κB signaling pathway, providing the basic pharmacological basis for the development of new drugs to treat toxoplasmic encephalitis.
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BACKGROUND: None of the current guidelines recommend antiviral therapy for inactive hepatitis B virus (HBV) carriers (IHCs). METHODS: In this real-world, multicenter, nonrandomized study, 32 participants meeting the inclusion criteria were enrolled 1:1 for treatment with peginterferon α-2b or monitoring without treatment based on participant preference. The expected treatment duration was 48 weeks. The primary end point was hepatitis B surface antigen (HBsAg) loss. The HBV vaccine could be injected after HBsAg loss. RESULTS: All patients had HBsAg levels of <20 IU/mL. The mean baseline HBsAg levels were 6.6 IU/mL and 5.8 IU/mL in the treated and untreated groups, respectively. Fifteen (93.8%) participants achieved HBsAg loss, 5 obtained HBsAg seroconversion after undergoing a mean of 19.7 weeks of therapy in the treated group, and no one in the follow-up group achieved HBsAg loss during a mean follow-up time of 12.6 months (P < .0001). Generally, the therapy was well tolerated. Nine of 11 individuals who exhibited HBsAg loss benefited from receiving the HBV vaccine. CONCLUSIONS: This study provides justification for further studies of short-course peginterferon α-2b for the functional cure of IHCs with low HBsAg levels. Additionally, HBV vaccine injection is beneficial after interferon-induced HBsAg loss.
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Inflammation is a potential factor in the pathophysiology of depression. A traditional Chinese herbal medicine, arctiin, and its aglycone, arctigenin, are the major bioactive components in Fructus arctii and exhibit neuroprotective and anti-inflammatory activities. Arctigenin has been reported to have antidepressant-like effects. However, the antidepressant-like effects of arctiin, its precursor, remain unknown. In this study, we investigated the antidepressant-like effects of arctiin and its underlying mechanisms by in vivo and in vitro experiments in mice. Our results showed that arctiin significantly attenuated sucrose consumption and increased the immobility time in tail suspension and forced swimming tests. Arctiin decreased neuronal damage in the prefrontal cortex (PFC) of the brain. Arctiin also attenuated the levels of three inflammatory mediators, indoleamine 2,3-dioxygenase, 5-hydroxytryptamine, and dopamine, that were elevated in the PFC or serum of chronic unpredictable mild stress (CUMS)-exposed mice. Arctiin reduced excessive activation of microglia and neuroinflammation by reducing high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4)- and tumor necrosis factor-α (TNF-α)/TNF receptor 1 (TNFR1)-mediated nuclear factor-kappa B (NF-κB) activation in the PFC of CUMS-exposed mice and HMGB1- or TNF-α-stimulated primary cultured microglia. These findings demonstrate that arctiin ameliorates depression by inhibiting the activation of microglia and inflammation via the HMGB1/TLR4 and TNF-α/TNFR1 signaling pathways.
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Proteína HMGB1 , NF-kappa B , Animais , Antidepressivos/farmacologia , Depressão , Furanos , Glucosídeos , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral , Receptor 4 Toll-Like , Fator de Necrose Tumoral alfaRESUMO
Currently, COVID-19 has been reported in nearly all countries globally. To date, little is known about the viral shedding duration, clinical course and treatment efficacy of COVID-19 near Hubei Province, China. This multicentre, retrospective study was performed in 12 hospitals in Henan and Shaanxi Provinces from 20 January to 8 February 2020. Clinical outcomes were followed up until 26 March 2020. The viral shedding duration, full clinical course and treatment efficacy were analysed in different subgroups of patients. A total of 149 COVID-19 patients were enrolled. The median age was 42 years, and 61.1% (91) were males. Of them, 133 (89.3%) had fever, 131 of 144 (91%) had pneumonia, 27 (18.1%) required intensive care unit (ICU) management, 3 (2%) were pregnant, and 3 (2%) died. Two premature newborns were negative for SARS-CoV-2. In total, the median SARS-CoV-2 shedding period and clinical course were 12 (IQR: 9-17; mean: 13.4, 95% CI: 12.5, 14.2) and 20 (IQR: 16-24; mean: 21.2, 95% CI: 20.1, 22.3) days, respectively, and ICU patients had longer median viral shedding periods (21 [17-24] versus 11 [9-15]) and clinical courses (30 [22-33] vs. 19 [15.8-22]) than non-ICU patients (both p < .0001). SARS-CoV-2 clearances occurred at least 2 days before fatality in 3 non-survivors. Current treatment with any anti-viral agent or combination did not present the benefit of shortening viral shedding period and clinical course (all p > .05) in real-life settings. In conclusion, the viral shedding duration and clinical course in Henan and Shaanxi Provinces were shorter than those in Hubei Province, and current anti-viral therapies were ineffective for shortening viral shedding duration and clinical course in real-world settings. These findings expand our knowledge of the SARS-CoV-2 infection and may be helpful for management of the epidemic outbreak of COVID-19 worldwide. Further studies concerning effective anti-viral agents and vaccines are urgently needed.
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Antivirais/administração & dosagem , COVID-19/terapia , SARS-CoV-2/fisiologia , Eliminação de Partículas Virais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/virologia , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Toxoplasmosis is a parasitic zoonosis with the highest incidence in humans. Severe lesions due to acute toxoplasmosis have been recorded in the visceral organs including the liver, where hepatocytes and Kupffer cells are important innate immune cells. Arctigenin (AG) is a bioactive ingredient of Arctium lappa L. and increasing evidence suggests that AG exhibits anti-oxidant, anti-inflammatory and anti-Toxoplasma gondii (T. gondii) effects. However, the role of AG in acute liver damage induced by T. gondii infection remains unclear. In this study, we analyzed the effects of AG against T. gondii-induced liver damage by establishing an in vitro infection model using a murine liver cell line (NCTC-1469 cells) and an in vivo mouse model with acute T. gondii infection of virulent RH strain. In the current study, AG effectively attenuated hepatocytes apoptosis and inhibited the reproduction of T. gondii. The results of in vitro and in vivo studies showed that AG significantly reduced alanine aminotransferase/aspartate aminotransferase activities and lessened pathological damage of liver. Moreover, AG suppressed T. gondii-induced inducible nitric oxide synthase production. AG also attenuated liver inflammation by inhibiting T. gondii-induced activation of the high-mobility group box1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway. These findings demonstrated that AG exhibited prominent hepatoprotective activities in toxoplasmic liver injury with anti-inflammatory effects by inhibiting the HMGB1/TLR4/NF-κB signaling axis. Thus, this study provides the basis for the development of new drugs to treat toxoplasmic hepatitis.
Assuntos
Furanos/uso terapêutico , Lignanas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Toxoplasmose/tratamento farmacológico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Linhagem Celular , Feminino , Furanos/farmacologia , Proteína HMGB1/imunologia , Lignanas/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Toxoplasma , Toxoplasmose/imunologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma wenyujin is a Chinese traditional herbal medicine that is commonly used as an anti-oxidant, anti-proliferative, and anti-tumorigenic agent. Curcumol is a representative index component for the quality control of the essential oil of Curcuma wenyujin, which is currently used as an anti-cancer drug, and is included in the State Pharmacopoeia Commission of the People's Republic of China (2005). However, the mechanisms of action and molecular functions of curcumol are not yet fully elucidated. AIM OF THE STUDY: This study aimed to identify new effects of curcumol from the perspective of cancer immunotherapy. MATERIALS AND METHODS: The underlying mechanism of the inhibition of programmed cell death-ligand 1 (PD-L1) activation by curcumol was investigated in vitro via homology modeling, molecular docking experiments, luciferase reporter assays, MTT assays, RT-PCR, western blotting, and immunofluorescence assays. Changes in cellular proliferation, angiogenesis, and the tumor-killing activity of T-cells were analyzed via EdU labeling, colony formation, flow cytometry, wound-healing, Matrigel Transwell invasion, tube formation, and T-cell killing. The anti-tumor activity of curcumol was assessed in vivo in a murine xenograft model using Hep3B cells. RESULTS: Curcumol reduced the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) via JAK1, JAK2, and Src pathways and inhibited hypoxia-inducible factor-1α (HIF-1α) protein synthesis via mTOR/p70S6K/eIF4E and MAPK pathways. Furthermore, we revealed crosstalk between STAT3 and HIF-1α pathways, which collaboratively regulated PD-L1 activation, and that curcumol played a role in this regulation. Curcumol inhibited cell proliferation, S-phase progression, tube formation, invasion, and metastasis by inhibiting PD-L1. In addition, curcumol restored the activity of cytotoxic T-cells and their capacity for tumor cell killing by inhibiting PD-L1. In vivo experiments confirmed that curcumol inhibited tumor growth in a xenograft model. CONCLUSIONS: These results illustrated that curcumol inhibits the expression of PD-L1 through crosstalk between HIF-1α and p-STAT3 (T705) signaling pathways in hepatic cancer. Thus, curcumol might represent a promising lead compound for the development of new targeted anti-cancer therapeutics.
Assuntos
Antígeno B7-H1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/farmacologia , Células A549 , Animais , Linhagem Celular Tumoral , Células HeLa , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Janus Quinase 2 , Masculino , Camundongos , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neovascularização Patológica/tratamento farmacológico , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Panaxadiol is a triterpenoid sapogenin monomeric compound found in the roots of Panax ginseng and has a variety of biological activities such as neuroprotective and anti-tumour functions. However, the mechanisms how panaxadiol exerts the anticancer effects remain unknown. The current study aimed to investigate the potential activity of panaxadiol on programmed cell death-ligand 1 (PD-L1) expression and tumour proliferation in human colon cancer cells and to identify the underlying mechanism. Results showed that panaxadiol showed little cytotoxicity as assessed by a cytotoxicity assay and significantly inhibited PD-L1 expression at the protein and mRNA level in a dose-dependent manner. Furthermore, panaxadiol supressed the hypoxia-induced synthesis of hypoxia-inducible factor (HIF)-1α via the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways without affecting HIF-1α degradation. Simultaneously, panaxadiol inhibited STAT3 activation through the JAK1, JAK2, and Src pathways. Moreover, pre-treatment with panaxadiol enhanced the activity of cytotoxic T lymphocytes (CTL) and regained their capacity of tumour cell killing in a T cell and tumour cell co-culture system. Immunoprecipitation showed that panaxadiol inhibited PD-L1 expression by blocking the interaction between HIF-1α and STAT3. The inhibitory effect of panaxadiol on tumour proliferation was further demonstrated by colony formation and EdU labelling assays. The anti-proliferative effect of panaxadiol was also proved by a xenograft assay in vivo. Taken together, the current work highlights the anti-tumour effect of panaxadiol, providing insights into development of cancer therapeutic through PD-L1 inhibition.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Ginsenosídeos/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Convallatoxin (CNT) is a cardiac glycoside isolated from Adonis amurensis Regel et Radde and has both anti-inflammatory and anti-proliferative properties. In the present study, the anti-inflammatory mechanisms of action of CNT was investigated in vitro and in vivo. Stimulation of mouse macrophages with lipopolysaccharide induced secretion of proinflammatory cytokines via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) and activation of nuclear factor-κB (NF-κB), two transcription factors implicated in many inflammatory diseases. Notably, the effects of lipopolysaccharide were reversed by concomitant treatment of macrophages with CNT. Knockdown of PPARγ by siRNA inhibited the effect of convallatoxin on NF-κB activation. Because these transcription factors play a role in the development of ulcerative colitis in humans, the mice with experimental colitis induced by dextran sodium sulfate (DSS) was employed. Indeed, concomitant treatment with CNT ameliorated DSS-induced colitis symptoms, tissue damage, inflammatory cell infiltration, and proinflammatory cytokine production in the colon, and also reversed the activation of NF-κB and suppression of PPARγ. Collectively, these data indicate that CNT ameliorates colitic inflammation via activation of PPARγ and suppression of NF-κB, and suggest that CNT may be a promising treatment for inflammatory bowel disease (IBD).
Assuntos
Anti-Inflamatórios/farmacologia , Colite/metabolismo , Citocinas/metabolismo , NF-kappa B/antagonistas & inibidores , Estrofantinas/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/sangue , Citocinas/genética , Sulfato de Dextrana , Feminino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos , Estrofantinas/uso terapêuticoRESUMO
Dictamnine (DTM) is a natural alkaloid isolated from the root of Dictamnus dasycarpus Turcz and has been shown to exhibit multiple biological functions, including anti-inflammatory, antifungal, anti-angiogenic and anticancer activity. However, the mechanisms by which dictamnine inhibits tumor growth are not fully understood. In this study, we investigated the effectiveness of dictamnine as a treatment for cancer and to identify the underlying mechanisms of its anticancer activity. Here, dictamnine showed the potent inhibitory activity against HIF-1α and Slug activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α and Slug protein in a dose-dependent manner. Further analysis revealed that dictamnine inhibited HIF-1α protein synthesis, without affecting its degradation. Our results demonstrated that dictamnine reduced HIF-1α protein synthesis by downregulating the mTOR/p70S6K/eIF4E and MAPK pathways, and reduced the expression of Slug by inhibiting the GSK-3ß/Slug signaling pathway. Moreover, epithelial-mesenchymal transition (EMT) was inhibited in dictamnine-treated tumors by downregulation of HIF-1α and Slug, as reflected by the upregulation of E-cadherin and Occludin, and the downregulation of N-cadherin and Vimentin. Phenomenological experiments showed that dictamnine reduced migration and invasion, inhibited HCT116â¯cell proliferation and promoted HCT116â¯cell apoptosis by downregulating HIF-1α and Slug. In vivo studies further confirmed that dictamnine treatment caused significant inhibition of tumor growth in a xenograft tumor model. These findings suggest that dictamnine is a potent cancer inhibitor, providing a rationale for anticancer pathway-targeted therapy.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinolinas/farmacologia , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Dictamnus/química , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Raízes de Plantas/química , Quinolinas/química , Quinolinas/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
BACKGROUND: Scavenger receptor class B type I (SR-BI) has been reported to be involved in carcinogenesis of several human cancers. However, it is currently unknown whether SR-BI plays a role in clear cell renal cell carcinoma (ccRCC). Here, we aimed to evaluate a tumor promotive mechanism for SR-BI in ccRCC. METHODS: The expression of SR-BI was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry (IHC) in ccRCC tissues and cell lines. Lipid droplets in ccRCC tissues and normal kidney tissues were examined by Oil Red O (ORO) and hematoxylin-eosin (HE) staining. The correlation between SR-BI mRNA levels and clinicopathological features was analyzed by Pearson's chi-square test or Fisher's exact test. Kaplan-Meier analysis and Cox model were used to evaluate the difference in progression-free survival (PFS) associated with expression of SR-BI. Inhibition of SR-BI was conducted by using small interfering RNA (siRNA). In vitro assays were performed to assess the impact of SR-BI knockdown on cell biological behaviors. High density lipoprotein (HDL)-cholesterol content in ccRCC cells and extracellular media was also measured after transfection with siRNA. RESULTS: The expression of SR-BI was markedly up-regulated in ccRCC tissues and tumor cell lines. ORO and HE staining revealed huge amounts of lipid droplets accumulation in ccRCC. Clinical analysis showed that over-expression of SR-BI was positively associated with tumor size, grade, distant metastasis and inversely correlated with PFS. Furthermore, SR-BI was proved to be an independent prognostic marker in ccRCC patients. The inhibition of SR-BI attenuated the tumorous behaviors of ccRCC cells, expression of metastasis and AKT pathway related proteins. The content of HDL-cholesterol was reduced in cells while increased in extracellular media after transfection with si-SR-BI. CONCLUSIONS: Our results demonstrate that SR-BI functions as an oncogene and promotes progression of ccRCC. SR-BI may serve as a potential prognostic biomarker and therapeutic target for ccRCC.