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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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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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Labio Leporino , Fisura del Paladar , Hepatitis B Crónica , Hepatitis B , Femenino , Humanos , Embarazo , Recién Nacido , Adulto , Antígenos de Superficie de la Hepatitis B , Hepatitis B Crónica/tratamiento farmacológico , Mujeres Embarazadas , Estudios Prospectivos , Labio Leporino/inducido químicamente , Labio Leporino/tratamiento farmacológico , Fisura del Paladar/inducido químicamente , Fisura del Paladar/tratamiento farmacológico , Tenofovir/efectos adversos , Adenina/efectos adversos , China , Antivirales/efectos adversos , Hepatitis B/diagnósticoRESUMEN
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/farmacología , Proliferación Celular/efectos de los fármacos , Linfocitos T/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Línea Celular Tumoral , Células HeLa , Humanos , Parmeliaceae/químicaRESUMEN
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.
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Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Ginsenósidos/uso terapéutico , Animales , Antineoplásicos/farmacología , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Ginsenósidos/farmacología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
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).
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Antiinflamatorios/farmacología , Colitis/metabolismo , Citocinas/metabolismo , FN-kappa B/antagonistas & inhibidores , Estrofantinas/farmacología , Animales , Antiinflamatorios/uso terapéutico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/genética , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Citocinas/sangre , Citocinas/genética , Sulfato de Dextran , Femenino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Células RAW 264.7 , ARN Interferente Pequeño , Transducción de Señal/efectos de los fármacos , Estrofantinas/uso terapéuticoRESUMEN
Low-level and unstable transgene expression are common issues using the CHO cell expression system. Matrix attachment regions (MARs) enhance transgene expression levels, but additional research is needed to improve their function and to determine their mechanism of action. MAR-6 from CHO chromosomes actively mediates high and consistent gene expression. In this study, we compared the effects of two new MARs and MAR-6 on transgene expression in recombinant CHO cells and found one potent MAR element that can significantly increase transgene expression. Two MARs, including the human CSP-B MAR element and DHFR intron MAR element from CHO cells, were cloned and inserted downstream of the poly(A) site in a eukaryotic vector. The constructs were transfected into CHO cells, and the expression levels and stability of eGFP were detected by flow cytometry. The three MAR sequences can be ranked in terms of overall eGFP expression, in decreasing order, as follows: human CSP-B, DHFR intron MAR element and MAR-6. Additionally, as expected, the three MAR-containing vectors showed higher transfection efficiencies and transient transgene expression in comparison with those of the non-MAR-containing vector. Bioinformatics analysis indicated that the NFAT and VIBP elements within MAR sequences may contribute to the enhancement of eGFP expression. In conclusion, the human CSP-B MAR element can improve transgene expression and its effects may be related to the NFAT and VIBP elements.
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Genoma Humano , Regiones de Fijación a la Matriz/genética , Transfección , Animales , Sitios de Unión , Células CHO , Cricetinae , Cricetulus , Dosificación de Gen , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteínas Recombinantes/metabolismo , Factores de Transcripción/metabolismo , TransgenesRESUMEN
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.
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Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Pronóstico , Receptores Depuradores de Clase B/genética , Adulto , Anciano , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , HDL-Colesterol/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , ARN Mensajero/genéticaRESUMEN
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a complex that regulates several hundreds of genes, including those involved in immunity and inflammation, survival, proliferation, and the negative feedback of NF-κB signaling. Chelidonine, a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus, exhibits antiinflammatory pharmacological properties. However, its antiinflammatory molecular mechanisms remain unclear. In this work, we explored the effect of chelidonine on TNF-induced NF-κB activation in HCT116 cells. We found chelidonine inhibited the phosphorylation and degradation of the inhibitor of NF-κB alpha and nuclear translocation of RELA. Furthermore, by inhibiting the activation of NF-κB, chelidonine downregulated target genes involved in inflammation, proliferation, and apoptosis. Chelidonine also inhibited mitogen-activated protein kinase pathway activation by blocking c-Jun N-terminal kinase and p38 phosphorylation. These results suggest that chelidonine may be a potential therapeutic agent against inflammatory diseases in which inhibition of NF-κB activity plays an important role.
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Benzofenantridinas/uso terapéutico , Alcaloides de Berberina/uso terapéutico , Células HCT116/metabolismo , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Apoptosis , Benzofenantridinas/administración & dosificación , Benzofenantridinas/farmacología , Alcaloides de Berberina/administración & dosificación , Alcaloides de Berberina/farmacología , Humanos , Transducción de Señal , TransfecciónRESUMEN
BACKGROUND & AIMS: Few patients from developing countries can afford brand name direct-acting antiviral agents for treating hepatitis C virus (HCV) infection, and controversy regarding the bioequivalence of generics exists. This study aimed to observe the safety and efficacy of 8 or 12weeks of generic ledipasvir-sofosbuvir with or without ribavirin for Chinese genotype 1b HCV-infected patients. METHODS: In this open-labelled observational study, 63 cirrhotic (group 1) and 65 non-cirrhotic (group 2) patients were administered generic ledipasvir-sofosbuvir plus 1000-1200mg of ribavirin daily for 12 and 8weeks, respectively; and 64 non-cirrhotic patients (group 3) received ledipasvir-sofosbuvir for 8weeks. The primary efficacy endpoint was undetectable HCV RNA at week 12 (SVR12) after cessation of therapy. Safety and pharmacokinetic data were collected. RESULTS: One hundred and eighty-seven patients completed treatment, and the latest undetectable HCV RNA was observed in three patients with cirrhosis at week 5 during treatment. Intention-to-treat analysis revealed 96.8% (61/63), 96.9% (63/65), and 96.9% (62/64) of SVR12 rates in groups 1, 2, and 3, respectively. One patient in group 3 relapsed at post-treatment week 4. The regimens were generally well-tolerated. The most common adverse events were fatigue (17.8%), diarrhea (10.9%), and headache (9.9%). Four patients discontinued therapy due to diarrhea and vomiting. One patient from group 2 discontinued treatment on day 29 because of drug-unaffordability; fortunately, she achieved SVR12. CONCLUSION: This study demonstrated that 8 or 12weeks of generic ledipasvir-sofosbuvir with or without ribavirin are safe and effective for patients with genotype 1b HCV infection. LAY SUMMARY: The price of Harvoni® has led to restrictions and access limitations in many developing and even developed countries with limited healthcare budgets. Gilead approved generic ledipasvir-sofosbuvir costs far less than Harvoni® and presents a similar cure rate for patients with chronic hepatitis C.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Medicamentos Genéricos/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Antivirales/administración & dosificación , Antivirales/economía , Bencimidazoles/administración & dosificación , Bencimidazoles/economía , China , Costos de los Medicamentos , Quimioterapia Combinada , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/economía , Femenino , Fluorenos/administración & dosificación , Fluorenos/economía , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Masculino , Turismo Médico/economía , Persona de Mediana Edad , ARN Viral/sangre , Ribavirina/administración & dosificación , Sofosbuvir , Respuesta Virológica Sostenida , Equivalencia Terapéutica , Resultado del Tratamiento , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/economía , Uridina Monofosfato/uso terapéutico , Carga ViralRESUMEN
CONTEXT: Amorfrutin A is a natural product isolated from the fruits of Amorpha fruticosa L. and has been shown to exhibit multiple bioeffector functions. In the present study, we investigated whether amorfrutin A exerts anticancer effects by inhibiting STAT3 activation in cervical cancer cells. OBJECTIVE: To investigate the effectiveness of amorfrutin A as a treatment of cancer, and determine the underlying pharmacological mechanism of action. MATERIALS AND METHODS: HeLa, SK-Hep1, MDA-MB-231 and HCT116 cells were used in this study. Major assays were luciferase reporter assay, MTT, Western blot analysis, immunofluorescence assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, EdU labeling and immunofluorescence, xenografted assay. RESULTS: Amorfrutin A significantly inhibited tumor necrosis factor-α (TNF-α)-induced phosphorylation and nuclear translocation of STAT3 in human cervical carcinoma cells. Amorfrutin A also inhibited activation of the upstream kinases Janus-activated kinase 1 (JAK1), JAK2 and Src signaling pathways. Furthermore, amorfrutin A increased the expression of p53, p21, p27, induced cell cycle arrest in the G1 phase as well as decreased levels of various oncogene protein products. In vivo studies further confirmed the inhibitory effect of amorfrutin A on the expression of STAT3 proteins, leading to a decrease growth of HeLa cells in a xenograft tumor model. DISCUSSION AND CONCLUSIONS: The results indicated that amorfrutin A is a potent inhibitor of STAT3 and provide new perspectives into the mechanism of its anticancer activity.
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Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Salicilatos/farmacología , Estilbenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Artemisinin, isolated from the Chinese plant Artemisia annua, has been used for many years to treat different forms of malarial parasites. In this study, we explored the anti-inflammatory activity of artemisinin and the underlying mechanism of this action. We demonstrated that the anti-inflammatory effects of artemisinin in TPA-induced skin inflammation in mice. Then the artemisinin significantly inhibited the expression of NF-κB reporter gene induced by TNF-α in a dose-dependent manner. Artemisinin also inhibited TNF-α induced phosphorylation and degradation of IκBα, p65 nuclear translocation. Artemisinin also has an impact on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Furthermore, pretreatment of cells with artemisinin prevented the TNF-α-induced expression of NF-κB target genes, such as anti-apoptosis (c-IAP1, Bcl-2, and FLIP), proliferation (COX-2, cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, iNOS, and MCP1). We also proved that artemisinin potentiated TNF-α-induced apoptosis. Moreover, artemisinin significantly impaired the ROS production and phosphorylation of p38 and ERK, but did not affect the phosphorylation of JNK. Taken together, artemisinin may be a potentially useful therapeutic agent for inflammatory-related diseases.
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Artemisininas/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/inmunología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Proteínas de Complejo Poro Nuclear/inmunología , Proteínas de Unión al ARN/inmunología , Factor 1 Asociado a Receptor de TNF/inmunología , Factor 2 Asociado a Receptor de TNF/inmunología , Factor de Necrosis Tumoral alfa/efectos adversos , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Nuclear factor-kappa B (NF-κB) has been reported to play a pivotal role in many physiological processes including inflammation, apoptosis, and angiogenesis. We discovered a potent natural NF-κB inhibitor, dihydromyricetin, from the traditional herb Ampelopsis grossedentata, which has a long history of use in food and medicine. In this study, we demonstrated the effect of dihydromyricetin on NF-κB activation in TNF-α-induced HeLa cells. Dihydromyricetin was found to markedly inhibit the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα), and subsequent nuclear translocation of p65. Dihydromyricetin also has an impact on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2), and receptor-interacting protein 1 (RIP1). Furthermore, the current results reveal that dihydromyricetin led to the downregulation of target genes involved in inflammation, proliferation, as well as potentiation of TNF-α-induced apoptosis through suppressing the activation of NF-κB. In conclusion, our data indicate that dihydromyricetin may be a potentially useful therapeutic agent for inflammatory diseases.
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Apoptosis/efectos de los fármacos , Núcleo Celular/metabolismo , Flavonoles/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Transporte Activo de Núcleo Celular/efectos de los fármacos , Células HeLa , Humanos , Quinasa I-kappa B/metabolismo , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismoRESUMEN
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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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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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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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 , Carcinogénesis/efectos de los fármacos , Isoflavonas/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias del Cuello Uterino/fisiopatología , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Técnicas de Cocultivo , Regulación hacia Abajo , Femenino , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Lisosomas/metabolismo , Biogénesis de Organelos , Proteínas Proto-Oncogénicas c-myc/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Linfocitos T/inmunología , Neoplasias del Cuello Uterino/inmunología , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Antivirales , Hepacivirus , Hepatitis C , Hepatitis C Crónica , Humanos , IncidenciaRESUMEN
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 , Bibencilos/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Fenol/farmacología , Linfocitos T Citotóxicos/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Bibencilos/uso terapéutico , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Lisosomas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Neovascularización Patológica/metabolismo , Fenol/uso terapéutico , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Linfocitos T Citotóxicos/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/metabolismo , Proteínas ras/metabolismoRESUMEN
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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Hepatitis Animal/prevención & control , Hígado/efectos de los fármacos , Resveratrol/farmacología , Toxoplasmosis/complicaciones , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Proteína HMGB1/metabolismo , Hepatitis Animal/inmunología , Hepatitis Animal/parasitología , Hepatitis Animal/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/inmunología , Hepatocitos/patología , Humanos , Hígado/citología , Hígado/inmunología , Hígado/patología , Ratones , FN-kappa B/metabolismo , Resveratrol/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Receptor Toll-Like 4/metabolismo , Toxoplasmosis/tratamiento farmacológico , Toxoplasmosis/inmunología , Toxoplasmosis/parasitologíaRESUMEN
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.