RESUMO
Renal fibrosis is the pathological change process of chronic kidney disease deteriorating continuously. When the renal organ is stimulated by external stimuli, it will trigger the damage and phenotypic changes of some intrinsic cells in the kidney. When the body's autoimmune regulation or external treatment is not prompted enough to restore the organ, the pathological process is gradually aggravating, inducing a large amount of intracellular collagen deposition, which leads to the appearance of fibrosis and scarring. The renal parenchyma (including glomeruli and tubules) begins to harden, making it difficult to repair the kidney lesions. In the process of gradual changes in the kidney tissue, the kidney units are severely damaged and the kidney function shows a progressive decline, eventually resulting in the clinical manifestation of end-stage renal failure, namely uremia. This review provides a brief description of the diagnosis, pathogenesis, and potential therapeutic inhibitors of renal fibrosis. Since renal fibrosis has not yet had a clear therapeutic target and related drugs, some potential targets and relevant inhibitors are discussed, especially pharmacological effects and interactions with targets. Some existing natural products have potential efficacy for renal fibrosis, which is also roughly summarized, hoping that this article would have reference significance for the treatment of renal fibrosis.
Assuntos
Produtos Biológicos , Nefropatias , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Rim , Nefropatias/tratamento farmacológico , Nefropatias/patologia , FibroseRESUMO
Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.
Assuntos
Neoplasias Encefálicas , Ferroptose , Glioblastoma , Humanos , Animais , Camundongos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Autofagossomos/metabolismo , Amidas/farmacologia , Transdução de Sinais , Lisossomos/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proteínas Qa-SNARERESUMO
Protein kinases constitute the largest group within the kinase family, and mutations and translocations of protein kinases due to genetic alterations are intimately linked to the pathogenesis of numerous diseases. Bruton's tyrosine kinase (BTK) is a member of the protein kinases and plays a pivotal role in the development and function of B cells. BTK belongs to the tyrosine TEC family. The aberrant activation of BTK is closely associated with the pathogenesis of B-cell lymphoma. Consequently, BTK has always been a critical target for treating hematological malignancies. To date, two generations of small-molecule covalent irreversible BTK inhibitors have been employed to treat malignant B-cell tumors, and have exhibited clinical efficacy in hitherto refractory diseases. However, these drugs are covalent BTK inhibitors, which inevitably lead to drug resistance after prolonged use, resulting in poor tolerance in patients. The third-generation non-covalent BTK inhibitor Pirtobrutinib has obtained approval for marketing in the United States, thereby circumventing drug resistance caused by C481 mutation. Currently, enhancing safety and tolerance constitutes the primary issue in developing novel BTK inhibitors. This article systematically summarizes recently discovered covalent and non-covalent BTK inhibitors and classifies them according to their structures. This article also provides a detailed discussion of binding modes, structural features, pharmacological activities, advantages and limitations of typical compounds within each structure type, providing valuable references and insights for developing safer, more effective and more targeted BTK inhibitors in future studies.
Assuntos
Neoplasias , Humanos , Relação Estrutura-Atividade , Tirosina Quinase da Agamaglobulinemia , Neoplasias/tratamento farmacológico , Linfócitos B/metabolismo , Inibidores de Proteínas Quinases/químicaRESUMO
Pulmonary fibrosis is the end-stage change of a large class of lung diseases characterized by the proliferation of fibroblasts and the accumulation of a large amount of extracellular matrix, accompanied by inflammatory damage and tissue structure destruction, which also shows the normal alveolar tissue is damaged and then abnormally repaired resulting in structural abnormalities (scarring). Pulmonary fibrosis has a serious impact on the respiratory function of the human body, and the clinical manifestation is progressive dyspnea. The incidence of pulmonary fibrosis-related diseases is increasing year by year, and no curative drugs have appeared so far. Nevertheless, research on pulmonary fibrosis have also increased in recent years, but there are no breakthrough results. Pathological changes of pulmonary fibrosis appear in the lungs of patients with coronavirus disease 2019 (COVID-19) that have not yet ended, and whether to improve the condition of patients with COVID-19 by means of the anti-fibrosis therapy, which are the questions we need to address now. This review systematically sheds light on the current state of research on fibrosis from multiple perspectives, hoping to provide some references for design and optimization of subsequent drugs and the selection of anti-fibrosis treatment plans and strategies.
Assuntos
COVID-19 , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , COVID-19/patologia , Pulmão , Fibrose , FibroblastosRESUMO
Triclocarban (TCC), an antimicrobial ingredient in personal care products, is associated with immunosuppression and physiological dysfunctions of aquatic organisms. The aim of this study was to investigate whether TCC can induce common carp NETosis (neutrophil death by neutrophil extracellular trap (NET) release) and then to attempt to identify the potential molecular mechanisms. Herein, scanning electron microscopy and flow cytometric assays showed that revealed that TCC triggers DNA-containing web-like structures and increases extracellular DNA content. In the proteomic analysis, we observed that NET-related proteins, extracellular regulated protein kinase (Mapk1, Mapk14, Jak2) and apoptotic protein (caspase3) were significantly increased, and defender against cell death 1 (Dad1) was significantly decreased after TCC treatments. Meanwhile, we confirmed that TCC stress can trigger NETosis in common carp by activating the reactive oxygen species (ROS)/ERK1/2/p38 signaling. We think that the upregulated NDUFS1 expression is closely related to oxidative stress induced by TCC. Importantly, we discovered that SIRT3 expression was significantly decreased in the process of TCC-induced NETs. Importantly, pretreatment with the SIRT3 agonist honokiol (HKL) effectively suppressed TCC-induced NET release. In contrast, the SIRT3 antagonist 3-TYP escalated TCC-induced NET formation. Mechanistically, SIRT3 degradation serves as a potential mediator for regulating oxidative stress crosstalk between ERK1/2/p38 signals in the process of TCC-induced NET formation. These findings unveil new insights into the TCC-evoked health risk of fish and other aquatic organisms and suggest that SIRT3 is a potential pharmacological intervention target to alleviate TCC-induced common carp NETosis.
Assuntos
Carpas , Armadilhas Extracelulares , Proteína Quinase 14 Ativada por Mitógeno , Sirtuína 3 , Animais , Carbanilidas , Carpas/genética , Carpas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Neutrófilos , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo , Sirtuína 3/farmacologiaRESUMO
BACKGROUND & AIMS: The nuclear factor of activated T-cells (NFAT) plays an important role in immune responses by regulating the expression of inflammatory genes. However, it is not known whether NFAT plays any role in the bile acid (BA)-induced hepatic inflammatory response. Thus, we aimed to examine the functional role of NFATc3 in cholestatic liver injury in mice and humans. METHODS: Gene and protein expression and cellular localization were assessed in primary hepatocyte cultures (mouse and human) and cholestatic liver tissues (murine models and patients with primary biliary cholangitis [PBC] or primary sclerosing cholangitis [PSC]) by quantitative PCR, western blot and immunohistochemistry. Specific NFAT inhibitors were used in vivo and in vitro. Gene reporter assays and ChIP-PCR were used to determine promoter activity. RESULTS: NFAT isoforms c1 and c3 were expressed in human and mouse hepatocytes. When treated with cholestatic levels of BAs, nuclear translocation of NFATc3 was increased in both human and mouse hepatocytes and was associated with elevated mRNA levels of IL-8, CXCL2, and CXCL10 in these cells. Blocking NFAT activation with pathway-specific inhibitors or knocking down Nfatc3 expression significantly decreased BA-driven induction of these cytokines in mouse hepatocytes. Nuclear expression of NFATc3/Nfatc3 protein was increased in cholestatic livers, both in mouse models (bile duct ligation or Abcb4-/- mice) and in patients with PBC and PSC in association with elevated tissue levels of Cxcl2 (mice) or IL-8 (humans). Gene reporter assays and ChIP-PCR demonstrated that the NFAT response element in the IL-8 promoter played a key role in BA-induced human IL-8 expression. Finally, blocking NFAT activation in vivo in Abcb4-/- mice reduced cholestatic liver injury. CONCLUSIONS: NFAT plays an important role in BA-stimulated hepatic cytokine expression in cholestasis. Blocking hepatic NFAT activation may reduce cholestatic liver injury in humans. LAY SUMMARY: Bile acid induces liver injury by stimulating the expression of inflammatory genes in hepatocytes through activation of the transcription factor NFAT. Blocking this activation in vitro (in hepatocyte cultures) and in vivo (in cholestatic mice) decreased the expression of inflammatory genes and reduced liver injury.
Assuntos
Colangite Esclerosante/metabolismo , Citocinas/metabolismo , Cirrose Hepática Biliar/metabolismo , Fígado/metabolismo , Fatores de Transcrição NFATC/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hepatócitos/metabolismo , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Transdução de Sinais/genética , Resultado do Tratamento , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor ß1 (TGFß1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.
Assuntos
1-Naftilamina/farmacologia , Descoberta de Drogas , Cirrose Hepática/tratamento farmacológico , 1-Naftilamina/síntese química , 1-Naftilamina/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Proteínas Smad/antagonistas & inibidores , Proteínas Smad/metabolismo , Relação Estrutura-AtividadeRESUMO
The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.
Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidadeRESUMO
Published studies indicate the MTHFR C677T and A1298C polymorphisms are associated with abnormal homocysteine levels, which may cause various pregnancy complications and birth defects. However, the results obtained from different studies have been inconsistent. Therefore, this meta-analysis explores the association between MTHFR polymorphisms and birth defects and adverse pregnancy outcomes. The PubMed, ScienceDirect, Embase, and China Biology Medicine literature databases and ClinicalTrials were searched. Analyses of public bias, meta-regression, subgroups, and sensitivity were used to ensure the robustness of our results. MTHFR C677T was significantly associated with recurrent pregnancy loss in developing countries (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.20-1.50) but not in developed countries (OR, 0.87; 95% CI, 0.68-1.11). No significant relationship was found between MTHFR A1298C and recurrent pregnancy loss (OR, 1.04; 95% CI, 0.93-1.18). MTHFR C677T and A1298C were not associated with preeclampsia (OR, 1.06; 95% CI, 0.97-1.16 and OR, 1.16; 95% CI, 0.97-1.39, respectively), and C677T was not associated with placental abruption (OR, 1.03; 95% CI, 0.87-1.21), intrauterine growth retardation (OR, 1.02; 95% CI, 0.90-1.15), or congenital heart disease (OR, 1.05; 95% CI, 0.89-1.25). MTHFR C677T, but not A1298C, was associated with neural tube defects (OR, 1.24; 95% CI, 1.08-1.42) and Down syndrome (OR, 1.65; 95% CI, 1.39-1.95). CONCLUSION: Although MTHFR C677T and A1298C are significantly associated with some types of congenital defects and adverse pregnancy outcomes, the impact of these polymorphisms is moderate.
Assuntos
Anormalidades Congênitas/enzimologia , Anormalidades Congênitas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Resultado da Gravidez/genética , Aborto Habitual/enzimologia , Aborto Habitual/genética , Ensaios Clínicos como Assunto , Países em Desenvolvimento , Síndrome de Down/enzimologia , Síndrome de Down/genética , Feminino , Retardo do Crescimento Fetal/enzimologia , Retardo do Crescimento Fetal/genética , Humanos , Defeitos do Tubo Neural/enzimologia , Defeitos do Tubo Neural/genética , Razão de Chances , GravidezRESUMO
BACKGROUND & AIMS: Cholestatic liver injury is mediated by bile acid-induced inflammatory responses. We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation. METHODS: Bile duct-ligated (BDL) rats and Mdr2(Abcb4)-/- mice were treated with all-trans retinoic acid (atRA), a potent inhibitor of bile acid synthesis, 5 mg/kg/d by gavage, or Cenicriviroc (CVC), a known antagonist of CCR2 and CCR5, 50 mg/kg/d alone or in combination for 14 days and 1 month respectively. RESULTS: All-trans retinoic acid alone reduced bile acid pool size and liver necrosis in BDL rats. However, the combination with CVC further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the atRA treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro-inflammatory cytokines emphasizing the synergistic effects of these two agents. Profiling of hepatic inflammatory cells revealed that combination therapy reduced neutrophils and T cells but not macrophages. The superior therapeutic effects of combination treatment were also confirmed in Mdr2-/- mice where a significant reduction in plasma liver enzymes, bilirubin, liver fibrosis, bile duct proliferation and hepatic infiltration of neutrophils and T cells and expression of cytokines were found. CONCLUSIONS: Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of CVC with atRA or other FXR activators may warrant a clinical trial in patients with cholestatic liver disease.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/tratamento farmacológico , Imidazóis/farmacologia , Hepatopatias/tratamento farmacológico , Tretinoína/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Colestase/complicações , Colestase/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Ligadura , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Receptores de Citocinas/antagonistas & inibidores , Sulfóxidos , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
The Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na+-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [3H]TCA uptake assay revealed that skSlc10a1 functioned as a Na+-dependent transporter, but with low affinity for TCA (Km = 92.4 µM) and scymnol sulfate (Ki = 31 µM), compared with hNTCP (TCA, Km = 5.4 µM; Scymnol sulfate, Ki = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na+-dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution.
Assuntos
Ácidos e Sais Biliares/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Rajidae/metabolismo , Sódio/metabolismo , Simportadores/química , Simportadores/metabolismo , Ácido Taurocólico/metabolismo , Animais , Ácidos e Sais Biliares/química , Sítios de Ligação , Humanos , Fígado/metabolismo , Especificidade de Órgãos , Transportadores de Ânions Orgânicos Dependentes de Sódio/sangue , Ligação Proteica , Homologia de Sequência , Rajidae/classificação , Sódio/química , Especificidade da Espécie , Relação Estrutura-Atividade , Simportadores/sangue , Ácido Taurocólico/química , Distribuição TecidualRESUMO
Recently, tumor initiating cells are considered as the central role of tumorigenicity in hepatocellular carcinoma. Enediyne anticancer antibiotic lidamycin with great potential antitumor activity is currently evaluated in Phase II clinical trials. In this study, we evaluated the effect of lidamycin on tumor initiating cells of hepatocellular carcinoma Huh7 and identified the potential mechanism. Flow cytometry analysis and sorting assay, surface marker assay, sphere formation assay, and aldefluor assay were used to evaluate the effect of lidamycin on Huh7 tumor initiating cells in vitro. To investigate the potential mechanism, the activity of GSK3ß/ß-catenin pathway was detected by Western blot and T cell factors transcriptional activity assay. Subcutaneous tumor model in nude mice was used to observe in vivo effect of lidamycin on Huh7 cells. Lidamycin decreased the proportion of EpCAM+ cells and the expression of EpCAM protein. Lidamycin inhibited sphere formation of sorted EpCAM+ cells in 7 d, and of parental cells in three serial passages. The population of aldehyde dehydrogenase-positive cells was reduced by lidamycin. In addition, lidamycin restrained tumor volume and incidence in vivo. Lidamycin activated GSK3ß, and degraded the activity of ß-catenin. Consequently, transcriptional activity of ß-catenin/T cell factors was decreased. In brief, these results suggest that lidamycin suppressed Huh7 tumor initiating cells via GSK3ß/ß-catenin pathway. These findings reveal the potential mechanism of lidamycin on tumor initiating cells and the benefit for further clinical evaluation.
Assuntos
Aminoglicosídeos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Enedi-Inos/farmacologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas Experimentais , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismoRESUMO
AIM: (-)-Epigallocatechin-3-gallate (EGCG) is one of the most abundant polyphenols in green tea with strong antioxidant activity and various therapeutic effects. In this study, we investigated the anti-fibrotic effects of EGCG and underlying mechanisms in bile duct-ligated (BDL) rats and a liver fibrosis model in vitro. METHODS: BDL rats were treated with EGCG (25 mg·kg(-1)·d(-1), po) for 14 d, and then the serum, bile and liver samples were collected. Liver fibrosis was assessed by serum, urine and bile biochemistry analyses and morphological studies of liver tissues. TGF-ß1-stimulated human hepatic stellate LX-2 cells were used as a liver fibrosis model in vitro. The expression of liver fibrogenic genes and signaling proteins in the PI3K/Akt/Smad pathway was examined using Western blotting and/or real-time PCR. RESULTS: In BDL rats, EGCG treatment significantly ameliorates liver necrosis, inflammation and fibrosis, and suppressed expression of the genes associated with liver inflammation and fibrogenesis, including TNF-α, IL-1ß, TGF-ß1, MMP-9, α-SMA, and COL1A1. In LX-2 cells, application of EGCG (10, 25 µmol/L) dose-dependently suppressed TGF-ß1-stimulated expression of COL1A1, MMP-2, MMP-9, TGF-ß1, TIMP1, and α-SMA. Furthermore, EGCG significantly suppressed the phosphorylation of Smad2/3 and Akt in the livers of BDL rats and in TGF-ß1-stimulated LX-2 cells. Application of LY294002, a specific inhibitor of PI3K, produced similar effects as EGCG did in TGF-ß1-stimulated LX-2 cells, but co-application of EGCG and LY294002 did not produce additive effects. CONCLUSION: EGCG exerts anti-fibrotic effects in BDL rats and TGF-ß1-stimulated LX-2 cells in vitro via inhibiting the PI3K/Akt/Smad pathway.
Assuntos
Catequina/análogos & derivados , Colestase/complicações , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Transdução de Sinais/efeitos dos fármacos , Animais , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Catequina/uso terapêutico , Linhagem Celular , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Smad/metabolismoRESUMO
Drug-induced liver injury is a prevalent severe adverse event in clinical settings, leading to increased medical burdens for patients and presenting challenges for the development and commercialization of novel pharmaceuticals. Research has revealed a close association between gut microbiota and drug-induced liver injury in recent years. However, there has yet to be a consensus on the specific mechanism by which gut microbiota is involved in drug-induced liver injury. Gut microbiota may contribute to drug-induced liver injury by increasing intestinal permeability, disrupting intestinal metabolite homeostasis, and promoting inflammation and oxidative stress. Alterations in gut microbiota were found in drug-induced liver injury caused by antibiotics, psychotropic drugs, acetaminophen, antituberculosis drugs, and antithyroid drugs. Specific gut microbiota and their abundance are associated closely with the severity of drug-induced liver injury. Therefore, gut microbiota is expected to be a new target for the treatment of drug-induced liver injury. This review focuses on the association of gut microbiota with common hepatotoxic drugs and the potential mechanisms by which gut microbiota may contribute to the pathogenesis of drug-induced liver injury, providing a more comprehensive reference for the interaction between drug-induced liver injury and gut microbiota.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Animais , Estresse Oxidativo/efeitos dos fármacos , Acetaminofen/efeitos adversosRESUMO
Bletilla striata has been used for thousands of years and shows the functions of stopping bleeding, reducing swelling, and promoting healing in traditional applications. For Bletilla striata, Bletilla striata polysaccharides (BSP) is the main active ingredient, exhibiting biological functions of anti-inflammatory, anti-oxidant, anti-fibrotic, immune modulation, anti-glycation, and so on. In addition, BSP has exhibited the characteristics of excipient such as bio-adhesion, bio-degradability, and bio-safety and has been prepared into a series of preparations such as nanoparticles, microspheres, microneedles, hydrogels, etc. BSP, as both a drug and an excipient, has already aroused more and more attention. In this review, publications in recent years related to the extraction and identification, biological activities, and excipient application of BSP are reviewed. Specifically, we focused on the advances in the application of BSP as a formulation excipient. We hold opinion that BSP not only needed more researches in the mechanisms, but also the development into hydrogels, nano-formulations, tissue engineering, and so on. And we believe that this paper provides a beneficial reference for further BSP innovation and in-depth research and promotes the use of these natural products in pharmaceutical applications.
Assuntos
Excipientes , Orchidaceae , Polissacarídeos/farmacologia , Cicatrização , Hidrogéis/farmacologiaRESUMO
The treatment of hepatocellular carcinoma (HCC) remains a challenge and the future of cancer therapy will incorporate rational combinations directed to molecular targets that cooperate to drive critical pro-survival signaling. Sphingosine kinase 1 (SphK1) has been shown to regulate various processes important for cancer progression. Given the up-regulated expression of SphK1 in response to the silence of N-ras and other interactions between Ras/ERK and SphK1, it was speculated that combined inhibition of Ras/ERK and SphK1 would create enhanced antitumor effects. Experimental results showed that dual blockage of N-ras/ERK and SphK1 resulted in enhanced growth inhibitions in human hepatoma cells. Similarly, MEK1/2 Inhibitor U0126 potentiated SKI II-induced apoptosis in hepatoma HepG2 cells, consistently with the further attenuation of Akt/ERK/NF-κB signaling pathway. It was also shown that the combination of SKI II and U0126 further attenuated the migration of hepatoma HepG2 cells via FAK/MLC-2 signaling pathway. Taken together, the dual inhibition of SphK1 and Ras/ERK pathway resulted in enhanced effects, which might be an effective therapeutic approach for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Tiazóis/administração & dosagem , Proteínas ras/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sinergismo Farmacológico , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Proteínas ras/genéticaRESUMO
The transcription factor EB (TFEB) is a transcription factor of the MiT/TFE family that translocations from the cytoplasm to the nucleus in response to various stimuli, including lysosomal stress and nutrient starvation. By activating genes involved in lysosomal function, autophagy, and lipid metabolism, TFEB plays a crucial role in maintaining cellular homeostasis. Dysregulation of TFEB has been implicated in various diseases, including cancer, neurodegenerative diseases, metabolic diseases, cardiovascular diseases, infectious diseases, and inflammatory diseases. Therefore, modulating TFEB activity with agonists or inhibitors may have therapeutic potential. In this review, we reviewed the recently discovered regulatory mechanisms of TFEB and their impact on human diseases. Additionally, we also summarize the existing TFEB inhibitors and agonists (targeted and non-targeted) and discuss unresolved issues and future research directions in the field. In summary, this review sheds light on the crucial role of TFEB, which may pave the way for its translation from basic research to practical applications, bringing us closer to realizing the full potential of TFEB in various fields.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Doenças Neurodegenerativas , Humanos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Autofagia/fisiologia , Núcleo Celular/metabolismo , Lisossomos/metabolismo , Regulação da Expressão Gênica , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismoRESUMO
In recent years, a new target closely linked to a variety of diseases has appeared in the researchers' vision, which is the NLRP3 inflammasome. With the deepening of the study of NLRP3 inflammasome, it was found that it plays an extremely important role in a variety of physiological pathological processes, and NLRP3 inflammasome was also found to be associated with some age-related diseases. It is associated with the development of insulin resistance, Alzheimer's disease, Parkinson's, cardiovascular aging, hearing and vision loss. At present, the only clinical approach to the treatment of NLRP3 inflammasome-related diseases is to use anti-IL-1ß antibodies, but NLRP3-specific inhibitors may be better than the IL-1ß antibodies. This article reviews the relationship between NLRP3 inflammasome and aging diseases: summarizes some of the relevant experimental results reported in recent years, and introduces the biological signals or pathways closely related to the NLRP3 inflammasome in a variety of aging diseases, and also introduces some promising small molecule inhibitors of NLRP3 inflammasome for clinical treatment, such as: ZYIL1, DFV890 and OLT1177, they have excellent pharmacological effects and good pharmacokinetics.
Assuntos
Envelhecimento , Inflamassomos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologiaRESUMO
Benzotriazole ultraviolet stabilizers (BUVSs) are a group of anthropogenic chemicals widely used in commodities and industrial products, posing a potential threat to aquatic organisms. However, limited data are available on the toxicity effects of BUVSs in the liver, and no data are available on effective therapeutic strategies. In this study, we exployed aimed to explore the hepatotoxicity of 2-(benzotriazol-2-yl)-4,6-bis(2-phenylpropan-2-yl)phenol (UV-234) and reveal the preventive function of Genistein. At first, yellow catfish (Pelteobagrus fulvidraco) exposed to UV-234 (10 µg/L) showed up-regulated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) and hepatic reactive oxygen species (ROS) overproduction, along with significantly reduced activities of antioxidants enzymes and nuclear factor erythroid-derived 2-related factor 2 (Nrf2) basal levels. In contrast, 100 mg/kg diet of Genistein improve the hepatic antioxidative capability of fish via activating Nrf2 pathway. Furthermore, we confirmed that UV-234 exposure could induce nuclear factor-κB (NF-κB)-driven inflammatory response, as evidenced by the hepatic inflammatory cells infiltration, lower levels of plasma complement C3 (C3) and complement C4 (C4) as well as higher mRNA levels of NF-κB and inflammatory cytokines. Conversely, feeding UV-234-exposed fish on Genistein-supplemented diets attenuated above adverse effects. Meanwhile, we confirmed that Genistein supplement protected liver apoptosis induced by UV-234 via suppressing up-regulated expression levels of pro-apoptotic genes (Bax, caspase3). In summary, our findings revealed that Genistein positively regulates the Nrf2-mediated antioxidant defenses and reduce NF-κB-driven inflammatory response, thus indirectly inhibiting hepatic damage induced by UV-234 in yellow catfish (Pelteobagrus fulvidraco).
Assuntos
Peixes-Gato , Doença Hepática Induzida por Substâncias e Drogas , Animais , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Genisteína/farmacologia , Genisteína/metabolismo , Peixes-Gato/metabolismo , Fígado/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
This review examines advances in the metabolites, pharmacological research, and therapeutic applications of the medicinal fruit of Brucea javanica (L.) Merr. Brucea javanica (BJ) is derived from the fruit of the Brucea javanica (L.) Merr. There are nearly 200 metabolites present in BJ, and due to the diversity of its metabolites, BJ has a wide range of pharmacological effects. The traditional pharmacological effects of BJ include anti-dysentery, anti-malaria, etc. The research investigating the contemporary pharmacological impacts of BJ mainly focuses on its anti-tumor properties. In the article, the strong monomeric metabolites among these pharmacological effects were preliminarily screened. Regarding the pharmacological mechanism of action, current research has initially explored BJ's pharmacological agent and molecular signaling pathways. However, a comprehensive system has yet to be established. BJ preparations have been utilized in clinical settings and have demonstrated effectiveness. Nevertheless, clinical research is primarily limited to observational studies, and there is a need for higher-quality research evidence to support its clinical application. There are still many difficulties and obstacles in studying BJ. However, it is indisputable that BJ is a botanical drugs with significant potential for application, and it is expected to have broader global usage.