ABSTRACT
Silicosis is a progressive disease characterized by interstitial fibrosis resulting from inhalation of silica particles, and currently lacks specific treatment. Hydrogen (H2) has demonstrated antioxidative, anti-inflammatory, and anti-fibrotic properties, yet its efficacy in treating silicosis remains unexplored. In this study, rats exposed to silica were administered interventions of H2 combined with tetrandrine, and euthanized at 14, 28, and 56 days post-intervention. Lung tissues and serum samples were collected for analysis. Histological examination, MDA assay, enzyme-linked immunosorbent assay, hydroxyproline assay, and Western blotting were employed to assess the impact of H2 combined with tetrandrine on pulmonary fibrosis. The results revealed that this combination significantly alleviated inflammation in silicosis-afflicted rats, effectively suppressed levels of MDA, TNF-α, and IL-1ß expression, and inhibited epithelial-mesenchymal transition (EMT), thereby ameliorating pulmonary fibrosis. Notably, protein expression level of E-cadherin was increasedï¼however protein expression levels of vimentin and α-SMA were reduced, and TGF-ß were reduced, alongside a significant decrease in hydroxyproline content. Furthermore, H2 combined with tetrandrine downregulated protein expression of NF-κB p65, NF-κB p-p65, Caspase-1, ASC, and NLRP3. These findings substantiate the hypothesis that H2 combined with tetrandrine mitigates inflammation associated with silicosis and suppresses the EMT process to ameliorate fibrosis via the NF-κB/NLRP3 signaling pathway. However, the pressure of airway opening was not assessed in this study and dynamic readings of lung physiological function were not obtained, which is a major limitation of this study.
Subject(s)
Benzylisoquinolines , Epithelial-Mesenchymal Transition , Hydrogen , NF-kappa B , NLR Family, Pyrin Domain-Containing 3 Protein , Pulmonary Fibrosis , Signal Transduction , Silicon Dioxide , Silicosis , Animals , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Benzylisoquinolines/administration & dosage , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Epithelial-Mesenchymal Transition/drug effects , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Signal Transduction/drug effects , NF-kappa B/metabolism , Male , Silicosis/drug therapy , Silicosis/metabolism , Rats , Hydrogen/therapeutic use , Hydrogen/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Lung/pathology , Lung/drug effects , Lung/metabolism , Rats, Sprague-Dawley , Disease Models, Animal , Inflammation/drug therapy , HumansABSTRACT
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with immune dysregulation affecting colon inflammatory response. Recent studies have highlighted that neutrophil extracellular traps (NETs) play an important role in the pathogenesis of UC. Berbamine (BBM), one of the bioactive ingredients extracted from Chinese herbal medicine Berberis vulgaris L, has attracted intensive attentions due to its significant anti-inflammatory activity and a marketing drug for treating leukemia in China. However, the exact role and potential molecular mechanism of BBM against UC remains elusive. In the present study, our results showed that BBM could markedly improve the pathological phenotype and the colon inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. Then, comprehensive approaches combining network pharmacology and molecular docking analyses were employed to predict the therapeutic potential of BBM in treating UC by peptidyl-arginine deiminase 4 (PAD4), a crucial molecule involved in NETs formation. The molecular docking results showed BBM had a high affinity for PAD4 with a binding energy of -9.3 kcal/mol Moreover, PAD4 expression and NETs productions, including citrullination of histone H3 (Cit-H3), neutrophil elastase (NE), myeloperoxidase (MPO) in both neutrophils and colonic tissue were reduced after BBM administration. However, in the mice with DSS-induced colitis pretreated with GSK484, a PAD4-specific inhibitor, BBM could not further reduce disease related indexes, expression of PAD4 and NETs productions. Above all, the identification of PAD4 as a potential target for BBM to inhibit NETs formation in colitis provides novel insights into the development of BBM-derived drugs for the clinical management of UC.
Subject(s)
Benzylisoquinolines , Dextran Sulfate , Extracellular Traps , Molecular Docking Simulation , Protein-Arginine Deiminase Type 4 , Animals , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Protein-Arginine Deiminase Type 4/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Mice , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Benzylisoquinolines/chemistry , Male , Colitis/drug therapy , Colitis/chemically induced , Colitis/pathology , Colitis/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Neutrophils/immunology , Colon/drug effects , Colon/pathology , Colon/metabolism , Mice, Inbred C57BL , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/chemistry , Disease Models, AnimalABSTRACT
Inflammation can be triggered by any factor. The primary pathological manifestations can be summarized as the deterioration, exudation, and proliferation of local tissues, which can cause systemic damage in severe cases. Inflammatory lesions are primarily localized but may interact with body systems to cause provocative storms, parenchymal organ lesions, vascular and central nervous system necrosis, and other pathologic responses. Tetrandrine (TET) is a bisbenzylquinoline alkaloid extracted from the traditional Chinese herbal medicine Stephania tetrandra, which has been shown to have significant efficacy in inflammatory conditions such as rheumatoid arthritis, hepatitis, nephritis, etc., through NF-κB, MAPK, ERK, and STAT3 signaling pathways. TET can regulate the body's imbalanced metabolic pathways, reverse the inflammatory process, reduce other pathological damage caused by inflammation, and prevent the vicious cycle. More importantly, TET does not disrupt body's normal immune function while clearing the body's inflammatory state. Therefore, it is necessary to pay attention to its dosage and duration during treatment to avoid unexpected side effects caused by a long half-life. In summary, TET has a promising future in treating inflammatory diseases. The author reviews current therapeutic studies of TET in inflammatory conditions to provide some ideas for subsequent anti-inflammatory studies of TET.
Subject(s)
Benzylisoquinolines , Inflammation , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Humans , Animals , Inflammation/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Signal Transduction/drug effectsABSTRACT
This study aimed to explore the effects and mechanism of action of stachydrine hydrochloride (Sta) against myocardial infarction (MI) through sarcoplasmic/endoplasmic reticulum stress-related injury. The targets of Sta against MI were screened using network pharmacology. C57BL/6 J mice after MI were treated with saline, Sta (6 or 12 mg kg-1) for 2 weeks, and adult mouse and neonatal rat cardiomyocytes (AMCMs and NRCMs) were incubated with Sta (10-4-10-6 M) under normoxia or hypoxia for 2 or 12 h, respectively. Echocardiography, Evans blue, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used for morphological and functional analyses. Endoplasmic reticulum stress (ERS), unfolded protein reaction (UPR), apoptosis signals, cardiomyocyte contraction, and Ca2+ flux were detected using transmission electron microscopy (TEM), western blotting, immunofluorescence, and sarcomere and Fluo-4 tracing. The ingredient-disease-pathway-target network revealed targets of Sta against MI were related to apoptosis, Ca2+ homeostasis and ERS. Both dosages of Sta improved heart function, decreased infarction size, and potentially increased the survival rate. Sta directly alleviated ERS and UPR and elicited less apoptosis in the border myocardium and hypoxic NRCMs. Furthermore, Sta upregulated sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) in both ischaemic hearts and hypoxic NRCMs, accompanied by restored sarcomere shortening, resting intracellular Ca2+, and Ca2+ reuptake time constants (Tau) in Sta-treated hypoxic ARCMs. However, 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ) (25 µM), a specific SERCA inhibitor, totally abolished the beneficial effect of Sta in hypoxic cardiomyocytes. Sta protects the heart from MI by upregulating SERCA2a to maintain intracellular Ca2+ homeostasis, thus alleviating ERS-induced apoptosis.
Subject(s)
Apoptosis , Calcium , Endoplasmic Reticulum Stress , Homeostasis , Mice, Inbred C57BL , Myocytes, Cardiac , Proline/analogs & derivatives , Sarcoplasmic Reticulum Calcium-Transporting ATPases , Animals , Endoplasmic Reticulum Stress/drug effects , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Calcium/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Homeostasis/drug effects , Apoptosis/drug effects , Mice , Male , Cardiotonic Agents/pharmacology , Cardiotonic Agents/therapeutic use , Rats , Myocardial Infarction/pathology , Myocardial Infarction/metabolism , Myocardial Infarction/drug therapy , Myocardial Infarction/prevention & control , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Unfolded Protein Response/drug effectsABSTRACT
Oxidative stress and neuroinflammation are two major causes leading to early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor E2-related factor 2 (Nrf2) is a critical transcription factor that contributes to antioxidant responses. Additionally, Nrf2 could inhibit transforming growth factor beta-activated kinase 1 (TAK1), which plays a vital role in microglial activation-mediated neuroinflammation. Neferine (NE) exhibits considerable protective effects in diverse disease models. However, the detailed effect and mechanism of NE on SAH remain unknown. Our data showed that NE treatment significantly reduced behavior and cognitive impairment, and brain edema in the early period after SAH. In addition, NE mitigated SAH-induced oxidative damage, neuroinflammation, and neural death. Moreover, NE inhibited M1 microglial polarization and enhanced M2 phenotype microglia both in vivo and in vitro. Further investigations revealed that NE enhanced the Nrf2-antioxidant response element (ARE) signaling pathway and suppressed TAK1-NF-κB signaling. In contrast, depletion of Nrf2 by ML385 suppressed Nrf2-ARE signaling, induced TAK1-NF-κB activation, and further promoted M1 microglial polarization. Additionally, ML385 abated the neuroprotective effects of NE against SAH. Notably, LPS also aggravated TAK1-NF-κB activation and reversed the beneficial effects of NE after SAH. In summary, NE provides protection after SAH by inhibiting oxidative stress and modulating microglial polarization through Nrf2 activation and TAK1-NF-κB suppression.
Subject(s)
Benzylisoquinolines , Microglia , NF-E2-Related Factor 2 , NF-kappa B , Neuroinflammatory Diseases , Subarachnoid Hemorrhage , Male , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Disease Models, Animal , Mice, Inbred C57BL , Microglia/pathology , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/etiology , NF-E2-Related Factor 2/agonists , NF-kappa B/metabolism , Signal Transduction , Subarachnoid Hemorrhage/complications , AnimalsABSTRACT
Dysfunction of tight junctions such as zonula occludens protein-1 (ZO-1)-associated aggravation of blood-brain barrier (BBB) permeability plays an important role in the progression of stroke. Cepharanthine (CEP) is an extract from the plant Stephania cepharantha. However, the effects of CEP on stroke and BBB dysfunction have not been previously reported. In this study, we report that CEP improved dysfunction in neurological behavior in a middle cerebral artery occlusion (MCAO) mouse model. Importantly, CEP suppressed blood-brain barrier (BBB) hyperpermeability by increasing the expression of ZO-1. Notably, we found that CEP inhibited the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) in the cortex of MCAO mice. Additionally, the results of in vitro experiments demonstrate that treatment with CEP ameliorated cytotoxicity of human bEnd.3 brain microvascular endothelial cells against hypoxia/reperfusion (H/R). Also, CEP attenuated H/R-induced aggravation of endothelial permeability in bEND.3 cells by restoring the expression of ZO-1. Further study proved that the protective effects of CEP are mediated by inhibition of VEGF-A and VEGFR2. Based on the results, we conclude that CEP might possess a therapeutic prospect in stroke through protecting the integrity of the BBB mediated by the VEGF/VEGFR2/ZO-1 axis.
Subject(s)
Benzodioxoles , Benzylisoquinolines , Blood-Brain Barrier , Signal Transduction , Stroke , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-2 , Zonula Occludens-1 Protein , Animals , Zonula Occludens-1 Protein/metabolism , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Vascular Endothelial Growth Factor A/metabolism , Mice , Signal Transduction/drug effects , Stroke/metabolism , Stroke/drug therapy , Humans , Male , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/drug therapy , Disease Models, Animal , Mice, Inbred C57BL , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Cell LineABSTRACT
During the last five decades, there has been tremendous development in our understanding of cancer biology and the development of new and novel therapeutics to target cancer. However, despite these advances, cancer remains the second leading cause of death across the globe. Most cancer deaths are attributed to the development of resistance to current therapies. There is an urgent and unmet need to address cancer therapy resistance. Tetrandrine, a bis-benzyl iso-quinoline, has shown a promising role as an anti-cancer agent. Recent work from our laboratory and others suggests that tetrandrine and its derivatives could be an excellent adjuvant to the current arsenal of anti-cancer drugs. Herein, we provide an overview of resistance mechanisms to current therapeutics and review the existing literature on the anti-cancer effects of tetrandrine and its potential use for overcoming therapy resistance in cancer.
Subject(s)
Benzylisoquinolines , Drug Resistance, Neoplasm , Neoplasms , Humans , Benzylisoquinolines/pharmacology , Benzylisoquinolines/chemistry , Benzylisoquinolines/therapeutic use , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic useABSTRACT
OBJECTIVE: To explore the role of bone marrow mesenchymal stem cells (BMSC)ï¼an essential element of the bone marrow microenvironment, in multidrug resistance(MDR) of K562 cells, as well as the reversal effect of tetrandrine (TET) on BMSC-mediated MDR and its potential mechanism. METHODS: A mixed co-culture system and a transwell co-culture system for BMSC and K562 cells were established, and the cells were divided into different groups and treated with daunorubicin (DNR) alone or combined with TET and DNR. The CCK-8 assay was used to detect the proliferation of K562 cells in each group, and the cell inhibition rate was calculated. Cytometric bead array (CBA) was used to detect the expression levels of IFN, IL-2, IL-6 and IL-10 in the supernatant of different groups. RT-qPCR and Western blot were used to detected the expression of STAT3 at mRNA and protein levels, respectively. RESULTS: Compared with K562+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR group was significantly decreased (P < 0.05), while the levels of IL-6 in the culture supernatant and phosphorylated STAT3 in K562 cells were significantly increased (P < 0.05). Compared with K562+BMSC+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR+TET group was significantly increased (P < 0.05), while the level of IL-6 and phosphorylated STAT3 was significantly decreased (P < 0.05). CONCLUSION: BMSC can promote the drug resistance of leukemia cells, and TET may reverse the BMSC-mediated drug resistance via inhibiting IL-6/STAT3 signaling pathway.
Subject(s)
Benzylisoquinolines , Leukemia , Humans , Interleukin-6 , Drug Resistance, Neoplasm , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Daunorubicin/pharmacology , K562 Cells , Leukemia/drug therapy , Tumor MicroenvironmentABSTRACT
BACKGROUND: Asthma associated with obesity is a chronic disease characterized by earlier airway remodeling, severe wheezing, and increased insensitivity to hormone therapy. Reticuline, a bioactive compound of Magnoliae Flos, exerts anti-inflammatory activity and can inhibit neutrophil recruitment. Thus, this study investigated the role of reticuline in obesity-related asthma. METHODS: The BALB/c mice fed a low-fat diet (LFD) and high-fat diet (HFD) were intranasally challenged with house dust mites (HDMs) or ovalbumin (OVA). Reticuline (0.25 mg/kg) was administrated into mice by intragastrical gavage. Airway hyper-responsiveness was examined after the final challenge. Body weight was measured, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The number of inflammatory cells in BALF was estimated. Histological changes were assessed by performing hematoxylin-eosin staining, and production of proinflammatory cytokines and IgE was examined by ELISA kits. Related pathways were studied with western blotting. RESULTS: Reticuline suppressed airway resistance and inflammatory infiltration in lung tissue and reduced inflammatory cell recruitment in BALF in obesity mice with asthma. Additionally, the levels of IL-17A, IL-1ß, IL-5, macrophage inflammatory protein 2, and regulated on activation, normal T cell expressed and secreted in the lung were reduced by reticuline. Mechanistically, reticuline inactivated the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathways in obesity-related asthma. CONCLUSION: Reticuline alleviates airway inflammation in obesity-related asthma by inactivating the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathways.
Subject(s)
Asthma , Benzylisoquinolines , Janus Kinase 2 , NF-kappa B , STAT3 Transcription Factor , Animals , Mice , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Asthma/drug therapy , Asthma/metabolism , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Bronchoalveolar Lavage Fluid , Cytokines/metabolism , Disease Models, Animal , Inflammation/metabolism , Janus Kinase 2/drug effects , Janus Kinase 2/metabolism , Lung/pathology , Mice, Inbred BALB C , NF-kappa B/drug effects , NF-kappa B/metabolism , Obesity/complications , Obesity/drug therapy , p38 Mitogen-Activated Protein Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/pharmacology , p38 Mitogen-Activated Protein Kinases/therapeutic use , Signal Transduction , STAT3 Transcription Factor/drug effects , STAT3 Transcription Factor/metabolism , Suppressor of Cytokine Signaling 3 Protein/drug effects , Suppressor of Cytokine Signaling 3 Protein/metabolismABSTRACT
The COVID-19 pandemic caused by SARS-CoV-2, lead to mild to severe respiratory illness and resulted in 6.9 million deaths worldwide. Although vaccines are effective in preventing COVID-19, they may not be sufficient to protect immunocompromised individuals from this respiratory illness. Moreover, novel emerging variants of SARS-CoV-2 pose a risk of new COVID-19 waves. Therefore, identification of effective antivirals is critical in controlling SARS and other coronaviruses, such as MERS-CoV. We show that Fangchinoline (Fcn), a bisbenzylisoquinoline alkaloid, inhibits replication of SARS-CoV, SARS-CoV-2, and MERS-CoV in a range of in vitro assays, by blocking entry. Therapeutic use of Fcn inhibited viral loads in the lungs, and suppressed associated airway inflammation in hACE2. Tg mice and Syrian hamster infected with SARS-CoV-2. Combination of Fcn with remdesivir (RDV) or an anti-leprosy drug, Clofazimine, exhibited synergistic antiviral activity. Compared to Fcn, its synthetic derivative, MK-04-003, more effectively inhibited SARS-CoV-2 and its variants B.1.617.2 and BA.5 in mice. Taken together these data demonstrate that Fcn is a pan beta coronavirus inhibitor, which possibly can be used to combat novel emerging coronavirus diseases.
Subject(s)
Benzylisoquinolines , COVID-19 , Middle East Respiratory Syndrome Coronavirus , Humans , Mice , Animals , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Pandemics , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic useABSTRACT
OBJECTIVE: Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood. METHODS: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic enzymes were examined by quantitative PCR. RESULTS: We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and oxidative phosphorylation process were downregulated by CEP. Several enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages. CONCLUSION: CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.
Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Benzylisoquinolines , Animals , Mice , Lipopolysaccharides , Arthritis, Rheumatoid/drug therapy , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Arthritis, Experimental/drug therapy , InflammationABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) exhibits poor response to the present chemotherapeutic agents and frequently develops drug resistance. Finding novel anticancer drugs might enhance patient outcomes. Tiliacorinine, a bisbenzylisoquinoline alkaloid from the Thai medicinal plant Tiliacora triandra, effectively induced apoptosis of human CCA cell lines and inhibited tumor growth in mice. Here, we elucidate further the molecular mechanisms underlining the cytotoxicity of tiliacorinine and its implication in overcoming gemcitabine-resistance of CCA cells. METHODS: Cytotoxicity of tiliacorinine against CCA cell lines was assessed using MTT assay. The molecular signaling was determined using Western blot analysis. Molecular docking simulations were applied to predict the binding affinity and orientation of tiliacorinine to the possible binding site(s) of the target proteins. RESULTS: Tiliacorinine induced apoptotic cell death of CCA cells in a dose- and time-dependent manner. Tiliacorinine significantly suppressed the expression of anti-apoptotic proteins, Bcl-xL and XIAP; activated apoptotic machinery proteins, caspase-3, caspase-9, and PARP; and decreased the levels of pAkt and pSTAT3. EGF/EGFR activation model and molecular docking simulations revealed EGFR, Akt, and STAT3 as potent targets of tiliacorinine. Molecular docking simulations indicated a strong binding affinity of tiliacorinine to the ATP-binding pockets of EGFR, PI3K, Akt, JAK2, and SH2 domain of STAT3. Tiliacorinine could synergize with gemcitabine and restore the cytotoxicity of gemcitabine against gemcitabine-resistant CCA cells. CONCLUSION: Tiliacorinine effectively induced apoptosis via binding and blocking the actions of EGFR, Akt, and STAT3. GENERAL SIGNIFICANCE: Tiliacorinine is a novel multi-kinase inhibitor and possibly a potent anti-cancer agent, in cancers with high activation of EGFR.
Subject(s)
Antineoplastic Agents , Benzylisoquinolines , Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Mice , Animals , Proto-Oncogene Proteins c-akt , Molecular Docking Simulation , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Cell Line, Tumor , Apoptosis , Gemcitabine , Antineoplastic Agents/pharmacology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , ErbB ReceptorsABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.
Subject(s)
Benzylisoquinolines , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Proto-Oncogene Proteins p21(ras)/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptors, Death Domain , Pancreatic NeoplasmsABSTRACT
This investigation assessed the potential of cepharanthine (CEP), a compound from Stephania cepharantha Hayata, in mitigating atherosclerosis in a hyperlipidemic rat model. Using Wistar rats, four distinct diet and drug treatment groups were established: a high-fat high sucrose diet (HFHS), HFHS supplemented with intraperitoneal cepharanthine (HFHS-C) or oral atorvastatin (HFHS-A) from the 8th week, and a normal-fat diet (NFD). The study aimed to evaluate diet and drug impact on aortic histopathological changes over 16 weeks. Our results revealed significant atherosclerosis prevention in the aorta of the HFHS-C group, marked by preserved endothelial integrity, absence of inflammation, and lack of atherosclerotic plaques. Additionally, CEP demonstrated a crucial role in preventing the emergence of cholesterol clefts and foamy macrophages. These findings suggest that CEP effectively curbs atherosclerosis progression in hyperlipidemic rats, reducing arterial fat deposition and offering a potential natural preventative strategy against this disease.
Subject(s)
Atherosclerosis , Benzylisoquinolines , Plaque, Atherosclerotic , Rats , Animals , Rats, Wistar , Atherosclerosis/drug therapy , Atherosclerosis/prevention & control , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic useABSTRACT
Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, possesses anti-inflammatory and immune-modulatory properties. Chemokine-like factor 1 (CKLF1) is known to play a crucial role in both peripheral and central inflammatory processes. This study aimed to investigate the potential anti-NP effects of TET and the involvement of CKLF1 in the action of TET. A male C57BL/6J mice model of NP caused by spared nerve injury (SNI) was established and mechanical withdrawal thresholds were measured using von Frey filaments. The results showed that TET improved mechanical allodynia in SNI mice and the propofol-induced sleep assay demonstrated that the TET group did not exhibit central inhibition, while the pregabalin (PGB) group showed significant central inhibition. Western blotting and immunofluorescence staining showed that TET significantly inhibited spinal protein expression levels of CKLF1, p-NF-κB/NF-κB, p-IKK/IKK, pro-inflammatory cytokines IL-1ß and TNF-α, and increased protein expression levels of the anti-inflammatory cytokine IL-10, while inhibiting the expression levels of microglia and astrocyte markers IBA-1 and GFAP of SNI mice. Moreover, immunofluorescence double-labeling results revealed that CKLF1 was predominantly colocalized with microglia of the spinal cord (SC) in SNI mice. C19 (an antagonism peptide of CKLF1) alleviated SNI-induced mechanical pain hypersensitivity, while C27 (an analog peptide of CKLF1) induced mechanical allodynia in normal mice. TET significantly attenuated mechanical allodynia induced by C27 in mice. TET may effectively alleviate NP by reducing neuroinflammation and decreasing CKLF1.
Subject(s)
Benzylisoquinolines , Neuralgia , Rats , Male , Mice , Animals , NF-kappa B/metabolism , Rats, Sprague-Dawley , Hyperalgesia/etiology , Hyperalgesia/complications , Mice, Inbred C57BL , Cytokines/metabolism , Spinal Cord/metabolism , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Benzylisoquinolines/metabolism , Anti-Inflammatory Agents/pharmacology , Neuralgia/metabolismABSTRACT
Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid compound found in plants of the Stephania genus, which has biological functions such as regulating autophagy, inhibiting inflammation, oxidative stress, and apoptosis. It is often used for the treatment of inflammatory diseases, viral infections, cancer, and immune disorders and has great clinical translational value. However, there is no detailed research on its specific mechanism and dosage and administration methods, especially clinical research is limited. In recent years, CEP has shown significant effects in the prevention and treatment of COVID-19, suggesting its potential medicinal value waiting to be discovered. In this article, we comprehensively introduce the molecular structure of CEP and its derivatives, describe in detail the pharmacological mechanisms of CEP in various diseases, and discuss how to chemically modify and design CEP to improve its bioavailability. In summary, this work will provide a reference for further research and clinical application of CEP.
Subject(s)
Alkaloids , Benzylisoquinolines , COVID-19 , Humans , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Alkaloids/pharmacology , ApoptosisABSTRACT
Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S., which is a bis-benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthesized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC50 value of 0.26 µM, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC50 value of 27.05 µM. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC.
Subject(s)
Antineoplastic Agents , Benzylisoquinolines , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mice , Animals , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Mice, Nude , Lung Neoplasms/metabolism , Cell Proliferation , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Cell Line, Tumor , Apoptosis , Proto-Oncogene Proteins c-akt/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic useABSTRACT
Objective: To analyze the safety, effectiveness, economics, innovation, suitability and accessibility of tetrandrine in the treatment of pneumoconiosis, and provide evidence-based basis for health policy decision-making and clinical practice. Methods: In July 2022, the system searched PubMed, Embase, the Cochrane Library, CNKI, Wanfang, SinoMed databases (the retrieval time was from the establishment of the database to June 30, 2022), screened the documents that meet the standards, extracted and evaluated the data, and used the "HTA checklist" developed by the International Network of Agencies for Health Technology Assessment (INAHTA) to evaluate the HTA report. AMSTAR-2 Scale was used to evaluate the quality of systematic evaluation/Meta analysis. CHEERS Scale was used to evaluate the quality of pharmacoeconomics research. The included cohort study or case-control study was evaluated with the Newcastle-Ottawa Scale. The included randomized controlled trial (RCT) studies were evaluated using the Cochrane Risk Bias Assessment Tool (Cochrane RCT) quality evaluation criteria. Comprehensive comparison and analysis based on the characteristics of the data included in the study. Results: A total of 882 related literatures were detected from the initial screening. According to relevant standards, 8 RCT studies were finally selected for analysis. Statistical results showed that basic treatment with tetrandrine could better improve FEV(1) (MD=0.13, 95%CI: 0.06-0.20, P<0.001), FEV(1)/FVC (MD=4.48, 95%CI: 0.61-8.35, P=0.02) and clinical treatment efficiency. Tetrandrine had a low incidence of adverse reactions. The affordability coefficient of tetrandrine tablets was 0.295-0.492. Conclusion: Tetrandrine can improve the clinical symptoms and pulmonary ventilation function of pneumoconiosis patients, most of the adverse reactions are mild, and the clinical application is safe.
Subject(s)
Benzylisoquinolines , Drugs, Chinese Herbal , Pneumoconiosis , Humans , Pneumoconiosis/drug therapy , Benzylisoquinolines/therapeutic use , Case-Control StudiesABSTRACT
Hepatocellular carcinoma (HCC) causes 830000 deaths every year and is becoming the third malignant tumor worldwide. One of the primary reasons is the lack of effective drugs. Hernandezine (HER), a bisbenzylisoquinoline alkaloid of Thalictrum simplex, has been confirmed to have antitumor activity. But there are few reports about its effect on HCC and the underlying mechanisms still remain unclear. Therefore, the antitumor effects and mechanisms of HER on HCC were evaluated in HepG2 and Hep3B cells. The in vitro experiments demonstrated that HER significantly induced G0/G1 phase arrest, inhibited the proliferation and promoted cell apoptosis in liver cancer cell lines. In the mechanisms, the antitumor effects of HER on liver cancer cells were mediated by phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway and reactive oxygen species (ROS), simultaneously. In one way, HER inhibited the activities of PI3K-AKT pathway, which interrupt the dimer formation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1) and result to G0/G1 phase arrest. In another way, after HER treatment, ROS accumulated in liver cancer cells and caused mitochondria injury which further influenced the expression of apoptosis-related proteins and eventually resulted to HepG2 and Hep3B cell apoptosis. In addition, HER showed a tumor restrain function in HepG2 and Hep3B bearing nude mice. Overall, these findings indicated that HER is a promising antitumor drug, which may provide a new direction for clinical HCC treatment.
Subject(s)
Antineoplastic Agents , Benzylisoquinolines , Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Apoptosis Regulatory Proteins , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Proliferation , Liver Neoplasms/metabolism , Mice, Nude , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species , Hep G2 CellsABSTRACT
Dengue virus (DENV) infection is a public health problem in tropical and subtropical regions. It can cause a spectrum of clinical manifestations ranging from mild dengue fever (DF) to severe dengue haemorrhagic fever (DHF) and potentially life-threatening disease including dengue shock syndrome (DSS). Severe DENV infection is caused by high viral load and cytokine storm in dengue-infected patients. Currently, there is no specific antiviral drug for DENV infection. An anti-DENV agent that demonstrates inhibitory effects on both DENV replication and cytokine secretion is urgently needed. In this study, cepharanthine (CEP), which is an anti-inflammatory, anti-HIV, and anti-tumor compound isolated from Stephania cepharantha Hayata, was tested for inhibition of DENV infection. We investigated the efficacy of CEP to inhibit DENV infection, replication, and cytokine production. The inhibitory effect of CEP treatment was studied in DENV-infected human chronic myeloid leukemia (K562) cells. The levels of DENV E protein and DENV production were determined by flow cytometry and FFU assay, respectively. CEP treatment significantly reduced viral E protein and viral production in all DENV-1, 2, 3, 4 serotypes. In addition, CEP treatment reduced the IL-6 proinflammatory cytokine production in DENV-infected A549 cells. Taken together, CEP has inhibitory effects on DENV infection specifically at the initial viral replication states and proinflammatory cytokine secretion, and is a promising candidate for further development as an anti-DENV treatment.