ABSTRACT
OBJECTIVE: Diabetic kidney disease (DKD) is the most common cause of the end-stage renal disease, which has limited treatment options. Rutaecarpine has anti-inflammatory effects, however, it has not been studied in DKD. Pyroptosis is a newly discovered mode of podocyte death related to inflammation. This study aimed to explore whether Rutaecarpine can ameliorate DKD and to clarify its possible mechanism. METHODS: In this study, we investigated the effects of Rutaecarpine on DKD using diabetic mice model (db/db mice) and high glucose (HG)-stimulated mouse podocyte clone 5 (MPC5) cells. Quantitative reverse transcription polymerase chain reaction and western blot were performed to detect the related gene and protein levels. We applied pharmacological prediction, co-immunoprecipitation assay, cellular thermal shift assay, surface plasmon resonance to find the target and pathway of the substances. Gene knockdown experiments confirmed this view in HG-stimulated MPC5 cells. RESULTS: Rutaecarpine significantly reduced proteinuria, histopathological damage, and pyroptosis of podocytes in a dose-dependent manner in db/db mice. Rutaecarpine also protected high glucose induced MPC5 injury in vitro experiments. Mechanistically, Rutaecarpine can inhibit pyroptosis in HG-stimulated MPC5 by reducing the expression of VEGFR2. VEGFR2 is a target of Rutaecarpine in MPC5 cells and directly binds to the pyroptosis initiation signal, NLRP3. VEGFR2-knockdown disrupted the beneficial effects of Rutaecarpine in HG-stimulated MPC5 cells. CONCLUSION: Rutaecarpine inhibits renal inflammation and pyroptosis through VEGFR2/NLRP3 pathway, thereby alleviating glomerular podocyte injury. These findings highlight the potential of Rutaecarpine as a novel drug for DKD treatment.
Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Indole Alkaloids , Podocytes , Pyroptosis , Quinazolinones , Animals , Mice , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/drug therapy , Glucose/metabolism , Indole Alkaloids/pharmacology , Indole Alkaloids/therapeutic use , Inflammation/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Podocytes/drug effects , Pyroptosis/drug effects , Quinazolinones/pharmacology , Quinazolinones/therapeutic use , Mice, Inbred C57BL , MaleABSTRACT
Evodia rutaecarpa, the near-ripe fruit of Euodia rutaecarpa (Juss.) Benth, Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang, is a famous herbal medicine with several biological activities and therapeutic values, which has been applied for abdominalgia, abdominal distension, vomiting, and diarrhea as a complementary and alternative therapy in clinic. Indole alkaloids, particularly evodiamine (EVO), rutaecarpine (RUT), and dedhydroevodiamine (DHE), are received rising attention as the major bioactivity compounds in Evodia rutaecarpa. Therefore, this review summarizes the physicochemical properties, pharmacological activities, pharmacokinetics, and therapeutic effects on gastrointestinal diseases of these three indole alkaloids with original literature collected by PubMed, Web of Science Core Collection, and CNKI up to June 2023. Despite sharing the same parent nucleus, EVO, RUT, and DHE have different structural and chemical properties, which result in different advantages of biological effects. In their wide range of pharmacological activities, the anti-migratory activity of RUT is less effective than that of EVO, and the neuroprotection of DHE is significant. Additionally, although DHE has a higher bioavailability, EVO and RUT display better permeabilities within blood-brain barrier. These three indole alkaloids can alleviate gastrointestinal inflammatory in particular, and EVO also has outstanding anti-cancer effect, although clinical trials are still required to further support their therapeutic potential.
Subject(s)
Evodia , Gastrointestinal Diseases , Plants, Medicinal , Humans , Evodia/chemistry , Indole Alkaloids/pharmacology , Indole Alkaloids/therapeutic use , Plants, Medicinal/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Extracts/analysis , Gastrointestinal Diseases/drug therapy , Fruit/chemistryABSTRACT
Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy due to the overexpression of ATP-binding cassette drug-efflux transporters, namely P-glycoprotein (P-gp)/ATP-binding cassette subfamily B member 1. In this study, derivatives of N-alkylated monoterpene indole alkaloids such as N-(para-bromobenzyl) (NBBT), N-(para-methylbenzyl) (NMBT), and N-(para-methoxyphenethyl) (NMPT) moieties were investigated for the reversal of P-gp-mediated MDR in drug-resistant KB colchicine-resistant 8-5 (KB-ChR-8-5) cells. Among the three indole alkaloid derivatives, the NBBT exhibited the highest P-gp inhibitory activity in a dose-dependent manner. Further, it significantly decreased P-gp overexpression by inactivating the nuclear translocation of the nuclear factor kappa B p-50 subunit. In the cell survival assay, doxorubicin showed 6.3-fold resistance (FR) in KB-ChR-8-5 cells compared with its parental KB-3-1 cells. However, NBBT significantly reduced doxorubicin FR to 1.7, 1.3, and 0.4 and showed strong synergism with doxorubicin for all the concentrations studied in the drug-resistant cells. Furthermore, NBBT and doxorubicin combination decreased the cellular migration and showed increased apoptotic incidence by downregulating Bcl-2, then activating BAX, caspase 3, and p53. The present findings suggest that NBBT could be a lead candidate for the reversal of P-gp- mediated multidrug resistance in cancer cells.
Subject(s)
Alkaloids , Antineoplastic Agents , Neoplasms , Humans , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Colchicine/pharmacology , Drug Resistance, Neoplasm , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Resistance, Multiple , ATP Binding Cassette Transporter, Subfamily B , Neoplasms/drug therapy , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , ATP-Binding Cassette Transporters , Alkaloids/pharmacology , Indole Alkaloids/pharmacology , Indole Alkaloids/therapeutic use , Adenosine Triphosphate , Cell Line, TumorABSTRACT
Cryptolepine (1,5-methyl-10H-indolo[3,2-b]quinoline), an indoloquinoline alkaloid, found in the roots of Cryptolepis sanguinolenta (Lindl.) Schltr (family: Periplocaceae), is associated with the suppression of cancer and protozoal infections. Cryptolepine also exhibits anti-bacterial, anti-fungal, anti-hyperglycemic, antidiabetic, anti-inflammatory, anti-hypotensive, antipyretic, and antimuscarinic properties. This review of the latest research data can be exploited to create a basis for the discovery of new cryptolepine-based drugs and their analogues in the near future. PubMed, Scopus, and Google Scholar databases were searched to select and collect data from the existing literature on cryptolepine and their pharmacological properties. Several in vitro studies have demonstrated the potential of cryptolepine A as an anticancer and antimalarial molecule, which is achieved through inhibiting DNA synthesis and topoisomerase II. This review summarizes the recent developments of cryptolepine pharmacological properties and functional mechanisms, providing information for future research on this natural product.
Subject(s)
Alkaloids , Antimalarials , Quinolines , Indole Alkaloids/pharmacology , Indole Alkaloids/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Alkaloids/pharmacology , Alkaloids/therapeutic use , Antimalarials/pharmacologyABSTRACT
An in-depth understanding of the lung microbiota in tuberculosis (TB) infection could provide optimal strategies for the prophylaxis, diagnosis, and treatment of the disease. Only a few studies have investigated the impact of Mycobacterium tuberculosis (Mtb) infection and anti-TB treatment on the lung microbiota. Bronchoalveolar lavage fluid and blood samples were collected from 23 active TB patients (TBZ), 17 latent tuberculosis infection patients (LTBI), 13 healthy controls (HC), and 14 active TB patients with 1-month anti-TB therapy (TBM) for 16S RNA sequencing and serological indexes, respectively. Low body mass index, albumin, and total triglyceride levels were detected in TBZ. Pulmonary Mtb infection led to a minor decrease in the alpha diversity of the lung microbiota in TBZ than HC, but a significant difference was noted in beta diversity. Subsequently, anti-TB therapy caused a rapid alteration in the lung community structure due to reduced alpha and beta diversity. Proteobacteria were abundant in TBZ samples, while Firmicutes was predominant in the LITB and HC samples. Lactobacillus and Subdoligranulum (genera) were the most unique in the LTBI and HC group, respectively. The TBM group showed the most predominant abundance of Bacteroides, Oscillospira, and Ruminococcus (genera). Functional pathways, such as indole alkaloid biosynthesis, Wnt signaling pathway, endocytosis, and metabolism of xenobiotics by cytochrome P450, significantly decreased in the TBM group compared with TBZ group. Pulmonary TB and anti-TB treatment caused a distinct dysbiosis of the lung microbiome. The current findings suggested potential links between the lung microbiota and TB onset, progression, and treatment.
Subject(s)
Microbiota , Tuberculosis, Pulmonary , Albumins/therapeutic use , Antitubercular Agents/therapeutic use , Humans , Indole Alkaloids/therapeutic use , Lung/microbiology , Triglycerides/therapeutic use , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/drug therapyABSTRACT
Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by genetic signals or drug interventions. Meanwhile, RCD is closely related to the occurrence and therapy of multiple human cancers. Generally, RCD subroutines are the key signals of tumorigenesis, which are contributed to our better understanding of cancer pathogenesis and therapeutics. Indole alkaloids derived from natural sources are well defined for their outstanding biological and pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, and 3,3'-diindolylmethane, which are currently used in the clinic or under clinical assessment. Moreover, such compounds play a significant role in discovering novel anticancer agents. Thus, here we systemically summarized recent advances in indole alkaloids as anticancer agents by targeting different RCD subroutines, including the classical apoptosis and autophagic cell death signaling pathways as well as the crucial signaling pathways of other RCD subroutines, such as ferroptosis, mitotic catastrophe, necroptosis, and anoikis, in cancer. Moreover, we further discussed the cross talk between different RCD subroutines mediated by indole alkaloids and the combined strategies of multiple agents (e.g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy.
Subject(s)
Antineoplastic Agents , Neoplasms , Regulated Cell Death , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Indole Alkaloids/therapeutic use , Neoplasms/drug therapy , OxindolesABSTRACT
Indigo is a bis-indolic alkaloid that has antioxidant and anti-inflammatory effects reported in literature and is a promissory compound for treating chronic inflammatory diseases. This fact prompted to investigate the effects of this alkaloid in the experimental model of Duchenne muscular dystrophy. The main aim of this study was to evaluate the potential role of the indigo on oxidative stress and related signaling pathways in primary skeletal muscle cell cultures and in the diaphragm muscle from mdx mice. The MTT and Neutral Red assays showed no indigo dose-dependent toxicities in mdx muscle cells at concentrations analyzed (3.12, 6.25, 12.50, and 25.00 µg/mL). Antioxidant effect of indigo, in mdx muscle cells and diaphragm muscle, was demonstrated by reduction in 4-HNE content, H2O2 levels, DHE reaction, and lipofuscin granules. A significant decrease in the inflammatory process was identified by a reduction on TNF and NF-κB levels, on inflammatory area, and on macrophage infiltration in the dystrophic sample, after indigo treatment. Upregulation of PGC-1α and SIRT1 in dystrophic muscle cells treated with indigo was also observed. These results suggest the potential of indigo as a therapeutic agent for muscular dystrophy, through their action anti-inflammatory, antioxidant, and modulator of SIRT1/PGC-1α pathway.
Subject(s)
Muscular Dystrophy, Duchenne , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/metabolism , Disease Models, Animal , Hydrogen Peroxide/metabolism , Indigo Carmine/metabolism , Indigo Carmine/pharmacology , Indigo Carmine/therapeutic use , Indole Alkaloids/metabolism , Indole Alkaloids/pharmacology , Indole Alkaloids/therapeutic use , Mice , Mice, Inbred mdx , Models, Theoretical , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/drug therapy , Signal Transduction , Sirtuin 1/metabolismABSTRACT
Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum, a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an inhibitor of proteasomes), and RUT concentration-dependently (1-6 µM) inhibited platelet aggregation and P-selectin expression. RUT was found to have a similar effect to that of BAY11-7082; however, it exhibits more effectiveness than Ro106-9920. RUT suppresses the NF-κB pathway as it inhibits IKK, IκBα, and p65 phosphorylation and reverses IκBα degradation in activated platelets. This study also investigated the role of p38 and NF-κB in cell signaling events and found that SB203580 (an inhibitor of p38) markedly reduced p38, IKK, and p65 phosphorylation and reversed IκBα degradation as well as p65 activation in a confocal microscope, whereas BAY11-7082 had no effects in p38 phosphorylation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay shows that RUT and BAY11-7082 did not exhibit free radical scavenging activity. In the in vivo study, compared with BAY11-7082, RUT more effectively reduced mortality in adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism without affecting the bleeding time. In conclusion, a distinctive pathway of p38-mediated NF-κB activation may involve RUT-mediated antiplatelet activation, and RUT could act as a strong prophylactic or therapeutic drug for cardiovascular diseases.
Subject(s)
Fibrinolytic Agents/pharmacology , Indole Alkaloids/pharmacology , NF-kappa B/metabolism , Nitriles/pharmacology , Quinazolines/pharmacology , Sulfones/pharmacology , Thrombosis/drug therapy , Thrombosis/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Disease Models, Animal , Fibrinolytic Agents/therapeutic use , Free Radical Scavengers/pharmacology , Free Radical Scavengers/therapeutic use , Free Radicals/antagonists & inhibitors , Humans , I-kappa B Kinase/antagonists & inhibitors , Imidazoles/pharmacology , Imidazoles/therapeutic use , Indole Alkaloids/therapeutic use , Male , Mice, Inbred ICR , NF-kappa B/antagonists & inhibitors , Nitriles/therapeutic use , P-Selectin/metabolism , Platelet Activation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pulmonary Embolism/drug therapy , Pulmonary Embolism/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Quinazolines/therapeutic use , Sulfones/therapeutic use , Transcription Factor RelA/metabolismABSTRACT
Gelsemium elegans Benth (GEB), also known as heartbreak grass, is a highly poisonous plant belonging to the family Loganiaceae and genus Gelsemium that has broad application prospects in medicine. This article reviews its chemical components, pharmacological effects, toxicity mechanisms, and research progress in clinical applications in recent years. Indole alkaloids are the main active components of GEB and have a variety of pharmacological and biological functions. They have anti-tumor, anti-inflammatory, analgesic, and immunomodulation properties, with the therapeutic dose being close to the toxic dose. Application of small-dose indole alkaloids fails to work effectively, while high-dose usage is prone to poisoning, aggravating the patient's conditions. Special caution is needed, especially to observe the changes in the disease condition of the patients in clinical practice. In-depth research on the chemical components and mechanisms of GEB is essential to the development of promising lead compounds and lays the foundation for extensive clinical application and safe usage of GEB in the future.
Subject(s)
Gelsemium/chemistry , Indole Alkaloids/chemistry , Plant Extracts/chemistry , Plants, Toxic/chemistry , Analgesics/chemistry , Analgesics/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Gelsemium/toxicity , Humans , Immunomodulating Agents/chemistry , Immunomodulating Agents/therapeutic use , Indole Alkaloids/isolation & purification , Indole Alkaloids/therapeutic use , Plant Extracts/therapeutic use , Plants, Toxic/toxicityABSTRACT
The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.
Subject(s)
Indole Alkaloids/pharmacology , Platelet Activation/drug effects , Quinazolines/pharmacology , Thrombosis/prevention & control , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Cell Adhesion Molecules/metabolism , Cells, Cultured , Evodia/chemistry , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Indole Alkaloids/isolation & purification , Indole Alkaloids/therapeutic use , Male , Mice , Mice, Inbred ICR , Microfilament Proteins/metabolism , Nucleotides, Cyclic/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/metabolism , Plant Extracts/chemistry , Plant Extracts/pharmacology , Platelet Aggregation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Quinazolines/isolation & purification , Quinazolines/therapeutic use , Quinolines/chemistry , Quinolines/pharmacology , Signal Transduction/drug effects , Thrombosis/metabolism , Thrombosis/pathologyABSTRACT
Stroke is the second leading cause of death and long-term disability worldwide, which lacks effective treatment. Perioperative stroke is associated with much higher rates of mortality and disability. The neuroprotective role of dexmedetomidine (Dex), a highly selective agonist of alpha2-adrenergic receptor, has been reported in a stroke rat model, and it was found that pretreatment of Dex before stroke could alleviate blood-brain barrier (BBB) breakdown. However, the underlying mechanisms are still unknown. As the brain endothelial cells are the main constituents of BBB and in high demand of energy, mitochondrial function of endothelial cells plays an important role in the maintenance of BBB. Given that dynamin-related protein 1 (Drp1) is a protein mediating mitochondrial fission, with mitochondrial fusion that balances mitochondrial morphology and ensures mitochondria function, the present study was designed to investigate the possible role of Drp1 in endothelial cells involved in the neuroprotective effects of Dex in ischemic stroke. Our results showed that preconditioning with Dex reduced infarction volume, alleviated brain water content and BBB damage, and improved neurological scores in middle cerebral artery occlusion rats. Meanwhile, Dex enhanced cell activity and decreased cell apoptosis in oxygen-glucose deprivation human brain microvascular endothelial cells in vitro. These protective effects of Dex were correlated with the mitochondrial morphology integrality of endothelial cells, mediated by increased phosphorylation of serine 637 in Drp1, and could be reversed by α2-adrenergic receptor antagonist Yohimbine and AMP-activated protein kinase inhibitor Compound C. These findings suggest new molecular pathways involved in the neuroprotective effects of Dex in ischemic stroke. As Dex is routinely used as a sedative drug clinically, our findings provide molecular evidence that it has perioperative neuroprotection from ischemic stroke.
Subject(s)
Blood-Brain Barrier/metabolism , Dexmedetomidine/pharmacology , Dynamins/metabolism , Ischemic Stroke/drug therapy , Mitochondria/metabolism , Neuroprotective Agents/pharmacology , Adenylate Kinase/antagonists & inhibitors , Adenylate Kinase/metabolism , Adrenergic alpha-2 Receptor Antagonists/pharmacology , Adrenergic alpha-2 Receptor Antagonists/therapeutic use , Animals , Blood-Brain Barrier/drug effects , Cell Line , Cytokines/metabolism , Dexmedetomidine/therapeutic use , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Glial Fibrillary Acidic Protein/metabolism , Humans , Indole Alkaloids/pharmacology , Indole Alkaloids/therapeutic use , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/pathology , Ischemic Stroke/etiology , Ischemic Stroke/metabolism , Ischemic Stroke/pathology , Male , Mitochondria/drug effects , Mitochondria/pathology , Mitochondrial Dynamics/drug effects , Neuroprotective Agents/therapeutic use , Phosphorylation/drug effects , Rats, Sprague-Dawley , Zonula Occludens-1 Protein/metabolismABSTRACT
This study was aimed to explore the mechanism of rutaecarpine (RUT) on ethanol-induced gastric ulcer (GU) in mice by integrated approaches. At first, the efficacy was determined through the macroscopic and microscopic state of stomach tissue and the expression levels of GU-related factors. Then, the serum metabolomics method based on UPLC-Q-TOF/MS was used to explore the specific metabolites and metabolic pathways. Finally, the upstream key protein targets of these specific metabolites were analyzed by network pharmacology and verified by PCR to explore the potential mechanism. RUT alleviated the histological and pathological damage of gastric tissue caused by ethanol, and could remarkably ameliorate the level of GU-related factors. Subsequently, a total of 7 potential metabolites involved in 9 metabolic pathways were identified by metabolomics analysis. Then, a 'component-targets-metabolites' interaction network was constructed, and therefore 4 key target proteins (PLA2G1B, PDE5A, MIF and SRC) that may regulate the specific metabolites were obtained. This case was further verified by the results of PCR. ALL the above results strongly demonstrated that RUT exerted a gastroprotective effect against GU. And it is the first time to combine metabolomics combined with network pharmacology to elucidate the mechanism of RUT on GU, which may be related to the regulation of energy metabolism, oxidative stress, and inflammation, and these pathways may be regulated through the upstream protein PLA2G1B, PDE5A, MIF and SRC.
Subject(s)
Ethanol/toxicity , Indole Alkaloids/therapeutic use , Metabolomics/methods , Quinazolines/therapeutic use , Rutaceae , Stomach Ulcer/drug therapy , Stomach Ulcer/metabolism , Animals , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Indole Alkaloids/pharmacology , Male , Mice , Quinazolines/pharmacology , Stomach Ulcer/chemically inducedABSTRACT
Alcoholic liver disease (ALD) is the most common chronic liver disease worldwide. Currently, there is no definitive treatment for alcohol-induced liver injury (ALI). Inflammatory response and oxidative stress play a crucial role in ALI. Cyclooxygenase 2 (COX-2) can be induced by inflammation and it has been reported that the enhanced expression of COX-2 in alcoholic liver injury. Rutaecarpine (RUT) was extracted from evodia rutaecarpa. RUT has a wide range of pharmacological activities. In order to increase its anti-inflammatory activity, our group introduced sulfonyl group to synthesized the 3-[2-(trifluoromethoxy)benzenesulfonamide]-rutaecarpine (3-B-RUT). In this study, we explored the protective effect of 3-B-RUT on alcoholic liver injury in vivo and in vitro and preliminarily explore its mechanism. Mice ALI model was established according to the chronic-plus-binge ethanol model. Results showed that 3-B-RUT (20 µg/kg) attenuated alcohol-induced liver injury and suppressed liver inflammation and oxidative stress, and the effect was comparable to RUT (20 mg/kg). In vitro results are consistent with in vivo results. Mechanistically, the 3-B-RUT might suppress inflammatory response and oxidative stress by regulating activation of NF-κB/COX-2 pathway. In summary, 3-B-RUT, a derivative of RUT, may be a promising clinical candidate for ALI treatment.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Indole Alkaloids/therapeutic use , Liver Diseases, Alcoholic/drug therapy , Quinazolines/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Cyclooxygenase 2/genetics , Cyclooxygenase 2/immunology , Indole Alkaloids/pharmacology , Liver/drug effects , Liver/immunology , Liver/pathology , Liver Diseases, Alcoholic/immunology , Liver Diseases, Alcoholic/pathology , Macrophages/drug effects , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/antagonists & inhibitors , NF-kappa B/immunology , Oxidative Stress/drug effects , Quinazolines/pharmacology , RAW 264.7 CellsABSTRACT
Canthin-6-one (Cant) is an indole alkaloid found in several botanical drugs used as medicines, reported to be gastroprotective, anti-inflammatory, anti-microbial, anti-diarrheal and anti-proliferative. We aimed to explore Cant in the management of colitis using a trinitrobenzenesulfonic acid (TNBS)-induced rat model. Cant (1, 5 and 25 mg/kg) was administered by oral gavage to Wistar rats followed by induction of colitis with TNBS. Macroscopic and histopathological scores, myeloperoxidase (MPO), malondialdehyde (MDA) and reduced glutathione (GSH) were assessed in colon tissues. Pro- (TNF-α, IL-1ß and IL-12p70) and anti-inflammatory (IL-10) cytokines, and vascular endothelial growth factor (VEGF) were also quantified. Mitogen-activated protein kinase 14 (MAPK14) and Toll-like receptor-8 (TLR8), as putative targets, were considered through in silico analysis. Cant (5 and 25 mg/kg) reduced macroscopic and histological colon damage scores in TNBS-treated rats. MPO and MDA were reduced by up to 61.69% and 92.45%, respectively, compared to TNBS-treated rats alone. Glutathione concentration was reduced in rats administered with TNBS alone (50.00% of sham group) but restored to 72.73% (of sham group) with Cant treatment. TNF-α, IL-1ß, IL-12p70 and VEGF were reduced, and anti-inflammatory IL-10 was increased following Cant administration compared to rats administered TNBS alone. Docking ligation results for MAPK14 (p38α) and TLR8 with Cant, confirmed that these proteins are feasible putative targets. Cant has an anti-inflammatory effect in the intestine by down-regulating molecular immune mediators and decreasing oxidative stress. Therefore, Cant could have therapeutic potential for the treatment of inflammatory bowel disease and related syndromes.
Subject(s)
Carbolines/therapeutic use , Colitis/metabolism , Computer Simulation , Indole Alkaloids/therapeutic use , Inflammation Mediators/metabolism , Oxidative Stress/drug effects , Trinitrobenzenesulfonic Acid/toxicity , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Carbolines/chemistry , Carbolines/pharmacology , Colitis/chemically induced , Colitis/drug therapy , Fungicides, Industrial/chemistry , Fungicides, Industrial/pharmacology , Fungicides, Industrial/therapeutic use , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Inflammation Mediators/antagonists & inhibitors , Male , Oxidative Stress/physiology , Protein Structure, Secondary , Rats , Rats, WistarABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Cinobufacini is extracted from the skins and parotid venom glands of the toad for treating symptoms like swelling and pain in ancient times. Nowadays, cinobifucini injection has also achieved satisfactory therapeutic effects on hepatocellular carcinoma (HCC) in China. AIM OF THE STUDY: Our previous work found that bufothionine, an alkaloid abundant in cinobufacini injection, induced mitochondria-mediated apoptosis. In this work, the underlying effects of bufothionine on autophagy in HCC and its possible dependent pathway were investigated. METHODS: CCK-8 and Hoechst staining assays were performed to verify effects of drugs on proliferation and apoptosis of SMMC7721 cell. H22-tumor-bearing mice model was established by inoculating ascites fluid. HE staining was used to observe pathological changes in liver and tumor tissues. ELISA and Western blot experiments were conducted to investigate IL-6/JAK2/STAT3 signaling pathway. The effects of drugs on expressions of autophagic relative proteins were investigated by Western blot in vitro and in vivo. RESULTS: In vitro, CCK-8 and Hoechst staining assays showed that bufothionine inhibited SMMC7721 cell proliferation and promoted apoptosis at 100 µM. In vivo, bufothionine relieved symptoms of H22-tumor-bearing mice and exerted anti-inflammation activity. ELISA and Western blot demonstrated that bufothionine significantly reduced serum IL-6 concentration, suppressed p-Stat3tyr705, p-Stat3ser727 and Jak2 expressions in tumor tissues and upregulated Atg5, Atg7 and LC3â ¡ expressions in SMMC7721 cell and H22 tumor. CONCLUSION: This is the first report showing that bufothionine might induce autophagy in HCC by inhibiting JAK2/STAT3 pathway, presenting a possible anti-cancer mechanism of bufothionine in cinobufacini injection.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Autophagy/drug effects , Bufanolides/pharmacology , Indole Alkaloids/pharmacology , Liver Neoplasms, Experimental/drug therapy , Neoplasms/pathology , Quinolinium Compounds/pharmacology , Signal Transduction/drug effects , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Bufanolides/chemistry , Bufanolides/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indole Alkaloids/therapeutic use , Interleukin-6/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Male , Mice , Neoplasms/metabolism , Quinolinium Compounds/therapeutic use , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolismABSTRACT
In our continuous search for cytotoxic compounds from the genus Zanthoxylum, chromatographic separation of the MeOH/CH2Cl2 (1:1) extract of Z. chalybeum yielded one new alkamide; 4-(isoprenyloxy)-3-methoxy-3,4-deoxymethylenedioxyfagaramide (1) and a known one; fagaramide (2). Similarly, from the MeOH/CH2Cl2 (1:1) extract of the stem bark of Z. parachanthum four known compounds; canthin-6-one (3), dihydrochelerythrine (4), lupeol (5) and sesamin (6) were isolated. Characterization of the structures of these compounds was achieved using spectroscopic techniques (NMR and MS). Using resazurin reduction assay 1, 3 and 6 displayed moderate cytotoxicity with IC50 values below 50 µM against the drug sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cell lines. It is interesting to note that 3 was more active than the standard drug, doxorubicin against CEM/ADR5000 leukemia cells. Compounds 3 and 6 showed good selectivity on leukemia cells than normal cells. In future studies 3 should be tested against a panel of drug resistant human cells.
Subject(s)
Carbolines/therapeutic use , Cinnamates/therapeutic use , Dioxoles/therapeutic use , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Indole Alkaloids/therapeutic use , Leukemia/drug therapy , Polyunsaturated Alkamides/therapeutic use , Zanthoxylum/chemistry , Apoptosis/drug effects , Carbolines/chemistry , Carbolines/pharmacology , Carbon-13 Magnetic Resonance Spectroscopy , Cell Death/drug effects , Cell Line, Tumor , Cinnamates/chemistry , Cinnamates/pharmacology , Dioxoles/chemistry , Dioxoles/pharmacology , Humans , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Membrane Potential, Mitochondrial/drug effects , Plant Extracts/chemistry , Polyunsaturated Alkamides/chemistry , Polyunsaturated Alkamides/pharmacologyABSTRACT
Indole, a heterocyclic organic compound, is one of the most promising heterocycles found in natural and synthetic sources since its derivatives possess fascinating structural diversity and various therapeutic properties. Indole alkaloids, synthetic dimers and hybrids could act on diverse targets in cancer cells, and consequently, possess potential antiproliferative effects on various cancers both in vitro and in vivo. Vinblastine, midostaurin, and anlotinib as the representative of indole alkaloids, synthetic dimers and hybrids respectively, have already been clinically applied to treat many types of cancers, demonstrating indole alkaloids, synthetic dimers and hybrids are useful scaffolds for the development of novel anticancer agents. Covering articles published between 2010 and 2020, this review emphasizes the recent development of indole alkaloids, synthetic dimers and hybrids with potential in vivo therapeutic application for cancers.
Subject(s)
Antineoplastic Agents/therapeutic use , Indole Alkaloids/therapeutic use , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Dimerization , Drug Screening Assays, Antitumor , Humans , Indole Alkaloids/chemistryABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Toad venom is one of widely used traditional Chinese medicines due to its analgesic and anti-inflammatory activities. However, hydrophilic alkaloids from toad venom, which may have certain pharmacological activities, have not been systematic studied. AIM OF THE STUDY: The aim of the study was to identify the indolealkylamines (IAAs) from toad venom and investigate the analgesic and anti-inflammatory actions. MATERIALS AND METHODS: The alkaloids were extracted and identified by high-resolution mass spectrometry. The analgesic abilities were determined using hot-plate test, formalin test and von Frey test. High-sensitivity lipidomics was used to investigate the regulatory function of IAAs on inflammatory eicosanoids. Besides, network pharmacology and molecular docking were used to demonstrate the candidate targets of IAAs. RESULTS: 22 constituents have been characterized by high performance liquid chromatography (HPLC)-Triple TOF 5600, including six specific IAAs (serotonin, N-methyl serotonin, bufotenine, bufotenidine, bufothionine and dehydrobufotenine). Pharmacological studies showed that the IAAs from toad venom exerted significant analgesic activities at doses of 5, 15 and 45 mg/kg in vivo. Moreover, lipids analysis revealed IAAs might down-regulate inflammatory mediators from COX, LOX, DHA and LA pathways in formalin models, thus showing anti-inflammatory effect. The potent pharmacological function might because of the binding of IAAs and protein targets, such as sigma-1 receptor. CONCLUSION: The studies provided a systemic evidence for the analgesic and anti-inflammatory activities of IAAs from toad venom. It suggested that IAAs might be a potential candidate to reduce inflammatory pain disorders.
Subject(s)
Amphibian Venoms/therapeutic use , Analgesics/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Indole Alkaloids/therapeutic use , Lipidomics/methods , Molecular Docking Simulation/methods , Amphibian Venoms/isolation & purification , Amphibian Venoms/pharmacology , Analgesics/isolation & purification , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Female , Indole Alkaloids/isolation & purification , Indole Alkaloids/pharmacology , Male , Mice , Mice, Inbred ICR , Pain Measurement/drug effects , Pain Measurement/methods , Random AllocationABSTRACT
Calcitonin generelated peptide (CGRP) is the predominant neurotransmitter located in sensory nerves. This peptide is extensively distributed in central and peripheral tissues. CGRP causes relaxation of cardiovascular smooth muscle cells and confers protection against ischaemic myocardium and cardiac remodeling. The pharmacological effects of nitroglycerine and rutaecarpine have been demonstrated to be associated with an increase in the synthesis and release of CGRP. In the gastrointestinal tissues, CGRP participates in the regulation of gastrointestinal function, and exerts protective effects on gastric mucosa. Rutaecarpine, capsaicin and its derivatives, such as evodiamine, decrease gastric mucosal damage induced by several factors, including increased synthesis and release of CGRP. Taken together, this review focuses on the pharmacological effects of several CGRP related canonical drugs and suggests that synthesis and secretion of CGRP exhibit significant therapeutic effects in the occurrence and development of cardiovascular and gastrointestinal diseases.
Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Cardiovascular Diseases/metabolism , Gastrointestinal Diseases/metabolism , Indole Alkaloids/pharmacology , Nitroglycerin/pharmacology , Quinazolines/pharmacology , Cardiovascular Diseases/drug therapy , Gastrointestinal Diseases/drug therapy , Gene Expression Regulation/drug effects , Humans , Indole Alkaloids/therapeutic use , Molecular Targeted Therapy , Nitroglycerin/therapeutic use , Quinazolines/therapeutic use , Up-RegulationABSTRACT
Gramine is a natural indole alkaloid with a wide range of biological activities, but its anti-gastric cancer activity is poor. Herein, a pharmacophore fusion strategy was adopted to design and synthesize a new series of indole-azole hybrids on the structural basis of gramine. Based on our previous studies, different nitrogen-containing five-membered heterocyclic rings and terminal alkyne group were introduced into the indole-based scaffold to investigate their effect on improving the anti-gastric cancer activity of gramine derivatives. Structure-activity relationship (SAR) studies highlighted the role played by terminal alkyne in enhancing the inhibitory effect, and compound 16h displayed the best antiproliferative activity against gastric cancer MGC803 cells with IC50 value of 3.74 µM. Further investigations displayed compound 16h could induce mitochondria-mediated apoptosis, and caused cell cycle arrest at G2/M phase. Besides, compound 16h could inhibit the metastasis ability of MGC803 cells. Our studies may provide a new strategy for structural optimization of gramine to enhance anti-gastric cancer activity, and provide a potential candidate for the treatment of gastric cancer.