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2.
Curr Protein Pept Sci ; 20(10): 996-1003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389311

RESUMO

Abstract:Throughout the last decade, extensive efforts have been devoted to developing a percutaneous catheter ablation and implantable cardioverter-defibrillator technique for patients suffering from ventricular arrhythmia. Antiarrhythmic drug efficacy for preventing arrhythmias remains disappointing because of adverse cardiovascular effects. Allocryptopine is an isoquinoline alkaloid widely present in medicinal herbs. Studies have indicated that allocryptopine exhibits potential anti-arrhythmic actions in various animal models. The potential therapeutic benefit of allocryptopine in arrhythmia diseases is addressed in this study, focusing on multiple ion channel targets and reduced repolarization dispersion. The limitations of allocryptopine research are clear given a lack of parameters regarding toxicology and pharmacokinetics and clinical efficacy in patients with ventricular arrhythmias. Much remains to be revealed about the properties of allocryptopine.


Assuntos
Antiarrítmicos , Arritmias Cardíacas/tratamento farmacológico , Alcaloides de Berberina , Plantas Medicinais/química , Traqueófitas/química , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Alcaloides de Berberina/química , Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/uso terapêutico , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
3.
Psychopharmacology (Berl) ; 236(11): 3169-3182, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31172225

RESUMO

RATIONALE: Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance. OBJECTIVES: To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition. METHODS: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP. RESULTS: Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. CONCLUSIONS: These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.


Assuntos
Analgésicos não Entorpecentes/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Analgésicos não Entorpecentes/farmacologia , Animais , Alcaloides de Berberina/farmacologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/fisiopatologia , Receptores de Dopamina D1/agonistas
4.
Food Chem Toxicol ; 131: 110583, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220533

RESUMO

We investigated the anti-inflammatory activity of protopine (PTP) and sought to determine its mechanism of action in LPS-stimulated BV2 cells and a carrageenan (CA)-induced mouse model. Treatment with PTP (5, 10, and 20 µM) significantly suppresses the secretion of NO and PGE2 in a concentration-dependent manner without affecting cell viability by downregulating iNOS and COX-2 expression in LPS-induced BV2 cells. PTP also attenuates the production of pro-inflammatory chemokines, such as MCP-1, and cytokines, including TNF-α, IL-1ß and IL-6, and augments the expression of the anti-inflammatory cytokine IL-10. In addition, PTP suppresses the nuclear translocation of NF-κB by hindering the degradation of IκB and downregulating the expression of mitogen-activated protein kinases (MAPKs), including p38, ERK1/2 and JNK protein. Furthermore, PTP treatment significantly suppresses CA-induced paw oedema in mice compared to that seen in untreated mice. Expression of iNOS and COX-2 proteins is also abrogated by PTP (50 mg/kg) treatment in CA-induced mice. PTP treatment also abolishes IκB phosphorylation, which hinders the activation of NF-κB. Collectively, these results suggest PTP has potential for attenuating CA- and LPS-induced inflammatory symptoms through modulation of MAPKs/NF-κB signaling cascades.


Assuntos
Anti-Inflamatórios/uso terapêutico , Benzofenantridinas/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Anti-Inflamatórios/toxicidade , Benzofenantridinas/toxicidade , Alcaloides de Berberina/toxicidade , Carragenina , Linhagem Celular Transformada , Quimiocinas/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos
5.
Phytother Res ; 33(6): 1689-1696, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30932278

RESUMO

The tumor suppressor p53 plays essential roles in cellular protection mechanisms against a variety of stress stimuli and its activation induces apoptosis or autophagy in certain cancer cells. Here, we identified protopine, an isoquinoline alkaloid isolated from Nandina domestica, as an activator of the p53 pathway from cell-based natural compound screening based on p53-responsive transcription. Protopine increased the p53-mediated transcriptional activity and promoted p53 phosphorylation at the Ser15 residue, resulting in stabilization of p53 protein. Moreover, protopine up-regulated the expression of p21WAF1/CIP1 and BAX, downstream genes of p53, and inhibited the proliferation of HCT116 colon cancer cells. Apoptosis was elicited by protopine as indicated by caspase-3/7 activation, poly ADP ribose polymerase cleavage, and increased population of Annexin V-FITC-positive cells. Furthermore, protopine induced the formation of microtubule-associated protein 1 light chain 3 (LC3) puncta and LC3-II turnover, typical biochemical markers of autophagy, in HCT116 cells. Our findings suggest that protopine exerts its antiproliferative activity by stimulating the p53 pathway and may have potential as a chemopreventive agent for human colon cancer.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzofenantridinas/isolamento & purificação , Benzofenantridinas/uso terapêutico , Alcaloides de Berberina/isolamento & purificação , Alcaloides de Berberina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ranunculales/química , Apoptose/fisiologia , Autofagia/fisiologia , Benzofenantridinas/farmacologia , Berberidaceae/química , Berberidaceae/classificação , Alcaloides de Berberina/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Ranunculales/classificação , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Int Immunopharmacol ; 70: 435-445, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856394

RESUMO

BACKGROUND: Hepatic ischemia/reperfusion (IR) injury is a common medical phenomenon that occurs during a number of clinical conditions, such as liver transplantation, severe injuries, and shock. In our study, we determined the protective functions of levo-tetrahydropalmatine (L-THP) on hepatic IR injury in mice by inhibiting the ERK/NF-κB signaling pathway. METHOD: BALB/c mice were randomly divided into six groups as follows: normal control (NC); sham; L-THP (40 mg/kg); IR; L-THP (20 mg/kg) + IR; and L-THP (40 mg/kg) + IR. Liver tissues and sera were collected at three time points after reperfusion (2, 8, and 24 h). The liver enzyme, inflammatory factor, and other protein levels in the serum and liver tissues were detected. RESULTS: L-THP pretreatment alleviated hepatocyte injury caused by IR and reduced the production of proinflammatory cytokines, such as IL-6 and TNF-α. Furthermore, L-THP could inhibit the ERK/NF-κB signaling pathway to attenuate hepatocyte apoptosis and autophagy. And the protective effect of L-THP is positively correlated with its dose. CONCLUSION: L-THP protects the liver from IR injury by inhibiting the release of inflammatory factors and alleviating liver cell apoptosis and autophagy. The protective functions of L-THP may be partly based on the downregulation of the ERK/NF-κB pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Hepatócitos/efeitos dos fármacos , Fígado/fisiologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células Cultivadas , Hepatócitos/fisiologia , Humanos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Pharmacol Res ; 137: 34-46, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30243842

RESUMO

Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1) and the positive drug Sulfasalazine (SASP, 200 mg kg-1) were orally administered for 7 days. Disease activity index (DAI) was evaluated on day 8, and colonic tissues were collected for biochemistry analysis. The fecal microbiota was characterized by high-throughput Illumina MiSeq sequencing. And plasma metabolic changes were detected by UPLC-MS. Our results showed that Pal treatment significantly reduced DAI scores and ameliorated colonic injury in mice with DSS-induced colitis. Mucosal integrity was improved and cell apoptosis was inhibited. Moreover, gut microbiota analysis showed that mice received Pal-treatment have higher relative abundance of Bacteroidetes and Firmicutes, but reduced amount of Proteobacteria. Moreover, Pal not only suppressed tryptophan catabolism in plasma, but also decreased the protein expression of indoleamine 2,3-dioxygenase 1 (IDO-1, the rate-limiting enzyme of tryptophan catabolism) in colon tissue. This is consolidated by molecular docking, which suggested that Pal is a potent IDO-1 inhibitor. Taken together, our findings demonstrate that Pal ameliorated DSS-induced colitis by mitigating colonic injury, preventing gut microbiota dysbiosis, and regulating tryptophan catabolism, which indicated that Pal has great therapeutic potential for colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/uso terapêutico , Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Triptofano/metabolismo , Animais , Colite/metabolismo , Colite/microbiologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos BALB C , Mucinas/genética , Proteínas de Junções Íntimas/genética
8.
J Mol Neurosci ; 65(3): 391-399, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29974381

RESUMO

Ischemic stroke is one of the most dangerous acute diseases which causes death or deformity. Apoptosis has been shown to play an important role in the development and pathogenesis of cerebral ischemia-reperfusion injury (I/R injury), but the related mechanism is unclear. Levo-tetrahydropalmatine (L-THP), a bioactive ingredient extracted from the Chinese herb Corydalis, can penetrate the blood-brain barrier and exert various pharmacological effects on neural tissues. The present study examined the neuroprotective effect of L-THP on neuronal apoptosis induced by cerebral I/R injury. Results showed that pretreatment with L-THP (12.5, 25, and 50 mg/kg) improved neurological outcomes and reduced infarct volume and cerebral edema in comparison with the brains of the middle cerebral artery occlusion (MCAO) group. These findings provided evidence for the neuroprotective effects of L-THP against cerebral I/R injury. Furthermore, administration of L-THP enhanced the expression of Bcl-2 and attenuated the content of Bax, cleaved caspase-3, and PARP. L-THP could improve the reduction of NeuN-positive cells induced by I/R injury. These results suggested that L-THP could inhibit neuroapoptosis in cerebral ischemic rats. c-Abl was discovered as the critical protein responsible for neurocyte apoptosis; however, few data have been published on the relation between ischemic stroke and the expression of c-Abl. We found that both c-Abl expression and neuronal apoptosis were significantly increased in the MCAO group, while pretreatment with L-THP could ameliorate this effect. Therefore, we deduced that reduced c-Abl overexpression may play a role in the anti-apoptosis effect of L-THP after cerebral I/R injury. Thus, L-THP may provide a potential therapeutic approach for the treatment of ischemic stroke. Graphical Abstract ᅟ.


Assuntos
Apoptose , Alcaloides de Berberina/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Inflammation ; 41(5): 1640-1647, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29748730

RESUMO

Corynoline, a bioactive compound isolated from Corydalis bungeana Turcz., has been known to have anti-inflammatory activity. However, its effects on the inflammation of the cardiovascular system have not been reported yet. The aim of this study was to investigate the anti-inflammatory effects of corynoline on lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). The results showed that LPS significantly increased the expression of VCAM-1 and ICAM-1. The production of cytokines TNF-α and IL-8 was also up-regulated by LPS. However, these increases were concentration-dependently suppressed by the treatment of corynoline. To investigate the anti-inflammatory mechanism of corynoline, we checked the activation of NF-κB and the expression of Nrf2. The results showed that LPS-induced NF-κB activation was suppressed by corynoline. The expression of Nrf2 and HO-1 was up-regulated by the treatment of corynoline. Knockdown of Nrf2 could reverse the anti-inflammatory effects of corynoline. In conclusion, the results indicated that corynoline exhibited anti-inflammatory activity by activating Nrf2.


Assuntos
Alcaloides de Berberina/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Alcaloides de Berberina/uso terapêutico , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Humanos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo
10.
Bioorg Med Chem ; 26(9): 2586-2598, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29680749

RESUMO

In this study, quaternary palmatine is used as a lead compound to design and synthesize derivatives to evaluate bioactivities, with twenty-seven compounds of four series being obtained. Antibacterial activity was examined by determining the minimal inhibitory concentration (MIC) values on Staphylococcus aureus, Escherichia coli, and Candida albicans, three series of derivatives being found to exhibit activity in vitro with significant structure-activity relationship (SAR). Elongating the carbon chain led to the antibacterial activity increased, with quaternary 13-hexanoylpalmatine chloride, quaternary 13-(ω-ethoxycarbonyl)heptylpalmatine chloride, and 8-oxo-13-(N-n-nonyl)aminomethyldihydropalmatine, all of which possess the longest aliphatic carbon chain in the corresponding series of derivatives, showing the MIC values of 62.5, 7.81, and 15.63 µg/ml against S. aureus, respectively. The property of anti-ulcerative colitis (anti-UC) was assessed at the levels of both in vitro and in vivo, with X-box-binding protein 1 (XBP1) being targeted in vitro. Seven compounds were found not only to be hypocytotoxic toward intestinal epithelial cells, but also to exhibit activity of activating the transcription of XBP1 in vitro. Five compounds were found to possess significant dose-effect relationship with EC50 values at a level of 10-7 µM in vitro. 8-Oxo-13-formyldihydropalmatine as an intermediate was found to display significant curative effect on UC in vivo based on the biomarkers of body weight change, colon length change, and calculated values of disease activity index and colon macroscopic damage index of the experimental animals, as well as the examination into the pathological changes of the colon tissue of the modeled animals.


Assuntos
Antibacterianos/farmacologia , Antiulcerosos/farmacologia , Alcaloides de Berberina/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/uso terapêutico , Antiulcerosos/síntese química , Antiulcerosos/química , Antiulcerosos/uso terapêutico , Alcaloides de Berberina/síntese química , Alcaloides de Berberina/química , Alcaloides de Berberina/uso terapêutico , Peso Corporal/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Colo/metabolismo , Escherichia coli/efeitos dos fármacos , Levofloxacino/farmacologia , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfassalazina/farmacologia , Proteína 1 de Ligação a X-Box/metabolismo
11.
Mol Med Rep ; 17(5): 6873-6880, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29512789

RESUMO

Tetrahydropalmatine exerts numerous pharmacological activities, including analgesic and narcotic effects; anti-arrhythmic, blood pressure lowering and cardioprotective effects; protective effects against cerebral ischemia-reperfusion injury; inhibition of platelet aggregation; prevention of ulcerative diseases and inhibition of gastric acid secretion; antitumor effects; and beneficial effects on the withdrawal symptoms associated with drug addiction. The present study aimed to investigate the protective effects of tetrahydropalmatine against ketamine­induced learning and memory impairment in mice. The Morris water maze test and open field test were used to analyzed learning and memory impairment in mice. ELISA kits and western blotting were used to analyze oxidative stress, inflammation factors, caspease­3 and caspase­9, iNOS, glial fibrillary acidic protein (GFAP), glial cell­derived neurotrophic factor (GDNF), cytochrome c and phospholipase C (PLC)­Î³1 protein expression. The results demonstrated that tetrahydropalmatine treatment significantly decreased escape latency in the learning phase and increased the number of platform site crossings in ketamine­induced mice. In addition, tetrahydropalmatine significantly inhibited oxidative stress, inflammation and acetylcholinesterase activity, and decreased acetylcholine levels in ketamine­induced mice. Tetrahydropalmatine also suppressed iNOS protein expression, weakened caspase­3 and caspase­9 activation, inhibited nuclear factor­κB, glial fibrillary acidic protein, cytochrome c and phospholipase C­Î³1 protein expression, and induced glial cell­derived neurotrophic factor protein expression in ketamine­induced mice. Taken together, these results indicated that tetrahydropalmatine may protect against ketamine­induced learning and memory impairment in mice via antioxidative, anti­inflammatory and anti­apoptotic mechanisms. The present study provided an experimental basis for the clinical application of tetrahydropalmatine to reduce the severe side effects associated with ketamine therapy in future studies.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Ketamina/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/patologia , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
12.
Brain Res Bull ; 139: 56-66, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29427595

RESUMO

Diabetic neuropathic pain (DNP) is one of the common complications of diabetes. Depression (DP) is also one of the common complications of diabetes. P2X7 receptors play an important role in the transmission of nociceptive signal and are associated with depressive illness. In the study, the hyperalgesia, allodynia and depressive behaviours of rats with comorbidity of DNP and DP were confirmed by the thermal withdrawal latency (TWL) test, mechanical withdrawal threshold (MWT) test, sucrose preference test (SPT), immobility time of forced swimming test (IMFST) and open-field test (OFT). The change in expression of the P2X7 receptor of the hippocampus was observed through RT-PCR, qPCR, Western blotting and immunohistochemical staining methods The results showed that palmatine treatment can alleviate the hyperalgesia, allodynia and depressive behaviours of rats with comorbidity of DNP and DP. Meanwhile, the expression of P2X7 receptors, GFAP, TNF-α and IL-1ß in the hippocampus of the rats with comorbidity of DNP and DP was significantly increased compared with the control rats, and palmatine treatment could decrease the expression. Furthermore, the enhanced phosphorylation of ERK1/2 in the hippocampus of rats with DNP and DP was decreased noticeably by palmatine treatment. The results of this study suggest that palmatine can alleviate the comorbidity of DNP and DP by inhibiting the expression of P2X7 receptors in the hippocampus, and its action may be related to suppression of the phosphorylation of ERK1/2 and the release of TNF-α and IL-1ß in the hippocampus.


Assuntos
Analgésicos/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Depressão/complicações , Depressão/tratamento farmacológico , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/tratamento farmacológico , Animais , Depressão/patologia , Neuropatias Diabéticas/patologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Privação de Alimentos , Preferências Alimentares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiperalgesia/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Medição da Dor , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7/metabolismo , Natação , Fator de Necrose Tumoral alfa/metabolismo
13.
Med Sci Monit ; 24: 652-660, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29388563

RESUMO

BACKGROUND Levo-tetrahydropalmatine (L-THP) is a tetrahydro protoberberine isoquinoline alkaloid obtained from the genera Stephania and Corydalis. In the present research, we evaluated the effects of L-THP on the progression of aortic aneurysms (AAs) in experimental rats induced with perfusion of elastase. MATERIAL AND METHODS Thirty-six Sprague-Dawley rats were divided into sham-operated, control, and L-THP treated groups (n=12 in each group). The rats in the control group and the L-THP group received intra-aortic perfusion of elastase to induce AAs; the sham-operated group received perfusion of saline. The rats in the L-THP group received a dose of 15 mg/kg/day, the control and the sham group received saline treatment. The animals were evaluated for aortic diameters (ADs) and systolic blood pressure (SBP) just before and after the elastase perfusion, and 24 days after perfusion. The extracts of the aortas were evaluated by western blotting and immunohistochemistry. RESULTS In the control group, a significant increase in aortic size was observed (p<0.05) compared to the sham group after 24 days post-perfusion, whereas the L-THP group showed a decrease in diameter compared to the control group (p<0.05). The SBP increased significantly in the control group compared to the sham group. The L-THP group showed reduction in SBP, exhibited decreased expression of metalloproteinase and monocyte chemotactic protein-1, and the tissue samples also exhibited significant decreased levels of iNOS compared to the control group. L-THP treatment prevented loss of vascular smooth muscle cells (VSMCs) of the aortic walls. CONCLUSIONS L-THP inhibited progression of AAs in rats by curbing inflammation, oxidative stress, and conserving VSMCs, suggesting a new therapeutic approach for managing AAs.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/patologia , Alcaloides de Berberina/uso terapêutico , Quimiocina CCL2/metabolismo , Progressão da Doença , Metaloproteinases da Matriz/metabolismo , Perfusão , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/fisiopatologia , Alcaloides de Berberina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Elastase Pancreática , Ratos Sprague-Dawley , Coloração e Rotulagem , Sístole/efeitos dos fármacos
14.
Chem Biol Interact ; 285: 27-39, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29486184

RESUMO

Photodynamic therapy (PDT) provides an effective cancer treatment option but it requires sufficient cellular oxygen concentration to exert its photosensitizing effects. Due to hypoxic nature of most tumors, widespread clinical application of PDT is restricted and warrants development of photosensitizers which can kill cancer cells in ROS independent manner. Previously, we reported significant enhancement of the anti-cancer property of coralyne in presence of ultraviolet-A (UVA) light exposure against several human carcinoma cell lines. This study aimed at unravelling molecular cascades of events in CUVA treatment (coralyne and UVA light)-mediated photosensitization of human skin cancer. The CUVA-treatment caused robust apoptosis of A431 cancer cells, primarily through mitochondrial and lysosomal dysfunctions. Silencing of BAX conferred a significant protection against CUVA-induced apoptosis. Both lysosomal proteases and caspase-8 activation contributed to BID cleavage. Further, our results revealed that a dual signaling axis e.g., ATR-p38 MAPK and JAK2-STAT1 pathways functioned upstream of BAX activation in apoptosis response. Moreover, transient silencing of ATR and pharmacological inhibition of p38-MAPK or JAK2 significantly abolished the effect of CUVA treatment induced BAX expression and cell death, linking the extrinsic and intrinsic pathways with the observed cell death. Our data suggest that coralyne, which is known topoisomerase-I inhibitor, may be an attractive agent for photo-chemotherapeutic treatment of human skin cancers.


Assuntos
Alcaloides de Berberina/farmacologia , Transtornos de Fotossensibilidade , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Alcaloides de Berberina/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Janus Quinase 2/metabolismo , Queratinócitos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fator de Transcrição STAT1/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Phytother Res ; 32(1): 65-75, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29044876

RESUMO

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a complex that regulates several hundreds of genes, including those involved in immunity and inflammation, survival, proliferation, and the negative feedback of NF-κB signaling. Chelidonine, a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus, exhibits antiinflammatory pharmacological properties. However, its antiinflammatory molecular mechanisms remain unclear. In this work, we explored the effect of chelidonine on TNF-induced NF-κB activation in HCT116 cells. We found chelidonine inhibited the phosphorylation and degradation of the inhibitor of NF-κB alpha and nuclear translocation of RELA. Furthermore, by inhibiting the activation of NF-κB, chelidonine downregulated target genes involved in inflammation, proliferation, and apoptosis. Chelidonine also inhibited mitogen-activated protein kinase pathway activation by blocking c-Jun N-terminal kinase and p38 phosphorylation. These results suggest that chelidonine may be a potential therapeutic agent against inflammatory diseases in which inhibition of NF-κB activity plays an important role.


Assuntos
Benzofenantridinas/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Células HCT116/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Apoptose , Benzofenantridinas/administração & dosagem , Benzofenantridinas/farmacologia , Alcaloides de Berberina/administração & dosagem , Alcaloides de Berberina/farmacologia , Humanos , Transdução de Sinais , Transfecção
16.
Mediators Inflamm ; 2018: 4032484, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30622431

RESUMO

Aims: Levo-tetrahydropalmatine (L-THP) is an active ingredient of Corydalis yanhusuo W. T. Wang, which has many bioactive properties. Herein, we investigated the protective effects of L-THP on concanavalin A- (ConA-) induced hepatitis in mice and explored its possible mechanisms of these effects. Main Methods: Balb/c mice were intravenously injected with 25 mg/kg ConA to generate a model of acute autoimmune hepatitis, and L-THP (20 or 40 mg/kg) was administered orally once daily for 5 d before the ConA injection. The liver enzyme levels, proinflammatory cytokine levels, and other marker protein levels were determined 2, 8, and 24 h after ConA injection. Results: L-THP could decrease serum liver enzymes and pathological damage by reducing the release of inflammatory factors like IL-6 and TNF-α. The results of Western Blot and PCR indicated that L-THP could ameliorate liver cell apoptosis and autophagy. L-THP could suppress T lymphocyte proliferation and the production of TNF-α and IL-6 induced by ConA in a dose-dependent manner in vitro. Additionally, the protective functions of L-THP depended on downregulating TRAF6/JNK signaling. Conclusion. The present study indicated that L-THP attenuated acute liver injury in ConA-induced autoimmune hepatitis by inhibiting apoptosis and autophagy via the TRAF6/JNK pathway.


Assuntos
Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Concanavalina A/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , MAP Quinase Quinase 4/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Fígado/lesões , Masculino , Camundongos
17.
Int J Immunopathol Pharmacol ; 30(4): 406-412, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29164959

RESUMO

This study aimed to exploit the potential therapeutic value of palmatine in treatment of cardiac hypertrophy and the underlying molecular mechanism. Rat hypertrophy model was established by intraperitoneal isoproterenol (ISO) injection. The hypertrophy was evaluated with cardiac hypertrophic parameters, hemodynamic parameters, lipid profile, and non-specific cardiac markers. The animals were intraperitoneally administrated with either palmatine or vehicle. The relative expressions of ANP, BNP, HDAC2, HDAC5, KLF4, and INPP5F transcripts were determined by real-time polymerase chain reaction (PCR). The relative protein levels of HDAC2, HDAC5, KLF4, and INPP5F were analyzed by immunoblotting. Palmatine treatment significantly attenuated ISO-induced hypertrophy in rats and elicited remarkable repressions in ANP, BNP, and HDAC2 transcriptions but not HDAC5. The downstream effector genes KLF4 and INPP5F were greatly restored in a dose-dependent manner in response to palmatine treatment. Our data demonstrated that palmatine possessed promising therapeutic potential against hypertrophy, which was mediated by modulation of HDAC2-KLF4/INPP5F pathway.


Assuntos
Alcaloides de Berberina/farmacologia , Cardiomegalia/genética , Cardiotônicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Animais , Fator Natriurético Atrial/genética , Alcaloides de Berberina/uso terapêutico , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiotônicos/uso terapêutico , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/genética , Inibidores de Histona Desacetilases/uso terapêutico , Inositol Polifosfato 5-Fosfatases/genética , Isoproterenol , Fatores de Transcrição Kruppel-Like/genética , Masculino , Peptídeo Natriurético Encefálico/genética , RNA Mensageiro/metabolismo , Ratos Wistar
18.
Int Immunopharmacol ; 48: 96-101, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28486213

RESUMO

Corynoline, isolated from Corydalis bungeana Turcz, has been reported to possess anti-inflammatory and antibacterial activities. In this study, we aimed to explore the treatment effect of corynoline on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. In the present study, the signaling pathways were measured by Western blot analysis. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assays (ELISA). Additionally, the effects of corynoline on LPS-induced myeloperoxidase (MPO) activity was examined. The results showed that corynoline markedly inhibited LPS-induced neutrophils influx, MPO activity, and inflammatory cytokines IL-1ß, TNF-α and IL-6 release. Corynoline also attenuated lung histopathological changes induced by LPS. Furthermore, corynoline inhibited LPS-induced NF-κB activation. In addition, corynoline up-regulated the expression of Nrf2 and HO-1 in a dose-dependent manner. The data suggest that corynoline has a treatment effect on LPS-induced ALI in mice by inhibiting inflammatory response.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Alcaloides de Berberina/farmacologia , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Feminino , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Peroxidase/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Inflammation ; 40(4): 1111-1122, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28365871

RESUMO

Acute lung injury (ALI) is characterized by widespread inflammation in the lungs and alveolar-capillary destruction, causing high morbidity and mortality. Cavidine, isolated from Corydalis impatiens, have been exhibited to have potent anti-inflammatory effects in previous studies. The purpose of this study was to evaluate the protective effect of cavidine on lipopolysaccharide (LPS)-induced ALI and to enunciate the underlying in vivo and in vitro mechanisms. Mice were intraperitoneally administrated with cavidine (1, 3, or 10 mg/kg) at 1 and 12 h, prior to the induction of ALI by intranasal administration of LPS (30 mg/kg). Blood samples, lung tissues, and bronchoalveolar lavage fluid (BALF) were harvested after LPS challenge. Furthermore, we used LPS-induced lung epithelial cells A549 to examine the mechanism of cavidine to lung injury. The results showed that pretreatment with cavidine significantly decreased lung wet-to-dry weight (W/D) ratio, reduced pro-inflammatory cytokine levels including TNF-α and IL-6 in BALF and serum from LPS-stimulated mice, and attenuated lung histopathological changes. In addition, western blot results showed that cavidine inhibited the phosphorylation of nuclear factor-kappaB (NF-κB) p65 and IκBα induced by LPS. In conclusion, our results demonstrate that cavidine protects against LPS-induced acute lung injury in mice via inhibiting of pro-inflammatory cytokine TNF-α and IL-6 production and NF-κB signaling pathway activation. Taken together, cavidine may be useful for the prevention and treatment of pulmonary inflammatory diseases, such as ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Alcaloides de Berberina/uso terapêutico , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Alcaloides de Berberina/farmacologia , Líquido da Lavagem Broncoalveolar/química , Humanos , Inflamação/prevenção & controle , Mediadores da Inflamação/análise , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Lipopolissacarídeos , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
20.
Int Immunopharmacol ; 46: 87-96, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28278436

RESUMO

Huanglian Jiedu Decoction (HJD), one of the classic recipes for relieving toxicity and fever, is a common method for treating sepsis in China. However, the effective components of HJD have not yet been identified. This experiment was carried out to elucidate the effective components of HJD against sepsis. Thus, seven fractions from HJD were tested using a biosensor to test their affinity for lipid A. The components obtained that had high lipid A-binding fractions were further separated, and their affinities to lipid A were assessed with the aid of a biosensor. The levels of LPS in the blood were measured, and pathology experiments were conducted. The LPS levels and mRNA expression analysis of TNF-α and IL-6 of the cell supernatant and animal tissue were evaluated to investigate the molecular mechanisms. Palmatine showed the highest affinity to lipid A and was evaluated by in vitro and in vivo experiments. The results of the in vitro and in vivo experiments indicated that the levels of LPS, TNF-α and IL-6 of the palmatine group were significantly lower than those of the sepsis model group (p<0.01). The group treated with palmatine showed strong neutralizing LPS activity in vivo. The palmatine group exhibited stronger protective activity on vital organs compared to the LPS-induced animal model. This verifies that HJD is a viable treatment option for sepsis given that there are multiple components in HJD that neutralize LPS, decrease the release of IL-6 and TNF-α induced by LPS, and protect vital organs.


Assuntos
Alcaloides de Berberina/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Sepse/terapia , Animais , Alcaloides de Berberina/química , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipídeo A/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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