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1.
Can J Urol ; 29(4): 11209-11215, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35969724

RESUMO

INTRODUCTION: The use of alvimopan at the time of cystectomy has been associated with improved perioperative outcomes. Naloxegol is a less costly alternative that has been used in some centers. This study aims to compare the perioperative outcomes of patients undergoing cystectomy with urinary diversion who receive the mu-opioid antagonist alvimopan versus naloxegol. MATERIALS AND METHODS: This was a retrospective review that included all patients who underwent cystectomy with urinary diversion at our institution between 2007-2020. Comparisons were made between patients who received perioperative alvimopan, naloxegol and no mu-opioid antagonist (controls). RESULTS: In 715 patients who underwent cystectomy, 335 received a perioperative mu-opioid antagonist, of whom 57 received naloxegol. Control patients, compared to naloxegol and alvimopan patients, experienced a significantly (p < 0.05) delayed return of bowel function (4.3 vs. 2.5 vs. 3.0 days) and longer hospital length of stay (7.9 vs. 7.5 vs. 6.5 days), respectively. The incidence of nasogastric tube use (14.2% vs. 12.5% vs. 6.5%) and postoperative ileus (21.6% vs. 21.1% vs. 13.3%) was also most common in the control group compared to the naloxegol and alvimopan cohorts, respectively. A multivariable analysis revealed that when comparing naloxegol and alvimopan, there was no difference in return of bowel function (OR 0.88, p = 0.17), incidence of postoperative ileus (OR 1.60, p = 0.44), or hospital readmission (OR 1.22, p = 0.63). CONCLUSIONS: Naloxegol expedites the return of bowel function to the same degree as alvimopan in cystectomy patients. Given the lower cost of naloxegol, this agent may be a preferable alternative to alvimopan.


Assuntos
Íleus , Derivação Urinária , Cistectomia/efeitos adversos , Fármacos Gastrointestinais/efeitos adversos , Humanos , Íleus/tratamento farmacológico , Íleus/epidemiologia , Íleus/etiologia , Tempo de Internação , Morfinanos , Antagonistas de Entorpecentes , Piperidinas , Polietilenoglicóis , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Derivação Urinária/efeitos adversos
2.
J Enzyme Inhib Med Chem ; 37(1): 1870-1883, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35801430

RESUMO

Sinomenine, a morphinane-type isoquinoline-derived alkaloid, was first isolated from stems and roots of Sinomenium diversifolius (Miq.) in 1920. Later discovery by researchers confirmed various essential biological efficacy sinomenine exerted in vitro and in vivo. In this study, a series of 15 sinomenine/furoxan hybrid compounds were designed and synthesised in search of a TNBC drug candidate. Some of the target compounds exhibited strong antiproliferative activities against cancer cell lines, especially for TNBC cells, compared to positive controls. Among them, hybrid 7Cc exerted superior cytotoxic effects on cancer cell lines with exceptionally low IC50 (0.82 µM) against MDA-MB-231 cells with the highest safety index score. Further studies in mechanism displayed that 7Cc could induce an S phase cell cycle arrest, stimulate apoptosis in MDA-MB-231 cells, disrupt mitochondrial membrane potential and exert a genotoxic effect on DNA in cancer cells. In addition, 7Cc also notably inhibited MDA-MB-231 cells in both migration, invasion and adhesion.


Assuntos
Antineoplásicos , Morfinanos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Morfinanos/farmacologia
3.
J Med Chem ; 65(15): 10377-10392, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35900351

RESUMO

Undue central nervous system (CNS) side effects including dysphoria and sedation remain to be a challenge for the development of κ opioid receptor (KOR) agonists as effective and safe analgesics. On the basis of our previous work on morphinan-based KOR agonists, a series of 7α-methyl-7ß-substituted northebaine derivatives were designed, synthesized, and biologically assayed. Among others, compound 4a (SLL-627) has been identified as a highly selective and potent KOR agonist both in vitro and in vivo, and its molecular basis was also examined and discussed. Besides low liability to conditioned place aversion (CPA) test, treatment of SLL-627 was associated with a nonreduction in locomotor activity, compared to most of the other arylacetamide- or morphinan-based KOR agonists which generally exhibited apparently sedative effects. This unexpected finding provides new insights to dissociate analgesia from sedation for future discovery of innovative KOR agonists.


Assuntos
Morfinanos , Receptores Opioides kappa , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Locomoção , Morfinanos/farmacologia , Receptores Opioides kappa/agonistas
4.
Hum Cell ; 35(5): 1453-1463, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35854195

RESUMO

Diabetic nephropathy (DN) is one of the main complications of diabetes. It is closely associated with the dysfunction of glomerular endothelial cells (GECs) under hyperglycemia. Severe inflammation is an important inducer for the development of GECs dysfunction, and it contributes to the disruption of tight junctions in GECs and the increased endothelial permeability. Sinomenine, an alkaloid monomer extracted from the rhizome of Sinomenium acutum, is recognized for its multiple pharmacological functions, including an anti-DN property. The present study aimed to explore the potential functional mechanism of Sinomenine against DN. Animals were randomly divided into Sham, DN, DN + Sinomenine (20 mg/kg), and DN + Sinomenine (40 mg/kg) groups. The Sinomenine or vehicle was administered every day for 6 weeks, followed by collecting renal tissues for further detection. Increased body weights, elevated blood glucose levels and UAE values, aggravated renal tissue pathology, higher concentrations of IL-18 and IL-1ß in renal tissues, and reduced claudin-5 expression were observed in DN rats. However, the administration of Sinomenine significantly alleviated all these DN-related changes. Furthermore, human renal glomerular endothelial cells (HrGECs) were treated with high glucose (HG, 30 mM) with or without Sinomenine (50, 100 µM) for 24 h. We found that Sinomenine treatment ameliorated the elevated production of IL-18 and IL-1ß, increased fluorescence intensity of FITC-dextran, declined trans-endothelial electrical resistance (TEER) value, and reduction of claudin-5 and C/EBP-α in HG-treated HrGECs. Moreover, the regulatory effect of Sinomenine on endothelial monolayer permeability in HG-treated HrGECs was abolished by the knockdown of C/EBP-α, indicating C/EBP-α is required for the effect of Sinomenine. We concluded that Sinomenine alleviated diabetic nephropathy-induced renal glomerular endothelial dysfunction via activating the C/EBP-α/claudin-5 axis.


Assuntos
Nefropatias Diabéticas , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/farmacologia , Proteína alfa Estimuladora de Ligação a CCAAT/uso terapêutico , Claudina-5/metabolismo , Claudina-5/farmacologia , Nefropatias Diabéticas/metabolismo , Células Endoteliais/metabolismo , Humanos , Interleucina-18/metabolismo , Interleucina-18/farmacologia , Interleucina-18/uso terapêutico , Morfinanos , Permeabilidade , Ratos , Transdução de Sinais
5.
Nat Commun ; 13(1): 3150, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672295

RESUMO

The STORR gene fusion event is considered essential for the evolution of the promorphinan/morphinan subclass of benzylisoquinoline alkaloids (BIAs) in opium poppy as the resulting bi-modular protein performs the isomerization of (S)- to (R)-reticuline essential for their biosynthesis. Here, we show that of the 12 Papaver species analysed those containing the STORR gene fusion also contain promorphinans/morphinans with one important exception. P. californicum encodes a functionally conserved STORR but does not produce promorphinans/morphinans. We also show that the gene fusion event occurred only once, between 16.8-24.1 million years ago before the separation of P. californicum from other Clade 2 Papaver species. The most abundant BIA in P. californicum is (R)-glaucine, a member of the aporphine subclass of BIAs, raising the possibility that STORR, once evolved, contributes to the biosynthesis of more than just the promorphinan/morphinan subclass of BIAs in the Papaveraceae.


Assuntos
Alcaloides , Benzilisoquinolinas , Morfinanos , Papaver , Alcaloides/metabolismo , Benzilisoquinolinas/metabolismo , Fusão Gênica , Morfinanos/metabolismo , Papaver/genética , Papaver/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
6.
Arch Microbiol ; 204(7): 441, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35773566

RESUMO

Mycoplasma pneumoniae (MPP) induced pneumonia is a common disease of children. Sinomenine (SIN) is an isoquinoline mainly sequestered from Sinomenium acutum. It is a promising drug for treating arthritis, lung, colon, liver and gastric cancer. Hence, the present study investigated the role and mechanism of SIN treatment in MPP induced pneumonia in experimental in-vivo mice model. The BALB/c male mice were separated into four groups (n = 6 mice/group): normal, MPP, MPP + SIN (20 mg/kg bw), and SIN (20 mg/kg bw) alone. Results were expressed as mean ± SD. Data were analyzed using one way Analysis of Variance (ANOVA) with the Dunnett's post hoc test using SPSS v 18.0. P value < 0.05 was considered significant. The total protein, cell count, inflammatory cytokines, MP-IgM, Monocyte chemo attractant protein-1 (MCP-1), and MP-DNA were measured. The protein expressions of Bax/Bcl-2, ERK, JNK, NF-κB were analyzed and histopathology of lungs was examined. SIN treatment significantly (p < 0.05) reduced the total proteins, cell counts in BALF, inflammatory cytokines, MP-IgM, MCP-1, MP-DNA and reversed the histological alterations. SIN attenuated the apoptotic pathway through the modulation of Bax/Bcl-2 expression. SIN alleviated pulmonary inflammatory mediators and apoptosis in MPP-infected mice via suppression of ERK/JNK/NF-κB signaling. SIN administration diminished inflammation and lung fibrosis by inhibiting apoptosis in MPP mice. Hence, SIN is a potential natural protective remedy for MPP.


Assuntos
Sistema de Sinalização das MAP Quinases , Morfinanos , Mycoplasma pneumoniae , NF-kappa B , Pneumonia por Mycoplasma , Animais , Citocinas/metabolismo , Imunoglobulina M , Inflamação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Morfinanos/farmacologia , Mycoplasma pneumoniae/efeitos dos fármacos , NF-kappa B/metabolismo , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/metabolismo , Proteína X Associada a bcl-2/metabolismo
7.
Molecules ; 27(9)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35566212

RESUMO

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels-Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.


Assuntos
Morfinanos , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Morfinanos/farmacologia , Morfina/farmacologia , Naloxona/farmacologia , Receptores Opioides , Receptores Opioides mu/agonistas
8.
ChemMedChem ; 17(14): e202200234, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35612514

RESUMO

Natural products have been widely considered as an important resource for new drugs or lead compounds. Sinomenine (SIN) and its derivatives exert antitumor activity via regulation of inflammatory mediators. For these reasons we synthesized three series of SIN derivatives (compounds 4 a-i, 7 a-c and 11 a-c) as antitumor agents from this natural product. All compounds were prepared by modification at the C1 and C4 positions of the A ring, the C4 position of the A ring, and the C6 and C7 positions of the C ring, respectively. All the derivatives were subjected to in vitro antitumor activity against HeLa, A549, HepG-2, MCF-7 and HT-29 cell lines. To observe the apoptotic induction of SIN derivatives and its mechanism, fluorescent staining and western blot assays were carried out for active compound against MCF-7. Based on the screening results, most of the SIN derivatives showed better antitumor activity than SIN. Some of them were found to possess broad-spectrum antitumor activity. Most notably, 11 c exhibited obvious antitumor activity in both cell lines with IC50 values less than 11 µM. Besides, 11 c induced apoptosis of MCF-7 in a dose-dependent manner. Western blot assay demonstrated that 11 c inhibited IL-6-mediated activation of PI3K/Akt pathway. A docking study revealed that 11 c had stronger binding interaction with the residues of IL-6 than SIN. All these results indicate that 11 c may be a potential anti-breast cancer agent by directly targeting IL-6.


Assuntos
Antineoplásicos , Fosfatidilinositol 3-Quinases , Antineoplásicos/química , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interleucina-6 , Células MCF-7 , Estrutura Molecular , Morfinanos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
9.
J Control Release ; 348: 42-56, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35569587

RESUMO

Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant of Sinomenium acutum (Thunb.) Rehd.et Wils. Currently, sinomenine hydrochloride (SIN) preparations, classified as a natural disease-modifying anti-rheumatic drug (nDMARD), have been used for therapy of rheumatoid arthritis (RA); however, the efficacy of SIN was seriously limited by its short half-life, low bioavailability, and dose-dependent adverse reactions. In this study, a biomimetic nanocomplex based on Prussian blue nanoparticles (PB NPs) was developed for overcoming clinical limitations of SIN and accordingly improving its efficacy. In vitro studies showed that the nanocomplexes significantly inhibited abnormal proliferation of fibroblast-like synoviocytes (FLSs) by scavenging reactive oxygen species (ROS) and inhibiting secretion of proinflammatory cytokines. In vivo imaging demonstrated that the improved immune-escape properties of the nanocomplexes resulted in markedly increased half-life of circulation and levels of accumulated drugs at arthritic sites of adjuvant-induced arthritis (AIA) rats. Notably, the nanocomplexes significantly suppressed joint inflammation and protected against bone destruction of AIA rats by inhibiting inflammatory cytokine secretion of the synovial macrophages and FLSs. These results indicate that the nanocomplexes provide an excellent carrier for controlled release and targeted accumulation of SIN within the arthritic sites, which consequently achieve disease-remitting effects of SIN on RA.


Assuntos
Artrite Reumatoide , Morfinanos , Nanopartículas Multifuncionais , Animais , Artrite Reumatoide/tratamento farmacológico , Citocinas , Morfinanos/farmacologia , Morfinanos/uso terapêutico , Ratos
10.
J Mol Neurosci ; 72(8): 1609-1621, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35543800

RESUMO

Sinomenine is the main bioactive ingredient of the medicinal plant Sinomenium acutum with neuroprotective potential. This study was designed to assess beneficial effect of sinomenine in alleviation of trimethyltin (TMT)-induced cognitive dysfunction. TMT was administered i.p. (8 mg/kg, once) and sinomenine was daily given p.o. 1 h after TMT for 3 weeks at doses of 25 or 100 mg/kg. Cognitive performance was assessed in various behavioral tests. In addition, oxidative stress- and inflammation-associated factors were measured and histochemical evaluation of the hippocampus was conducted. Sinomenine at a dose of 100 mg/kg significantly and partially increased discrimination index in novel object recognition (NOR), improved alternation in short-term Y maze, increased step-through latency in passive avoidance paradigm, and also reduced probe trial errors and latency in the Barnes maze task. Moreover, sinomenine somewhat prevented inappropriate hippocampal changes of malondialdehyde (MDA), reactive oxygen species (ROS), protein carbonyl, nitrite, superoxide dismutase (SOD), tumor necrosis factor α (TNFα), interleukin 6 (IL 6), acetylcholinesterase (AChE) activity, beta secretase 1 (BACE 1) activity, and mitochondrial membrane potential (MMP) with no significant effect on glutathione (GSH), catalase, glutathione reductase, glutathione peroxidase, and myeloperoxidase (MPO). In addition, lower reactivity (IRA) for glial fibrillary acidic protein (GFAP) as an index of astrocyte activity was observed and loss of CA1 pyramidal neurons was attenuated following sinomenine treatment. This study demonstrated that sinomenine could lessen TMT-induced cognitive dysfunction which is partly due to its attenuation of hippocampal oxidative stress and neuroinflammation.


Assuntos
Disfunção Cognitiva , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Glutationa/metabolismo , Hipocampo/metabolismo , Aprendizagem em Labirinto , Morfinanos , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Ratos , Ratos Wistar , Compostos de Trimetilestanho
11.
Int J Pharm ; 621: 121789, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35525469

RESUMO

Transdermal drug delivery systems have drawn increasing attention in recent decades. Estimation of the correlation between ex vivo permeation and in vivo absorption (EVIVC) is an indispensable issue in the research and development of transdermal pharmaceutical products. In this paper, sinomenine hydrochloride (SH) transfersomes (SHTs) were prepared with sodium deoxycholate as edge activator, while SH liposomes (SHLs) were prepared as a control preparation. The transdermal permeation characteristics differences between them were explored by an ex vivo skin permeation experiment with Franz diffusion cell and an in vivo skin/blood pharmacokinetic experiment facilitated by double-sited microdialysis sampling technique. The curves of percentage absorbed versus time (absorption curves) under the skin and in the blood were plotted according to the percentages calculated by the deconvolution approach with the application of Wagner-Nelson model, and were correlated with the ex vivo permeation curves to evaluate a level A correlation, while a level C correlation evaluation was conducted based on the in vivo steady-state blood concentration (Css) and the ex vivo steady-state transdermal permeation rate. The ex vivo permeation test indicated that the cumulative transdermal permeated amount of SH at 36 h in SHTs was about 1.7 times of that in SHLs. The skin pharmacokinetic data showed that the Css and AUC0-t of SHTs were about 8.8 and 8.0 times of those of SHLs, respectively, and the MRT0-t of SHTs was shorter. The blood pharmacokinetic data showed that the Css and AUC0-t of SHTs were about 3.7 and 2.9 times of those of SHLs, respectively. The in vivo absorption curves were correlated well with the ex vivo permeation curves. The squares of correlation coefficient (R2) for SHTs and SHLs were 0.9153 and 0.9355 respectively in the skin, were 0.8536 and 0.7747 respectively in the blood. As to level C EVIVC, there was no significant difference between the predicted Css from ex vivo and the measured Cssin vivo. The transfersomes can be employed as effective vehicles to promote the transdermal absorption of SH, and it is feasible to predict the in vivo skin/blood pharmacokinetic properties of SHLs and SHTs based on the ex vivo skin permeation characteristics.


Assuntos
Morfinanos , Absorção Cutânea , Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Microdiálise , Pele/metabolismo
12.
Pharmacol Biochem Behav ; 217: 173394, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35513117

RESUMO

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01-0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.32-1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01-0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0-56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.


Assuntos
Analgésicos Opioides , Oxicodona , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Proteínas de Ligação ao GTP , Hipnóticos e Sedativos , Macaca mulatta/metabolismo , Masculino , Morfinanos , Oxicodona/farmacologia , Receptores Opioides kappa/agonistas , Compostos de Espiro , Triazóis/farmacologia
13.
Sci Rep ; 12(1): 7311, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508514

RESUMO

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima's pruritus score. Nalfurafine hydrochloride 2.5 µg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima's pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.


Assuntos
Hepatopatias , Morfinanos , Compostos de Espiro , Humanos , Hepatopatias/complicações , Hepatopatias/tratamento farmacológico , Morfinanos/uso terapêutico , Prurido/complicações , Prurido/etiologia , Receptores Opioides kappa/agonistas , Compostos de Espiro/uso terapêutico
14.
Pharmacol Res ; 179: 106222, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35413424

RESUMO

Sinomenine hydrochloride (SH) has anti-breast cancer effect, but whether it can act on breast cancer stem cells (BCSCs) is unclear. Here, we explored the effect of SH on BCSCs and its mechanism. We observed that SH decreased the ratio of CD44+/CD24- BCSCs and the expression of BCSCs-related genes in MCF-7 and MDA-MB-231 cells. SH significantly inhibited the stemness of CD44+/CD24- BCSCs, including the capacity of self-renewal, oncosphere formation, migration and invasion, and the expression of stemness-related genes. Furthermore, SH obviously inhibited the expression of Wnt signaling pathway genes in CD44+/CD24- BCSCs, especially the expression of WNT10B and its downstream target genes. While WNT10B was overexpressed, the inhibitory effect of SH on the stemness of BCSCs was blocked, indicating that SH inhibited the stemness of BCSCs by down-regulating WNT10B. When WNT10B was knocked down, the stemness of BCSCs was significantly inhibited, indicating that WNT10B was involved in the stemness maintenance of BCSCs. SH also significantly inhibited the growth of MDA-MB-231 BCSCs xenografts, decreased the expression of BCSCs related genes and suppressed Wnt signaling pathway in vivo. In conclusion, SH negatively regulates the stemness of CD44+/CD24- BCSCs by inhibiting Wnt signaling pathway through down-regulation of WNT10B expression.


Assuntos
Neoplasias da Mama , Via de Sinalização Wnt , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Morfinanos , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Wnt/metabolismo
15.
Phytomedicine ; 100: 154050, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35397284

RESUMO

BACKGROUND: Sinomenine (SIN) is an anti-inflammatory drug that has been used for decades in China to treat arthritis. In a previous study, SIN acted on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit inflammatory responses in macrophages, which indicates a new anti-inflammatory mechanism of SIN. However, the level of α7nAChR was increased in the inflammatory responses and was downregulated by SIN in vitro, so the underlying mechanisms of SIN acting on α7nAChR remain unclear. PURPOSE: To analyze the role of α7nAChR in inflammation and the effect and mechanism of SIN regulation of α7nAChR. METHODS: The effects of SIN on α7nAChR in endotoxemic mice and LPS-stimulated macrophages were observed. Nicotine (Nic) was used as a positive control, and berberine (Ber) was used as a negative control targeting α7nAChR. The antagonists of α7nAChR, α-bungarotoxin (BTX) and mecamylamine (Me), were used to block α7nAChR. In RAW264.7 macrophage cells in vitro, α7nAChR short hairpin RNA (shRNA) was used to knock down α7nAChR. Macrophage polarization was analyzed by the detection of TNF-α, IL-6, iNOS, IL-10, Arg-1, and Fizz1. U0126 was used to block ERK phosphorylation. The cytokines α7nAChR, ERK1/2, p-ERK1/2 and Egr-1 were detected. RESULTS: SIN decreased the levels of TNF-α, IL-6 and the expression of α7nAChR increased by LPS in endotoxemic mice. The above effects of SIN were attenuated by BTX. In the α7nAChR shRNA transfected RAW264.7 cells, compared with the control, α7nAChR was knocked down, and M1 phenotype markers (including TNF-α, IL-6, and iNOS) were significantly downregulated, whereas M2 phenotype markers (including IL-10, Arg-1, and Fizz1) were significantly upregulated when stimulated by LPS. SIN inhibited the expression of p-ERK1/2 and the transcription factor Egr-1 induced by LPS in RAW264.7 cells, and the above effects of SIN were attenuated by BTX. The expression of α7nAChR was suppressed by U0126, which lessened the expression of p-ERK1/2 and Egr-1. CONCLUSIONS: SIN acts on α7nAChR to inhibit inflammatory responses and downregulates high expression of α7nAChR in vivo and in vitro. The increase of α7nAChR expression is correlated with inflammatory responses and participates in macrophage M1 polarization. SIN downregulates α7nAChR via a feedback pathway of α7nAChR/ERK/Egr-1, which contributes to inhibiting macrophage M1 polarization and inflammatory responses.


Assuntos
Interleucina-10 , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Retroalimentação , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Camundongos , Morfinanos , RNA Interferente Pequeno/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
16.
Biochim Biophys Acta Gene Regul Mech ; 1865(3): 194813, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35417776

RESUMO

Prostaglandin E2 (PGE2) in cancer and inflammatory diseases is a key mediator of disease progression. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to inhibit the expression of PGE2 by depressing cyclooxygenase (COX) in inflammatory treatments. However, the inhibition to COXs may cause serious side effects. Thus, it is urgent to develop new anti-inflammatory drugs aiming new targets to inhibit PGE2 production. Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the final step of PGE2 biosynthesis. Therefore, the selective inhibition of mPGES-1 has become a promising strategy in the treatments of cancer and inflammatory diseases. Our previous studies confirmed that sinomenine (SIN) is a specific mPGES-1 inhibitor. However, the exact mechanism by which SIN inhibits mPGES-1 remains unknown. This study aimed to explain the regulation effect of SIN to mPGES-1 gene expression by its DNA methylation induction effect. We found that the demethylating agent 5-azacytidine (5-AzaC) reversed the inhibitory effect of SIN to mPGES-1. Besides, SIN selectively increased the methylation level of the promoter region in the mPGES-1 gene while the pretreatment of 5-AzaC suppressed this effect. The results also shows that pretreatment with SIN increased the methylation level of specific GCG sites in the promoter region of mPGES-1. This specific methylation site may become a new biomarker for predicting and diagnosing RA and cancer with high expression of mPGES-1. Also, our research provides new ideas and solutions for clinical diagnosis and treatment of diseases related to mPGES-1 and for targeted methylation strategy in drug development.


Assuntos
Anti-Inflamatórios , Dinoprostona , Dinoprostona/metabolismo , Metilação , Morfinanos , Regiões Promotoras Genéticas , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo
17.
Int J Pharm ; 620: 121743, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35427752

RESUMO

The work aims to explore the feasibility of Raman mapping in predicting the dissolution profiles of solid oral dosage form. In this study, N = 36 batches of representative sinomenine hydrochloride sustained-release tablets were prepared, using a D-optimal design, to introduce adequate variability, and the Raman mapping data of each tablet were acquired. The partial least squares regression models were established using three kinds of different modes, named single point mode, average mode and multi-point mode, to predict the dissolution profiles based on Raman mapping data. The percent dissolutions at specific time points and the parameters of an exponential function, which was employed to fit the dissolution profiles, were predicted, and the accuracy and precision of prediction were tested. The results showed that the multi-point mode displayed the best accuracy and precision in the prediction of both the dissolutions at the specific time points and the function parameters. In summary, the established method based on Raman mapping avoids the shortcomings of traditional dissolution testing protocols, such as complex operation, time-consuming and high analysis cost, thus has great potential of application and popularization.


Assuntos
Morfinanos , Preparações de Ação Retardada , Solubilidade , Comprimidos
18.
Angew Chem Int Ed Engl ; 61(27): e202203186, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35389545

RESUMO

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven-step, asymmetric chemical synthesis of (-)-codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double-Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo-redox hydroamination protocol provides a novel, atom-economical means for assembling the piperidine D-ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N-demethyl codeine. Our work highlights the capacity for contemporary, stand-alone chemical synthesis regimes to diversify access to essential opiate medicines.


Assuntos
Morfinanos , Analgésicos Opioides , Catálise , Codeína , Ciclização , Estereoisomerismo
19.
Bioorg Chem ; 122: 105711, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35247807

RESUMO

Overexpression of thioredoxin reductase (TrxR) has been linked to tumorigenesis and phenotypic maintenance of malignant tumors. Thus, targeting TrxR with natural molecules is a promising strategy for developing anticancer drugs. Sinomenine is a naturally occurring alkaloid isolated from Sinomenium acutum. The drug, Zhengqing Fengtongning made from sinomenine, has been universally applied in rheumatoid arthritis treatment in China as well as other Asian countries for decades. Recently, increasing evidence indicates that sinomenine appears to be a promising therapeutic agent against various cancer cells. However, the exact mechanism underlying the anticancer activity of sinomenine remains unclear. In this study, we identified sinomenine as a kind of new inhibitor for TrxR. Pharmacological inhibition of TrxR by sinomenine results in the decrease of thiols content, increases the levels of reactive oxygen species, and finally facilitates oxidative stress-mediated cancer cell apoptosis. It is vital that knockdown in TrxR1 by shRNA can increase cell sensitivity to sinomenine. Treatment with sinomenine in vivo leads to a decrease in TrxR activity and tumor growth, and an increase in apoptosis. Our findings provide a novel action mechanism related to sinomenine and presents an insight on how to develop sinomenine as a chemotherapeutic agent for cancer therapy.


Assuntos
Morfinanos , Tiorredoxina Dissulfeto Redutase , Neoplasias do Colo do Útero , Antirreumáticos , Apoptose , Reposicionamento de Medicamentos , Feminino , Humanos , Morfinanos/farmacologia , Espécies Reativas de Oxigênio , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico
20.
Biomed Res Int ; 2022: 4914005, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309179

RESUMO

Hypoxia and its induced vasculogenic mimicry (VM) formation, which both closely related with stem-like side population (SP) cells, are the main culprits leading to tumor invasion and metastasis. Sinomenine exhibits excellent anticancer activity in breast cancer, but whether and how it affects hypoxia-triggered VM formation in breast cancer SP cells remains unclear. In this study, breast cancer SP cells were sorted from MDA-MB-231 cells and cultured with sinomenine under hypoxic conditions. Sinomenine obviously repressed the migration and VM formation of breast cancer SP cells. Through downregulating SIAH2 and HIF-1α, sinomenine can inhibit epithelial-mesenchymal transition process of breast cancer SP cells. SIAH2 was identified as a target of miR-340-5p and was downregulated by it, and sinomenine can upregulate miR-340-5p. Hypoxia-induced downregulation of miR-340-5p and activation of SIAH2/HIF-1α pathway can be both counteracted by the sinomenine. Moreover, miR-340-5p inhibition and SIAH2 overexpression can partly counteract the anticancer effects of sinomenine. Taken together, sinomenine inhibits hypoxia-caused VM formation and metastasis of breast cancer SP cells by regulating the miR-340-5p/SIAH2 axis.


Assuntos
Neoplasias da Mama , MicroRNAs , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Morfinanos , Células da Side Population/metabolismo , Células da Side Population/patologia
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