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1.
Oxid Med Cell Longev ; 2022: 3858500, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36124086

RESUMO

Background: Berberine (BER) is a natural isoquinoline alkaloid which extensively been applied to treat bacterial infection in TCM for a long time. Alginate is an important component of Pseudomonas aeruginosa biofilm. Herein, we investigated the effects of berberine and azithromycin (AZM) on alginate in the biofilm of P. aeruginosa PAO1. Methods: The MIC and synergistic activity of BER and AZM against PAO1 were determined using the micro broth dilution and checkerboard titration methods, respectively. The effect of BER on PAO1 growth was evaluated using a time-kill assay. Moreover, the effects of BER, AZM, and a combination of both on PAO1 biofilm formation, kinesis, and virulence factor expression were evaluated at subinhibitory concentrations. The alginate content in the biofilm was detected using ELISA, and the relative expression of alginate formation-related genes algD, algR, and algG was detected by qRT-PCR. Results: Simultaneous administration of berberine significantly reduced the MIC of azithromycin, and berberine at a certain concentration inhibited PAO1 growth. Moreover, combined berberine and azithromycin had synergistic effects against PAO1, significantly reducing biofilm formation, swarming, and twitching motility, and the production of virulence factors. The relative expression of alginate-related regulatory genes algG, algD, and algR of the combined treatment group was significantly lower than that of the control group. Conclusion: In summary, berberine and azithromycin in combination had a significant synergistic effect on the inhibition of alginate production by P. aeruginosa. Further molecular studies are in great need to reveal the mechanisms underlying the synergistic activity between berberine and azithromycin.


Assuntos
Berberina , Pseudomonas aeruginosa , Alginatos/metabolismo , Azitromicina/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Berberina/farmacologia , Isoquinolinas/farmacologia , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Fatores de Virulência/farmacologia
2.
Transl Vis Sci Technol ; 11(9): 2, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36048012

RESUMO

Purpose: The purpose of this study was to evaluate the tolerability and efficacy of topical rho-kinase inhibitor ripasudil in the treatment of primary corneal endothelial degeneration (PCED) in dogs. Methods: Twenty-one eyes of 12 client-owned, PCED-affected dogs received topical ripasudil 4 times daily. Ophthalmic examination, ultrasonic pachymetry (USP), Fourier-domain optical coherence tomography (FD-OCT), and in vivo confocal microscopy were performed at baseline and 1, 3, 6, and 12 months. Effects of treatment on corneal thickness, corneal edema extent, and endothelial cell density (ECD) were evaluated by repeated-measures ANOVA or Friedman test. Individual eyes were classified as improved, progressed, or stable at 12 months using clinical response criteria. Kaplan-Meier curves and log-rank test were used to compare ripasudil-treated eyes to age-, breed/size-, and disease stage-matched historical controls. Results: During treatment, 12 dogs developed conjunctival hyperemia, 4 demonstrated reticular bullous epithelial edema, and 2 developed corneal stromal hemorrhage. No adverse event necessitated permanent cessation of ripasudil. Central corneal thickness measured by USP significantly progressed from baseline to 12 months. Corneal thickness by FD-OCT, ECD, and edema extent did not differ over time. Considered individually, 5 eyes improved, 8 remained stable, and 8 progressed. The log-rank test found less edema progression in ripasudil-treated eyes compared to historical controls. Conclusions: Ripasudil was well-tolerated in PCED-affected dogs. Response to therapy varied; 62% of eyes showed improved or stable disease whereas 38% progressed. Ripasudil-treated eyes progressed more slowly than historical controls. Translational Relevance: Topical ripasudil offered a therapeutic benefit in a subset of patients using a canine model of endothelial degeneration, which may guide future trials in humans.


Assuntos
Distrofias Hereditárias da Córnea , Edema da Córnea , Animais , Cães , Humanos , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico
3.
Molecules ; 27(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36080340

RESUMO

A new series of pyrazolo[3,4-g]isoquinoline derivatives, diversely substituted at the 4- or 8-position, were synthesized. The results of the kinase inhibitory potency study demonstrated that the introduction of a bromine atom at the 8-position was detrimental to Haspin inhibition, while the introduction of an alkyl group at the 4-position led to a modification of the kinase inhibition profiles. Altogether, the results obtained demonstrated that new pyrazolo[3,4-g]isoquinolines represent a novel family of kinase inhibitors with various selectivity profiles.


Assuntos
Isoquinolinas , Isoquinolinas/farmacologia , Relação Estrutura-Atividade
4.
Acc Chem Res ; 55(17): 2370-2383, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-35980132

RESUMO

ConspectusThe naphthylisoquinoline (NIQ) alkaloids are a thrilling class of natural biaryls─structurally, biosynthetically, and pharmacologically. A common feature of these metabolites is the biaryl bond between their naphthalene and isoquinoline moieties, which in most cases is rotationally hindered, leading to the phenomenon of axial chirality. Depending on their individual structures, including the respective axial configurations, NIQs show promising bioactivities. Their total synthesis is a challenging but rewarding goal, with the stereocontrolled construction of the biaryl linkage as the key step.The position of the biaryl axis and its configuration determine the overall molecular shape and thus the choice of the best possible method for efficient asymmetric aryl-aryl bond formation. The axis in NIQs can cover a broad range of steric hindrance, from freely rotating to configurationally stable. For dioncophylline B (1) and dioncophylline F (2a/b), with only two ortho-substituents next to the axis, the synthesis is easy to accomplish by direct coupling of the intact naphthalene moiety with the isoquinoline unit, and no atropo-selectivity is required.Naphthylisoquinolines with a configurationally stable biaryl axis are the focus of the present Account. They are more difficult to synthesize because, in addition to the problem of decreased chemical yields with increasing steric hindrance at the axis, the synthesis needs to proceed stereoselectively. Within this class of NIQs, 5,8'-coupled representatives, such as korupensamine A (3a), have received considerable synthetic attention because the rotational barrier is high enough for the existence of atropisomerism without being too excessive, and they show potent bioactivities. Their synthesis, as systematically presented herein, thus occupies a central role in this report. For their aryl-aryl bond formation, both intra- and intermolecular approaches can be successfully applied. Axial stereoinformation is introduced by internal asymmetric induction from stereogenic elements already present in the isoquinoline or its precursors, from chiral auxiliary elements artificially introduced, or by external asymmetric induction using chiral catalysts.To overcome even higher steric hindrance, as in ancistrocladine (4a), innovative approaches were developed. A most successful strategy is the "lactone concept" developed by the Bringmann group, which allows the directed synthesis of any desired atropisomer in high chemical and optical yields, thus permitting the atropo-divergent preparation of the two isomers from a single joint precursor. In this approach, the two formal tasks of stereoselective biaryl synthesis, which are usually done simultaneously─the C-C linkage and the asymmetric induction─are achieved consecutively. The coupling step is performed intramolecularly after prefixation of the coupling partners by an ester bridge. The resulting biaryl lactone already possesses the biaryl axis but is still configurationally unstable; it can then, with internal or external asymmetric induction, be cleaved atropo-divergently with high stereoselectivities. Besides its unique concept, the procedure excels by its broad applicability; among all presented methods, it has been used for the synthesis of the largest number of NIQs, more than 20 representatives, including those with the highest steric hindrance.This Account gives comprehensive insight into the plethora of conceptual approaches for the efficient formation of the hindered biaryl bond of NIQs.


Assuntos
Alcaloides , Isoquinolinas , Alcaloides/química , Isoquinolinas/química , Isoquinolinas/farmacologia , Lactonas , Naftalenos
5.
Phytochemistry ; 202: 113321, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35921889

RESUMO

Four pairs of undescribed enantiomeric isoquinoline alkaloids (6S/R-(N,N-diethylacetamido)yl-dihydrochelerythrine, 6R/S-acetonyl-9-hydroxy-dihydrochelerythrine, 6S/R-acroleinyl-dihydrochelerythrine, 6S/R-acetatemethyl-dihydrochelerythrine), five undescribed isoquinoline alkaloids (6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-hydroxy-dihydrochelerythrine, 9-methoxy-10-hydroxy-norchelerythrine, chelidoniumine A), together with 13 known isoquinoline alkaloids were isolated from an extract of the roots and rhizomes of Hylomecon japonica. The structures of the undescribed compounds were identified by NMR, HRESIMS, UV, IR, and their absolute configurations were defined via electronic circular dichroism data and optical rotation. All of the isolated compounds were tested for their anti-breast cancer activities in MCF-7 cells. Among them, the undescribed alkaloids 6S/R-acroleinyl-dihydrochelerythrine, 6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-methoxy-10-hydroxy-norchelerythrine and other known alkaloids 6-methoxydihydrosanguinarine, 6-acetaldehyde-dihyrochelerythrine, dihydrosanguinaline and 10-methoxy boconoline had good inhibitory effects on MCF-7 cells of breast cancer with an IC50 lower than 20 µM.


Assuntos
Alcaloides , Neoplasias , Alcaloides/química , Isoquinolinas/química , Isoquinolinas/farmacologia , Estrutura Molecular , Raízes de Plantas/química , Rizoma
6.
Biomaterials ; 288: 121730, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35995622

RESUMO

Transforming growth factor ß (TGF-ß) is a well-known key mediator for the progression and metastasis of lung carcinoma. However, cost-effective anti-TGF-ß therapeutics for lung cancer remain to be explored. Specifically, the low efficacy in drug delivery greatly limits the clinical application of small molecular inhibitors of TGF-ß. In the present study, specific inhibitor of Smad3 (SIS3) is developed into a self-carried nanodrug (SCND-SIS3) using the reprecipitation method, which largely improves its solubility and bioavailability while reduces its nephrotoxicity. Compared to unmodified-SIS3, SCND-SIS3 demonstrates better anti-cancer effects through inducing tumor cell apoptosis, inhibiting angiogenesis, and boosting NK cell-mediated immune responses in syngeneic Lewis Lung Cancer (LLC) mouse model. Better still, it could achieve comparable anti-cancer effect with just one-fifth the dose of unmodified-SIS3. Mechanistically, RNA-sequencing analysis and cytokine array results unveil a TGF-ß/Smad3-dependent immunoregulatory landscape in NK cells. In particular, SCND-SIS3 promotes NK cell cytotoxicity by ameliorating Smad3-mediated transcriptional inhibition of Ndrg1. Furthermore, improved NK cell cytotoxicity by SCND-SIS3 is associated with higher expression of activation receptor Nkp46, and suppressed levels of Trib3 and TSP1 as compared with unmodified-SIS3. Taken together, SCND-SIS3 possesses superior anti-cancer effects with enhanced bioavailability and biocompatibility, therefore representing as a novel therapeutic strategy for lung carcinoma with promising clinical potential.


Assuntos
Carcinoma , Neoplasias Pulmonares , Nanopartículas , Animais , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Nanopartículas/uso terapêutico , Piridinas/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
7.
Proc Natl Acad Sci U S A ; 119(32): e2116289119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35917342

RESUMO

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.


Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II , Compostos Benzidrílicos , Neoplasias Encefálicas , Reposicionamento de Medicamentos , Glioblastoma , Isoquinolinas , Receptor Tipo 2 de Angiotensina , Analgésicos/farmacologia , Angiotensina II/química , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/uso terapêutico , Apoptose , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Conformação Proteica em alfa-Hélice , Receptor Tipo 2 de Angiotensina/química , Receptor Tipo 2 de Angiotensina/metabolismo , Carga Tumoral/efeitos dos fármacos
8.
Molecules ; 27(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36014324

RESUMO

A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus) strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant S. aureus (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias , Isoquinolinas/farmacologia , Testes de Sensibilidade Microbiana , Proteoma , Staphylococcus aureus
9.
Naunyn Schmiedebergs Arch Pharmacol ; 395(10): 1225-1238, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35881165

RESUMO

Despite the advances made in cancer therapeutics, their adverse effects remain a major concern, putting safer therapeutic options in high demand. Since chalcones, a group of flavonoids and isoflavonoids, act as promising anticancer agents, we aimed to evaluate the in vivo anticancer activity of a synthetic isoquinoline chalcone (CHE) in a mice model with Ehrlich solid carcinoma. Our in vivo pilot experiments revealed that the maximum tolerated body weight-adjusted CHE dose was 428 mg/kg. Female BALB/c mice were inoculated with Ehrlich ascites carcinoma cells and randomly assigned to three different CHE doses administered intraperitoneally (IP; 107, 214, and 321 mg/kg) twice a week for two consecutive weeks. A group injected with doxorubicin (DOX; 4 mg/kg IP) was used as a positive control. We found that in CHE-treated groups: (1) tumor weight was significantly decreased; (2) the total antioxidant concentration was substantially depleted in tumor tissues, resulting in elevated oxidative stress and DNA damage evidenced through DNA fragmentation and comet assays; (3) pro-apoptotic genes p53 and Bax, assessed via qPCR, were significantly upregulated. Interestingly, CHE treatment reduced immunohistochemical staining of the proliferative marker ki67, whereas BAX was increased. Notably, histopathological examination indicated that unlike DOX, CHE treatment had minimal toxicity on the liver and kidney. In conclusion, CHE exerts antitumor activity via induction of oxidative stress and DNA damage that lead to apoptosis, making CHE a promising candidate for solid tumor therapy.


Assuntos
Carcinoma de Ehrlich , Chalcona , Chalconas , Animais , Apoptose , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Chalcona/farmacologia , Chalcona/uso terapêutico , Chalconas/farmacologia , Dano ao DNA , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Isoquinolinas/farmacologia , Camundongos , Estresse Oxidativo , Proteína X Associada a bcl-2/genética
10.
Bioorg Med Chem ; 69: 116910, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35777271

RESUMO

Superparamagnetic iron nanoparticles (SPIONs) have become one of the most useful colloidal systems in nanomedicine. We report here the preparation of new hybrid core@shell systems based on SPION nanoparticles coated with a SiO2 shell (SPION@SiO2) and functionalized with carboxyl groups (SPION@SiO2-COOH). A series of new N-alkylamino- and N-alkylamido-terminated 1-phenyl- tetrahydroisoquinolines (THIQs) and 3-tetrahydrobenzazepines (THBs) derivatives presenting -SMe and -Cl groups, respectively, with potential dopaminergic activity, are synthesized and incorporated to the hybrid system. We include the synthetic details for THIQs and THBs derivatives preparation and investigate the influence of the terminal-functional group as well as the number of carbon atoms linked to THIQ and THB molecules during the coupling to the SPION@SiO2-COOH. Nuclear magnetic resonance (NMR) and electron ionization mass spectrometry (EI-MS) are used to characterize the synthesized THIQs and THBs. High-angle annular dark-field transmission electron microscopy (HAADF-TEM), energy dispersive X-ray transmission electron microscopy (EDX-TEM), and proton high-resolution magic angle spinning NMR spectroscopy1H HRMAS-NMR) are used to confirm the presence of THB and THIQ molecules onto the surface of the nanoparticles. The hybrid SPION@SiO2-THIQ and THB systems show significant activity toward the D2 receptor, reaching Ki values of about 20 nM, thus having potential application in the treatment of central nervous system (CNS) diseases.


Assuntos
Compostos Férricos , Nanopartículas , Benzazepinas/farmacologia , Isoquinolinas/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro , Nanopartículas/química , Dióxido de Silício/química
11.
Molecules ; 27(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35807390

RESUMO

Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.


Assuntos
Alcaloides , Corantes Fluorescentes , Alcaloides/farmacologia , Batraquiotoxinas/metabolismo , Batraquiotoxinas/farmacologia , Viés , Células HEK293 , Humanos , Isoquinolinas/farmacologia , Ligantes , Sódio/metabolismo
12.
ACS Chem Neurosci ; 13(14): 2164-2175, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35797238

RESUMO

Type-2 diabetes mellitus (T2DM) is one of the most concerning public health problems because of its high incidence, multiple complications, and difficult treatment. Human islet amyloid polypeptide (hIAPP) is closely linked to T2DM because its abnormal self-assembly causes membrane damage and cell dysfunction. The development of potential inhibitors to prevent hIAPP fibrillation is a promising strategy for the intervention and treatment of diabetes. Natural isoquinoline alkaloids are used as effective medication that targets different biomolecules. Although studies explored the efficacy of berberine, jatrorrhizine, and chelerythrine in diabetes, the underlying mechanism remains unclear. Herein, three isoquinoline alkaloids are selected to reveal their roles in hIAPP aggregation, disaggregation, and cell protection. All three compounds displayed good inhibitory effects on peptide fibrillation, scattered the preformed fibrils into small oligomers and most monomers, and upregulated cell viability by reducing hIAPP oligomerization. Moreover, combined biophysical analyses indicated that the compounds affected the ß-sheet structure and hydrophobicity of polypeptides significantly, and the benzo[c]phenanthridine structure of chelerythrine was beneficial to the inhibition of hIAPP aggregation and their hydrophobic interaction, compared with that of berberine and jatrorrhizine. Our work elaborated the effects of these alkaloids on hIAPP fibrillation and reveals a possible mechanism for these compounds against T2DM.


Assuntos
Amiloide , Berberina , Diabetes Mellitus Tipo 2 , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Amiloide/farmacologia , Berberina/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Conformação Proteica em Folha beta
13.
Phytomedicine ; 104: 154314, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35841665

RESUMO

BACKGROUND: Berberine is a quaternary isoquinoline alkaloid that possesses a significant therapeutic effect on a variety of cancers. However, due to poor bioavailability, an increased dose is often required to achieve therapeutic goals. To improve the activities of natural berberine, most modifications were focused on the positive isoquinoline unit by grafting long aliphatic chains or heterocycles. However, the negative part is ignored. At this point, the strategy of salt formation modifications with short- and medium-chain fatty acids was proposed in this article. PURPOSE: Using salt modification to enhance the antitumor activity of berberine and explore the mechanism. METHODS: Four short- and medium-chain fatty acid salts of berberine were prepared from berberine hydrochloride by salt formation modification with the sodium salt of butyric, caproic, octanoic, and decanoic acid, respectively. The cytotoxicity of four berberine salts on B16-F10, A549, HepG2, and U373 cancer cell lines was explored. Through cell localization, Mitochondrial membrane potential assay, and Western blotting analysis explored the mechanism of berberine salt-induced apoptosis. Its anticancer activity in vivo was demonstrated by the mouse xenograft model. RESULTS: The four berberine fatty acid salts exhibited an enhanced inhibitory effect on B16-F10, A549, HepG2, and U373 cancer cell lines, particularly on B16-F10 cells. Meanwhile, the four berberine fatty acid salts can inhibit the migration of B16-F10 cells. The four berberine fatty acid salts induce cancer cell apoptosis through the mitochondrial pathway, which was confirmed by the mitochondrial colocalization, the decreased mitochondrial membrane potential as well as activation of caspase-3, cytochrome C (Cyt-C), and down-regulated expression of B-cell lymphoma 2 (Bcl-2). Most importantly, the four berberine fatty acid salts inhibited tumor growth in the in vivo B16-F10 melanoma model without generating side effects intraperitoneally. CONCLUSIONS: This study revealed that salt formation modification may be an effective strategy to optimize the anticancer property of berberine hydrochloride and demonstrated the four berberine fatty acid salts induced apoptosis through the mitochondrial apoptotic pathway.


Assuntos
Berberina , Neoplasias , Animais , Apoptose , Berberina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Graxos/farmacologia , Humanos , Isoquinolinas/farmacologia , Camundongos , Sais/farmacologia
14.
Bioorg Chem ; 127: 106027, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35878451

RESUMO

A total of 33 structurally diverse isoquinoline alkaloids were isolated from the rhizomes of Menispermum dauricum, including seventeen benzylisoquinoline analogues (menisperdaurines A-Q, 1-17), five protoberberine analogues (menisperdaurines R-V, 18-22), a quaternary phenanthrene alkaloid (menisperdaurine W, 23) and ten known compounds (24-33). Compound structures, including absolute configurations, were determined by extensive spectroscopic methods, quantum chemical calculations of chemical shifts, and calculated and experimental electronic circular dichroism (ECD) data. Compounds 1-5 were glycosidic benzylisoquinolines with glucose moieties attached at the C-12 position. Compound 8 was the first example that was isolated from the rhizomes of Menispermum dauricum, benzylisoquinoline and an aromatic unit connected by a sugar bridge. Compounds were evaluated for their inhibitory effects on the dopamine D1 receptor. Compounds 1, 8, 21, 24 and 29 showed potent D1 antagonistic activities, with IC50 values ranging from 1.0 to 4.5 µM. Compound 1 exhibited the highest antagonistic activity with an IC50 value of 1.0 ± 0.2 µM.


Assuntos
Alcaloides , Benzilisoquinolinas , Menispermum , Alcaloides/química , Alcaloides/farmacologia , Isoquinolinas/farmacologia , Menispermum/química , Estrutura Molecular , Receptores de Dopamina D1
15.
Toxins (Basel) ; 14(7)2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35878229

RESUMO

Isoquinoline alkaloids have multiple biological activities, which might be associated with positive pharmacological effects as well as negative adverse reactions. As bleeding was suggested to be a side effect of the isoquinoline alkaloid berberine, we decided to ascertain if different isoquinoline alkaloids could influence hemocoagulation through the inhibition of either platelet aggregation or blood coagulation. Initially, a total of 14 compounds were screened for antiplatelet activity in whole human blood by impedance aggregometry. Eight of them demonstrated an antiplatelet effect against arachidonic acid-induced aggregation. Papaverine and bulbocapnine were the most potent compounds with biologically relevant IC50 values of 26.9 ± 12.2 µM and 30.7 ± 5.4 µM, respectively. Further testing with the same approach confirmed their antiplatelet effects by employing the most physiologically relevant inducer of platelet aggregation, collagen, and demonstrated that bulbocapnine acted at the level of thromboxane receptors. None of the alkaloids tested had an effect on blood coagulation measured by a mechanical coagulometer. In conclusion, the observed antiplatelet effects of isoquinoline alkaloids were found mostly at quite high concentrations, which means that their clinical impact is most likely low. Bulbocapnine was an exception. It proved to be a promising antiplatelet molecule, which may have biologically relevant effects.


Assuntos
Alcaloides , Agregação Plaquetária , Alcaloides/farmacologia , Plaquetas , Humanos , Isoquinolinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia
16.
Zhongguo Zhong Yao Za Zhi ; 47(10): 2676-2680, 2022 May.
Artigo em Chinês | MEDLINE | ID: mdl-35718486

RESUMO

The chemical constituents from the roots of Thalictrum cultratum and T. baicalense were investigated. By various isolation methods, such as silica gel, aluminium oxide, ODS, and Sephadex LH-20 column chromatographies, and semi-preparative HPLC, 11 simple isoquinoline alkaloids were isolated from the ethanol extract of the roots of these two plants, including a new compound, named dehydrothalflavine(1), and ten known ones(2-11): N-methylcorydaline(2), N-methylthalidaldine(3), thaliflavine(4), oxyhydrastinine(5), noroxyhydrastinine(6), dimethoxyisoquinolone(7), thalactamine(8), dehydronoroxyhydrastinine(9), 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline(10), and isopicnarrhine(11). Their structures were elucidated on the basis of HR-ESI-MS and 1 D and 2 D NMR techniques. Compound 1 was a new isoquinoline alkaloid. Compound 11 was obtained from Tha-lictrum plant for the first time. All compounds did not show cytotoxic activities against HL-60, U937, HCT116, Caco-2, and HepG2 cancer cell lines.


Assuntos
Alcaloides , Thalictrum , Alcaloides/análise , Células CACO-2 , Humanos , Isoquinolinas/farmacologia , Raízes de Plantas/química , Thalictrum/química
17.
Zhonghua Yi Xue Za Zhi ; 102(21): 1574-1578, 2022 Jun 07.
Artigo em Chinês | MEDLINE | ID: mdl-35644957

RESUMO

Objective: To compare the anesthetic effects of mivacurium and cisatracurium besylate in laser laryngeal microsurgery, and to provide clinical evidence and reference for further optimization of muscle relaxation application. Methods: From October 2021 to January 2022, fifty-six patients of Beijing Tongren Hospital, Capital Medical University, scheduled for laser laryngeal microsurgery with general anesthesia, were enrolled. These patients, aged 18-65 years old, 25 males and 31 females, were divided into two groups (n=28) by random number table method. Cisatracurium besylate group (group C): cisatracurium besylate was injected at 0.1 mg/kg. Normal saline was continuously infused during operation. Mivacurium group (group M):Mivacurium was injected at 0.25 mg/kg and continuously infused at 0.3 mg·kg-1·h-1 during operation.The intubation time, the extubation time, recovery index, Cooper's score, Cormack-Lehane grade, surgical condition grade, postoperative residual neuromuscular block and allergic related adverse events were compared between the two groups. Results: The intubation time and the extubation time of group M were (3.7±1.1) and (16.2±5.0) min, which were statistically significant shorter than those of group C (4.9±0.7) and (26.4±8.6) min (all P<0.05). The recovery indexes of the patients in group M and group C were (4.5±3.4) and (6.2±5.0) min. The Cooper's scores of the two groups were both 9(9, 9). The Cormack-Lehane grades of the two groups were all grade Ⅰ. The number of cases with good/excellent surgical condition grades in group M and group C were 5/23 and 0/28. There were no significant differences in recovery index, Cooper's score, Cormack-Lehane grades and surgical condition grades between the two groups (all P>0.05). The TOF ratio of group M in the post anesthesia care unit (PACU) was (95.7±2.6) %, which was significantly higher than (92.9±3.9) % of group C(P=0.015). There were no significant differences in MAP and HR between the two groups at different time points (all P>0.05). The incidence of skin flushing in group M and group C was 10.7% (3/28) and 0, and the difference was not statistically significant (P=0.074). There were no cases of severe hypotension, significantly elevated airway pressure or airway spasm in both groups. Conclusion: In laser laryngeal microsurgery, compared with cisatracurium besylate, mivacurium has shorter intubation time and extubation time, stable hemodynamics, no significant increase in allergic related adverse events. mivacurium is safe and effective.


Assuntos
Anestésicos , Fármacos Neuromusculares não Despolarizantes , Adolescente , Adulto , Idoso , Atracúrio/análogos & derivados , Feminino , Humanos , Isoquinolinas/farmacologia , Lasers , Masculino , Microcirurgia , Pessoa de Meia-Idade , Mivacúrio , Fármacos Neuromusculares não Despolarizantes/efeitos adversos , Adulto Jovem
18.
Int Immunopharmacol ; 109: 108779, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35490666

RESUMO

Dihydrosanguinarine (DS) is one of the main chemical constituents of Corydalis bungeana Turcz. which demonstrates anti-inflammatory, antioxidant, and antimicrobial in vitro. The present study aimed to investigate the anti-inflammatory effect and its underlying mechanism of DS in vivo. The network pharmacology method was used to predict the anti-inflammatory target of DS, and it was found that PI3K-AKT signal transduction pathway was the most obvious, and the anti-inflammatory effect of DS was more specific in liver. Herein, we used AKT inhibitor AZD 5363 to block PI3K-AKT signaling pathway, to carry out animal experiments to verify the predicted results of network pharmacology. The results showed that DS exerts protective effects on LPS-induced liver inflammation in mice, and the anti-inflammatory effect of DS was attenuated after inhibiting AKT. To elucidate the potential molecular mechanisms, we performed RNA-sequence analysis in liver tissues. Transcriptome analysis showed that the "TNF signaling pathway" and "IL-17 signaling pathway" had the highest enrichment of differentially expressed genes (DEGs). Then, TNF/IL-17/PI3K-AKT signal pathways were analyzed by GSEA. It was found that AKT3, CCL2, FOS, IL-17A, IL-17RA, IL-17RE, PI3KCA, TRAF3IP2, CREB5, ICAM-1, VCAM-1, IL-1ß, IL-6, TNF-α and CXCL1/2/3 were significantly regulated by DS. The results of RNA-seq immuneCC predictive showed that DS could inhibit the inflammatory response mainly by reducing the degree of macrophage infiltration induced by LPS. At the same time, we use RT-qPCR, IF, WB techniques to verify the core anti-inflammatory differential genes of DS at the gene and protein expression level, confirming that DS can regulate the inflammatory response by regulating the gene expression level of TNF/IL-17/PI3K-AKT signal pathway. We also used HPLC-Q-TOF/MS technology to explore the biotransformation products of DS in the blood and liver of mice under inflammatory conditions and established the docking model of DS and its transformed compound with TNF-α, IL-17A, AKT3 and IL-6, which is the key target from RNA-seq analysis in this study. The results showed that DS strongly interacted with four proteins in the form of prototypes and demethylated products and exhibited anti-inflammatory effects. Our research shows that DS exerts its anti-hepatitis effect mainly by inhibiting the excessive infiltration of macrophages in mice liver induced by LPS and down-regulating the expression of genes related to TNF/IL-17/PI3K-AKT pathway. This study provides a new perspective on the potential therapeutic application of DS and the plasticity of anti-LPS-induced liver inflammation in DS.


Assuntos
Anti-Inflamatórios , Benzofenantridinas , Inflamação , Isoquinolinas , Animais , Anti-Inflamatórios/farmacologia , Benzofenantridinas/farmacologia , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Interleucina-17/genética , Interleucina-6/genética , Isoquinolinas/farmacologia , Lipopolissacarídeos , Fígado/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA-Seq , Fator de Necrose Tumoral alfa/genética
19.
Cell Mol Life Sci ; 79(6): 319, 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35622143

RESUMO

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (As2O3) or/and all-trans retinoic acid. The protein arginine methyltransferase 5 (PRMT5) is involved in tumorigenesis. However, little is known about the biological function and therapeutic potential of PRMT5 in APL. Here, we show that PRMT5 is highly expressed in APL patients. PRMT5 promotes APL by interacting with PML-RARα and suppressing its ubiquitination and degradation. Mechanistically, PRMT5 attenuates the interaction between PML-RARα and its ubiquitin E3 ligase RNF4 by methylating RNF4 at Arg164. Notably, As2O3 treatment triggers the dissociation of PRMT5 from PML nuclear bodies, attenuating RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Moreover, knockdown of PRMT5 and pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 significantly inhibit APL cells growth. The combination of EPZ015666 with As2O3 shows synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with As2O3, might be a promising therapeutic strategy against APL.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Promielocítica Aguda , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Metilação , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/uso terapêutico , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitinação
20.
Mol Pharm ; 19(6): 1839-1852, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35559658

RESUMO

Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity toward cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent. Herein, we use neutron spin-echo (NSE) spectroscopy, molecular dynamics (MD) simulations, and supporting small angle scattering techniques to study PST's effect on membrane dynamics using biologically representative model membranes. Our data suggests that PST stiffens the inner mitochondrial membrane (IMM) by being preferentially associated with cardiolipin, which would lead to the relocation and release of cytochrome c. Second, PST has an ordering effect on the lipids and disrupts their distribution within the IMM, which would interfere with the maintenance and functionality of the active forms of proteins in the electron transport chain. These previously unreported findings implicate PST's effect on mitochondrial apoptosis.


Assuntos
Alcaloides de Amaryllidaceae , Antineoplásicos , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Antineoplásicos/química , Apoptose , Isoquinolinas/química , Isoquinolinas/farmacologia , Mitocôndrias
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