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1.
Biosci Biotechnol Biochem ; 84(1): 63-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31462179

RESUMO

A natural isoquinoline alkaloid, berberine, has been known to exhibit anti-tumor activity in various cancer cells via inducing cell cycle arrest. However, it has not been investigated whether berberine and its analogs inhibit the growth of rhabdomyosarcoma (RMS), which is the most frequent soft tissue tumor in children. The present study examined the anti-tumor effects of berberine and palmatine on expansions of three human embryonal RMS cell lines; ERMS1, KYM1, and RD. Intracellular incorporation of berberine was relatively higher than that of palmatine in every RMS cell line. Berberine significantly inhibited the cell cycle of all RMS cells at G1 phase. On the other hand, palmatine only suppressed the growth of RD cells. Both of berberine and palmatine strongly inhibited the growth of tumorsphere of RD cells in three-dimensional culture. These results indicate that berberine derivatives have the potential of anti-tumor drugs for RMS therapy.Abbreviations: ARMS: alveolar rhabdomyosarcoma; ERMS: embryonal rhabdomyosarcoma; RMS: rhabdomyosarcoma.


Assuntos
Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Berberina/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/patologia , Antineoplásicos/química , Berberina/análogos & derivados , Berberina/química , Alcaloides de Berberina/química , Linhagem Celular Tumoral , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/genética , Conformação Molecular , Simulação de Acoplamento Molecular , Phellodendron/química , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Embrionário/metabolismo
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 359-362, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701723

RESUMO

OBJECTIVE: To investigate the effects of berberine on learning and memory ability in vascular cognitive impairment rats. METHODS: Sixty-eight Wistar rats were randomly divided into control group (n=10), sham operated group (n=10) and the modeling group of vascular cognitive impairment rat (n=48), then the rats in modeling group were randomly divided into four groups (n=10): vehicle group, berberine low dose group (20 mg/kg), medium dose group (40 mg/kg) and high dose group (60 mg/kg). Bilateral common carotid arteries were occluded in rats to establish vascular cognitive impairment (VCI) model. Different doses of berberine were intraperitoneally injected into the treatment group and normal saline was intraperitoneally injected into the other groups once a day for a total of 34 days. After 28 days of administration, Morris water maze was used to test the learning and memory ability of rats. After the water maze experiment, the levels of superoxide dismutase (SOD) activity, glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor alpha(TNF-α), interleukin-1 beta (IL-1ß), 5-hydroxytryptamine (5-HT) and monoamine oxidase (MAO) in the forebrain cortex were detected. RESULTS: Compared to sham group, the escape latency in VCI group was significantly extended (P<0.01) and the times of passing through the platform were decreased remarkably (P<0.01). The levels of SOD, GSH and 5-HT in the hippocampus or anterior cortex were decreased significantly (P<0.01), while the contents of MDA, TNF-α, IL-1ß and MAO were increased remarkably (P<0.01). Compared with VCI group, the escape latency in berberine-treated groups was shortened significantly (P<0.01, P<0.05) and the times of passing through the platform were increased remarkably (P<0.01, P<0.05), the levels of SOD, GSH and 5-HT were increased significantly (P<0.01), while the contents of TNF-α, IL-1ß and MAO were decreased remarkably (P<0.01). CONCLUSION: Berberine could significantly improve the spatial learning and memory abilities of rats with vascular cognitive impairment. The mechanism may be related to the effects of berberine on the hippocampal antioxidant stress, anti-inflammatory response and the monoamine neurotransmitter system in the forebrain cortex. Berberine 60 mg/kg dose group had better effect.


Assuntos
Berberina/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Animais , Hipocampo , Inflamação , Estresse Oxidativo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ratos Wistar
3.
Postepy Biochem ; 65(3): 224-230, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643170

RESUMO

Berberine (BRB) is a compound belonging to the group of isoquinoline alkaloids of plant origin that has long been used in traditional chinese medicine (TMC). Due to, among others anti-inflammatory properties BRB is a potential therapeutic in the treatment of acute pancreatitis (OZT). In a study in the mouse model of L-arginine-induced acute pancreatitis, we showed that BRB administered by the intravenous route at 0.1 and 0.5 mg / kg body weight significantly reduces the level of myeloperoxidase activity (an indicator of inflammation) in the pancreas and lungs. Promising results point to the need for larger, randomized studies to assess the long-term efficacy and side effects of BRB therapy.


Assuntos
Berberina/uso terapêutico , Pancreatite/tratamento farmacológico , Doença Aguda/terapia , Animais , Berberina/farmacologia , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia
4.
Fitoterapia ; 139: 104371, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629051

RESUMO

Extrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia coli overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.


Assuntos
Antibacterianos/farmacologia , Aporfinas/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Alcaloides/farmacologia , Bacillus subtilis/efeitos dos fármacos , Berberina/farmacologia , Transporte Biológico , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Proteínas de Membrana Transportadoras , Testes de Sensibilidade Microbiana , Estrutura Molecular , Papaver/química , Componentes Aéreos da Planta/química , Turquia
5.
BMC Complement Altern Med ; 19(1): 218, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419978

RESUMO

BACKGROUND: Staphylococcal aureus (S. aureus) has become the leading causative pathogen of Prosthetic Joint Infection (PJI), which is the most devastating complication after arthroplasty surgeries. Due to the biofilm formation ability and emergence of multiple-drugs resistance strains of S. aureus, it has become an urgency to find new anti-staphylococcal agents to establish effective prophylaxis and treatment strategy for PJI. Extracted from a traditional Chinese herb, berberine is proved active in inhibiting S. aureus, while whether it exerts the same effect on PJI-related S. aureus remains unknown. This study aims to investigate the antimicrobial activity of berbrine against clinical derived PJI-related S. aureus and whether its inhibiting efficacy is associated with subtypes of S. aureus. METHODS: Eighteen PJI-associated S. aureus were collected and their Multi-locus Sequence Types (MLST) and susceptibility to berberine both in planktonic and biofilm form were investigated. Additionally, one S. aureus strain (ST1792) was selected from the group and its transcriptomic profiling in berberine incubation was performed. The statistical analyses were conducted using Student's t-test with SPSS 24.0(SPSS, IBM, USA). The data were expressed as the means ± standard deviation. Values of p < 0.05 were considered statistically significant. RESULTS: It was found out that the Minimum Inhibitory Concentration values of PJI-related S. aureus varied in a broad range (from 64 to 512 µg/ml) among different MLST subtypes and the bacteria were able to regain growth after 24 h in berberine of MIC value or higher concentrations. In addition, sub-inhibitory concentrations of berberine surprisingly enhanced biofilm formation in some S. aureus strains. CONCLUSION: Traditional medicine is utilised by a large number of individuals, which provides abundant resources for modern medical science. In our study, berberine was found bactericidal against PJI related S. aureus, however, its antibacterial property was impacted by the MLST subtypes of the bacteria, both in planktonic and biofilm growth forms.


Assuntos
Antibacterianos/farmacologia , Berberina/farmacologia , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus , Humanos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética
6.
Pharm Res ; 36(10): 149, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420752

RESUMO

PURPOSE: Combinatorial approach can be beneficial for cancer treatment with better patient recovery. Co-delivery of natural and synthetic anticancer drug not only valuable to achieve better anticancer effectivity but also to ascertain toxicity. This study was aimed to co-deliver berberine (natural origin) and doxorubicin (synthetic origin) utilizing conjugation/encapsulation strategy through poly (lactic-co-glycolic acid) (PLGA) nanoparticles. METHODS: Doxorubicin was efficiently conjugated to PLGA via carbodiimide chemistry and the PLGA-doxorubicin conjugate (PDC) was used for encapsulation of berberine (PDBNP). RESULTS: Significant anti-proliferative against MDA-MB-231 and T47D breast cancer cell lines were observed with IC50 of 1.94 ± 0.22 and 1.02 ± 0.36 µM, which was significantly better than both the bio-actives (p < 0.05). The ROS study revealed that the PDBNP portrayed the slight increase in the reactive oxygen species (ROS) pattern in MDA-MB-231 cell line in a dose-dependent manner, while in T47D cells, no significant change in ROS was seen. PDBNP exhibits significant alteration (depolarization) in mitochondrial membrane permeability and arrest of cell cycle progression at sub G1 phase while the Annexin V/PI assay followed by confocal microscopy resulted into cell death mode to be because of necrosis against MDA-MB-231 cells. In vivo studies in Sprague Dawley rats revealed almost 14-fold increase in half life and a significant increase in plasma drug concentration. CONCLUSION: The overall approach of PLGA based co-delivery of doxorubicin and berberine witnessed synergetic effect and reduced toxicity as evidenced by preliminary toxicity studies.


Assuntos
Antineoplásicos/administração & dosagem , Berberina/administração & dosagem , Doxorrubicina/administração & dosagem , Nanocápsulas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Berberina/farmacocinética , Berberina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Interações de Medicamentos , Liberação Controlada de Fármacos , Humanos , Masculino , Ratos Sprague-Dawley
7.
Pestic Biochem Physiol ; 159: 51-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400784

RESUMO

Isoquinoline alkaloids possess broad pharmacological activities. In this study, the antifungal activity of twelve isoquinoline alkaloids, including berberine (1), jatrorrhizine (2), coptisine (3), corydaline (4), tetrahydroberberine (5), chelidonine (6), dihydrosanguinarine (7), chelerythrine (8), sanguinarine (9), palmatine (10), tetrahydropalmatine (11) and columbamine (12) were evaluated against eight plant pathogenic fungi in vitro. All the tested compounds showed varying degrees of inhibition against the eight tested plant fungi. Among them, sanguinarine exhibited high antifungal activity (EC50 ranging from 6.96-59.36 µg/mL). It displayed the best inhibitory activity against Magnaporthe oryzae (EC50 = 6.96 µg/mL), compared with azoxystrobin (EC50 = 12.04 µg/mL), and significantly suppressed spore germination of M. oryzae with the inhibition rate reaching 100% (50 µg/mL). The optical microscopy and scanning electron microscopy observations revealed that after treating M. oryzae mycelia with sanguinarine at 10 µg/mL, the mycelia appeared curved, collapsed and the cell membrane integrity was eventually damaged. Furthermore, the reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia had been changed, and the membrane function and cell proliferation of mycelia were destroyed. These results will enrich our insights into action mechanisms of antifungal activity of sanguinarine against M. oryzae.


Assuntos
Alcaloides/farmacologia , Antifúngicos/farmacologia , Benzofenantridinas/farmacologia , Isoquinolinas/farmacologia , Berberina/análogos & derivados , Berberina/farmacologia , Alcaloides de Berberina/farmacologia , Magnaporthe/metabolismo , Magnaporthe/patogenicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo
8.
BMC Complement Altern Med ; 19(1): 216, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412862

RESUMO

BACKGROUND: Breast cancer is still the most common malignant tumor that threatens the female's life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes. Lack of targeted therapies brings about urgent demand for novel treatments. In this study we aim to investigate the anti-tumor activity of Berberine (BBR), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 and elucidate its mechanism referring to anti-inflammation. METHODS: Cell inhibition rate was measured by Cell Proliferation Assay, the cytotoxic effects was detected by Lactate dehydrogenase (LDH) leakage assay, the colony formation and migration potential were evaluated by colony formation assay and wound healing assay, the release of inflammatory cytokines was detected by EMD multifactor detection, and alterations of proteins and genes related to the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway were analyzed using western blotting and real-time Polymerase Chain Reaction (PCR). RESULTS: BBR reduce the viability of MDA-MB-231 cells and increased the release of LDH from the cells in a dose-dependent manner, with and inhibition of colony formation potential and migration of the cells. BBR also caused a marked reduction in the secretion of proinflammatory cytokines, Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Besides, a down-regulated behavior was observed with the expression of P2X purinoceptor 7 (P2X7), NLRP3, pro-caspase-1, apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1 p20, Interleukin-18 (IL-18), IL-1ß proteins and NLRP3, Caspase-1 and ASC mRNAs in the NLRP3 inflammasome cascade. CONCLUSIONS: Our results confirmed that BBR can effectively affect both tumor outgrowth and spontaneous metastasis in TNBC, and that we identified a new mechanism associated with inhibition the NLRP3 inflammasome pathway, suggesting its potential therapeutic relevance in clinical use.


Assuntos
Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Apoptose/efeitos dos fármacos , Caspase 1/genética , Caspase 1/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Life Sci ; 233: 116697, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351968

RESUMO

AIMS: The present study investigated if berberine might induce Zrt-Irt-like protein 14 (ZIP14) and affect zinc redistribution to protect intestinal barrier in sepsis. MAIN METHODS: Rodent model of sepsis was induced by cecal ligation and puncture (CLP). Plasma endotoxin was assayed by LAL test and plasma zinc was measured by flame atomic spectrophotometer. Gut mucosal permeability was determined by plasma FITC-dextran. Zinc content and ZIP14 mRNA in gut mucosa were assayed by spectrophotometer and qRT-PCR, respectively. Tight junction integrity of Caco-2 was evaluated by transepithelial electrical resistance (TEER). Tight junction (TJ) protein expression was detected by Western blotting. KEY FINDINGS: Berberine and zinc gluconate pretreatment to CLP rats improved survival rate, reduced plasma endotoxin level, alleviated hypozincemia, increased zinc accumulation and ZIP14 mRNA expression in the intestinal mucosa. Berberine and zinc gluconate pretreatment decreased CLP-elicited intestinal hyperpermeability to FITC-dextran. These effects of berberine in vivo were abolished by AG1024. In vitro, lipopolysaccharide (LPS) repressed zinc transfer into Caco-2 cells exposed to zinc gluconate. Berberine and IGF-I treatment increased ZIP14 protein expression and promoted zinc transfer into Caco-2 cells exposed to zinc gluconate plus LPS. Berberine treatment induced TJ protein (claudin-1 and occludin) and raised TEER in LPS-treated Caco-2 cells. These effects of berberine in vitro were partially inhibited by ZIP14 siRNA. SIGNIFICANCE: The present study reveals that berberine induces ZIP14 expression and affects zinc re- distribution to protect intestinal barrier in sepsis, which is partially linked with the activation of IGF-I signaling.


Assuntos
Berberina/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Coinfecção/prevenção & controle , Gluconatos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Sepse/prevenção & controle , Tirfostinas/farmacologia , Zinco/metabolismo , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Coinfecção/metabolismo , Coinfecção/microbiologia , Humanos , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Sepse/metabolismo , Sepse/microbiologia , Transdução de Sinais/efeitos dos fármacos
11.
J Biochem Mol Toxicol ; 33(9): e22368, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332900

RESUMO

Exposure to arsenic has been linked to the development of type 2 diabetes though its mechanism of toxicity remains unresolved. In this study berberine (BBR) effects on arsenic-induced sirtuin 3 (Sirt3) modifications in isolated mitochondria from rat pancreas were evaluated and compared with metformin (MET). With arsenic, mitochondrial reactive oxygen species (ROS), oxidative stress, and insulin resistance were obtained higher than control. From our results and in the presence of arsenic trioxide, insulin resistance and Sirt3 levels were found to be predominantly elevated that could be the result of compensating mechanisms. Apparently, BBR and MET recruit both direct (as an antioxidant) and indirect mechanisms (Sirt3 content) to deal with arsenic trioxide toxicity. Metformin compared with BBR exhibited a less significant effect on ROS levels and since its direct antioxidant property is minor, depressed the ROS level mainly through the Sirt3 modification.


Assuntos
Arsênico/farmacologia , Berberina/farmacologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Sirtuínas/metabolismo , Animais , Mitocôndrias/metabolismo , Ratos
12.
Biol Res ; 52(1): 37, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319879

RESUMO

BACKGROUND: Berberine (BBR), a compound extracted from a variety of medicinal herbs, has been shown multiple pharmacological effects against cancer cells of different origins. Cisplatin (DDP) is known as an effective chemotherapeutic agent against cancer by inducing DNA damage and cell apoptosis. However, the effect of the combined used of BBR and DDP on cell necroptosis in ovarian cancer has not been reported. METHODS: OVCAR3 and three patient-derived primary ovarian cancer cell lines (POCCLs) were chosen as the experimental objects. To determine the potential anti-cancer activity of BBR and DDP in combination, we firstly treated OVCAR3 and POCCLs cells with BBR and/or DDP. The cell viability of OVCAR3 and POCCLs with treatment of BBR or DDP for different hours was measured by CCK-8 assay. Flow cytometry was used to analyze cell cycle distribution and changes in apoptotic cells after treatment with BBR and/or DDP. The morphological changes of OVCAR3 cells were observed by using Transmission electron microscopy (TEM) analysis. Proliferation, apoptosis and necroptosis related markers of OVCAR3 and POCCLs with treatment of BBR or DDP were measured by RT-qPCR, western blotting and immunofluorescence assay. RESULTS: Our results demonstrated that BBR significantly inhibited the proliferation of OVCAR3 and primary ovarian cancer cells in a dose- and time-dependent manner. The combination treatment of BBR and DDP had a prominent inhibitory effect on cancer cell growth and induced G0/G1 cell cycle arrest. TEM revealed that the majority of cells after BBR or DDP treatment had an increasing tendency of typical apoptotic and necrotic cell death morphology. Besides, BBR and DDP inhibited the expression of PCNA and Ki67 and enhanced the expression and activation of Caspase-3, Caspase-8, RIPK3 and MLKL. CONCLUSION: This study proposed that the combination therapy of BBR and DDP markedly enhanced more ovarian cancer cell death by inducing apoptosis and necroptosis, which may improve the anticancer effect of chemotherapy drugs. The apoptosis involved the caspase-dependent pathway, while the necroptosis involved the activation of the RIPK3-MLKL pathway. We hope our findings might provide a new insight for the potential of BBR as a therapeutic agent in the treatment of ovarian cancer.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Berberina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Berberina/farmacologia , Caspases , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Necrose
13.
Molecules ; 24(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277363

RESUMO

Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated macrophage and septic mouse models. Thus, in this study, we aimed to examine the anticancer effects of 13-EBR and its mechanisms in radiotherapy-resistant (RT-R) MDA-MB-231 cells derived from the highly metastatic MDA-MB-231 cells. When we compared the gene expression between MDA-MB-231 and RT-R MDA-MB-231 cells with an RNA microarray, RT-R MDA-MB-231 showed higher levels of anti-apoptotic genes and lower levels of pro-apoptotic genes compared to MDA-MB-231 cells. Accordingly, we examined the effect of 13-EBR on the induction of apoptosis in RT-R MDA-MB-231 and MDA-MB-231 cells. The results showed that 13-EBR reduced the proliferation and colony-forming ability of both MDA-MB-231 and RT-R MDA-MB-231 cells. Moreover, 13-EBR induced apoptosis by promoting both intracellular and mitochondrial reactive oxygen species (ROS) and by regulating the apoptosis-related proteins involved in the intrinsic pathway, not in the extrinsic pathway. These results suggest that 13-EBR has pro-apoptotic effects in RT-R MDA-MB-231 and MDA-MB-231 cells by inducing mitochondrial ROS production and activating the mitochondrial apoptotic pathway, providing useful insights into new potential therapeutic strategies for RT-R breast cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Berberina/farmacologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Mitocôndrias/metabolismo , Transdução de Sinais , Berberina/química , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
14.
Eur J Pharmacol ; 856: 172413, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31152700

RESUMO

A characteristic of endothelia damage and repair is the turnover of extracellular matrix components. As a part of extracellular matrix glycosaminoglycan (GAG), hyaluronic acid (HA, main component of glycocalyx) is not only involved in inflammation, proliferation, differentiation of cells, and tissue remodeling, but also functions as a barrier of endothelium via preventing blood flow-induced injury from endothelial layer. Therefore, the metabolism of hyaluronic acid could allow the fine-tuning of cell behavior. In this study, we found that low shear stress decreased the expression of hyaluronic acid, whereas pretreatment with berberine could significantly increase the expression of hyaluronic acid in vitro and in vivo. On this background, it is very important to better understand the beneficial effect of berberine (BBR) on low shear stress-induced degradation of hyaluronic acid and its potential mechanism. By using siRNA and inhibitors, we testified that AMP-activated protein kinase (AMPK) and p47phox/hyaluronidase 2 (Hyal2) signaling pathway involved in the modulation of hyaluronic acid metabolism. Further, berberine, by increasing AMPK phosphorylation, decreased the dissociation of p47phox/Hyal2, and subsequently inhibited Hyal2 activation and p47phox phosphorylation, leading to the metabolic maintaining of hyaluronic acid. Importantly, we primarily demonstrated a direct binding between AMPKα and p47phox in HUVECs by co-immunoprecipitation. On the other hand, berberine also increased the expression of hyaluronic acid synthase 2 (HAS2) by regulating AMPKα/p47phox signaling pathway. Taken together, berberine treatment can attenuate low shear stress-induced hyaluronic acid degradation via increasing phosphorylation of AMPKa, and then not only downregulates p47phox and Hyal2 activity but also upregulates the expression of HAS2.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Berberina/farmacologia , Moléculas de Adesão Celular/metabolismo , Glicocálix/metabolismo , Hialuronoglucosaminidase/metabolismo , NADPH Oxidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Mecânico , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicocálix/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Ácido Hialurônico/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos
15.
Mol Med Rep ; 20(2): 995-1006, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173223

RESUMO

Berberine, a natural isoquinoline alkaloid derived from Berberis species, has been reported to have anticancer effects. However, the mechanisms of action in human colorectal cancer (CRC) are not well established to date. In the present study, the cell cytotoxicity effect of berberine on human CRC cells, as well as the possible mechanisms involved, was investigated. The results of the cell viability and apoptosis assay revealed that treatment of CRC cells with berberine resulted in inhibition of cell viability and activation of cell apoptosis in a concentration­dependent manner. To reveal the underlying mechanism of berberine­induced anti­tumor activity and cell apoptosis, RNA­sequencing followed by reverse­transcription quantitative PCR were performed. In addition, RNA immunoprecipitation, chromatin immunoprecipitation and western blot analysis were used to identify the functional regulation of CASC2/EZH2/BCL2 axis in berberine­induced CRC cell apoptosis. The data revealed that lncRNA CASC2 was upregulated by berberine treatment. Gain­ or loss­of­function assays suggested that lncRNA CASC2 was required for the berberine­induced inhibition of cell viability and activation of cell apoptosis. Subsequently, the downstream antiapoptotic gene BCL2 was identified as a functional target of the berberine/CASC2 mechanism, as BCL2 reversed the berberine/CASC2­induced cell cytotoxicity. lncRNA CASC2 silenced BCL2 expression by binding to the promoter region of BCL2 in an EZH2­dependent manner. In summary, berberine may be a novel therapeutic agent for CRC and lncRNA CASC2 may serve as an important therapeutic target to improve the anticancer effect of berberine.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Berberina/farmacologia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Longo não Codificante/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo
16.
Crit Rev Oncol Hematol ; 140: 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154235

RESUMO

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


Assuntos
Anoikis , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/fisiopatologia , Berberina/farmacologia , Berberina/uso terapêutico , Clorobenzoatos/farmacologia , Clorobenzoatos/uso terapêutico , Feminino , Humanos , Piranos/farmacologia , Piranos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Saponinas/farmacologia , Saponinas/uso terapêutico , Estirenos/farmacologia , Estirenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
17.
Int J Nanomedicine ; 14: 3967-3982, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239666

RESUMO

Background: The combination of chemotherapy with radiotherapy serves as a common therapeutic strategy in clinics. However, it is unsatisfactory due to its poor therapeutic efficiency and severe side-effects originating from chemotherapy-exerted systemic toxicity as well as radiation-induced injury. Purpose: Hence, Berberine (Ber), an isoquinolin alkaloid with low toxicity and protective effects against radiotherapy, was used as a novel chemotherapeutic agent for chemo-radiotherapy of liver cancer. Patients and methods: We preloaded Ber into folic acid targeting Janus gold mesoporous silica nanocarriers (FA-JGMSNs) for overcoming the poor bioavailability of Ber. Furthermore, FA-JGMSNs were not only employed as radiosensitizers for expanding radiotherapeutic effect, but also used as photothermal agents for supplementing chemo-radiotherapeutic effect by local photothermal therapy. Results: In vitro and in vivo experiemtal results demonstrated the highly efficient anti-tumor effect, good biosafety as well as the effective protection of normal tissue of this nanoplatform. Conclusion: Based on its superb performance, we believe our work provided a feasible strategy for triple-therapies of liver cancer.


Assuntos
Berberina/uso terapêutico , Ouro/química , Hipertermia Induzida , Neoplasias Hepáticas/terapia , Nanopartículas/química , Fototerapia , Lesões por Radiação/prevenção & controle , Dióxido de Silício/química , Animais , Berberina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos Nus , Nanopartículas/ultraestrutura , Tamanho da Partícula , Porosidade , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Lesões por Radiação/terapia , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Temperatura Ambiente
18.
Gen Physiol Biophys ; 38(4): 281-294, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31219431

RESUMO

In this study, the protective effect of coptisine on the oxidative damage-mediated apoptosis was evaluated in cultured human HaCaT keratinocytes. The results demonstrate that preincubation of cells with coptisine prior to H2O2 stimulation resulted in significant inhibition of cytotoxicity and DNA damage associated with the inhibition of reactive oxygen species (ROS) accumulation. Coptisine also restored H2O2-induced mitochondrial dysfunction and decrease of ATP production, and prevented apoptosis by inhibiting Bax/Bcl-2 ratio, caspase-3 activity, and poly(ADP-ribose) polymerase degradation. Interestingly, the expressions of nuclear factor-erythroid-2-related factor 2 (Nrf2) and its active form, phosphorylated Nrf2, were strikingly promoted by coptisine in the presence of H2O2, which was associated with a marked increase in the expression of heme oxygenase-1 (HO-1). However, coptisine-induced HO-1 expression was completely abrogated by Nrf2-specific small interfering RNA (Nrf2-siRNA), which suggests that the increased expression of HO-1 by coptisine is Nrf2-dependent. In addition, Nrf2-siRNA transfection significantly eliminated the protective effect of coptisine on H2O2-induced cytotoxicity, and this effect was similar to that by zinc protoporphyrin IX (ZnPP), an HO-1 specific inhibitor. Furthermore, the protective effects of coptisine against H2O2-induced cytotoxicity were abolished by ZnPP, indicating that coptisine protects keratinocytes against oxidative stress-induced injury through activation of the Nrf2/HO-1 signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Berberina/análogos & derivados , Dano ao DNA , Heme Oxigenase-1/metabolismo , Queratinócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Berberina/farmacologia , Linhagem Celular , Humanos , Peróxido de Hidrogênio/farmacologia , Queratinócitos/enzimologia , Queratinócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Cells ; 8(6)2019 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-31234575

RESUMO

Induced brown adipocytes (also referred to as beige cells) execute thermogenesis, as do the classical adipocytes by consuming stored lipids, being related to metabolic homeostasis. Treatment of phytochemicals, including berberine (BBR), was reported to induce conversion from white adipocytes to beige cells. In this study, results of microRNA (miRNA)-seq analyses revealed a decrease in miR-92a, of which the transcription is driven by the c13orf25 promoter in BBR-treated 3T3-L1 cells. BBR treatment manipulated the expressions of SP1 and MYC, in turn, reducing the activity of the c13orf25 promoter. A decrease in miR-92a led to an increase in RNA-binding motif protein 4a (RBM4a) expression, which facilitated the beige adipogenesis. Overexpression of miR-92a or depletion of RBM4a reversely interfered with the impact of BBR treatment on the beige adipogenic signatures, gene expressions, and splicing events in 3T3-L1 cells. Our findings demonstrated that BBR treatment enhanced beige adipogenesis of 3T3-L1 cells through transcription-coupled post-transcriptional regulation.


Assuntos
Adipócitos Bege/metabolismo , Adipogenia/genética , Berberina/farmacologia , Transcrição Genética , Células 3T3-L1 , Adipócitos Bege/efeitos dos fármacos , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Sequência de Bases , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fases de Leitura Aberta/genética , Regiões Promotoras Genéticas/genética , Processamento de RNA/efeitos dos fármacos , Processamento de RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcrição Genética/efeitos dos fármacos
20.
J Dairy Res ; 86(2): 171-176, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31142385

RESUMO

Subacute ruminal acidosis (SARA) can increase the level of inflammation and induce rumenitis in dairy cows. Berberine (BBR) is the major active component of Rhizoma Coptidis, which is a type of Chinese anti-inflammatory drug for gastrointestinal diseases. The purpose of this study was to investigate the anti-inflammatory effects of BBR on lipopolysaccharide (LPS)-stimulated rumen epithelial cells (REC) and the underlying molecular mechanisms. REC were cultured and stimulated with LPS in the presence or absence of different concentrations of BBR. The results showed that cell viability was not affected by BBR. Moreover, BBR markedly decreased the concentrations and mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in the LPS-treated REC in a dose-dependent manner. Importantly, Western blotting analysis showed that BBR significantly suppressed the protein expression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein (MyD88) and the phosphorylation of nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) in LPS-treated REC. Furthermore, the results of immunocytofluorescence showed that BBR significantly inhibited the nuclear translocation of NF-κB p65 induced by LPS treatment. In conclusion, the protective effects of BBR on LPS-induced inflammatory responses in REC may be due to its ability to suppress the TLR4-mediated NF-κB and MAPK signaling pathways. These findings suggest that BBR can be used as an anti-inflammatory drug to treat inflammation induced by SARA.


Assuntos
Berberina/farmacologia , Citocinas/metabolismo , Lipopolissacarídeos/toxicidade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Bovinos , Citocinas/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , NF-kappa B/genética , Rúmen , Receptor 4 Toll-Like/genética
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