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1.
PLoS One ; 19(3): e0298533, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38536776

RESUMO

An important cellular barrier to maintain the stability of the brain's internal and external environment is the blood-brain barrier (BBB). It also prevents harmful substances from entering brain tissue through blood circulation while providing protection for the central nervous system. It should be noted, however, that the intact BBB can be a barrier to the transport of most drugs into the brain via the conventional route of administration, which can prevent them from reaching effective concentrations for the treatment of disorders affecting the central nervous system. Electroacupuncture stimulation has been shown to be effective at opening the BBB in a series of experimental studies. This study systematically analyzes the possibility and mechanism by which electroacupuncture opens the BBB. In PubMed, Web of Science, VIP Database, Wanfang Database, and the Chinese National Knowledge Infrastructure, papers have been published for nearly 22 years aimed at opening the BBB and its associated structures. A comparison of EB content between electroacupuncture and control was selected as the primary outcome. There were also results on vascular endothelial growth factor (VEGF), nerve growth factor (NGF), P-Glycoprotein (P-gp), Matrix Metalloproteinase 9 (MMP-9), and glial fibrillary acidic protein (GFAP). We utilized Review Manager software analysis to analyze correlations between studies with a view to exploring the mechanisms of similarity. Evans Blue infiltration forest plot: pooled effect size of 2.04, 95% CI: 1.21 to 2.87, P < 0.01. These results indicate that electroacupuncture significantly increases EB penetration across the BBB. Most studies have reported that GFAP, MMP-9, and VEGF were upregulated after treatment. P-gp expression decreased as well. Electroacupuncture can open the BBB, and the sparse-dense wave is currently the most effective electroacupuncture frequency for opening the BBB. VEGF plays an important role in opening the BBB. It is also important to regulate the expression of MMP-9 and GFAP and inhibit the expression of P-gp.


Assuntos
Barreira Hematoencefálica , Eletroacupuntura , Ratos , Animais , Barreira Hematoencefálica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ratos Sprague-Dawley , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Permeabilidade
2.
Fitoterapia ; 174: 105854, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38331050

RESUMO

The chemical transformation of lathyrane nucleus through reduction and oxidation reactions using Euphorbia Factor L1 (EFL1) and Euphorbia Factor L1 (EFL3) as examples were investigated, along with a co-modification strategy of lathyrane nucleus and its side ester chain. A total of 38 lathyrane derivatives (5-42) including 34 new compounds were obtained, which greatly enriched the structural diversity of the lathyrane-type diterpenoids. Cytotoxicity against drug-sensitive and drug (adriamycin, ADM) resistant MCF-7 cells showed that 23 out of 38 transformed derivatives possessed obvious cytotoxic activity with IC50 values ranging from 7.0 to 41.1 µM and 3.2 to 45.5 µM, respectively, against both cells, compared to the noncytotoxic EFL1 and EFL3. The multidrug resistance (MDR) reversing activities of these lathyrane derivatives were further evaluated in MCF-7/ADM. Three transformed compounds (reversal fold, RF = 151.33, 62.94 and 47.3 for 27, 37 and 42) showed markedly higher activity than EFL1 (RF = 32.92) and EFL3 (RF = 39.68). Structure-activity relationship study revealed an essential role of C-6/17 and C-12/13 double bonds on lathyrane nucleus for exerting MDR reversal activity. Western blotting analysis showed that 42 could reduce the expression level of P-glycoprotein (P-gp) in MCF-7/ADM cells; however, the most active compound 27 with an unnatural 5/7/7/4 fused-ring diterpenoid skeleton, had no inhibitory effect on P-gp expression.


Assuntos
Diterpenos , Euphorbia , Fenilpropionatos , Estrutura Molecular , Euphorbia/química , Resistência a Múltiplos Medicamentos , Diterpenos/farmacologia , Diterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP
3.
Phytomedicine ; 126: 155460, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38394731

RESUMO

BACKGROUND: Multidrug resistance is the major obstacle to cancer chemotherapy. Modulation of P-glycoprotein and drug combination approaches have been considered important strategies to overcome drug resistance. PURPOSE: Aiming at generating a small library of Amaryllidaceae-type alkaloids to overcome drug resistance, two major alkaloids, isolated from Pancratium maritimum, lycorine (1), and 2α-10bα-dihydroxy-9-O-demethylhomolycorine (2), were derivatized, giving rise to nineteen derivatives (3 - 21). METHODS: The main chemical transformation of lycorine resulted from the cleavage of ring E of the diacetylated lycorine derivative (3) to obtain compounds that have carbamate and amine functions (5 - 16), while acylation of compound 2 provided derivatives 17 - 21. Compounds 1 - 21 were evaluated for their effects on cytotoxicity, and drug resistance reversal, using resistant human ovarian carcinoma cells (HOC/ADR), overexpressing P-glycoprotein (P-gp/ABCB1), as model. RESULTS: Excluding lycorine (1) (IC50 values of 1.2- 2.5 µM), the compounds were not cytotoxic or showed moderate/weak cytotoxicity. Chemo-sensitization assays were performed by studying the in vitro interaction between the compounds and the anticancer drug doxorubicin. Most of the compounds have shown synergistic interactions with doxorubicin. Compounds 5, 6, 9 - 14, bearing both carbamate and aromatic amine moieties, were found to have the highest sensitization rate, reducing the dose of doxorubicin 5-35 times, highlighting their potential to reverse drug resistance in combination chemotherapy. Selected compounds (4 - 6, 9 - 14, and 21), able of re-sensitizing resistant cancer cells, were further evaluated as P-gp inhibitors. Compound 11, which has a para­methoxy-N-methylbenzylamine moiety, was the strongest inhibitor. In the ATPase assay, compounds 9-11 and 13 behaved as verapamil, suggesting competitive inhibition of P-gp. At the same time, none of these compounds affected P-gp expression at the mRNA or protein level. CONCLUSIONS: This study provided evidence of the potential of Amaryllidaceae alkaloids as lead candidates for the development of MDR reversal agents.


Assuntos
Adenocarcinoma , Alcaloides , Alcaloides de Amaryllidaceae , Antineoplásicos , Fenantridinas , Humanos , Alcaloides de Amaryllidaceae/farmacologia , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Alcaloides/farmacologia , Carbamatos/farmacologia , Linhagem Celular Tumoral
4.
Acta Pharmacol Sin ; 45(5): 1060-1076, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38228910

RESUMO

Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Diterpenos , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi , Proteínas Hedgehog , Fator 1-alfa Nuclear de Hepatócito , Neoplasias Pulmonares , Paclitaxel , Fenantrenos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Hedgehog/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Animais , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Camundongos , Camundongos Endogâmicos BALB C , Células A549
5.
Phytomedicine ; 123: 155210, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38006807

RESUMO

BACKGROUND: Oncogenic multidrug resistance (MDR) is a tough question in cancer therapy. However, no effective medications targeting oncogenic MDR are currently available. Studies have demonstrated that mosloflavone exerts anti-inflammatory effects, yet, its potential to ameliorate MDR remains unclear. PURPOSE: This study aimed to access the capability and elucidate molecular mechanisms of mosloflavone as a MDR resensitizing candidate. METHODS: We investigated the ability of mosloflavone to reverse oncogenic MDR and investigated its underlying mechanisms through cytotoxicity assay, cell cycle assay, apoptosis assay, and zebrafish xenograft model. The modulatory interplay between mosloflavone and P-gp was investigated through analysis of calcein-AM uptake, substrate efflux, ATPase assays, and molecular docking simulation. RESULTS: Mosloflavone inhibited P-gp efflux function in an uncompetitive manner without altering ABCB1 gene expression. In addition, it stimulated P-gp ATPase activity by binding to an active site distinct from that of verapamil. Regarding MDR reversal potential, mosloflavone resensitized MDR cancer cells to chemotherapies by arresting cell cycle and triggering apoptosis, possibly by enhancing reactive oxygen species accumulation and reducing phospho-STAT3. Moreover, in the zebrafish xenograft model, mosloflavone significantly potentiated the antitumor effect of paclitaxel. CONCLUSION: Our findings underscore the potential of mosloflavone as a novel dual modulator of STAT3 and P-gp, indicating it is a promising candidate for overcoming MDR in cancer treatment.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos , Flavonoides , Animais , Humanos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peixe-Zebra/metabolismo , Simulação de Acoplamento Molecular , Resistencia a Medicamentos Antineoplásicos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos , Adenosina Trifosfatases/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Antineoplásicos/farmacologia , Fator de Transcrição STAT3/metabolismo
6.
J Ethnopharmacol ; 322: 117598, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38113989

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Multi-Drug Resistance (MDR), mediated by P-glycoprotein (P-gp) is one of the barriers to successful chemotherapy in colon cancer patients. Annona muricata L. (A.muricata), commonly known as soursop/Graviola, is a medicinal plant that has been traditionally used in treating diverse diseases including cancer. Phytochemicals of A.muricata (Annonaceous Acetogenins-AGEs) have been well-reported for their anti-cancer effects on various cancers. AIM OF THE STUDY: The study aimed to examine the effect of AGEs in reversing MDR in colorectal cancer cells. METHODS: Based on molecular docking and molecular dynamic simulation, the stability of annonacin upon P-gp was investigated. Further in vitro studies were carried in oxaliplatin-resistant human colon cancer cells (SW480R) to study the biological effect of annonacin, in reversing drug resistance in these cells. RESULTS: Molecular docking and simulation studies have indicated that annonacin stably interacted at the drug binding site of P-gp. In vitro analysis showed that annonacin was able to significantly reduce the expression of P-gp by 2.56 folds. It also induced apoptosis in the drug-resistant colon cancer cells. Moreover, the intracellular accumulation of P-gp substrate (calcein-AM) was observed to increase in resistant cells upon treatment with annonacin. CONCLUSION: Our findings suggest that annonacin could inhibit the efflux of chemotherapeutic drugs mediated by P-gp and thereby help in reversing MDR in colon cancer cells. Further in vivo studies are required to decipher the underlying mechanism of annonacin in treating MDR cancers.


Assuntos
Annona , Neoplasias do Colo , Furanos , Lactonas , Humanos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Annona/química , Acetogeninas/farmacologia , Simulação de Acoplamento Molecular , Resistência a Múltiplos Medicamentos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos
7.
Cell Mol Biol (Noisy-le-grand) ; 69(11): 254-259, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38015511

RESUMO

The purpose of this study was to detect the changes of P-Glycoprotein (P-GP) expression in rat brain microvessel endothelial cell line RBE4 after the action of Tetramethylpyrazine (TMP) on Carbamazepine (CBZ), so as to clarify the potential mechanism of TMP combined with CBZ against intractable epilepsy drug resistance. The RBE4 cell line was utilized for in vitro analysis. Cells were divided into control, CBZ, and CBZ-TMP group. The expression of P-GP was assessed using Western blot and reverse transcription polymerase chain reaction (RT-PCR). Intracellular concentration of CBZ was measured through high-performance liquid chromatography (HPLC). The differential expression of mRNA was evaluated by RNA sequencing. The intracellular concentration of CBZ in the CBZ-TMP group was significantly higher than that in other groups. The expression of P-GP in the CBZ group was significantly higher than that in the control group, while in the CBZ&TMP group, it was significantly lower than that in the other groups. Comparative analysis also revealed some differentially expressed genes. Compared with the CBZ group, FAM106A, SLC3A2, TENM2, etc. were upregulated most significantly in the CBZ&TMP group. ZBTB10, WDR7, STARD13, etc. were downregulated most significantly. Results suggest that TMP increases the intracellular concentration of CBZ, downregulates the expression of P-GP increased by CBZ, and modulates related cellular metabolism and signaling pathways, thus reversing the drug resistance mechanism of intractable epilepsy, providing a theoretical basis for the combination of traditional Chinese medicine and antiepileptic drugs.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Animais , Ratos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Células Endoteliais , Carbamazepina/farmacologia , Encéfalo
8.
Neurotox Res ; 41(5): 408-430, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37086338

RESUMO

Memory impairment is a result of multiple factors including amyloid-beta (Aß) accumulation. Several receptors are mediated for Aß transport and signaling. Moreover, blood lipids are involved in Aß signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aß signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aß. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer's disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood-brain barrier (BBB).


Assuntos
Doença de Alzheimer , Inibidores de Hidroximetilglutaril-CoA Redutases , Silimarina , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/uso terapêutico , Simulação de Acoplamento Molecular , Acetilcolinesterase/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Quercetina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Silimarina/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/uso terapêutico
9.
Phytother Res ; 37(7): 2939-2956, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36938853

RESUMO

This study investigated antimalarial efficacy and sensitization of chrysosplenetin against artemisinin-resistant Plasmodium berghei K173 and potential molecular mechanism. Our data indicated a risk of artemisinin resistance because a higher parasitaemia% and lower inhibition% under artemisinin treatment against resistant parasites than those in the sensitive groups were observed. Two non-antimalarial components, verapamil and chrysosplentin, being P-gp inhibitors, possessed a strong efficacy against resistant parasites but it was not the case for Bcrp inhibitor novobiocin. Artemisinin-chrysosplenetin combination improved artemisinin susceptibility of resistant P. berghei. Artemisinin activated intestinal P-gp and Abcb1/Abcg2 expressions and suppressed Bcrp whereas chrysosplenetin reversed them. Resistant parasite infection led to a decreased haemozoin in organs or an increased heme in peripheral bloods compared with the sensitives; however, that in Abcb1-deficient knockout (KO)-resistant mice reversely got increased or decreased versus wild type (WT)-resistant animals. Chrysosplenetin as well as rifampin (nuclear receptor agonist) increased the transcription levels of PXR/CAR while showed a versatile regulation on hepatic and enternal PXR/CAR in WT- or KO-sensitive or -resistant parasites. Oppositely, hepatic and enteric NF-κB p52 mRNA decreased conformably in WT but increased in KO-resistant mice. NF-κB pathway potentially involved in the mechanism of chrysosplenetin on inhibiting P-gp expressions while PXR/CAR play a more complicated role in this mechanism.


Assuntos
Antimaláricos , Artemisininas , Camundongos , Animais , Antimaláricos/farmacologia , Plasmodium berghei , Subunidade p52 de NF-kappa B/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Proteínas de Neoplasias , Artemisininas/farmacologia , Transdução de Sinais , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Homeostase , Heme/farmacologia
10.
Int J Mol Sci ; 24(5)2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36901808

RESUMO

The modulation of P-glycoprotein (P-gp, ABCB1) can reverse multidrug resistance (MDR) and potentiate the efficacy of anticancer drugs. Tea polyphenols, such as epigallocatechin gallate (EGCG), have low P-gp-modulating activity, with an EC50 over 10 µM. In this study, we optimized a series of tea polyphenol derivatives and demonstrated that epicatechin EC31 was a potent and nontoxic P-gp inhibitor. Its EC50 for reversing paclitaxel, doxorubicin, and vincristine resistance in three P-gp-overexpressing cell lines ranged from 37 to 249 nM. Mechanistic studies revealed that EC31 restored intracellular drug accumulation by inhibiting P-gp-mediated drug efflux. It did not downregulate the plasma membrane P-gp level nor inhibit P-gp ATPase. It was not a transport substrate of P-gp. A pharmacokinetic study revealed that the intraperitoneal administration of 30 mg/kg of EC31 could achieve a plasma concentration above its in vitro EC50 (94 nM) for more than 18 h. It did not affect the pharmacokinetic profile of coadministered paclitaxel. In the xenograft model of the P-gp-overexpressing LCC6MDR cell line, EC31 reversed P-gp-mediated paclitaxel resistance and inhibited tumor growth by 27.4 to 36.1% (p < 0.001). Moreover, it also increased the intratumor paclitaxel level in the LCC6MDR xenograft by 6 fold (p < 0.001). In both murine leukemia P388ADR and human leukemia K562/P-gp mice models, the cotreatment of EC31 and doxorubicin significantly prolonged the survival of the mice (p < 0.001 and p < 0.01) as compared to the doxorubicin alone group, respectively. Our results suggested that EC31 was a promising candidate for further investigation on combination therapy for treating P-gp-overexpressing cancers.


Assuntos
Antineoplásicos , Neoplasias da Mama , Catequina , Leucemia , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Leucemia/tratamento farmacológico , Paclitaxel/farmacologia , Polifenóis/farmacologia , Chá
11.
Sci Rep ; 13(1): 4528, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36941308

RESUMO

Red ginseng has been used in traditional medicine for centuries in Asia. In this study, we evaluated four types of red ginseng grown in different areas (Chinese red ginseng, Korean red ginseng A, Korean red ginseng B, and Korean red ginseng C) for their ability to inhibit lung tumor formation and growth induced by the carcinogen benzo(a)pyrene (B(a)P) in A/J mice and found that Korean red ginseng B was the most effective at lowering the tumor load among the four red ginseng varieties. Moreover, we analyzed the levels of various ginsenosides (Rg1, Re, Rc, Rb2, Rb3, Rb1, Rh1, Rd, Rg3, Rh2, F1, Rk1, and Rg5) in four kinds of red ginseng extract and found that Korean red ginseng B had the highest level of ginsenoside Rg3 (G-Rg3), which suggested that G-Rg3 may play an important role in its therapeutic efficacy. This work revealed that the bioavailability of G-Rg3 was relatively poor. However, when G-Rg3 was coadministered with verapamil, a P-glycoprotein inhibitor, the G-Rg3 efflux in Caco-2 cells was lowered, the small intestinal absorption rate of G-Rg3 in the rat models was increased, the concentration levels of G-Rg3 were elevated in the intestine and plasma, and its tumor-preventive abilities in the tumorigenesis rat model induced by B(a)P were also augmented. We also found that G-Rg3 reduced B(a)P-induced cytotoxicity and DNA adduct formation in human lung cells and rescued phase II enzyme expression and activity through Nrf2 pathways, which may be the potential mechanisms underlying the inhibitory effects of G-Rg3 on lung tumorigenesis. Our study showed a potentially vital role of G-Rg3 in targeting lung tumors in murine models. The oral bioavailability of this ginsenoside was augmented by targeting P-glycoprotein, which allowed the molecule to exert its anticancer effects.


Assuntos
Ginsenosídeos , Panax , Ratos , Humanos , Camundongos , Animais , Ginsenosídeos/farmacologia , Benzo(a)pireno/toxicidade , Células CACO-2 , Carcinogênese , Pulmão , Subfamília B de Transportador de Cassetes de Ligação de ATP
12.
Drug Metab Pharmacokinet ; 50: 100500, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36948091

RESUMO

Black ginger is used as an herbal medicine for self-care and health promotion. Black ginger extract has been shown to alter the function of transporters in several cell types. This study demonstrates the interaction between the extract and 5,7-dimethoxyflavone (DMF) on drug efflux mediated by breast cancer resistance proteins (BCRP) and P-glycoprotein (P-gp) in Caco-2 cells and heterologous cell systems [Madin-Darby canine kidney type II (MDCKII) stably transfected with human BCRP (MDCKII/BCRP) or human P-gp (MDCKII/P-gp)]. The transepithelial flux of 3H-Digoxin and 3H-Estrone sulfate, prototypic substrates of P-gp, and BCRP, respectively, across Caco-2 cell monolayers, MDCKII/BCRP, and MDCKII/P-gp cells were determined. The results demonstrate that black ginger extract (10 µg/ml) significantly increases 3H-Digoxin and 3H-Estrone sulfate transport from the apical to basolateral side while decreasing transport from the basolateral to apical side of Caco-2 cells and MDCKII cell overexpression of BCRP or P-gp. The effect of the extract on 3H-Digoxin and 3H-Estrone sulfate transport was related to a decrease in efflux ratio. Likewise, DMF (5 µM) significantly increased 3H-Digoxin and 3H-Estrone sulfate absorption with a decreased efflux ratio compared to the control. Interestingly, the extract also significantly increased absorption of paclitaxel, an anti-cancer drug, which has poor oral absorption. Taken together, co-administration of drugs as substrates of BCRP and P-gp, with the black ginger extract containing DMF, might alter the pharmacokinetic profiles of the medicine.


Assuntos
Absorção Intestinal , Proteínas de Neoplasias , Animais , Cães , Humanos , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Células CACO-2 , Proteínas de Neoplasias/metabolismo , Transporte Biológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Digoxina/farmacocinética
13.
ACS Chem Neurosci ; 14(4): 766-772, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36704945

RESUMO

Salvia miltiorrhiza Bunge (S. miltiorrhiza) is a traditional Chinese medicine that has been widely used in the treatment of various central nervous system (CNS) diseases. However, the mechanism of active components of S. miltiorrhiza crossing the blood-brain barrier (BBB) stays unclear. The purpose of this study was to clarify the mechanism of four ingredients of S. miltiorrhiza, i.e., cryptotanshinone (CTS), dihydrotanshinone I (DTS I), tanshinone IIA (TS IIA), and protocatechuic acid (PCTA) crossing the BBB using the in vitro model. The bidirectional transport of detectable components was tested using the MDCK-MDR1 monolayers. High performance liquid chromatography coupled to triple-quadrupole mass spectrometry (HPLC-QQQ/MS) was used to detect the content changes of S. miltiorrhiza monomer components transported through the BBB. Papp of CTS, DTS I, and TS IIA in the absorption direction were lower than 1.0 × 10-6 cm/s, suggesting that these components were poorly absorbed, while PCTA was moderately absorbed through the BBB. The efflux ratio (ER) of CTS, DTS I, TS IIA, and PCTA were 1.65, 0.92, 4.27, and 1.48, respectively. After treatment with P-gp inhibitor tariquidar, the efflux ratio (ER) of CTS, DTS I, and TS IIA significantly decreased from 1.65 to 1.27, 0.92 to 0.36, and 4.27 to 0.86 (P < 0.05), respectively, while the efflux ratio of PCTA decreased without significance from 1.48 to 0.80. This indicated that the transport of CTS, DTS I, and TS IIA might be related to P-gp. TS IIA and CTS were verified as the substrates of P-gp among the four components since the ER of TS IIA and CTS is greater than 1.5. For PCTA and DTS I, their transport mechanism may be related to other transport proteins or passive transport. The results were confirmed by molecular docking in our current work. In this study, an in vitro BBB model was established and applied to the trans-BBB study of active components in S. miltiorrhiza for the first time, which may provide a basis for further research on the mechanisms of other TCMs in treating CNS diseases and is of great significance in promoting the rational and effective use of TCMs.


Assuntos
Barreira Hematoencefálica , Salvia miltiorrhiza , Animais , Humanos , Ratos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Salvia miltiorrhiza/química , Salvia miltiorrhiza/metabolismo , Linhagem Celular
14.
Biosens Bioelectron ; 222: 115001, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36516634

RESUMO

P-glycoprotein (P-gp), a transmembrane glycoprotein widely expressed on the surface of various cells, is highly associated with multidrug resistance (MDR) that heralds the malignant progress of disease after drug treatment. Notably, there have been reported that serum P-gp is a potential marker for assessing the progression of disease resistance. Currently, there are few methods for point-of-care serum P-gp detection. In this study, we proposed a gold nanoparticles/electrochemically reduced graphene oxide@carbon nanotube (AuNPs/ERGO@CNT) modified immunosensor based on a one-step electrochemical co-reduction method. The limit of detection (LOD) of our constructed electrochemical immunosensor for P-gp detection reached 0.13 ng/mL, and the detection results in serum were consistent with ELISA. The developed immunosensor is expected to provide a scientific basis for the clinical application of serum P-gp monitoring and integrated medicine.


Assuntos
Técnicas Biossensoriais , Grafite , Nanopartículas Metálicas , Nanocompostos , Ouro , Imunoensaio/métodos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Limite de Detecção , Subfamília B de Transportador de Cassetes de Ligação de ATP
15.
Tissue Cell ; 78: 101898, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36049371

RESUMO

Individuals with Down syndrome (DS) exhibit impaired olfactory function and are at a higher risk of developing Alzheimer's disease (AD). Olfactory dysfunction may be an early clinical symptom of AD. Recent studies have demonstrated that vitamin D3 (VD3) exerts neuroprotective effects in mouse models of AD. In this study, we investigated the effects of VD3 on the morphology, immunolocalization, and markers involved in neuropathogenic processes, apoptosis, proliferation, cell survival, and clearance of amyloid peptides, along with neuronal markers in the olfactory bulb (OB) of an adult female mouse model of DS. Morphological and molecular analyses revealed that trisomic mice exhibited a volume reduction in the external plexiform layer, a decrease in the number of mitral and granule cells, and an increase in the expression of amyloid-ß 42, caspase-3 p12, and P-glycoprotein. VD3 reversed certain morphological abnormalities in the OB of control trisomic mice (Ts(CO)) and decreased the levels of caspase-3 p12 and methylenetetrahydrofolate reductase in the treated groups. The results demonstrated that trisomy factor causes morphofunctional abnormalities in the OB of Ts(CO) mice. Moreover, VD3 could represent a therapeutic target to attenuate morphological and molecular alterations in OB.


Assuntos
Doença de Alzheimer , Síndrome de Down , Fármacos Neuroprotetores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Caspase 3/metabolismo , Colecalciferol/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/metabolismo , Feminino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Camundongos , Camundongos Transgênicos , Bulbo Olfatório/metabolismo
16.
Bioorg Chem ; 129: 106170, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36174443

RESUMO

P-glycoprotein (P-gp), a transmembrane glycoprotein, is mainly involved in lung cancer multidrug resistance. Several P-gp inhibitors have been developed to enhance the efficacy of chemotherapeutics and overcome drug resistance. However, most of them failed in the clinical stages due to undesirable side effects. Therefore, there is a requirement to develop P-gp inhibitors from natural sources. Dietary spice bioactives have been well-known for their anticancer activities. However, their role in modulating the P-gp activity has not been well investigated. Therefore, we have screened for the potential bioactives from various spice plants with P-gp modulatory activity using computational molecular docking analysis. The computational analysis revealed several key bioactives from curry leaves, specifically mahanimbine, exhibited a strong binding affinity with P-gp. Unfortunately, mahanimbine is available with few commercial sources at very high prices. Therefore, we prepared a curry leaves extract and isolated mahanimbine by a novel, yet simple, extraction method that requires less time and causes minimum environmental hazards. After purification, structure, and mass were confirmed for the isolated compound by IR spectrum and LC-MS/MS analysis, respectively. In the mechanistic study, hydrolysis of ATP and substrate efflux by P-gp are coupled. Hence, ATP binding at the ATPase-binding site is one of the fundamental steps for the P-gp efflux cycle. We found that mahanimbine demonstrated to stimulate P-gp ATPase activity. Concurrently, it enhanced the intracellular accumulation of P-gp substrates Rhodamine 123 and Hoechst stain, which indicates that mahanimbine modulates the function of P-gp. In addition, we have analyzed the complementary effect of mahanimbine with the chemotherapeutic drug gefitinib. We found that mahanimbine synergistically enhanced gefitinib efficiency by increasing its intracellular accumulation in lung cancer cells. Overall, mahanimbine has been shown to be a potent P-gp modulator. Therefore, mahanimbine can be further developed as a potential candidate to overcome chemoresistance in lung cancer.


Assuntos
Neoplasias Pulmonares , Murraya , Humanos , Murraya/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos , Simulação de Acoplamento Molecular , Gefitinibe/farmacologia , Cromatografia Líquida , Espectrometria de Massas em Tandem , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Trifosfato de Adenosina , Adenosina Trifosfatases/metabolismo , Linhagem Celular Tumoral
17.
Phytochemistry ; 203: 113354, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35940427

RESUMO

Aiming at overcoming multidrug resistance (MDR) in cancer, we have been studying Momordica balsamina, a vegetable known as African pumpkin. Five undescribed cucurbitane-type triterpenoids (balsaminaepoxide, balsaminatriol, balsaminoic acid, balsaminal, and balsaminol G) along with five known cucurbitacins were isolated from the methanol extract of Momordica balsamina aerial parts, whose structures were elucidated by spectroscopic data, mainly 1D and 2D NMR experiments. Compounds were evaluated for their ability as P-glycoprotein (P-gp/ABCB1) inhibitors in multidrug resistant human ABCB1-transfected mouse lymphoma cells (L5178Y, MDR) and resistant human colon adenocarcinoma cells (COLO 320), using the rhodamine-123 exclusion test, by flow cytometry. Several compounds, which were found to be non-cytotoxic, strongly inhibited P-gp efflux activity in a dose-dependent manner in both cell models. In MRD mouse lymphoma cells, balsaminol G and karavilagenin B were the most active, while in resistant colon adenocarcinoma cells, the strongest inhibitory activity was found for balsaminaepoxide, balsaminatriol and karavilagenin C, being several-fold more active than the positive control verapamil. In chemosensitivity assays, in a model of combination chemotherapy, selected compounds showed to interact synergistically with doxorubicin, thus substantiating their potential as MDR reversers. The strongest synergistic interaction was found for balsaminal and balsaminol G.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Cucurbita , Linfoma , Momordica , Triterpenos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Cucurbitacinas , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Metanol , Camundongos , Momordica/química , Extratos Vegetais/farmacologia , Rodaminas , Triterpenos/química , Triterpenos/farmacologia , Verapamil
18.
Xenobiotica ; 52(5): 511-519, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35855663

RESUMO

Kampo medicines are widely used in Japan; however, their potential to cause drug interactions still remains unclear and needs to be further investigated. The effects of goreisan on the P-glycoprotein (P-gp) and the cytochrome P-450 (CYP), which are associated with drug interactions, were investigated.The inhibitory effect of goreisan extract on P-gp was evaluated using a Caco-2 cell permeability assay. The results indicated that it inhibited P-gp function in a concentration-dependent manner.The inhibitory effect of three goreisan ingredients (alisol A, tumulosic acid, and (E)-cinnamic acid) on seven CYP isoforms was evaluated using human liver microsomes (HLM). Of these, tumulosic acid and (E)-cinnamic acid exhibited less than 16% inhibition at concentrations of 10 µmol/L against any of the CYP isoforms tested. Alisol A inhibited only CYP3A but showed no inhibitory effect with pre-incubation.These results indicate that goreisan extract has inhibitory activity against P-gp and that alisol A, a goreisan ingredient, exhibits an inhibitory effect on CYP3A. However, these are thought to be minor or negligible in vivo. Overall, these findings will be useful to evaluate possible drug interactions and provide support for the interpretation of future clinical drug-drug interaction studies involving goreisan.


Assuntos
Citocromo P-450 CYP3A , Medicamentos de Ervas Chinesas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Células CACO-2 , Sistema Enzimático do Citocromo P-450 , Humanos , Microssomos Hepáticos
19.
Nutrients ; 14(13)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35807759

RESUMO

The single nucleotide polymorphisms (SNPs) rs3808607, rs2072183, rs2032582, and rs1761667 are associated with coenzyme Q10 (CoQ10) bioavailability in women after long-term CoQ10 supplementation. However, the beneficial aspects of the association between these SNPs and CoQ10 supplementation remain unknown. We investigated their relationship using the subjective quality of life score SF-36 by reanalyzing previous data from 92 study participants who were receiving ubiquinol (a reduced form of CoQ10) supplementation for 1 year. Two-way repeated-measures analysis of variance revealed a significant interaction between rs1761667 and the SF-36 scores of role physical (p = 0.016) and mental health (p = 0.017) in women. Subgrouping of participants based on the above four SNPs revealed significant interactions between these SNPs and the SF-36 scores of general health (p = 0.045), role emotional (p = 0.008), and mental health (p = 0.019) and increased serum CoQ10 levels (p = 0.008), suggesting that the benefits of CoQ10 supplementation, especially in terms of psychological parameters, are genotype-dependent in women. However, significant interactions were not observed in men. Therefore, inclusion of SNP subgrouping information in clinical trials of CoQ10 supplementation may provide conclusive evidence supporting other beneficial health effects exerted by the association between these SNPs and CoQ10 on women.


Assuntos
Qualidade de Vida , Ubiquinona , Subfamília B de Transportador de Cassetes de Ligação de ATP , Antioxidantes , Disponibilidade Biológica , Colesterol 7-alfa-Hidroxilase , Suplementos Nutricionais , Feminino , Humanos , Masculino , Proteínas de Membrana Transportadoras
20.
AAPS PharmSciTech ; 23(5): 130, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35487999

RESUMO

Multidrug resistance (MDR) is a key determinant for hepatocellular carcinoma chemotherapy failure. P-glycoprotein is one of the main causes of MDR by causing drug efflux in tumor cells. In order to solve this thorny problem, we prepared a sorafenib-loaded polylactic acid-glycolic acid (PLGA) - D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (SPTNs). SPTNs were successfully synthesized through an ultrasonic emulsion solvent evaporation method with a favourable encapsulation efficiency of 90.35%. SPTNs were almost spherical in shape with uniform particle size (215.70 ± 0.36 nm), narrow polydispersity index (0.27 ± 0.02) and negative surface charge (-26.01 ± 0.65 mV). In the cellular uptake assay, the intracellular coumarin-6 (C6) fluorescence of TPGS component-based PLGA nanoparticles (C6-PTNs) was 1.63-fold higher relative to that of PVA component-based PLGA nanoparticles (C6-PVNs). The half-maximal inhibitory concentration and apoptosis ratio of SPTNs against HepG2/MDR cells were 3.90 µM and 75.62%, respectively, which were notably higher than free SF and sorafenib-PLGA-PVA nanoparticles (SPVNs). The anti-drug efflux activities of SPTNs were assessed by the intracellular trafficking assay using verapamil as a P-gp inhibitor. SPTNs could effectively inhibit the drug efflux in tumor cells detected by flow cytometry, and suppressed relative MDR1 gene as well as P-glycoprotein expression in tumor cells. Attributed to the MDR reversion effect of SPTNs, the in vivo antitumor efficacy experiment showed that SPTNs significantly inhibited the tumor growth of HepG2/MDR xenograft-bearing nude mice, and obviously reduced the toxicity against liver and kidney compared with SF treatment. In summary, SPTNs, as highly efficient and safe antitumor nano delivery systems, showed promising potential for hepatocellular carcinoma therapy through reversing P-glycoprotein-mediated MDR. Graphical Abstract.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Subfamília B de Transportador de Cassetes de Ligação de ATP , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Resistência a Múltiplos Medicamentos , Glicolatos , Humanos , Ácido Láctico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Poliésteres , Polietilenoglicóis , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Vitamina E , alfa-Tocoferol/farmacologia
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