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1.
Pharmaceutics ; 15(6)2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37376227

RESUMO

The authors and the journal retract the article, 'Pyrvinium Treatment Confers Hepatic Metabolic Benefits via ß-Catenin Downregulation and AMPK Activation' [...].

2.
Pharmaceutics ; 13(3)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806415

RESUMO

Genetic evidence has indicated that ß-catenin plays a vital role in glucose and lipid metabolism. Here, we investigated whether pyrvinium, an anthelmintic agent previously reported as a down-regulator of cellular ß-catenin levels, conferred any metabolic advantages in treatment of metabolic disorders. Glucose production and lipid accumulation were analyzed to assess metabolic response to pyrvinium in hepatocytes. The expression of key proteins and genes were assessed by immunoblotting and RT-PCR. The in vivo efficacy of pyrvinium against metabolic disorders was evaluated in the mice fed with a high fat diet (HFD). We found that pyrvinium inhibited glucose production and reduced lipogenesis by decreasing the expression of key genes in hepatocytes, which were partially elicited by the downregulation of ß-catenin through AXIN stabilization. Interestingly, the AMPK pathway also played a role in the action of pyrvinium, dependent on AXIN stabilization but independent of ß-catenin downregulation. In HFD-fed mice, pyrvinium treatment led to improvement in glucose tolerance, fatty liver disorder, and serum cholesterol levels along with a reduced body weight gain. Our results show that small molecule stabilization of AXIN using pyrvinium may lead to improved glucose and lipid metabolism, via ß-catenin downregulation and AMPK activation.

3.
Pharmaceutics ; 13(4)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924306

RESUMO

Coordinated transcellular transport by the uptake via organic cation transporters (OCTs) in concert with the efflux via multidrug and toxin extrusion proteins (MATEs) is an essential system for hepatic and renal drug disposition. Despite their clinical importance, the regulation of OCTs and MATEs remains poorly characterized. It has been reported that cadmium (Cd2+) increase the activities of OCTs while being a substrate of MATEs. Here, we found that human (h) OCT2 protein, as compared with hMATE1, was more active in trafficking between the plasma membrane and cytoplasmic storage pool. Cd2+ exposure could significantly enhance the translocation of hOCT2 and hOCT1, but not hMATE1, to the plasma membrane. We further identified that candesartan, a widely prescribed angiotensin II receptor blocker, behaved similarly toward OCT2 and MATE1 as Cd2+ did. Importantly, Cd2+ and candesartan treatments could lead to an enhanced accumulation of metformin, which is a well-characterized substrate of OCTs/MATEs, in mouse kidney and liver, respectively. Altogether, our studies have uncovered possible divergent regulation of OCTs and MATEs by certain xenobiotics, such as Cd2+ and candesartan due to the different cellular trafficking of these two families of transporter proteins, which might significantly affect drug disposition in the liver and kidney.

4.
Kidney Int ; 97(4): 765-777, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32061436

RESUMO

Renal accumulation and exposure of cadmium originating from pollution in agricultural land and the prevalence of cigarette smoking remains an unneglectable human health concern. Whereas cadmium exposure has been correlated with increased incidence of a variety of kidney diseases, little is known pertaining to its effect on renal drug disposition and response in patients. Here, we report that cadmium exposure significantly increased the activity of organic cation transporter 2 (OCT2), a critical renal drug transporter recommended in United States Federal Drug Administration guidance for assessment during drug development. Cadmium enhanced OCT2 trafficking to the cell membrane both in vitro and in vivo. Mechanistically cadmium-mediated OCT2 translocation was found to involve protein-protein interaction between serine/threonine-protein kinase AKT2, calcium/calmodulin and the AKT substrate AS160 in in vitro cellular studies. The formed protein complex could selectively facilitate phosphorylation of AKT2 at T309, which induced translocation of OCT2 to the plasma membrane. Moreover, cadmium exposure markedly exacerbated nephrotoxicity induced by cisplatin, an OCT2 substrate, by increasing its accumulation in the mouse kidney. Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.


Assuntos
Antineoplásicos , Cisplatino , Antineoplásicos/efeitos adversos , Cádmio/toxicidade , Cisplatino/toxicidade , Humanos , Rim , Proteínas de Transporte de Cátions Orgânicos , Transportador 2 de Cátion Orgânico
5.
Clin Pharmacol Ther ; 108(1): 107-115, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31957006

RESUMO

Pharmacokinetic (PK) similarity studies are vital to assess the biosimilarity of a biosimilar to a reference product. Systematic bias in a bioanalytical method that quantify products could be a potential source of error affecting the variability of the data and influencing the outcome of a PK similarity study. We investigated the impact of six varying patterns of bioanalytical bias difference (biasdiff ) between the similar products on the probability passing the PK similarity test. A population PK model was used to simulate concentration-time profiles for a biosimilar and a reference product and added biasdiff ranging from 030%. The probability of achieving the PK similarity criteria (90% confidence interval between 0.8 and 1.25) for the maximum serum concentration (Cmax ) and area under the curve (AUC) was assessed. The data indicate that an increase in absolute biasdiff between products of ≥ 10% would decrease the power to assess the similarity criteria for Cmax and AUC.


Assuntos
Medicamentos Biossimilares/farmacocinética , Simulação por Computador , Modelos Biológicos , Área Sob a Curva , Viés , Medicamentos Biossimilares/administração & dosagem , Humanos , Equivalência Terapêutica
6.
ACS Biomater Sci Eng ; 6(4): 2346-2356, 2020 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33455311

RESUMO

High glucose condition inhibited osteoblast differentiation could be a main mechanism contributing to the decreased bone repair associated with diabetes. Metformin, a widely prescribed antidiabetic drug, was shown to have osteogenic properties in our previous study. Transplanted mesenchymal stromal cells (MSCs) may differentiate into osteoblasts and promote bone regeneration. Our study aimed to combine the benefits of metformin and MSCs transplantation on osteogenesis in high glucose conditions. We developed demineralized dentin matrix (DDM) as a carrier to target deliver metformin and dental pulp-derived MSCs (DPSCs). We collected clinically discarded teeth, isolated DPSCs from the dental pulp, and prepared the DDM from the dentin. The DDM was observed by scanning electron microscopy and was found to have well-distributed tubes. Then, metformin was loaded into the DDM to form the DDM-Met complex (DDM-Met); DDM-Met released metformin at a favorable concentration. The DPSCs seeded with the DDM-Met in a high glucose medium showed satisfactory attachment and viability together with increased mineralization and upregulated osteogenesis-related genes, including alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (Runx2), and osteopontin (OPN). A possible mechanism of the enhanced osteogenic differentiation of DPSCs was explored, and the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway was found to play a role in the enhancement of osteogenesis. DDM-Met appeared to be a successful metformin and DPSC carrier that allowed for the local delivery of metformin and DPSCs in high glucose conditions. DDM-Met-DPSC construct has promising prospects to promote osteogenesis and enhance the much-needed diabetic bone regeneration.


Assuntos
Metformina , Osteogênese , Polpa Dentária , Dentina , Glucose , Metformina/farmacologia , Células-Tronco
7.
J Med Chem ; 62(24): 11151-11164, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769984

RESUMO

Dysregulation of the Wnt/ß-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 (1c) which demonstrated excellent anti-CRC effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of ß-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity. The anti-CRC effect of YW2065 was highlighted by its promising efficacy in a mice xenograft model.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pirazóis/química , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/química , Animais , Antineoplásicos/química , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Fosforilação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
ACS Med Chem Lett ; 10(1): 127-131, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30655959

RESUMO

We report the design, synthesis, and evaluation of novel 5-fluorouracil (5FU) prodrugs 1a,1b that are efficiently activated by the high level of reactive oxygen species (ROS) in cancer cells. Prodrugs 1a,1b selectively kill cancer cells over normal cells and are well-tolerated in mice. The strategy described herein can extend application of chemotherapeutic drugs.

9.
J Med Chem ; 62(2): 727-741, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30605343

RESUMO

Wnt/ß-catenin signaling pathway is implicated in the etiology and progression of metabolic disorders. Although lines of genetic evidence suggest that blockage of this pathway yields favorable outcomes in treating such ailments, few inhibitors have been used to validate the promising genetic findings. Here, we synthesized and characterized a novel class of triazole-based Wnt/ß-catenin signaling inhibitors and assessed their effects on energy metabolism. One of the top inhibitors, compound 3a, promoted Axin stabilization, which led to the proteasome degradation of ß-catenin and subsequent inhibition of the Wnt/ß-catenin signaling in cells. Treatment of hepatocytes and high fat diet-fed mice with compound 3a resulted in significantly decreased hepatic lipid accumulation. Moreover, compound 3a improved glucose tolerance of high fat diet-fed mice without noticeable toxicity, while downregulating the genes involved in the glucose and fatty acid anabolisms. The new inhibitors are expected to be further developed for the treatment of metabolic disorders.


Assuntos
Dieta Hiperlipídica , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/etiologia , Triazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Teste de Tolerância a Glucose , Células HEK293 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Cloreto de Lítio/farmacologia , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêutico , beta Catenina/metabolismo
10.
Medchemcomm ; 9(10): 1722-1732, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429977

RESUMO

Colorectal cancer (CRC) remains the fourth leading cause of cancer deaths around the world despite the availability of many approved small molecules for treatment. The issues lie in the potency, selectivity and targeting of these compounds. Therefore, new strategies and targets are needed to optimize and develop novel treatments for CRC. Here, a group of novel hybrids derived from aspirin and chalcones were designed and synthesized based on recent reports of their individual benefits to CRC targeting and selectivity. The most active compound 7h inhibited proliferation of CRC cell lines with better potency compared to 5-fluorouracil, a currently used therapeutic agent for CRC. Importantly, 7h had 8-fold less inhibitory activity against non-cancer CCD841 cells. In addition, 7h inhibited CRC growth via the inhibition of the cell cycle in the G1 phase. Furthermore, 7h induced apoptosis by activating caspase 3 and PARP cleavage, as well as increasing ROS in CRC cells. Finally, 7h significantly retarded the CRC cell growth in a mouse xenograft model. These findings suggest that 7h may have potential to treat CRC.

11.
Bioorg Med Chem Lett ; 28(17): 2869-2874, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30037494

RESUMO

Colorectal cancer (CRC) is a leading cause of mortality worldwide. Current treatments of CRC involve anti-cancer agents with relatively good efficacy but unselectively target both cancer and non-cancer cells. Thus, there is a need to discover and develop novel CRC therapeutics that have potent anti-cancer effects, but show reduced off-target cell effects. Here, a novel series of cinnamaldehyde-based aspirin derivatives were designed and synthesized. Biological evaluation indicated that the most active compound 1f exhibited more than 10-fold increase in the anti-proliferation efficacy in HCT-8 cells compared to the parent compounds. Its effects were similarly reproduced in another CRC cell line, DLD-1, but with 7- to 11-fold less inhibitory activity in non-tumorigenic colon cells. Flow cytometry analysis showed that 1f induced cell cycle arrest and apoptosis, which was further validated with immunoblot analysis of the relative protein levels of cleaved caspase 3 and PARP as well as the ROS production in CRC cells. More so, 1f significantly inhibited the growth of implanted CRC in vivo in mouse xenograft model. Taken together, our results show that cinnamaldehyde-based aspirin derivatives such as 1f show promise as novel anti-CRC agent for further pharmaceutical development.


Assuntos
Acroleína/análogos & derivados , Antineoplásicos/farmacologia , Aspirina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Acroleína/química , Acroleína/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Aspirina/síntese química , Aspirina/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
12.
Mol Pharm ; 14(8): 2726-2739, 2017 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-28699756

RESUMO

Membrane transporters play a significant role in the transport of many endogenous and exogenous compounds. The knowledge of transporter substrate requirements has allowed further development of drugs that utilize them to ensure tissue permeation. In this study, we demonstrate that inclusion of a biguanide functionality can potentiate uptake by the organic cation transporters 1 and 2 (OCT1 and OCT2). We synthesized 18 pairs of structurally diverse compounds, each pair consisting of a parent amino compound and its biguanide analog; and then assessed their cellular uptake in HEK293 cells overexpressing human OCT1 or OCT2. Our results show that addition of the biguanide significantly improved OCT1- and OCT2-mediated transport for the majority of compounds. The biguanides also inhibited the uptake of prototypical substrates of both transporters, 1-methyl-4-phenylpyridinium (MPP+) and metformin. We found that molecular weight, molecular volume, Log D (pH 7.4), and accessible surface area were important determinants of OCT2 substrates, but none of these parameters was a significant factor for OCT1. More so, the inhibition of MPP+ uptake correlated linearly with that of metformin uptake for the tested biguanides in both cell lines. Taken together, we conclude that the inclusion of the biguanide scaffold in nonsubstrates of OCT1 and OCT2 increase their propensity to become substrates and inhibitors for these transporters.


Assuntos
1-Metil-4-fenilpiridínio/química , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Biguanidas/química , Células HEK293 , Humanos , Fígado/metabolismo , Metformina/química
13.
Toxicol Appl Pharmacol ; 314: 55-62, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27871888

RESUMO

Cadmium (Cd) is an environmentally prevalent toxicant posing increasing risk to human health worldwide. As compared to the extensive research in Cd tissue accumulation, little was known about the elimination of Cd, particularly its toxic form, Cd ion (Cd2+). In this study, we aimed to examine whether Cd2+ is a substrate of multidrug and toxin extrusion proteins (MATEs) that are important in renal xenobiotic elimination. HEK-293 cells overexpressing the human MATE1 (HEK-hMATE1), human MATE2-K (HEK-hMATE2-K) and mouse Mate1 (HEK-mMate1) were used to study the cellular transport and toxicity of Cd2+. The cells overexpressing MATEs showed a 2-4 fold increase of Cd2+ uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (Km) of 130±15.8µM for HEK-hMATE1; 139±21.3µM for HEK-hMATE2-K; and 88.7±13.5µM for HEK-mMate1, respectively. Cd2+ could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC50) of 97.5±6.0µM, 20.2±2.6µM, and 49.9±6.9µM in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd2+ out of the HEK-hMATE1 cells, thus resulting in a significant decrease of Cd2+-induced cytotoxicity. The present study has provided the first evidence supporting that MATEs transport Cd2+ and may function as cellular elimination machinery in Cd intoxication.


Assuntos
Cádmio/metabolismo , Proteínas de Transporte de Cátions Orgânicos/fisiologia , Transporte Biológico , Cádmio/toxicidade , Células HEK293 , Humanos , Metformina/metabolismo , Metformina/farmacologia
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