RETRACTED: Zhou et al. Pyrvinium Treatment Confers Hepatic Metabolic Benefits via β-Catenin Downregulation and AMPK Activation. 2021, , 330.

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

Divergent Regulation of OCT and MATE Drug Transporters by Cadmium Exposure.

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 (Cd) increase the activities of OCTs while being a substrate of MATEs.

Pyrvinium Treatment Confers Hepatic Metabolic Benefits via β-Catenin Downregulation and AMPK Activation.

Genetic evidence has indicated that β-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 β-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.

Effects of Targeted Delivery of Metformin and Dental Pulp Stem Cells on Osteogenesis via Demineralized Dentin Matrix under High Glucose Conditions.

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.

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity.

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.

A Simulation Approach to Evaluate the Impact of Patterns of Bioanalytical Bias Difference on the Outcome of Pharmacokinetic Similarity Studies.

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 (bias ) between the similar products on the probability passing the PK similarity test.

Pyrazole-4-Carboxamide (YW2065): A Therapeutic Candidate for Colorectal Cancer via Dual Activities of Wnt/β-Catenin Signaling Inhibition and AMP-Activated Protein Kinase (AMPK) Activation.

Dysregulation of the Wnt/β-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.

The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway.

Low-density lipoprotein receptor-related protein 6 (LRP6) is an important coreceptor in the Wnt/β-catenin upstream signaling pathway. Rs2302685 is a common functional mutation of LRP6 that has been previously associated with reduced alcoholic liver injury among alcoholic liver disease (ALD) patients, and the present research was designed to study the underlying mechanisms of that finding. A total of 107 ALD patients and 138 non-ALD patients were recruited from hospitalized alcoholics in China.

Enhanced Tumor Selectivity of 5-Fluorouracil Using a Reactive Oxygen Species-Activated Prodrug Approach.

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

Triazole-Based Inhibitors of the Wnt/β-Catenin Signaling Pathway Improve Glucose and Lipid Metabolisms in Diet-Induced Obese Mice.

Wnt/β-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/β-catenin signaling inhibitors and assessed their effects on energy metabolism.

Novel hybrids derived from aspirin and chalcones potently suppress colorectal cancer and .

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.

Selective Inhibition on Organic Cation Transporters by Carvedilol Protects Mice from Cisplatin-Induced Nephrotoxicity.

Purpose: The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common.

Methods: The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1.

Novel cinnamaldehyde-based aspirin derivatives for the treatment of colorectal cancer.

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.

Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2.

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).

Multidrug and toxin extrusion proteins mediate cellular transport of cadmium.

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 (Cd). In this study, we aimed to examine whether Cd is a substrate of multidrug and toxin extrusion proteins (MATEs) that are important in renal xenobiotic elimination.