L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice.

Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin.

Effect of 7-ketocholesterol incorporation on substrate binding affinity and turnover rate of the organic cation transporter 2 (OCT2).

The organic cation transporter 2 (OCT2) is pivotal in the renal elimination of several positively charged molecules. OCT2 mode of transport is profoundly influenced by the level of membrane cholesterol. The aim of this study was to investigate the effect of oxidized cholesterol on OCT2 transport activity in human embryonic kidney 293 cells stably transfected with OCT2 (OCT2-HEK293) and in primary renal proximal tubular epithelial cells (RPTEC).

Association Between Gadoxetic Acid-Enhanced Magnetic Resonance Imaging, Organic Anion Transporters, and Farnesoid X Receptor in Benign Focal Liver Lesions.

The organic anion uptake and efflux transporters [organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and multidrug resistance-associated protein (MRP)2 and MRP3] that mediate the transport of the hepatobiliary-specific contrast agent gadoxetate (Gd-EOB-DTPA) are direct or indirect targets of the farnesoid X receptor (FXR), a key regulator of bile acid and lipid homeostasis. In benign liver tumors, FXR expression and activation is not yet characterized. We investigated the expression and activation of FXR and its targets in hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) and their correlation with Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI).

Plasma Sphingoid Base Profiles of Patients Diagnosed with Intrinsic or Idiosyncratic Drug-induced Liver Injury.

Sphingolipids are exceptionally diverse, comprising hundreds of unique species. The bulk of circulating sphingolipids are synthesized in the liver, thereby plasma sphingolipid profiles represent reliable surrogates of hepatic sphingolipid metabolism and content. As changes in plasma sphingolipid content have been associated to exposure to drugs inducing hepatotoxicity both in vitro and in rodents, in the present study the translatability of the preclinical data was assessed by analyzing the plasma of patients with suspected drug-induced liver injury (DILI) and control subjects.

The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) decisively contributed in revolutionizing the therapeutic approach to cancer, offering non-invasive, tolerable therapies for a better quality of life. Nonetheless, degree and duration of the response to TKI therapy vary depending on cancer molecular features, the ability of developing resistance to the drug, on pharmacokinetic alterations caused by germline variants and unwanted drug-drug interactions at the level of membrane transporters and metabolizing enzymes. A great deal of approved TKIs are inhibitors of the organic cation transporters (OCTs).

From the Streets to the Judicial Evidence: Determination of Traditional Illicit Substances in Drug Seizures by a Rapid and Sensitive UHPLC-MS/MS-Based Platform.

According to the 2021 World Drug Report, around 275 million people use drugs of abuse, and 36 million people suffer from addiction, fostering a thriving market for illicit substances. In Italy, 30,083 people were reported to the Judicial Authority for offenses in violation of the Italian Law D.P.

The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity.

The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses.

Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth.

Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth.

Novel, User-Friendly Experimental and Analysis Strategies for Fast Voltammetry: Next Generation FSCAV with Artificial Neural Networks.

Fast-scan adsorption-controlled voltammetry (FSCAV) was recently derived from fast-scan cyclic voltammetry to estimate the absolute concentrations of neurotransmitters by using the innate adsorption properties of carbon fiber microelectrodes. This technique has improved our knowledge of serotonin dynamics . However, the analysis of FSCAV data is laborious and technically challenging.

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study.

Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke.

The Role of NF-kB in the Downregulation of Organic Cation Transporter 2 Expression and Renal Cation Secretion in Kidney Disease.

Organic cation transporter 2 (OCT2), encoded by the gene, is the main cation transporter on the basolateral membrane of proximal tubular cells. OCT2 facilitates the entry step of the vectorial transport of most cations from the peritubular space into the urine. OCT2 downregulation in kidney disease models is apparent, yet not clear from a mechanistic vantage point.

Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome.

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.

Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells.

The role of cholesterol recognition (CARC/CRAC) mirror codes in the allosterism of the human organic cation transporter 2 (OCT2, SLC22A2).

The human organic cation transporter 2 (OCT2) is a multispecific transporter with cholesterol-dependent allosteric features. The present work elucidates the role of evolutionarily conserved cholesterol recognition/interaction amino acid consensus sequences (CRAC and CARC) in the allosteric binding to 1-methyl-4-phenylpyridinium (MPP) in human embryonic kidney 293 cells stably or transiently expressing OCT2. Molecular blind simulations docked two mirroring cholesterol molecules in the 5th putative transmembrane domain, where a CARC and a CRAC sequence lie.

The Role of the Carnitine/Organic Cation Transporter Novel 2 in the Clinical Outcome of Patients With Locally Advanced Esophageal Carcinoma Treated With Oxaliplatin.

Esophageal cancer is the ninth most common malignancy worldwide, ranking sixth in mortality. Platinum-based chemotherapy is commonly used for treating locally advanced esophageal cancer, yet it is ineffective in a large portion of patients. There is a need for reliable molecular markers with direct clinical application for a prospective selection of patients who can benefit from chemotherapy and patients in whom toxicity is likely to outweigh the benefit.

Sensing the virus. How social capital enhances hoteliers' ability to cope with COVID-19.

In this study, we propose a broad conceptual model that incorporates social capital dimensions and problem-solving routines to understand the determinants behind hotel managements' perception of and ability to cope with the COVID-19 pandemic-and thus, to innovate their service offering. We provide empirical support for the notion that, due to uncertainty about reopening after lockdown, the hospitality sector has found existing problem-solving routines to be of little use. Although the local community has been unable to form a shared vision around the pandemic, hoteliers have nevertheless relied on their network of relationships to sense the crisis and find their own ways to adapt.

Cholesterol stimulates the cellular uptake of L-carnitine by the carnitine/organic cation transporter novel 2 (OCTN2).

The carnitine/organic cation transporter novel 2 (OCTN2) is responsible for the cellular uptake of carnitine in most tissues. Being a transmembrane protein OCTN2 must interact with the surrounding lipid microenvironment to function. Among the main lipid species that constitute eukaryotic cells, cholesterol has highly dynamic levels under a number of physiopathological conditions.

Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology.

Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1-3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6).

The Role of Mitochondria in Drug-Induced Kidney Injury.

The kidneys utilize roughly 10% of the body's oxygen supply to produce the energy required for accomplishing their primary function: the regulation of body fluid composition through secreting, filtering, and reabsorbing metabolites and nutrients. To ensure an adequate ATP supply, the kidneys are particularly enriched in mitochondria, having the second highest mitochondrial content and thus oxygen consumption of our body. The bulk of the ATP generated in the kidneys is consumed to move solutes toward (reabsorption) or from (secretion) the peritubular capillaries through the concerted action of an array of ATP-binding cassette (ABC) pumps and transporters.

Untargeted Metabolomics Reveals Anaerobic Glycolysis as a Novel Target of the Hepatotoxic Antidepressant Nefazodone.

Mitochondrial damage is considered a hallmark of drug-induced liver injury (DILI). However, despite the common molecular etiology, the evolution of the injury is usually unpredictable, with some cases that are mild and reversible upon discontinuation of the treatment and others characterized by irreversible acute liver failure. This suggests that additional mechanisms of damage play a role in determining the progression of the initial insult.

Application of IBM Watson to Support Literature Reviews: A Preliminary Experience in Restorative Dentistry.

Literature reviews are crucial in the choice of the best personalized material type and restauration type in restorative dentistry. We developed an IBM-Watson based system to support literature search for restorative dentistry, and compared its results to a literature search performed by a trained professional. We found that our system could assist the researcher in performing a literature review, but the grounding semantic model needs to be refined in order to provide more extensive results.

The anti-tumor activity of pralatrexate (PDX) correlates with the expression of RFC and DHFR mRNA in preclinical models of multiple myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy. While major advances have been made in the disease, it is still incurable. Although antifolate-based drugs are not commonly used to treat myeloma, new generation analogs with distinct patterns of preclinical and clinical activity may offer an opportunity to identify new classes of potentially active drugs.

Obeticholic Acid Ameliorates Valproic Acid-Induced Hepatic Steatosis and Oxidative Stress.

Farnesoid X receptor (FXR), or NR1H4, protects the liver from insults of various etiologies. A role of FXR in drug-induced liver injury has also been hypothesized yet only marginally investigated. The aim of this study was to assess the effect of FXR activation on gene expression and phenotype of the liver of mice treated with valproic acid (VPA), or 2-propylpentanoic acid, a prototypical hepatotoxic drug.