Journal of Pharmacology and Experimental Therapeutics

One cannot survive without regularly urinating and defecating. People with neurological injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool. Catheter-associated urinary tract infections frequently require hospitalization, while manual bowel programs are time-consuming (1-2 hours), stigmatizing, and cause rectal pain and discomfort...

Low efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door...

Organic anions (OA) are compounds including drugs or toxicants that are negatively charged at physiological pH and are typically transported by Organic Anion Transporters (OATs). Human OAT4 (SLC22A11) is expressed in the apical membrane of renal proximal tubules. Although there is no rodent ortholog of hOAT4, rodents express Oat5 (Slc22a19), an anion exchanger that is also localized to the apical membrane of renal proximal tubule cells. The purpose of this study was to determine the functional similarity between mouse Oat5 and human OAT4...

Delta opioid receptors hold potential as a target for neurological and psychiatric disorders, yet no delta opioid receptor agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the delta opioid receptor is nuclear. However, it is known that certain delta opioid receptor agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the SNC80/BW373U86 chemotype...

The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and ERK. The objective of this study was to generate ovarian cancer cells with genetically depleted PTP4A3; to assess their tumorigenicity; to examine their cellular phenotype; and to uncover changes in their intracellular signaling pathways and cytokine release profiles...

Invasive bacterial infections and sepsis are persistent global health concerns, complicated further by the escalating threat of antibiotic resistance. Over the past 40 years, collaborative endeavors to improve the diagnosis and critical care of septic patients have improved outcomes, yet grappling with the intricate immune dysfunction underlying the septic condition remains a formidable challenge. Anti-inflammatory interventions that exhibited promise in murine models failed to manifest consistent survival benefits in clinical studies through recent decades...

Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer and is associated with high probability of metastasis and poor prognosis. Chemotherapeutics and surgery remain the most common options for TNBC patients; however chemotherapeutic resistance and relapse of tumors limit the progression free survival and patient life span. This review provides an overview of recent chemotherapeutics that are in clinical trial, and the combination of drugs that are being investigated to overcome the drug resistance and to improve patient survival in different molecular subtypes of TNBCs...

Urologic Chronic Pelvic Pain Syndrome (UCPPS) is a painful chronic condition with persistent pain originating from the pelvis that often leads to detrimental lifestyle changes in the affected patients. The syndrome develops in both sexes, with an estimated prevalence of 5.7% to 26.6% worldwide. This narrative review summarizes currently recommended therapies for UCPPS, followed by the latest animal and clinical research advances in the field. The diagnosis of UCPPS by clinicians has room for improvement despite the changes in the past decade aiming to decrease the time to treatment...

Bromine domain protein 2 (BRD2), a member of the Bromodomain and extraterminal domain (BET) protein family, is a crucial epigenetic regulator with significant function in various diseases and cellular processes. The central function of BRD2 is modulating gene transcription by binding to acetylated lysine residues on histones and transcription factors. This review highlights key findings on BRD2 in recent years, emphasizing its roles in maintaining genomic stability, influencing chromatin spatial organization, and participating in transcriptional regulation...

There is controversy whether H1 -histamine receptors increase or decrease contractility in the mammalian heart. Therefore, we have generated mice that overexpress the human H1 -histamine receptor in the heart (H1 -TG). We hypothesized that histamine would either increase or decrease force of contraction and beating rate compared to littermate wild type mice (WT). In H1 -TG mice, we ascertained the presence of H1 -histamine receptors by autoradiography of atrium and ventricle using [3 H]mepyramine. The messenger RNA for human H1 -histamine-receptors was present in cardiac samples from H1 -TG and absent from WT...

DNA topoisomerase IIβ (TOP2β/180; 180 kDa) is a nuclear enzyme that regulates DNA topology by generation of short-lived DNA double-strand breaks primarily during transcription. TOP2β/180 can be a target for DNA damage-stabilizing anticancer drugs, whose efficacy is often limited by chemoresistance. Our laboratory previously demonstrated reduced levels of TOP2β/180 (and the paralog TOP2α/170) in an acquired etoposide-resistant K562 clonal cell line, K/VP.5 in part due to overexpression of microRNA-9-3p/5p impacting post-transcriptional events...

Adult-onset hypothyroidism impairs normal brain function. Research on animal models of hypothyroidism has revealed critical information on how deficiency of thyroid hormones impacts the electrophysiological and molecular functions of the brain, which lead to the well-known cognitive impairment in untreated hypothyroid patients. Currently, such information can only be obtained from experiments on animal models of hypothyroidism. This review summarizes important research findings that pertain to understanding the clinical cognitive consequences of hypothyroidism, which will provide a guiding path for therapy of hypothyroidism...

A problem for patients with diabetes is the rise of complications, such as peripheral neuropathy, nephropathy and retinopathy. Among them, peripheral neuropathy, characterized by numbness and/or hypersensitivity to pain in the extremities, is likely to develop in the early stages of diabetes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor, exerts hypoglycemic effects by preventing glucose reabsorption in proximal tubular cells. EMPA can improve cardiovascular and renal outcomes in diabetic patients, but its suppressive effect on the development of diabetic neuropathy remains unclear...

Hepatocellular carcinoma (HCC) is the predominant pathological type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an important player in the redox reaction of ethanol with endogenous aldehyde products released by lipid peroxidation...

The drug-drug interaction (DDI) between Amiodarone (AMIO) and Sofosbuvir (SOF), a direct-acting Hepatitis-C NS5B Nucleotide Polymerase Inhibitor, has been associated with severe bradyarrhythmia in patients. Recent Cryo-EM data has revealed that this DDI occurs at the α-subunit of L-type Cav channels (LTCC), with AMIO binding at the fenestration site and SOF (or MNI-1: analog of SOF) binding at the central cavity of the conductance pathway. In this study, we investigated the DDI between 21 AMIO analogs, including Dronedarone (DRON), and MNI-1 (or SOF) in hiPSC-CMs (human induced pluripotent stem cell-derived cardiomyocytes) and hCav1...

Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix (ECM) and progressive loss of nephron function, with a lack of effective treatment options in clinical practice. In this study, we discovered that the Beclin-1-derived peptide MP1 significantly inhibits the abnormal expression of fibrosis and Epithelial-mesenchymal transition (EMT)-related markers, including α-Smooth muscle actin (α-SMA), Fibronectin (FN), Collagen I (Col I), Matrix metallopeptidase 2 (MMP2), Snail1, and Vimentin (Vim) both in vitro and in vivo...

The benzimidazole opioids (BO, substituted nitazenes) are highly potent MOR agonists with heroin- or fentanyl-like effects. These compounds have caused hospitalizations and fatal overdoses. We characterized the in vitro pharmacology and structure-activity relationships of 19 nitazenes with substitutions at three positions of the benzimidazole core. Affinities were assessed using agonist radioligand binding assays at human mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) heterologously expressed in Chinese hamster ovary (CHO) cells...

The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2, and more recently also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy...

The organic anion transporting polypeptide (OATP) 2B1 (gene name SLCO2B1 ) is an uptake transporter that facilitates cellular accumulation of its substrates. In order to assess the in vivo relevance of the transporter, we applied SLCO2B1+/+ knock-in and Slco2b1-/- knock-out rats. A first pharmacological phenotyping with the OATP2B1 substrate-drug atorvastatin revealed reduced hepatic content and increased expression of rCYP3A1 in the humanized animals. It was the aim of this study to determine whether changes in metabolic activity affect the in vivo handling of the OATP2B1 and CYP3A1 substrate erlotinib, which is metabolized to OSI-420...

The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is hypoventilation that can be reversed by the µ-opioid receptor (MOR) antagonist naloxone; however, because of the very short duration of action of naloxone, re-emergence of MOR agonist-induced hypoventilation can occur, requiring additional doses of naloxone. The MOR antagonist methocinnamox (MCAM) antagonizes hypoventilation by the non-morphinan fentanyl and the morphinan heroin in laboratory animals with an unusually long duration of action...