Biochemical Pharmacology

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic kidney disease. Emerging research indicates that the Notch signaling pathway plays an indispensable role in the pathogenesis of numerous kidney diseases, including ADPKD. Herein, we identified that Notch3 but not other Notch receptors was overexpressed in renal tissues from mice with ADPKD and ADPKD patients. Inhibiting Notch3 with γ-secretase inhibitors, which block a proteolytic cleavage required for Notch3 activation, or shRNA knockdown of Notch3 significantly delayed renal cyst growth in vitro and in vivo...

Arrestins are key negative regulators of G Protein-Coupled Receptors (GPCRs) through mediation of G protein desensitisation and receptor internalisation. Arrestins can also contribute to signal transduction by scaffolding downstream signalling effectors for activation. GPCR kinase (GRK) enzymes phosphorylate the intracellular C-terminal domain, or intracellular loop regions of GPCRs to promote arrestin interaction. There are seven different GRK subtypes, which may uniquely phosphorylate the C-terminal tail in a type of 'phosphorylation barcode,' potentially differentially contributing to arrestin translocation and arrestin-dependent signalling...

GNEM (GNE Myopathy) is a rare neuromuscular disease caused due to biallelic mutations in sialic acid biosynthetic GNE enzyme (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine Kinase). Recently direct or indirect role of GNE in other cellular functions have been elucidated. Hyposialylation of IGF-1R leads to apoptosis due to mitochondrial dysfunction while hyposialylation of β1 integrin receptor leads to altered F-actin assembly, disrupted cytoskeletal organization and slow cell migration. Other cellular defects in presence of GNE mutation include altered ER redox state and chaperone expression such as HSP70 or PrdxIV...

The Fabkin complex, composed of FABP4, ADK, and NDPKs, emerges as a novel regulator of insulin-producing beta cells, offering promising prospects for diabetes treatment. Our approach, which combines literature review and database analysis, sets the stage for future research. These findings hold significant implications for both diabetes treatment and research, as they present potential therapeutic targets for personalized treatment, leading to enhanced patient outcomes and a deeper comprehension of the disease...

Agents that inhibit bromodomain and extra-terminal domain (BET) proteins have been actively tested in the clinic as potential anticancer drugs. NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy. In this study, we focus on the combination of BET inhibitors (BETis) and NAE inhibitors (NAEis) as a cancer therapeutic strategy and investigate its underlying mechanisms to explore and expand the application scope of both types of drugs...

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells...

Experimental and clinical research has reported beneficial effects of polyphenol intake on high prevalent diseases such as type 2 diabetes and obesity. These phytochemicals are ligands of taste 2 receptors (T2Rs) that have been recently located in a variety of organs and extra-oral tissues. Therefore, the interaction between polyphenol and T2Rs in brain structures can play a direct effect on appetite/satiety regulation and food intake. T2Rs are also expressed along the digestive tract, and their interaction with polyphenols can induce the release of gastrointestinal hormones (e...

Brusatol (Bru), a main extract from traditional Chinese medicine Brucea javanica, has been reported to exist antitumor effect in many tumors including melanoma. However, the underlying mechanism in its anti-melanoma effect still need further exploration. Here, we reported that the protein expression of KLF4 in melanoma cells were significantly downregulated in response to brusatol treatment. Overexpression of KLF4 suppressed brusatol-induced melanoma cell apoptosis; while knockdown of KLF4 enhanced antitumor effects of brusatol on melanoma cells not only in vitro but also in vivo...

Δ9-tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis. It is cleared predominantly via metabolism. Metabolism to 11-OH-THC by cytochrome P450 (CYP) 2C9 has been proposed as the main clearance pathway of THC, with the estimated fraction metabolized (fm ) about 70 %. The remaining clearance pathways are not well established, and it is unknown how THC is eliminated in individuals with reduced CYP2C9 activity. The goal of this study was to systematically identify the CYP enzymes contributing to THC clearance and characterize the metabolites formed...

Ovarian aging leads to infertility and birth defects. We aimed to clarify the role of Indole-3-carbinol (I3C) in resistance to oxidative stress, apoptosis, and fibrosis in ovarian aging. I3C was administered via intraperitoneal injection for 3 weeks in young or old mice. Immunohistochemistry; Masson, Sirius red, and TUNEL staining; follicle counting; estrous cycle analysis; and Western blotting were used for validating the protective effect of I3C against ovarian senescence. Human granulosa-like tumor cell line and primary granulosa cells were used for in vitro assay...

In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1β2γ2L γ-aminobutyric acid type A receptor (GABAA R), and the human voltage-gated N-type calcium channel (CaV 2.2 channel). Both compounds inhibited the nAChRs with the following receptor selectivity: α9α10 > α7 > α3β2 ≅ α3β4, indicating that β2/β4 subunits are relatively less important for their activity...

Recently published cryo-EM structures of human organic cation transporters of the SLC22 family revealed seven, sequentially arranged glutamic and aspartic acid residues, which may be relevant for interactions with positively charged substrates. We analyzed the functional consequences of removing those negative charges by creating D155N, E232Q, D382N, E390Q, E451Q, E459Q, and D478N mutants of OCT3. E232Q, E459Q, and D478N resulted in a lack of localization in the outer cell membrane and no relevant uptake activity...

Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in rat models of methamphetamine use disorder. Here, we report on the neurochemical and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3 H]dopamine uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over [3 H]dofetilide binding to hERG channels expressed by HEK293, suggesting relatively low potential for cardiotoxicity...

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Ischemic stroke is one of the leading causes of death and disability. Occlusion and reperfusion of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS) that contribute to brain cell death and dysfunction of the blood-brain barrier (BBB) via oxidative stress. BBB disruption influences the pathogenesis of ischemic stroke by contributing to cerebral edema, hemorrhagic transformation, and extravasation of circulating neurotoxic proteins. An improved understanding of mechanisms for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead to improved treatment paradigms for ischemic stroke...

Cardiac ATP production is tightly regulated in order to satisfy the evolving energetic requirements imposed by different cues during health and pathological conditions. In order to sustain high ATP production rates, cardiac cells are endowed with a vast mitochondrial network that is essentially acquired during the perinatal period. Nevertheless, adult cardiac cells also adapt their mitochondrial mass and oxidative function to changes in energy demand and substrate availability by fine-tuning the pathways and mitochondrial machinery involved in energy production...

Metabolic reprogramming underlies the etiology and pathophysiology of respiratory diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). The dysregulated cellular activities driving airway inflammation and remodelling in these diseases have reportedly been linked to aberrant shifts in energy-producing metabolic pathways: glycolysis and oxidative phosphorylation (OXPHOS). The rewiring of glycolysis and OXPHOS accompanying the therapeutic effects of many clinical compounds and natural products in asthma, IPF, and COPD, supports targeting metabolism as a therapeutic approach for respiratory diseases...

Despite the significant improvements made in breast cancer therapy during the last decades, this disease still has increasing incidence and mortality rates. Different targets involved in general processes, like cell proliferation and survival, have become alternative therapeutic options for this disease, with some of them already used in clinic, like the CDK4/6 inhibitors for luminal A tumors treatment. Nevertheless, there is a demand for novel therapeutic strategies focused not only on tumor cells, but also on their microenvironment...

The tripeptide glutathione (GSH) possesses two key structural features, namely the nucleophilic sulfur and the γ-glutamyl isopeptide bond. The former allows GSH to serve as a critical antioxidant and anti-electrophile. The latter allows GSH to translocate throughout the systemic circulation without being degraded. The kidneys exhibit several unique processes for handling GSH. This includes the extraction of 80% of plasma GSH, in part by glomerular filtration but mostly by transport across the basolateral plasma membrane...

Human Immunodeficiency virus (HIV) is known to cause cellular senescence and inflammation among infected individuals. While the traditional antiretroviral therapies (ART) have allowed the once fatal infection to be managed effectively, the quality of life of HIV patients on prolonged ART use is still inferior. Most of these individuals suffer from life-threatening comorbidities like chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and diabetes, to name a few. Interestingly, cellular senescence is known to play a critical role in the pathophysiology of these comorbidities as well...