Metabolic syndrome inhibits store-operated Ca2+ entry and calcium-induced calcium-release mechanism in coronary artery smooth muscle.
CONCLUSION AND IMPLICATIONS: The present manuscript provides evidence of impaired Ca2+ handling mechanisms in coronary arteries in metabolic syndrome where a decrease in both SOC entry and CICR mechanism but preserved vasoconstriction are reported in coronary arteries from obese Zucker rats. Remarkably, OZR CA VSM at this state of metabolic syndrome seemed to have developed a compensation mechanism for impaired CICR by overexpressing CaV1.2 channels. PMID: 32949582 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - September 16, 2020 Category: Drugs & Pharmacology Authors: Climent B, Santiago E, Sánchez A, Muñoz-Picos M, Pérez-Vizcaíno F, García-Sacristán A, Rivera L, Prieto D Tags: Biochem Pharmacol Source Type: research

Diphenyl diselenide alleviates diabetic peripheral neuropathy in rats with streptozotocin-induced diabetes by modulating oxidative stress.
This study aimed to evaluate its preventive and therapeutic effects on DPN in rats with streptozotocin (STZ)-induced diabetes and explore the underlying mechanisms. In vitro, RSC96 cells were exposed to high glucose (100 mM) and then treated with different concentrations of DPDs (1, 10, 25 and 50 μM). Notably, DPDs markedly suppressed high glucose-induced cytotoxicity and oxidative stress in Schwann cells by decreasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Furthermore, the DPDs treatment effectively activated Nrf2 signaling and inhibited Keap1 expression. An in vivo DPN model was established in...
Source: Biochemical Pharmacology - September 16, 2020 Category: Drugs & Pharmacology Authors: Wang X, Huan Y, Li C, Cao H, Sun S, Lei L, Liu Q, Liu S, Ji W, Liu H, Huang K, Zhou J, Shen Z Tags: Biochem Pharmacol Source Type: research

Fungal Mycotoxin Penisuloxazin A, A Novel C-terminal Hsp90 Inhibitor and Characteristics of Its Analogues on Hsp90 Function Related to Binding Sites.
Abstract Hsp90 is a promising drug target for cancer therapy. However, toxicity and moderate effect are limitations of current inhibitors owing to broad protein degradation. The fungal mycotoxin penisuloxazin A (PNSA) belongs to a new epipolythiodiketopiperazines (ETPs) possessing a rare 3H-spiro[benzofuran-2,2'-piperazine] ring system. PNSA bound to cysteine residues C572/C598 of CT-Hsp90 with disulfide bonds and inhibits Hsp90 activity, resulting in apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. We identified that analogues PEN-A and HDN-1 bound to C572/C597 and C572 of CT-Hsp90α res...
Source: Biochemical Pharmacology - September 16, 2020 Category: Drugs & Pharmacology Authors: Dai J, Zhu M, Qi X, Wang Y, Li H, Tang S, Wang Q, Chen A, Liu M, Gu Q, Li D, Li J Tags: Biochem Pharmacol Source Type: research

Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: non-genomic and genomic signaling.
Abstract Inflammation, an old medical problem, is being recognized as an active, well orchestrated biological process. When dysregulated, chronic inflammation may ensue, leading to tissue-dependent diseases. Depending upon the ligand and cellular context, aryl hydrocarbon receptor (AHR) may accelerate or attenuate inflammation and subsequent resolution. Three examples are discussed in which AHR modulates inflammation by a mixture of genomic and non-genomic signaling pathways: (i) AHR-agonistic bacterial virulence factors are leading to both microbial defense and resolution of inflammatory responses. (ii) TCDD-medi...
Source: Biochemical Pharmacology - September 14, 2020 Category: Drugs & Pharmacology Authors: Walter Bock K Tags: Biochem Pharmacol Source Type: research

Isoprenylcysteine carboxyl methyltransferase inhibitors exerts anti-inflammatory activity.
Abstract Isoprenylcysteine carboxylmethyltransferase (ICMT) has been reported to regulate the inflammatory response through the Ras/MAPK/AP-1 pathway. Nevertheless, the potential of ICMT inhibitors as therapeutic agents against inflammatory diseases has not been examined. Therefore, in this study, we investigated the anti-inflammatory properties of two ICMT inhibitors, cysmethynil (CyM) and 3-methoxy-N-[2-2,2,6,6-tetramethyl-4-phenyltetrahydropyran-4-yl)ethyl]aniline (MTPA), using in vitro analyses and in vivo analyses (lipopolysaccharide (LPS)/D-GalN-triggered hepatitis and DSS-induced colitis mouse models). CyM ...
Source: Biochemical Pharmacology - September 12, 2020 Category: Drugs & Pharmacology Authors: Seok Yang W, Gyung Kim H, Lee Y, Yoon K, Kim S, Hye Kim J, Youl Cho J Tags: Biochem Pharmacol Source Type: research

Triple therapy with pravastatin, low molecular weight heparin and low dose aspirin improves placental haemodynamics and pregnancy outcomes in obstetric antiphospholipid syndrome in mice and women through a nitric oxide-dependent mechanism.
CONCLUSION: LMWH+LDA+PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial. PMID: 32926874 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - September 11, 2020 Category: Drugs & Pharmacology Authors: Lefkou E, Varoudi K, Pombo J, Jurisic A, Jurisic Z, Contento G, Girardi G Tags: Biochem Pharmacol Source Type: research

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation.
Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation. Biochem Pharmacol. 2020 Sep 11;:114216 Authors: Sarnobat D, Moffett CR, Tanday N, Reimann F, Gribble FM, Flatt PR, I Tarasov A Abstract Gut incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance secretion of insulin in a glucose-dependent manner, predominantly by elevating cytosolic levels of cAMP in pancreatic β-cells. Successful targeting of the incretin pathway by several drugs, however, suggests the antidiabetic mechanism is li...
Source: Biochemical Pharmacology - September 11, 2020 Category: Drugs & Pharmacology Authors: Sarnobat D, Moffett CR, Tanday N, Reimann F, Gribble FM, Flatt PR, I Tarasov A Tags: Biochem Pharmacol Source Type: research

The inorganic polymer, polyphosphate, blocks binding of SARS-CoV-2 spike protein to ACE2 receptor at physiological concentrations.
ler WEG Abstract Inorganic polyphosphate (polyP) is a morphogenetically active and metabolic energy-delivering physiological polymer that is released from blood platelets. Here, we show that polyP efficiently inhibits the binding of the envelope spike (S)-protein of the coronavirus SARS-CoV-2, the causative agent of COVID-19, to its host cell receptor ACE2 (angiotensin-converting enzyme 2). To stabilize polyP against the polyP-degrading alkaline phosphatase, the soluble polymer was encapsulated in silica/polyP nanoparticles. Applying a binding assay, soluble Na-polyP (sizes of 40 Pi and of 3 Pi units) as well as s...
Source: Biochemical Pharmacology - September 6, 2020 Category: Drugs & Pharmacology Authors: Neufurth M, Wang X, Tolba E, Lieberwirth I, Wang S, Schröder HC, Müller WEG Tags: Biochem Pharmacol Source Type: research

Pitfalls and challenges of the purinergic signaling cascade in obesity.
te; P Abstract Obesity is a worldwide health problem which have reached pandemic proportions, now also including low and middle-income countries. Excessive or abnormal fat deposition in the abdomen especially in the visceral compartment is tightly associated with a high metabolic risk for arterial hypertension, type II diabetes, cardiovascular diseases, musculoskeletal disorders (especially articular degeneration) and some cancers. Contrariwise, accumulation of fat in the subcutaneous compartment has been associated with a neutral metabolic impact, favoring a lower risk of insulin resistance. Obesity results more ...
Source: Biochemical Pharmacology - September 6, 2020 Category: Drugs & Pharmacology Authors: de Oliveira M, Mathias LS, de Sibio MT, Noronha-Matos JB, Costa MA, Nogueira CR, Correia-de-Sá P Tags: Biochem Pharmacol Source Type: research

Cellular toxicity of the metabolic inhibitor 2-deoxyglucose and associated resistance mechanisms.
;on S Abstract Most malignant cells display increased glucose absorption and metabolism compared to surrounding tissues. This well-described phenomenon results from a metabolic reprogramming occurring during transformation, that provides the building blocks and supports the high energetic cost of proliferation by increasing glycolysis. These features led to the idea that drugs targeting glycolysis might prove efficient in the context of cancer treatment. One of these drugs, 2-deoxyglucose (2-DG), is a synthetic glucose analog that can be imported into cells and interfere with glycolysis and ATP generation. Its pre...
Source: Biochemical Pharmacology - September 2, 2020 Category: Drugs & Pharmacology Authors: Laussel C, Léon S Tags: Biochem Pharmacol Source Type: research

Esomeprazole reduces sperm motility index by targeting the spermic cholinergic machinery: A mechanistic study for the association between use of proton pump inhibitors and reduced sperm motility index.
rreh-Shori T Abstract Recent studies have linked prolonged use of the most commonly prescribed proton pump inhibitors (PPIs) with declined human sperm function and infertility. Here, we report for the first time the most plausible underlying mechanism for this unwarranted secondary mode of action. We followed up on a recent serendipitous discovery in our laboratory regarding PPIs' off-target action and performed detailed pharmacodynamic analyses by combining in silico and in vitro studies to determine the off-target effect of one of the most commonly used PPI, esomeprazole, on the key human acetylcholine biosynthe...
Source: Biochemical Pharmacology - August 28, 2020 Category: Drugs & Pharmacology Authors: Kumar A, Kumar R, Flanagan J, Långström B, Björndahl L, Darreh-Shori T Tags: Biochem Pharmacol Source Type: research

Design and pharmaceutical applications of proteolysis-targeting chimeric molecules.
Abstract Proteolysis-targeting chimeras (PROTACs), the hetero-bifunctional compounds containing a specific ligand to bind the target protein, a suitable linker, and an E3 ubiquitin ligase substrate, are being developed for therapeutic applications. PROTACs hijack the catalytic activity of ubiquitin E3 ligases to mediate proteasome dependent degradation of selected protein of interest (POI), by bringing the ligase and POI into close spatial proximity and initiating the poly-ubiquitination process. Compared to the traditional small-molecule drugs, PROTACs reduce the problems of dosage, drug resistance, side effects ...
Source: Biochemical Pharmacology - August 28, 2020 Category: Drugs & Pharmacology Authors: Liang Y, Nandakumar KS, Cheng K Tags: Biochem Pharmacol Source Type: research

A novel oral glucagon-like peptide 1 receptor agonist protects against diabetic cardiomyopathy via alleviating cardiac lipotoxicity induced mitochondria dysfunction.
Abstract Diabetic cardiomyopathy is one of the major cardiovascular complications of diabetes mellitus associated with left ventricular diastolic dysfunction. There are still no specific therapeutic guidelines for the disease. In recent years, glucagon-like peptide 1 receptor agonists were proved to exert cardioprotective effects in comprehensive studies. Therefore, we examined whether a new oral availably glucagon-like peptide 1 receptor agonist, oral hypoglycemic peptide 2 (OHP2), could protect against diabetic cardiomyopathy in high-fat diets and continuous streptozocin injection induced rat models. After treat...
Source: Biochemical Pharmacology - August 26, 2020 Category: Drugs & Pharmacology Authors: Qian P, Tian H, Wang Y, Lu W, Li Y, Ma T, Gao X, Yao W Tags: Biochem Pharmacol Source Type: research

Recognition of Nucleolin Through Interaction with RNA G-Quadruplex.
Abstract The development of novel biomarkers for early-stage diagnosis of prostate cancer (PCa) has attracted the attention of researchers in the last decade. Nucleolin (NCL) has emerged as a possible biomarker of PCa due to its high expression levels in the surface of PCa cells and affinity towards parallel G4s since it contains four RNA-binding domains (RBDs). Herein, we developed a novel strategy based on a microfluidic platform for the detection of NCL in biological samples, such as human plasma. The RNA G4 (rG4) sequence found in human precursor microRNA 92b (pre-miR-92b) was used as a molecular recognition p...
Source: Biochemical Pharmacology - August 26, 2020 Category: Drugs & Pharmacology Authors: Santos T, Miranda A, Paula Cabral Campello M, Paulo A, Salgado G, Cabrita EJ, Cruz C Tags: Biochem Pharmacol Source Type: research

Pharmacology and Therapeutic Potential of Venom Peptides.
PMID: 32857993 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 25, 2020 Category: Drugs & Pharmacology Authors: Robinson SD, Vetter I Tags: Biochem Pharmacol Source Type: research

Role of nitric oxide in the response to photooxidative stress in prostate cancer cells.
Abstract A continuous state of oxidative stress during inflammation contributes to the development of 25 % of human cancers. Epithelial and inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) that can damage DNA. ROS/RNS have biological implications in both chemoresistance and tumor recurrence. As several clinically employed anticancer drugs can generate ROS/RNS, we have addressed herein how inducible nitric oxide synthase and nitric oxide (iNOS/•NO) affect the molecular pathways implicated in the tumor response to oxidative stress. To mimic the oxidative stress associ...
Source: Biochemical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: D'Este F, Della Pietra E, Veronica Badillo Pazmay G, Xodo LE, Rapozzi V Tags: Biochem Pharmacol Source Type: research

Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection.
In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics. PMID: 32828803 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: Vigón L, Rodríguez-Mora S, Luna A, Sandonís V, Mateos E, Bautista G, Luis Steegmann J, Climent N, Plana M, Pérez-Romero P, de Ory F, Alcamí J, García-Gutierrez V, Planelles V, Rosa López-Huertas M, Coiras M Tags: Biochem Pharmacol Source Type: research

Proof that the high molecular weight immunophilin FKBP52 mediates the in vivo neuroregenerative effect of the macrolide FK506.
In this study it is demonstrated that FK506 shows efficient neurotrophic action in vitro and profound effects on the recovery of locomotor activity, behavioural features, and erectile function of mice that underwent surgical spinal cord injury. The recovery of the locomotor activity was studied in knock-out mice for either immunophilin, FKBP51 or FKBP52. The experimental evidence demonstrates that the neurotrophic actions of FK506 are the consequence of its binding to FKBP52, whereas FK506 interaction with the close-related partner immunophilin FKBP51 antagonises the function of FKBP52. Importantly, our study also demonstr...
Source: Biochemical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: Daneri-Becerra C, Patiño-Gaillez MG, Galigniana MD Tags: Biochem Pharmacol Source Type: research

A dual and conflicting role for imiquimod in inflammation: a TLR7 agonist and a cAMP phosphodiesterase inhibitor.
Abstract The Toll-like receptor 7 (TLR7) agonist imiquimod is an antitumor and antiviral drug used for the treatment of skin indications such as basal cell carcinoma, squamous cell carcinoma, and genital warts caused by the human papilloma virus. We show that imiquimod has TLR7-independent activity in which it directly inhibits phosphodiesterase (PDE), leading to cAMP increase, PKA-mediated CREB phosphorylation and subsequent CRE-dependent reporter transcription. The activation of the cAMP pathway by imiquimod is synergistically amplified by the β-adrenergic receptor agonist, isoproterenol. PDE inhibition is ...
Source: Biochemical Pharmacology - August 20, 2020 Category: Drugs & Pharmacology Authors: Ernst O, Failayev H, Athamna M, He H, Tsfadia Y, Zor T Tags: Biochem Pharmacol Source Type: research

Perillaldehyde: a promising antifungal agent to treat oropharyngeal candidiasis.
In this study, we show that PAE exhibits strong antifungal activity against C. albicans. Candida albicans, a fungal pathogen with high incidence of antifungal resistance in clinical settings, is the major cause of oropharyngeal candidiasis (OPC). OPC is characterized by inflammatory immunological responses to fungal infections. Our in vitro results show PAE inhibited several virulence attributes of C. albicans including biofilm formation, yeast-to-hyphal transition and SAPs (secreted aspartic proteinases) gene expression. Using an experimental murine model of OPC, we found that PAE inhibited NLRP3 inflammasome assembly, re...
Source: Biochemical Pharmacology - August 18, 2020 Category: Drugs & Pharmacology Authors: Chen L, Qu S, Yang K, Liu M, Li YX, Keller NP, Zeng X, Tian J Tags: Biochem Pharmacol Source Type: research

Aconitase 2 sensitizes MCF-7 cells to cisplatin eliciting p53-mediated apoptosis in a ROS-dependent manner.
Abstract Aconitase 2 (ACO2) belongs to the tricarboxylic acid (TCA) cycle, which represents a key metabolic hub for cellular metabolism that is frequently altered in cancer for satisfying bioenergetic and biosynthetic requirements of proliferating cells. The promotion of ACO2 activity in breast cancer cell lines was shown to slow down proliferation imposing a switch from aerobic glycolysis to oxidative metabolism. The alteration of metabolic pathways in cancer also impinges on the sensitivity to chemotherapeutic interventions. In this work, we evidence that the presence of ACO2 sensitizes cells to the treatment wi...
Source: Biochemical Pharmacology - August 18, 2020 Category: Drugs & Pharmacology Authors: Ciccarone F, De Falco P, Rosa Ciriolo M Tags: Biochem Pharmacol Source Type: research

The mechanisms of action of chromatin remodelers and implications in development and disease.
Abstract The eukaryotic genetic material is packaged in the form of chromatin by wrapping DNA around nucleosomes. Cells maintain chromatin in a dynamic state by utilising various ATP-dependent chromatin remodelling complexes which can induce structural transformations in chromatin. All chromatin remodelers contain an ATP hydrolysing-DNA translocase motor which facilitates nucleosomal DNA translocation. By DNA translocation ISWI and CHD subfamily remodelers slide nucleosomes and arrange them in a regularly spaced array. While SWI/SNF subfamily remodelers evict or displace nucleosomes from chromatin which promotes a...
Source: Biochemical Pharmacology - August 14, 2020 Category: Drugs & Pharmacology Authors: Sahu RK, Singh S, Tomar RS Tags: Biochem Pharmacol Source Type: research

PXR Phosphorylated at Ser350 transduces a glucose signal to repress the estrogen sulfotransferase gene in human liver cells and fasting signal in mouse livers.
Abstract Hepatic estrogen sulfotransferase (SULT1E1), the enzyme that inactivates estrogen, regulates metabolic estrogen homeostasis. Here, we have demonstrated how nuclear receptor PXR regulated the SULT1E1 gene in response to glucose in human hepatoma-derived cells and in response to fasting in mouse livers. The SULT1E1 gene was activated by a nuclear receptor HNF4α-ROR α complex binding on an upstream enhancer of the SULT1E1 promoter in cells cultured in high glucose medium [1]. The SULT1E1 gene was repressed in cells cultured in low glucose medium, in which PXR was phosphorylated at Ser350 by vacci...
Source: Biochemical Pharmacology - August 13, 2020 Category: Drugs & Pharmacology Authors: Hu H, Yokobori K, Negishi M Tags: Biochem Pharmacol Source Type: research

Inhibitors of DNA Double-Strand Break Repair at the Crossroads of Cancer Therapy and Genome Editing.
Abstract Conventional cancer treatment modalities such as radiation and chemotherapy, cause cancer cell death by inducing DNA damage, particularly DNA strand breaks. Over the years, newer avenues have emerged for overcoming radio/chemoresistance by harnessing repair proteins as targets for small molecule inhibitors. Analysis of genome-wide expression data in cancer subtypes and understanding synthetic lethal interactions among repair pathways are important stepping-stones. Several inhibitors targeting DNA strand break repair proteins have yielded good effects in preclinical studies, and have the potential to be de...
Source: Biochemical Pharmacology - August 13, 2020 Category: Drugs & Pharmacology Authors: Ray U, Raghavan SC Tags: Biochem Pharmacol Source Type: research

P2X7 receptor antagonism preserves retinal ganglion cells in glaucomatous mice.
Abstract To investigate the role of P2X7 receptor to preserve retinal ganglion cells (RGCs) structure and function in a genetic mouse model (DBA/2J mouse) of age-related glaucomatous neurodegeneration. Chronic treatment with P2X7 receptor antagonist eye drops was carried out in order to assess RGCs function and density by pattern electroretinogram (PERG) and RBPMS immunostaining, respectively. Further, microglia activation was assessed in flat-mounted retina by using Iba-1 immunostaining. Untreated glaucomatous eyes displayed significant microglia activation, alteration of PERG signal, and RGCs loss. In the P2X7 r...
Source: Biochemical Pharmacology - August 13, 2020 Category: Drugs & Pharmacology Authors: Romano GL, Amato R, Lazzara F, Porciatti V, Chou TH, Drago F, Bucolo C Tags: Biochem Pharmacol Source Type: research

The BCL-2 family members NOXA and BIM mediate fluorizoline-induced apoptosis in multiple myeloma cells.
In this study, we have assessed the pro-apoptotic effect of fluorizoline in 3 different multiple myeloma cell lines and 12 primary samples obtained from treatment-naïve multiple myeloma patients. Fluorizoline induced apoptosis in both multiple myeloma cell lines and primary samples at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline. Moreover, fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. Finally, NOXA-depletion by CRISPR/Cas9 in cells that do not express BIM conferred resis...
Source: Biochemical Pharmacology - August 13, 2020 Category: Drugs & Pharmacology Authors: Cosialls AM, Sánchez-Vera I, Pomares H, Perramon-Andújar J, Sanchez-Esteban S, Palmeri CM, Iglesias-Serret D, Saura-Esteller J, Núñez-Vázquez S, Lavilla R, González-Barca EM, Pons G, Gil J Tags: Biochem Pharmacol Source Type: research

MiR-23a-5p exacerbates intestinal ischemia-reperfusion injury by promoting oxidative stress via targeting PPAR alpha.
Abstract MiR-23a-5p is involved in the occurrence and development of some serious diseases, but its effects on intestinal ischemia-reperfusion (II/R) injury is unclear. In this research, the hypoxia/reoxygenation (H/R) model on IEC-6 cells and II/R model in mice were used. The data showed that the ROS level in model group was significantly increased compared with control group. The level of intestinal MPO was increased and serum SOD was decreased in mice compared with sham group. Moreover, the expression levels of miR-23a-5p in model groups were obviously increased in vitro and in vivo, while the expression levels...
Source: Biochemical Pharmacology - August 12, 2020 Category: Drugs & Pharmacology Authors: Li LX, Yin LH, Gao M, Xu LN, Qi Y, Peng JY Tags: Biochem Pharmacol Source Type: research

Antisense Drug Discovery and Development Technology Considered in a Pharmacological Context.
Abstract When coined, the term "antisense" included oligonucleotides of any structure, with any chemical modification and designed to work through any post-RNA hybridization mechanism. However, in practice the term "antisense" has been used to describe single stranded oligonucleotides (ss ASOs) designed to hybridize to RNAswhile the term "siRNA" has come to mean double stranded oligonucleotides designed to activate Ago2. However, the two approaches share many common features. The medicinal chemistry developed for ASOs greatly facilitated the development of siRNA technology and remains...
Source: Biochemical Pharmacology - August 12, 2020 Category: Drugs & Pharmacology Authors: Crooke ST, Liang XH, Crooke RM, Baker BF, Geary RS Tags: Biochem Pharmacol Source Type: research

Activation of AMPK/aPKC ζ/CREB pathway by metformin is associated with upregulation of GDNF and dopamine.
Activation of AMPK/aPKCζ/CREB pathway by metformin is associated with upregulation of GDNF and dopamine. Biochem Pharmacol. 2020 Aug 12;:114193 Authors: Katila N, Bhurtel S, Park PH, Hong JT, Choi DY Abstract Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to a decrease in striatal dopamine. There is no antiparkinsonian therapy that offers a true disease-modifying treatment till date and there is an urgent need for a safe and effective neuroprotective or neuroresto...
Source: Biochemical Pharmacology - August 12, 2020 Category: Drugs & Pharmacology Authors: Katila N, Bhurtel S, Park PH, Hong JT, Choi DY Tags: Biochem Pharmacol Source Type: research

MicroRNA-101 inhibits cadmium-induced angiogenesis by targeting cyclooxygenase-2 in primary human umbilical vein endothelial cells.
Abstract Exposure to toxic metal contaminants, such as cadmium complexes (Cd2+), has been shown to induce adverse effects on various organs and tissues. In particular, blood vessels are severely impacted by Cd2+ exposure, which may lead to cardiovascular diseases (CVDs). According to previous studies, CVDs are associated with increased cyclooxygenase 2 (COX-2) levels. However, the mechanisms by which CdCl2-induced COX-2 overexpression leads to cardiovascular dysfunction remain unclear. Herein, we show that the relative gene expressions of VEGF and PTGS2 (COX-2 encoding gene) are positively correlated in CVDs patie...
Source: Biochemical Pharmacology - August 9, 2020 Category: Drugs & Pharmacology Authors: Che L, Wu ZL, Huang LY, Wu JS, Du ZB, Lin JX, Su YH, Chen XX, Lin ZN, Lin YC Tags: Biochem Pharmacol Source Type: research

Histone deacetylases inhibitors as new potential drugs against Leishmania braziliensis, the main causative agent of New World Tegumentary Leishmaniasis.
va-Júnior A, de Souza Vasconcellos R, Márcia Suarez-Fontes A, Almeida-Silva J, André Vannier-Santos M, Pierce R, Sippl W, Lopes Rangel Fietto J Abstract The protozoan parasite Leishmania braziliensis is a major causative agent of the neglected tropical diseases Cutaneous and Mucocutaneous Leishmaniases in the New World. There are no vaccines to prevent the infection and the treatment relies on few drugs that often display high toxicity and costs. Thus, chemotherapeutic alternatives are required. Histone Deacetylases (HDACs) are epigenetic enzymes involved in the control of chromatin structure....
Source: Biochemical Pharmacology - August 7, 2020 Category: Drugs & Pharmacology Authors: Ângelo de Souza L, Silva E Bastos M, de Melo Agripino J, Souza Onofre T, Fanny Apaza Calla L, Heimburg T, Ghazy E, Bayer T, Hugo Ferraz da Silva V, Dutra Ribeiro P, Licursi de Oliveira L, Costa Bressan G, Rogéria de Almeida Lamêgo M, Silva-Júnior A, d Tags: Biochem Pharmacol Source Type: research

Pharmacokinetics and Drug Metabolism Expression of functional sulfotransferases (SULT) 1A1, 1A3, 1B1, 1C2, 1E1, and 2A1 in common marmosets.
In this study, marmoset SULT1A1, 1A3, 1B1, 1C2, 1E1, and 2A1 cDNAs were isolated and characterized, based on genome data. The deduced amino acid sequences of these marmoset SULT cDNAs had high identities (90-95%) with their human orthologs, except for marmoset SULT2A1, which was only 81% identical to human SULT2A1 cDNA. The amino acid sequences of the orthologs of these six SULTs in marmosets, monkeys, and humans were closely clustered in a phylogenetic tree. The structures and genomic organizations of marmoset SULT genes were similar to those of their human orthologs. Among the five marmoset tissues analyzed, SULT mRNAs s...
Source: Biochemical Pharmacology - August 5, 2020 Category: Drugs & Pharmacology Authors: Uno Y, Uehara S, Murayama N, Shimizu M, Yamazaki H Tags: Biochem Pharmacol Source Type: research

Angiotensin-(1-9) prevents vascular remodeling by decreasing vascular smooth muscle cell dedifferentiation through a FoxO1-dependent mechanism.
Abstract The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1-9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1-9), with special focus on the contr...
Source: Biochemical Pharmacology - August 5, 2020 Category: Drugs & Pharmacology Authors: Norambuena-Soto I, Paz Ocaranza M, Cancino-Arenas N, Sanhueza-Olivares F, Villar-Fincheira P, Leiva-Navarrete S, Mancilla C, Moya J, Novoa U, Jalil JE, Castro PF, Lavandero S, Chiong M Tags: Biochem Pharmacol Source Type: research

Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics.
Abstract Among the more promising treatments proposed for Alzheimer's disease (AD) and Parkinson's disease (PD) are those reducing brain insulin resistance. The antidiabetics in the class of incretin receptor agonists (IRAs) reduce symptoms and brain pathology in animal models of AD and PD, as well as glucose utilization in AD cases and clinical symptoms in PD cases after their systemic administration. At least 9 different IRAs are showing promise as AD and PD therapeutics, but we still lack quantitative data on their relative ability to cross the blood-brain barrier (BBB) reaching the brain parenchyma. We consequ...
Source: Biochemical Pharmacology - August 2, 2020 Category: Drugs & Pharmacology Authors: Salameh TS, Rhea EM, Talbot K, Banks WA Tags: Biochem Pharmacol Source Type: research

Resolvin E1 protects against doxorubicin-induced cardiotoxicity by inhibiting oxidative stress, autophagy and apoptosis by targeting AKT/mTOR signaling.
In conclusion, RvE1 protected against DOX-induced cardiotoxicity via the regulation of AKT/mTOR signaling. PMID: 32750329 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 1, 2020 Category: Drugs & Pharmacology Authors: Zhang J, Wang M, Ding W, Zhao M, Ye J, Xu Y, Wang Z, Ye D, Li D, Liu J, Wan J Tags: Biochem Pharmacol Source Type: research

Globular adiponectin antagonizes leptin-induced growth of cancer cells by modulating inflammasomes activation: Critical role of HO-1 signaling.
Abstract Accumulating evidence suggests that adipokines, a group of hormones secreted from adipose tissue, modulate tumor growth in a complicated manner. Among diverse adipokines, adiponectin exerts potent anti-tumor activities, whereas leptin exhibits pro-tumorigenic properties. Herein, we have examined the opposing effect of adiponectin on leptin-induced growth of cancer cells and investigated the underlying mechanisms, particularly in the context of inflammasomes activation, which plays a role in the growth of cancer cells. Globular adiponectin (gAcrp) significantly suppressed leptin-induced growth of human bre...
Source: Biochemical Pharmacology - July 31, 2020 Category: Drugs & Pharmacology Authors: Kumar Raut P, Park PH Tags: Biochem Pharmacol Source Type: research

COVID-19: An overview of the current pharmacological interventions, vaccines, and clinical trials.
Abstract COVID-19, the greatest public health emergency of the 21st century, has affected 215 countries and territories around the world resulting in 15,151,738 confirmed cases and 621,121 deaths. The outbreak has continued at breakneck pace despite stringent public health measures, ravaging the global economy and causing profound human casualties. Vaccination is currently the best bet for the prevention of COVID-19. Still, in its absence, there has been considerable interest in repurposing existing therapeutic agents to reduce the severity of the illness and ease the burden on the already strained healthcare syst...
Source: Biochemical Pharmacology - July 30, 2020 Category: Drugs & Pharmacology Authors: Chakraborty R, Parvez S Tags: Biochem Pharmacol Source Type: research

Roles of Lys191 and Lys179 in regulating thermodynamic binding forces of ligands to determine their binding affinity for human histamine H1 receptors.
In this study, we evaluated the roles of Lys1915.39 and Lys179ECL2 in regulating the thermodynamic binding forces of non-carboxylated and carboxylated antihistamines that determine their binding affinity for human H1 receptors. The binding enthalpy and entropy of the 3 sets of non-carboxylated and corresponding carboxylated antihistamines (doxepin and olopatadine, desloratadine and loratadine, and terfenadine and fexofenadine, respectively) were estimated using the van't Hoff equation with the dissociation constants obtained from the displacement curves of the non-carboxylated and carboxylated antihistamines against the bi...
Source: Biochemical Pharmacology - July 29, 2020 Category: Drugs & Pharmacology Authors: Kobayashi C, Tanaka A, Yasuda T, Hishinuma S Tags: Biochem Pharmacol Source Type: research

Vitamin K3 chloroderivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis and inhibits aggresome formation in hepatocellular carcinoma cells.
In this study, we identified one out of six vitamin K3 derivatives, VKT-2, as HDAC6 inhibitor using molecular docking and cell viability assays in HDAC6-overexpressing HuH-7 cancer cells. Microscale thermophoresis and HDAC6 enzymatic assays revealed that VKT-2 bound to HDAC6 and inhibited its function. We further identified its cytotoxic activity. VKT-2 hyperacetylated HDAC6 substrates and disturbed tubulin integrity leading to significant inhibition of tumor migration in both HuH-7 spheroids and U2OS-GFP-α-tubulin cells. Moreover, VKT-2 induced autophagic and apoptotic cell death in HuH-7, while aggresome formation ...
Source: Biochemical Pharmacology - July 25, 2020 Category: Drugs & Pharmacology Authors: Dawood M, Hegazy MF, Elbadawi M, Fleischer E, Klinger A, Bringmann G, Kuntner C, Shan L, Efferth T Tags: Biochem Pharmacol Source Type: research

Histamine H4 receptor agonists induce epithelial-mesenchymal transition events and enhance mammosphere formation via Src and TGF- β signaling in breast cancer cells.
In this study we proposed to investigate the effects of H4R ligands on EMT and mammosphere formation as a surrogate assay for cancer stem cells in breast cancer cells with different invasive phenotype. We also investigated the participation of Src and TGF-β signaling in these events. Breast cancer cells were treated with the H4R agonists Clobenpropit, VUF8430 and JNJ28610244 and the H4R antagonist JNJ7777120. Immunodetection studies showed cytoplasmic E-cadherin, cytoplasmic and nuclear beta-catenin, nuclear Slug and an increase in vimentin and α-smooth muscle actin expression. There was also an enhancement in c...
Source: Biochemical Pharmacology - July 25, 2020 Category: Drugs & Pharmacology Authors: Galarza TE, Delgado MAT, Mohamad NA, Martín GA, Cricco GP Tags: Biochem Pharmacol Source Type: research

Dehydrodieugenol improved lung inflammation in an asthma model by inhibiting the STAT3/SOCS3 and MAPK pathways.
CONCLUSION: The obtained data demonstrate, for the first time, that dehydrodieugenol was more effective than eugenol in counteracting allergic airway inflammation in mice, especially its inhibition of the JNK, p38 and ERk1/2, components of MAPK pathway. Therefore, dehydrodieugenol can be considered a prototype for the development of new and effective agents for the treatment of asthmatic patients. PMID: 32717226 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - July 24, 2020 Category: Drugs & Pharmacology Authors: Santana FPR, Silva RCD, Ponci V, Pinheiro AJMCR, Olivo CR, Caperuto LC, Arantes-Costa FM, Claudio SR, Ribeiro DA, Tibério IFLC, Lima-Neto LG, Lago JHG, Prado CM Tags: Biochem Pharmacol Source Type: research

Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells.
Abstract Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentra...
Source: Biochemical Pharmacology - July 24, 2020 Category: Drugs & Pharmacology Authors: Srinivasan MP, Bhopale KK, Caracheo AA, Amer SM, Khan S, Kaphalia L, Loganathan G, Balamurugan AN, Kaphalia BS Tags: Biochem Pharmacol Source Type: research

From Fatty Hepatocytes to Impaired Bile Flow: Matching Model Systems for Liver Biology and Disease.
Abstract A large variety of model systems are used in hepatobiliary research. In this review, we aim to provide an overview of established and emerging models for specific research questions. We specifically discuss the value and limitations of these models for research on metabolic associated fatty liver disease (MAFLD), (previously named non-alcoholic fatty liver diseases/non-alcoholic steatohepatitis (NAFLD/NASH)) and cholestasis-related diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). The entire range of models is discussed varying from immortalized cell lines, matur...
Source: Biochemical Pharmacology - July 24, 2020 Category: Drugs & Pharmacology Authors: Kunst RF, Niemeijer M, van der Laan LJW, Spee B, van de Graaf SFJ Tags: Biochem Pharmacol Source Type: research

TGF- β1-induced miR-424 promotes pulmonary myofibroblast differentiation by targeting Slit2 protein expression.
The objective of this study was to define the pro-fibrotic roles and mechanisms of miRs in TGF-β1-induced pulmonary myofibroblast differentiation. Using RNA sequencing, we identified miR-424 as an important TGF-β1-induced miR in human lung fibroblasts (HLFs). Quantitative RT-PCR confirmed that miR-424 expression was increased by 2.6-fold in HLFs in response to TGF-β1 and was 1.7-fold higher in human fibrotic lung tissues as compared to non-fibrotic lung tissues. TGF-β1-induced upregulation of miR-424 was blocked by the Smad3 inhibitor SIS3, suggesting the involvement of this canonical TGF-β1 signal...
Source: Biochemical Pharmacology - July 23, 2020 Category: Drugs & Pharmacology Authors: Huang Y, Xie Y, Abel PW, Wei P, Plowman J, Toews ML, Strah H, Siddique A, Bailey KL, Tu Y Tags: Biochem Pharmacol Source Type: research

Metabolomic insights into the mode of action of natural products in the treatment of liver disease.
Abstract The human population is burdened by morbidity and mortality from liver diseases that largely arise due to hepatitis virus infection, alcohol abuse, obesity, and diabetes. Despite 2 million global deaths per annum from liver disease, the number of drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of these disorders is sparse. Eastern medicine embodies a millennia long tradition in the use of natural product remedies for liver disease, which has attracted the interest of western medical practitioners and patients alike. Questions remain regarding the safety, efficacy, and quali...
Source: Biochemical Pharmacology - July 22, 2020 Category: Drugs & Pharmacology Authors: Beyoğlu D, Idle JR Tags: Biochem Pharmacol Source Type: research

Approaching Coronavirus Disease 2019: mechanisms of action of repurposed drugs with potential activity against SARS-CoV-2.
Abstract On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) a global pandemic. As of July 2020, SARS-CoV-2 has infected more than 14 million people and provoked more than 590,000 deaths, worldwide. From the beginning, a variety of pharmacological treatments has been empirically used to cope with the life-threatening complications associated with Corona Virus Disease 2019 (COVID-19). Thus far, only a couple of them and not consistently across reports have been shown to further decrease mortality, respect to what can be achieved ...
Source: Biochemical Pharmacology - July 22, 2020 Category: Drugs & Pharmacology Authors: Lisi L, Lacal PM, Barbaccia ML, Graziani G Tags: Biochem Pharmacol Source Type: research

Snake three-finger α-neurotoxins and nicotinic acetylcholine receptors: molecules, mechanisms and medicine.
Snake three-finger α-neurotoxins and nicotinic acetylcholine receptors: molecules, mechanisms and medicine. Biochem Pharmacol. 2020 Jul 22;:114168 Authors: Nirthanan S Abstract Snake venom three-finger α-neurotoxins (α-3FNTx) act on postsynaptic nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ) to produce skeletal muscle paralysis. The discovery of the archetypal α-bungarotoxin (α-BgTx), almost six decades ago, exponentially expanded our knowledge of membrane receptors and ion channels. This included the localisation, isolation and characteriz...
Source: Biochemical Pharmacology - July 22, 2020 Category: Drugs & Pharmacology Authors: Nirthanan S Tags: Biochem Pharmacol Source Type: research

The indirubin derivative 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference.
z O Abstract Indirubin is a natural bis-indole alkaloid contained as active ingredient in the traditional Chinese remedy Danggui Longhui Wan. Indirubin and its 3́-oxime derivatives exhibit anti-cancer and anti-inflammatory properties and they inhibit glycogen synthase kinase (GSK)-3 in cell-free assays where 6-bromoindirubin-3́-oxime (6BIO) is among the most potent analogs. Here, we reveal 6-bromoindirubin-3́-glycerol-oxime ether (6BIGOE) as highly potent derivative able to inhibit pro-inflammatory cytokine, chemokine and prostaglandin (PG) release in human primary monocytes while increasing anti-inflammatory i...
Source: Biochemical Pharmacology - July 22, 2020 Category: Drugs & Pharmacology Authors: Czapka A, König S, Pergola C, Grune C, Vougogiannopoulou K, Skaltsounis AL, Fischer D, Werz O Tags: Biochem Pharmacol Source Type: research

Alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of JNK pathway.
Abstract Naphthoquinone derivatives and metabolites are widely dispersed molecules in nature. Alkannin, a natural naphthoquinone compound, induces excellent cytotoxicity in cancer cells. However, the detailed mechanism by which alkannin inhibits cancer cell survival remains unclear. In the present study, we isolated alkannin from Arnebia euchroma and found that alkannin induced cytotoxic autophagy and apoptosis in many types of cancer cells in a dose-dependent manner. Alkannin treatment resulted in elevated accumulation of intracellular reactive oxygen species (ROS), leading to mitochondrial membrane potential los...
Source: Biochemical Pharmacology - July 20, 2020 Category: Drugs & Pharmacology Authors: Zheng Q, Li Q, Zhao G, Zhang J, Yuan H, Gong D, Guo Y, Liu X, Li K, Lin P Tags: Biochem Pharmacol Source Type: research

Inhibition of type 4 cAMP-phosphodiesterases (PDE4s) in mice induces hypothermia via effects on behavioral and central autonomous thermoregulation.
We report here that treatment with a number of distinct PDE4 inhibitors, including Rolipram, Piclamilast, Roflumilast and RS25344, but not treatment with the PDE3-selective inhibitor Cilostamide, induces a rapid (10-30 min), substantial (-5°C) and long-lasting (up to 5 h) decrease in core body temperature of C57BL/6 mice; thus, identifying a critical role of PDE4 also in the regulation of body temperature. As little as 0.04 mg/kg of the archetypal PDE4 inhibitor Rolipram induces hypothermia. As similar or higher doses of Rolipram were used in a majority of published animal studies, most of the reported findings are lik...
Source: Biochemical Pharmacology - July 20, 2020 Category: Drugs & Pharmacology Authors: McDonough W, Rich J, Aragon IV, Saleh LA, Boyd A, Richter A, Koloteva A, Richter W Tags: Biochem Pharmacol Source Type: research