Role of G-protein-coupled estrogen receptor in the pathogenesis of chronic asthma.

BACKGROUND AND AIM: G protein-coupled estrogen receptor (GPER) is an estrogen receptor located on the plasma membrane. We previously reported that the administration of G-1, a GPER-specific agonist, suppressed development of acute ovalbumin (OVA)-induced asthma in a mouse model. Herein, we evaluate the involvement of GPER in a mouse model of chronic OVA asthma. METHODS: G-1 or saline was administered subcutaneously to BALB/c mice with chronic OVA asthma, and pathological and immunological evaluation was performed. In addition, Foxp3-expressing CD4-positive T-cells in the spleen and ILC2 in the lungs were measured using flow cytometry. RESULTS: We observed a significant decrease in the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) in the G-1 treated group. In the airways, inflammatory cell accumulation, Th2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and epithelial cytokine TSLP were suppressed, while in the BALF, anti-inflammatory cytokines (IL-10 and TGF-ß) were increased. Furthermore, in splenic mononuclear cells, Foxp3-expressing CD4-positive T-cells were increased in the G-1 group, whereas treatment with G-1 did not change the percentage of ILC2 in the lungs. CONCLUSION: G-1 administration suppressed allergic airway inflammation in mice with chronic OVA asthma. GPER may be a potential therapeutic target for chronic allergic asthma.

TAOK3 Facilitates Esophageal Squamous Cell Carcinoma Progression and Cisplatin Resistance Through Augmenting Autophagy Mediated by IRGM.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers because of its robust aggressive phenotype and chemoresistance. TAO kinase belongs to mitogen-activated protein kinases, which mediate drug resistance in multiple cancers. However, the role of TAO kinase in ESCC progression and chemoresistance has never been explored. Here, it is reported that TAOK3 augments cell autophagy and further promotes ESCC progression and chemoresistance. Mechanistically, TAOK3 phosphorylates KMT2C at S4588 and strengthens the interaction between KMT2C and ETV5. Consequently, the nuclear translocation of KMT2C is increased, and the transcription of autophagy-relevant gene IRGM is further upregulated. Additionally, the inhibitor SBI-581 can significantly suppress cell autophagy mediated by TAOK3 and synergizes with cisplatin to treat ESCC in vitro and in vivo.

The G protein-coupled oestrogen receptor GPER in health and disease: an update.

Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-ß (ERß) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.

Oliceridine for the Management of Moderate to Severe Acute Postoperative Pain: A Narrative Review.

Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to chronic pain. Opioids have traditionally been the mainstay for treatment of moderate to severe acute pain. However, their use has been associated with opioid-related adverse events (ORAEs), such as respiratory depression, sedation, nausea, vomiting, pruritus, and decreased bowel motility. In addition, their liberal use has been implicated in the current opioid epidemic. As a result, there has been renewed interest in multimodal analgesia to target different mechanisms of action in order to achieve a synergistic effect and minimize opioid usage. Oliceridine is a novel mu-opioid receptor agonist that is part of a new class of biased ligands that selectively activate G-protein signaling and downregulate ß-arrestin recruitment. Since G-protein signaling has been associated with analgesia while ß-arrestin recruitment has been associated with ORAEs, there is potential for a wider therapeutic window. In this review, we will discuss the clinical evidence behind oliceridine and its potential role in acute postoperative pain management. We have systematically searched the PubMed database using the keywords oliceridine, olinvyk, and trv130. All articles identified were reviewed and evaluated, and all clinical trials were included.

Deoxyschizandrin ameliorates obesity and non-alcoholic fatty liver disease: Involvement of dual Farnesyl X receptor/G protein-coupled bile acid receptor 1 activation and leptin sensitization.

Natural dual farnesyl X receptor (FXR)/G protein-coupled bile acid receptor 1 (TGR5) activators have received little attention in the management of metabolic diseases. Deoxyschizandrin (DS), a natural lignan, occurs in S. chinensis fruit and has potent hepatoprotective effects, whereas its protective roles and mechanisms against obesity and non-alcoholic fatty liver disease (NAFLD) are largely elusive. Here, we identified DS as a dual FXR/TGR5 agonist using luciferase reporter and cyclic adenosine monophosphate (cAMP) assays. DS was orally or intracerebroventricularly administrated to high-fat diet-induced obesity (DIO) mice, and methionine and choline-deficient L-amino acid diet (MCD diet)-induced non-alcoholic steatohepatitis to evaluate its protective effects. Exogenous leptin treatment was employed to investigate the sensitization effect of DS on leptin. The molecular mechanism of DS was explored by Western blot, quantitative real-time PCR analysis, and ELISA. The results showed that DS activated FXR/TGR5 signaling and effectively reduced NAFLD in DIO and MCD diet-fed mice. DS countered obesity in DIO mice by promoting anorexia and energy expenditure and reversing leptin resistance, involving both peripheral and central TGR5 activation and leptin sensitization. Our findings indicate that DS may be a novel therapeutic approach for alleviating obesity and NAFLD through regulating FXR and TGR5 activities and leptin signaling.

Cellular Genome-wide Association Study Identifies Common Genetic Variation Influencing Lithium-Induced Neural Progenitor Proliferation.

BACKGROUND: Bipolar disorder is a highly heritable neuropsychiatric condition affecting more than 1% of the human population. Lithium salts are commonly prescribed as a mood stabilizer for individuals with bipolar disorder. Lithium is clinically effective in approximately half of treated individuals, and their genetic backgrounds are known to influence treatment outcomes. While the mechanism of lithium's therapeutic action is unclear, it stimulates adult neural progenitor cell proliferation, similar to some antidepressant drugs. METHODS: To identify common genetic variants that modulate lithium-induced proliferation, we conducted an EdU incorporation assay in a library of 80 genotyped human neural progenitor cells treated with lithium. These data were used to perform a genome-wide association study to identify common genetic variants that influence lithium-induced neural progenitor cell proliferation. We manipulated the expression of a putatively causal gene using CRISPRi/a (clustered regularly interspaced short palindromic repeats interference/activation) constructs to experimentally verify lithium-induced proliferation effects. RESULTS: We identified a locus on chr3p21.1 associated with lithium-induced proliferation. This locus is also associated with bipolar disorder risk, schizophrenia risk, and interindividual differences in intelligence. We identified a single gene, GNL3, whose expression temporally increased in an allele-specific fashion following lithium treatment. Experimentally increasing the expression of GNL3 led to increased proliferation under baseline conditions, while experimentally decreasing GNL3 expression suppressed lithium-induced proliferation. CONCLUSIONS: Our experiments reveal that common genetic variation modulates lithium-induced neural progenitor proliferation and that GNL3 expression is necessary for the full proliferation-stimulating effects of lithium. These results suggest that performing genome-wide associations in genetically diverse human cell lines is a useful approach to discover context-specific pharmacogenomic effects.

Circular RNA circ_0002360 regulates the Taxol resistance and malignant behaviors of Taxol-resistant non-small cell lung cancer cells by microRNA-585-3p-dependent modulation of G protein regulated inducer of neurite outgrowth 1.

Drug resistance has become the major obstacle for the treatment of non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) are tightly linked to the development of drug resistance of NSCLC. Herein, we tested the function of circ_0002360 in the Taxol resistance of NSCLC. Circ_0002360, microRNA (miR)-585-3p and G protein regulated inducer of neurite outgrowth 1 (GPRIN1) were quantified by quantitative real-time PCR (qRT-PCR). To identify the circular structure of circ_0002360, RNase R digestion was applied. To detect cell proliferation, colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays were used. For assessment of cell apoptosis, flow cytometry was adopted. For motility and invasion analyses, transwell assay was employed. Our data showed that circ_0002360 was mainly located in the cytoplasm and was highly expressed in the Taxol-resistant NSCLC. Silencing of circ_0002360 inhibited cell Taxol resistance, proliferation, motility, and invasiveness and induced apoptosis in vitro. MiR-585-3p was underexpressed in Taxol-resistant NSCLC and was targeted by circ_0002360. MiR-585-3p knockdown alleviated the influence of circ_0002360 silence on Taxol-resistant cells. GPRIN1 was directly targeted by miR-585-3p. The influence of miR-585-3p on cell Taxol resistance and functional behaviors was reversed by GPRIN1 overexpression. Moreover, circ_0002360 modulated GPRIN1 through miR-585-3p. Additionally, silencing of circ_0002360 weakened the growth of xenografts in vivo. Our study demonstrated that silencing of circ_0002360 enhanced the Taxol sensitivity and suppressed the malignant behaviors of Taxol-resistant NSCLC cells by miR-585-3p/GPRIN1 axis, providing novel targets for improving the anti-tumor efficacy of Taxol in NSCLC.

Randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine and nanoparticle albumin-bound paclitaxel combination therapy as neoadjuvant chemotherapy for resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC-GS/GA-rP2, CSGO-HBP-015).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and multimodal strategies, such as surgery plus neoadjuvant chemotherapy (NAC)/adjuvant chemotherapy, have been attempted to improve survival in patients with localized PDAC. To date, there is one prospective study providing evidence for the superiority of a neoadjuvant strategy over upfront surgery for localized PDAC. However, which NAC regimen is optimal remains unclear. METHODS: A randomized, exploratory trial is performed to examine the clinical benefits of two chemotherapy regimens, gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GA), as NAC for patients with planned PDAC resection. Patients are enrolled after the diagnosis of resectable or borderline resectable PDAC. They are randomly assigned to either NAC regimen. Adjuvant chemotherapy after curative resection is highly recommended for 6 months in both arms. The primary endpoint is tumor progression-free survival time, and secondary endpoints include the rate of curative resection, the completion rate of protocol therapy, the recurrence type, the overall survival time, and safety. The target sample size is set as at least 100. DISCUSSION: This study is the first randomized phase II study comparing GS combination therapy with GA combination therapy as NAC for localized pancreatic cancer. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000021484 . This trial began in April 2016.

The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats.

Mu-opioid agonists (e.g., oxycodone) are highly effective therapeutics for pain. However, they also produce reinforcing effects that increase their likelihood of abuse. Recent strategies in drug development have focused on opioids with biased receptor-signaling profiles that favor activation of specific intracellular pathways over others with the aim of increasing therapeutic selectivity. TRV130, a mu agonist biased towards G-protein signaling, produces antinociceptive effects comparable to the mu agonist, morphine, but exhibits reduced side effects. However, in terms of abuse potential, we know of no published preclinical data investigating the effects of TRV130 as a reinforcer. In the present study, we assessed the relative reinforcing effects of TRV130 and oxycodone, a commonly-prescribed mu agonist, in rats self-administering the drugs under a progressive-ratio (PR) schedule of reinforcement. In addition, we assessed the relative potency and efficacy of TRV130 and oxycodone in rats in a test of thermal antinociception (Hot Plate). For self-administration, male Sprague-Dawley rats (n = 7) self-administered intravenous infusions of TRV130 or oxycodone (0.01-0.32 mg/kg/inj) under a PR schedule of reinforcement. For the Hot-Plate test, male rats (n = 7) received subcutaneous injections of TRV130 (0.1-3.2 mg/kg/inj) or oxycodone (0.1-5.6 mg/kg/inj), and nociceptive response latencies were measured. TRV130 and oxycodone were equi-potent and equi-effective in self-administration and thermal antinociception. This study demonstrates that TRV130 produces reinforcing and antinociceptive effects that are quantitatively similar to oxycodone, and that a biased-signaling profile does not necessarily reduce abuse potential.

Therapeutic potential of ß-arrestin- and G protein-biased agonists.

Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disease processes. It is now appreciated that ß-arrestins, once viewed simply as negative regulators of traditional 7TMR-stimulated G protein signaling, act as multifunctional adapter proteins that regulate 7TMR desensitization and trafficking and promote distinct intracellular signals in their own right. Moreover, several 7TMR biased agonists, which selectively activate these divergent signaling pathways, have been identified. Here we highlight the diversity of G protein- and ß-arrestin-mediated functions and the therapeutic potential of selective targeting of these in disease states.

Inhibition of left ventricular remodelling in spontaneously hypertensive rats by G alpha q-protein carboxyl terminus imitation polypeptide GCIP-27 is not entirely dependent on blood pressure.

The G(q)-protein is located at the convergent point in the signal transduction pathway that leads to ventricular remodelling. In G-protein signalling pathways, the carboxyl terminus of the G(alpha)-subunit plays a vital role in G-protein-receptor interaction. The aim of the present study was to explore the effects of a synthetic G(alphaq) carboxyl terminus imitation peptide, namely GCIP-27, on left ventricular (LV) remodelling and blood pressure in spontaneous hypertensive rats (SHR). In the present study, 10, 30 or 90 microg/kg, i.p., GCIP-27 was administered for 8 weeks to SHR. In addition, another two groups of SHR were treated with either 6 mg/kg losartan or vehicle (saline). Wistar-Kyoto rats were used as controls. Systolic blood pressure (SBP) was measured using the standard tail-cuff method once every 2 weeks. At the end of the experiment, the LV mass index (LVMI) was evaluated. In addition, LV structure and function, collagen content, microstructure and ultrastructure were examined using echocardiography, the hydroxyproline assay, routine light microscopy and transmission electron microscopy, respectively. In the losartan- and GCIP-27 (10, 30 and 90 microg/kg)-treated groups, SBP was decreased significantly compared with that of the vehicle (saline) group. However, even at the highest concentration used, the hypotensive effect of GCIP-27 was weaker than that of losartan. For example, after 8 weeks treatment, SBP had decreased by 30.4% in the losartan-treated group compared with decreases of 10.5, 13.1 and 18.5% in the 10, 30 and 90 microg/kg GCIP-27-treated groups, respectively. Both GCIP-27 (10, 30 and 90 microg/kg) and losartan (6 mg/kg) significantly reduced LV posterior wall thickness, the thickness of the interventricular septum, collagen content and LVMI, with the effects of GCIP-27 at all three concentrations tested being greater than those of losartan. In conclusion, GCIP-27 effectively attenuates LV remodelling in SHR and the antiremodelling effect may not be dependent entirely on decreases in blood pressure.

Development of HER2-antagonistic peptides as novel anti-breast cancer drugs by in silico methods.

An antagonistic peptide called HRAP that binds to the human HER2 molecule was designed by our computational method. In silico docking study demonstrated the specific interaction of HRAP with the dimerization domain in the HER2 molecule. Interestingly, HRAP inhibited proliferation of HER2-overexpressed human breast cancer cell lines. However, it had little cellular cytotoxicity (apoptosis inducibility). The cell proliferation inhibition was associated with the suppression of phosphorylation of PTEN and Akt. Thus, HRAP is the first HER2-binding small peptide antagonist rationally designed by a computer-aided SBDD method and is useful for the development of peptide mimetics to generate novel anti-breast cancer drugs.

Molecular mechanisms responsible for the involvement of tissue transglutaminase in human diseases: Celiac Disease.

Tissue transglutaminase (tTG or TG2; E.C. 2.3.2.13) belongs to the transglutaminase family, a group of closely related enzymes that share the ability to catalyze the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. tTG is a multifunctional enzyme since it is also capable of catalyzing other biochemical reactions. The distribution and physiological roles of tTG have been widely studied in numerous cell types and tissues, but only recently its role in human diseases has started to be clarified. For example, transglutaminase activity has been hypothesized to be involved in the pathogenetic mechanisms responsible for several human diseases, including neurodegenerative diseases, such as polyglutamine diseases hitherto identified. Among human diseases, a large and recent series of studies have clearly shown that the activity of the tTG is critical for a very diffuse human pathology known as Celiac Disease. This disease is due to intolerance to a food component, gliadin, and is characterized by a very complex clinical syndrome, including gastrointestinal pathological manifestations, often associated with extra-intestinal manifestations. Interestingly, a subset of celiac patients also develops certain neurological disorders. In this review we describe the roles played by tTG in the molecular mechanisms responsible for pathophysiology of Celiac Disease.

Receptores acoplados à proteina G: implicaçöes para a fisiologia e doenças endócrinas / Connect receptors to G protein: implications for the physiology and endocrine diseases

A maioria dos hormônios polipeptídicos e mesmo o cálcio extracelular atuam em suas células-alvo através de receptores acoplados á proteína G (GPCRs). Nos últimos anos, tem sido frequente a identificação e associação causal de mutações em proteínas G e em GPCRs com diversas endocrinopatias, como diabetes insipidus nefrogênico, hipotiroidismo familiar, puberdade precoce familiar no sexo masculino e nódulos tiroidianos hiperfuncionantes. Nesta revisão, abordamos aspectos referentes ao mecanismo de transdução do sinal acoplado à proteína G, e descrevemos como mutações em GPCRs podem levar a algumas doenças endócrinas. Finalmente, comentamos a respeito das implicações diagnósticas e terapêuticas associadas com o maior conhecimento dos GPCRs.

Chimaeric G alpha proteins: their potential use in drug discovery.

Approaches that allow ligand occupancy of a wide range of G protein-coupled receptors to be converted into robust assays amenable to relatively high-throughput analysis are ideal for screening for novel ligands at this class of receptor. Many attempts have been made to design universal ligand-screening systems such that any GPCR can be screened using a common assay end-point. Manipulation of the G protein within the assay system offers the possibility of achieving this. To better understand the domains involved in the interactions between G protein-coupled receptors, G proteins and effector polypeptides and the fine details of these contacts, a wide range of chimaeric G protein alpha subunits have been produced. Graeme Milligan and Stephen Rees discuss the information generated by such studies and the ways in which such chimaeric G proteins can be integrated into assay systems for drug discovery.