Research progress on receptor activity-modifying proteins and their application prospects in disease prevention / 中国生物制品学杂志

@#Receptor activity-modifying proteins(RAMPs) are type I transmembrane proteins,which are activity-modifying proteins of a variety of G-protein-coupled receptors(GPCRs).RAMPs are related to physiological and pathological phenomena such as neurological diseases,cardiovascular diseases,renal function,skeletal development and obesity,and of great significance for disease prevention,which are potential targets for the treatment of various diseases and also closely related to the prognosis of diseases.At present,there are few studies on proteins that may regulate the expression of RAMPs.This paper focuses on the sterol regulatory element-binding factor-2(SREBF-2) that may regulate the transcription and expression of RAMP3, and reviews the research progress of RAMPs in biology,pathology and pharmacology,providing a reference for the further research on RAMPs and the prevention and detection of related diseases.

Research progress on role of free fatty acid receptors in nervous system diseases / 中国生物制品学杂志

@#Free fatty acid receptors(FFARs)are a series of orphan G protein-coupled receptors(GPCRs)activated by free fatty acids(FFAs)and their derivatives. As transmembrane receptors,GPCRs are involved in the occurrence and development of many diseases and provide a wide range of therapeutic targets for these diseases. FFARs combined with FFAs are mainly involved in the secretion of endocrine hormones such as insulin,adipocyte differentiation,inflammatory response,autoimmune response and other processes,which was a potential therapeutic target for energy metabolism disorders and immune diseases. However,recent studies have shown that FFAs and its receptor FFARs are widely involved in neuroinflammation and neuroimmunity directly or through the brain-intestinal axis,and are expected to be a therapeutic target for multiple sclerosis,Alzheimer′s disease(AD),Parkinson′s disease(PD),depression and other diseases. This paper reviews the research progress of the role of FFARs in nervous system diseases.

Los receptores acoplados a proteínas G como blanco terapéutico / G protein-coupled receptors as therapeutic target

Resumen Los receptores son proteínas codificadas por el ADN, algunos de los cuales ya han sido cristalizados, lo que permite conocer los detalles de su estructura a nivel atómico y algunos aspectos de su función. Esta revisión se enfoca en los más diversos y abundantes, los receptores acoplados a la proteína G. Esta familia de receptores reconoce y media la acción de varios ligandos endógenos (hormonas, neurotransmisores, factores de crecimiento y hormonas locales) y también interviene en la patogenia de diversas enfermedades, por lo que son el blanco terapéutico de aproximadamente 30 a 40 % de los medicamentos que se emplean en la práctica clínica cotidiana y de diversas drogas ilegales. La cristalografía de rayos X es una de las herramientas clave que ha permitido observar la estructura de estos receptores en los aminoácidos que participan en esta interacción, lo que posibilita conocer el sitio de unión del ligando endógeno y de moléculas sintéticas que actúan sobre ellos para modular su acción. El modelado molecular es también una herramienta bioinformática computacional que apoya la investigación sobre la unión receptor-ligando, que hace posible el diseño y desarrollo de fármacos cada vez más específicos. A estos desarrollos se suman importantes cambios en los conceptos farmacodinámicos fundamentales.

Abstract Receptors are proteins coded by DNA, some of which have already been crystalized, thus allowing the details of their structure at the atomic level and some aspects of their function to be known. This review focuses on the most diverse and abundant family of receptors, G protein-coupled receptors. This family of receptors recognizes and mediates the action of several endogenous ligands (hormones, neurotransmitters, growth factors and local hormones) and also intervenes in the pathogenesis of various diseases, which is why they are targeted by approximately 30 to 40% of medications that are used in daily clinical practice and of various illegal drugs as well. X-ray crystallography is one of the essential tools that has allowed to observe the structure of these receptors in the amino acids that participate in this interaction, which allows to know the binding site of the endogenous ligand and of synthetic molecules that act on them to modulate their action. Molecular modeling or "docking" is also a computational bioinformatics tool that supports research on receptor-ligand binding, which allows the design and development of increasingly specific drugs. These developments have brought along significant changes in fundamental pharmacodynamic concepts.

The interplay between oat beta glucan, gut microbiota and gut-liver axis in treatment of obesity associated non-alcoholic steatohepatitis and Type II diabetes mellitus

Dietary fibers regulate host health through various mechanisms related to their physicochemical structure and physiological properties in the gut. The interplay between diet, gut microbiota and human host appear to play a significant role in pathogenesis of obesity associated complications. This study was designed to unravel oat beta glucan modulatory effect on non-alcoholic steatohepatitis and type II diabetes mellitus in high fat fed rats and to explain possible pathomechanics involving gut microbiota and gut liver axis. Sixty male albino rats were included and randomly divided into four equal groups: control group; positive control group; diet induced obesity group; oat beta glucan treated group. All were subjected to assessment of glycemic profile; liver enzymes; serum trimethylamine-N-oxide levels; hepatic G-protein coupled receptor 43 relative gene expression. Histopathological examination of hepatic tissue was performed. Results revealed that oat beta glucan administration improved the biochemical changes. The histopathological findings confirmed the biochemical changes. Gut microbiota appeared to be highly implicated via its metabolites short chain fatty acids and trimethylamine. Our conclusion was that oat beta glucan was a successful compliance in the management strategy of hepatic steatosis and diabetes mellitus via modulating a number of gut microbial products.

Relationship Between TRPV1 and TRPM8 in Reflux Esophagitis Models / 胃肠病学

Background: Studies have shown that transient receptor potential (TRP) channels play important roles in gastroesophageal reflux disease (GERD), however, the relationship between TRPV1 and TRPM8 in reflux esophagitis (RE) remains unclear. Aims: To investigate the expressions of TRPV1, TRPM8 and their correlation in guinea pigs with RE. Methods: Thirty male guinea pigs aged 3⁃4 weeks were randomly divided into 3 groups: blank control group, negative control group and model group, with 10 animals in each group. Guinea pigs in model group and negative control group were given esophageal perfusion with 0.1 mol/L HCl containing 0.5% pepsin and normal saline, respectively, once a day for 14 days; guinea pigs in blank control group were free to drink sterile water for 14 days. On day 15, the esophagus was dissected for macroscopic and histopathological examination, and Western blotting and/or real⁃time PCR were used to detect the expression levels of TRPV1, TRPM8, GNAQ (an isoform of G protein), and the tight junction proteins and proinflammatory cytokines in esophageal tissue. The co⁃localization of TRPV1 and TRPM8 was assessed by immunofluorescence. Results: Esophageal mucosal congestion, hyperplasia of esophageal epithelial cells, infiltration of inflammatory cells, as well as up⁃regulation of proinflammatory cytokines and down⁃regulation of tight junction proteins were observed in esophageal tissue of guinea pigs in model group, which indicated the successful RE model construction. As compared with the negative control group, expression levels of TRPV1 and GNAQ mRNA and protein were significantly increased, while expression levels of TRPM8 mRNA and protein were significantly reduced in esophageal tissue of guinea pigs in model group (all P<0.05). TRPV1 and TRPM8 channels were co ⁃ localized in the lamina propria of esophageal mucosa. Conclusions: There is a certain equilibrium mechanism between TRPV1 and TRPM8 channels in RE models. G protein⁃coupled receptor signaling pathway and the downstream TRPV1/TRPM8 might be involved in the occurrence and development of GERD.

Peptide Drugs Targeting G Protein-coupled Receptors / 中国生物化学与分子生物学报

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in mammals that contain seven transmembrane helices. The human genome encodes about 800 different types of GPCRs, which are widely involved in the pathological processes underlying different diseases, e.g. metabolic diseases and tumors, rendering them popular therapeutic targets. Peptides are organic substances consisted of two to dozens of amino acids linked by peptide bonds. They are bioactive substances involved in various cellular activities. To date, over 7 000 natural peptides have been identified as hormones, neurotransmitters, growth factors, ion channel ligands and antibiotics. Peptide drugs are valued for being selective and efficacious, and at the same time relatively safe and with low costs of production. In recent years, based on the increased understanding of GPCR structures, the development of GPCR-targeting peptide drugs has made great progress. Up to now, there have been nearly 50 peptide drugs targeting GPCRs approved by FDA for the treatment of metabolic diseases, nervous system diseases, cancer or other diseases. The research and development of peptide drugs have gone through three stages: development based on human peptides, on natural peptides and by modern biotechnology. At present, most of the marketed GPCR-targeting peptide drugs are derivatives of human natural peptides. In this review, we sum up the recent marketed GPCR-targeting peptide drugs, and also summarize the current strategies and further directions of peptide drug development.

ARMC5 mutations are associated with high levels of proliferating cell nuclear antigen and the presence of the serotonin receptor 5HT4R in PMAH nodules

ABSTRACT Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH.

Effect and potential signaling pathway of hedgehog protein on the function of human retinal microvascular endothelial cell / 中华实验眼科杂志

Objective@#To explore the impact of Hedgehog protein on human retinal microvascular endothelial cell(HRMEC)and its signaling pathway.@*Methods@#The cultured HRMECs were divided into normal control group, 0.5 μmol/L agonist group and 1.0 μmol/L agonist group, and were cultured in medium with final concentration of 0, 0.5 and 1.0 μmol/L Hedgehog agonist, respectively; HRMECs cultured in high glucose medium were divided into high glucose control group, 1.5 μmol/L inhibitor group and 2.5 μmol/L inhibitor group.Erismodegib, the Smoothed inhibitor with final concentration of 0, 1.5 and 2.5 μmol/L was added into corresponding group, respectively.MTS method and Transwell cell migration method were used to detect the proliferation(A490 value)and relative mobility of HRMEC.The phosphorylation of PLCγ1, Akt and Erk proteins were detected by Western blot.@*Results@#The relative expression of Hedgehog protein in the high glucose control group was 6.24±0.11, which was significantly higher than 1.00±0.00 in the normal control group(t=667.573, P<0.001). The A490 value was 1.349±0.050 and 1.422±0.053, and the relative mobility rate was 2.34±0.14 and 3.59±0.32 in the0.5 μmol/L agonist group and the 1.0 μmol/L agonist group, respectively, which were significantly higher than 1.203±0.101 and 1.00±0.00 in the normal control group(all at P<0.01). The A490 value was 0.849±0.010 and 0.737±0.030, and the relative mobility rate was 0.43±0.02 and 0.27 ±0.01 in the 1.5 μmol/L inhibitor group and the 2.5 μmol/L inhibitor group, respectively, which were significantly lower than 1.000±0.040 and 1.00±0.00 in the high glucose control group(all at P<0.01). The phosphorylation ratios of PLCγ1, Akt and Erk in the 0.5 μmol/L agonist group and the 1.0 μmol/L agonist group were significantly higher than those in the normal control group(all at P<0.01). The phosphorylation ratios of PLCγ1, Akt and Erk in the 1.5 μmol/L inhibitor group and the 2.5 μmol/L inhibitor group were significantly lower than those in the high glucose control group(all at P<0.01).@*Conclusions@#High glucose induces the expression of Hedgehog protein in HRMEC.Hedgehog protein may regulate the function of HRMEC by regulating the phosphorylation of PLCγ1, Akt and Erk in G Protein-coupled receptors pathway.

Role of brain-specific angiogenesis inhibitor 1 in synapse and cognitive impairment / 中华行为医学与脑科学杂志

Adhesion G protein-coupled receptors(aGPCRs) play a significant role in cognitive impairment related diseases.As an important member of aGPCRs,brain-specific angiogenesis inhibitor 1 (BAI1) has a prominent impact on anti-angiogenesis,anti-tumor and participating in immune phagocytosis.Recent research found out that BAI1 exerts a great influence on synaptogenesis and synaptic plasticity,but few studying concerning BAI1 in nervous system.Nowadays,the aging of population aggravates the occurrence of cognitive impairment.The pathogenesis of Alzheimer's disease and vascular cognitive impairment remains elusive,and identification of cognitive impairment at an early stage faces challenges.In the stage of mild cognitive impairment,synaptic damage is evident.BAI1 can regulate the function of postsynaptic membrane,synaptogenesis,synaptic signal transmission and the morphological development of dendritic spines.Therefore,it may potentially act as an early-warning index and intervention target for cognitive impairment.

Role of brain-specific angiogenesis inhibitor 1 in synapse and cognitive impairment / 中华行为医学与脑科学杂志

Adhesion G protein-coupled receptors(aGPCRs) play a significant role in cognitive impairment related diseases. As an important member of aGPCRs, brain-specific angiogenesis inhibitor 1(BAI1) has a prominent impact on anti-angiogenesis, anti-tumor and participating in immune phagocytosis. Recent research found out that BAI1 exerts a great influence on synaptogenesis and synaptic plasticity, but few studying concerning BAI1 in nervous system. Nowadays, the aging of population aggravates the occurrence of cognitive impairment. The pathogenesis of Alzheimer's disease and vascular cognitive impairment remains elusive, and identification of cognitive impairment at an early stage faces challenges. In the stage of mild cognitive impairment, synaptic damage is evident. BAI1 can regulate the function of postsynaptic membrane, synaptogenesis, synaptic signal transmission and the morphological development of dendritic spines. Therefore, it may potentially act as an early-warning index and intervention target for cognitive impairment.

Effect and potential signaling pathway of hedgehog protein on the function of human retinal microvascular endothelial cell / 中华实验眼科杂志

Objective To explore the impact of Hedgehog protein on human retinal microvascular endothelial cell(HRMEC) and its signaling pathway. Methods The cultured HRMECs were divided into normal control group,0. 5μmol/L agonist group and 1. 0μmol/L agonist group,and were cultured in medium with final concentration of 0,0. 5 and 1. 0μmol/L Hedgehog agonist,respectively;HRMECs cultured in high glucose medium were divided into high glucose control group,1. 5μmol/L inhibitor group and 2. 5μmol/L inhibitor group. Erismodegib,the Smoothed inhibitor with final concentration of 0,1. 5 and 2. 5 μmol/L was added into corresponding group,respectively. MTS method and Transwell cell migration method were used to detect the proliferation( A490 value) and relative mobility of HRMEC. The phosphorylation of PLCγ1, Akt and Erk proteins were detected by Western blot. Results The relative expression of Hedgehog protein in the high glucose control group was 6. 24±0. 11,which was significantly higher than 1. 00±0. 00 in the normal control group(t=667. 573,P<0. 001). The A490 value was 1. 349±0. 050 and 1. 422±0. 053,and the relative mobility rate was 2. 34±0. 14 and 3. 59±0. 32 in the 0. 5μmol/L agonist group and the 1. 0μmol/L agonist group, respectively, which were significantly higher than 1. 203 ± 0. 101 and 1. 00 ± 0. 00 in the normal control group(all at P<0. 01). The A490 value was 0. 849±0. 010 and 0. 737±0. 030,and the relative mobility rate was 0. 43 ± 0. 02 and 0. 27 ± 0. 01 in the 1. 5 μmol/L inhibitor group and the 2. 5 μmol/L inhibitor group, respectively,which were significantly lower than 1. 000±0. 040 and 1. 00±0. 00 in the high glucose control group(all at P<0. 01). The phosphorylation ratios of PLCγ1,Akt and Erk in the 0. 5μmol/L agonist group and the 1. 0μmol/L agonist group were significantly higher than those in the normal control group ( all at P<0. 01 ) . The phosphorylation ratios of PLCγ1,Akt and Erk in the 1. 5μmol/L inhibitor group and the 2. 5μmol/L inhibitor group were significantly lower than those in the high glucose control group ( all at P<0. 01 ) . Conclusions High glucose induces the expression of Hedgehog protein in HRMEC. Hedgehog protein may regulate the function of HRMEC by regulating the phosphorylation of PLCγ1,Akt and Erk in G Protein-coupled receptors pathway.

New insights into the transcriptional regulation of aquaporin-2 and the treatment of X-linked hereditary nephrogenic diabetes insipidus

The kidney collecting duct (CD) is a tubular segment of the kidney where the osmolality and final flow rate of urine are established, enabling urine concentration and body water homeostasis. Water reabsorption in the CD depends on the action of arginine vasopressin (AVP) and a transepithelial osmotic gradient between the luminal fluid and surrounding interstitium. AVP induces transcellular water reabsorption across CD principal cells through associated signaling pathways after binding to arginine vasopressin receptor 2 (AVPR2). This signaling cascade regulates the water channel protein aquaporin-2 (AQP2). AQP2 is exclusively localized in kidney connecting tubules and CDs. Specifically, AVP stimulates the intracellular translocation of AQP2-containing vesicles to the apical plasma membrane, increasing the osmotic water permeability of CD cells. Moreover, AVP induces transcription of the Aqp2 gene, increasing AQP2 protein abundance. This review provides new insights into the transcriptional regulation of the Aqp2 gene in the kidney CD with an overview of AVP and AQP2. It summarizes current therapeutic approaches for X-linked nephrogenic diabetes insipidus caused by AVPR2 gene mutations.

Recent advances in understanding the fungal G-protein-coupled receptors

Abstract@#Transmission of extracellular signal across the plasma membrane into the cells of organisms is impossible without cell surface receptors. One of the most broadly studied receptor is the G-protein coupled receptor. This receptor is coupled with heterotrimeric G proteins with α, β and γ subunits that perceives external stimuli and transduces the signal into the cell for suitable physiological and biochemical responses. They have also been reported as potential receptors to sense light and fatty acids, but their exact mechanism remains unclear in fungi. Signalling and regulation via G proteins has been extensively studied in various models including pathogenic fungi. Fungal GPCRs are broadly required in fungal defence stimulation, vegetative growth, and pathogenicity mechanism. This review aims to highlight the research in fungal GPCRs including classification, physiological roles, mechanisms of action and signalling in GPCR function. Through fungal genome sequencing, mammalian GPCRs have been identified apart from fungal-specific GPCRs which adds another dimension to the classification. The deorphanisation of unclassified fungal GPCRs is necessary to further understand their role in fungi. While the mechanism of action has been well documented in mammals, the glucose and pheromone sensing are the only two well mapped systems in yeast. However, we are yet to ascertain if there are any additional mechanisms of signalling at work in fungi. Further we endeavour to compare and contrast between the eukaryotic GPCRs in various aspects of functionality. Through the information derived we hope to determine the gaps in knowledge and by so doing determine the future directions of GPCR research in fungi.

Inhibition of GPR35 attenuates ischemic myocardial injury / 解放军医学杂志

Objective To investigate the protective role of GPR35 inhibition on hypoxic myocardial cell line and mouse myocardial infarction (MI) model.Methods For investigating the changes of GPR35 expression in hypoxic environment,the murine myocardial cells (MCM) were divided into normoxia group and hypoxia group,the mRNA expression of GPR35 was determined by q-PCR and the protein level was measured by Western blotting 6h after incubation.For further studying the role of GPR35,MCM were divided into four groups:normoxia,hypoxia,hypoxia+vehicle,hypoxia+CID2745678 (GPR35 inhibitor,3μmol/L) group.Accordingly,the apoptosis of cardiomyocytes was measured by flow cytometer and TUNEL.For investigating the changes of GPR35 expression in the state of myocardial ischemia,the C57 male mice were divided into sham group (n=6) and MI group (n=8),the mRNA expression of GPR35 was determined by q-PCR and the protein level was measured by Western blotting 3 days after MI.For further studying the role of GPR35,the C57 mice were divided into four groups:sham (n=6),MI (n=8),MI+vehicle (n=8) and MI+CID2745678 (n=8) group.Ultrasound echocardiography was performed 4 weeks after MI.Mice were then sacrificed and the hearts were removed and stained with Masson to measure the myocardial fibrosis area.Results Compared with normoxia group,the levels of GPR35 mRNA and protein increased obviously in hypoxia group (P＜0.01,P＜0.05);Compared with hypoxia+vehicle group,the myocardial cells apoptosis in hypoxia+CID2745678 group decreased markedly (P＜0.05).Three days after MI,compared with the sham group,the levels of GPR35 mRNA and protein increased obviously (P＜0.01,P＜0.05) in MI group;Compared with MI+vehicle group,the left ventricular fraction shortening (LVFS) and left ventricular ejection fraction (LVEF) relieved obviously (P＜0.05) and myocardial fibrosis level declined markedly in MI+CID2745678 group (P＜0.05).Conclnsion Inhibition of GPR35 could decrease the apoptosis of cardiomyocytes cultured in hypoxia and attenuated the injury of myocardial ischemia.

Network pharmacology study of Xiaoxuming Decoction based on vasodilatory and vasoconstrictory related GPCR targets / 中国中药杂志

In this study, bioinformatics methods such as molecular docking and network pharmacology were adopted to establish Xiaoxuming Decoction (XXMD) "compound-vasodilatory and vasoconstrictory related G protein-coupled receptors (GPCR) targets" network, then the vascular function regulatory effective components and the potential targets of XXMD were analyzed. Based on the XXMD herb sources, the chemical structures of the compounds were retrieved from the national scientific data sharing platform for population and health pharmaceutical information center, TCMSP database and the latest research literatures. The chemical molecular library was established after class prediction and screening for medicinal and metabolic properties. Then, five kinds of vasodilatory and vasoconstrictory related GPCR crystal structure including 5-HT receptors (5-HT1AR, 5-HT1BR), AT1R, β2-AR, hUTR and ETB were retrieved from RCSB Protein Data Bank database or constructed by homology modeling of Discovery Studio 4.1 built-in modeling tools. After virtual screening by Libdock molecular docking, the highest rated 50 compounds of each target were collected and analyzed. The collected data were further used to construct and analyze the network by Cytoscape 3.4.0. The results showed that most of the chemical composition effects were associated with different vasodilatory and vasoconstrictory related GPCR targets, while a few effective components could be applied to multiple GPCR targets at the same time, therefore forming synergies and vasorelaxant effects of XXMD.

Network pharmacology study of Chinese medicine Xiao-Xu-Ming decoction based on vasoconstrictor related GPCR targets / 中国药理学与毒理学杂志

OBJECTIVE Using bioinformatics methods, to establish Xiao-Xu-Ming decoction (XX-MD)"compound-vasoconstriction G Protein-Coupled Receptors(GPCR)targets"network,and analyze the vasoconstriction regulatory effective components and the potential targets of XXMD. METHODS Ac-cording to the XXMD herb sources,we retrieved the chemical structures from the national scientific da-ta sharing platform for population and health pharmaceutical information center,TCMSP database and the latest research literature.The chemical molecular library was established after class prediction and screening for medicinal and metabolic properties.Five kinds of vasoconstriction GPCR crystal structure including 5-HT receptors(5-HT1AR,5-HT1BR),AT1R,β2-AR,hUTR and ETB were retrieved from Bank Pro-tein Data Bank database or homology modeling using Discovery Studio 4.1 built-in modeling tools.After virtual screening by Libdock molecular docking,the highest rated 50 compounds of each target were col-lected and analyzed. The collected data were further used to construct and analyze the network. RE-SULTS 859 single compound structures information in XXMD were generalized following the screen-ing of obtained 2043 compounds.The complicated compound-vasoconstriction GPCR targets network of XXMD was then constructed and analyzed by molecular docking with the above five kinds of GPCR target receptors. Most of the chemical composition effects were associated with different vasoconstric-tion GPCR targets,while a few effective components can be applied to multiple GPCR targets at the same time,therefore forming synergies.CONCLUSION Vasorelaxant effects of XXMD may not only result from the collaborative interaction between a variety of active ingredients in Chinese medicine and multi-ple targets,but also from the interaction between some effective component and multiple targets.

Research progress on targets for analgesics / 中国药理学通报

Pain as a clinical common symptom is one of the most serious problems to threaten human health,therefore,pain management is one of the main aspects of clinical medication.This review briefly described the existing and the novel analgesic targets,in order to study and develop new kinds of analgesic drugs with high efficacy,less side effects and no resistance and addiction,which aims to provide a reference for the clinical application.

Can oliceridine (TRV130), an ideal novel µ receptor G protein pathway selective (µ-GPS) modulator, provide analgesia without opioid-related adverse reactions?

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to µ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the β-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the β-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the µ receptor G protein pathway selective (µ-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased µ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.

The search for novel insecticide targets in the post-genomics era, with a specific focus on G-protein coupled receptors

Insects are considered pests globally, implicated in the destruction of agricultural fields and transmission of pathogens that cause deadly human diseases, such as dengue, Zika and malaria. The diversity of the insecticide arsenal has remained stagnant for decades, but the recent rise of insecticide resistance fueled the discovery of novel modes of action, and the power of genomics has reinvigorated this search. This review discusses the importance of comparative and functional insect genomics in the identification of potential gene targets for an insecticidal mode of action with low off-target toxicity. Due to the global participation in the sequencing and annotation of insect genomes, the targeting of specific genes with molecular tools like RNAi and CRISPR/Cas9 for genome engineering and consequent functional identification and validation has become more efficient. While there are multiple avenues to explore for insecticidal candidates, this review identifies G-protein coupled receptors as attractive targets, and hones in on the octopamine and dopamine receptors due to their potential.

Functions and characteristics of calcium-sensing receptorsand effects of CaSR on characteristics of adult stem cells / 中国药理学通报

Calcium-sensing receptor(CaSR) is a widely distributed G-protein coupled receptor.The activated CaSR plays an important role in many kinds of signaling pathway regulation, such as Ca2+ signaling pathway.It not only maintains the body calcium balance, but also is involved in the regulation of a variety of cell secretion, proliferation, apoptosis, and ion channel opening processes.CaSR expression is involved in stem cell migration, adhesion and homing in hematopoietic stem cells and mesenchymal stem cells.The activated CaSR also regulated the function of itself and characteristics in stem cells through a variety of cell signaling pathways.We introduce the functions and characteristics of CaSR, the relationship between CaSR and disease, and review the effects of the biological characteristics on hematopoietic stem cells and mesenchymal stem cells.