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Current Molecular Pharmacology 2019Diabetes mellitus and concomitant dyslipidemia, being referred to as 'diabetic dyslipidemia', are the foremost detrimental factors documented to play a pivotal role in... (Review)
Review
BACKGROUND
Diabetes mellitus and concomitant dyslipidemia, being referred to as 'diabetic dyslipidemia', are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated.
CONCLUSION
Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.
Topics: Diabetes Mellitus, Type 2; Disease Management; Dyslipidemias; Humans; Insulin Resistance; PPAR alpha; PPAR gamma; Phenylpropionates; Pyrroles
PubMed: 30636619
DOI: 10.2174/1874467212666190111165015 -
Trends in Pharmacological Sciences Dec 2013Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin... (Review)
Review
Somatostatin analogs for the diagnosis and therapy of neuroendocrine tumors (NETs) have been used in clinical applications for more than two decades. Five somatostatin receptor subtypes have been identified and molecular mechanisms of somatostatin receptor signaling and regulation have been elucidated. These advances increased understanding of the biological role of each somatostatin receptor subtype, their distribution in NETs, as well as agonist-specific regulation of receptor signaling, internalization, and phosphorylation, particularly for the sst2 receptor subtype, which is the primary target of current somatostatin analog therapy for NETs. Various hypotheses exist to explain differences in patient responsiveness to somatostatin analog inhibition of tumor secretion and growth as well as differences in the development of tumor resistance to therapy. In addition, we now have a better understanding of the action of both first generation (octreotide, lanreotide, Octreoscan) and second generation (pasireotide) FDA-approved somatostatin analogs, including the biased agonistic character of some agonists. The increased understanding of somatostatin receptor pharmacology provides new opportunities to design more sophisticated assays to aid the future development of somatostatin analogs with increased efficacy.
Topics: Animals; Humans; Neuroendocrine Tumors; Phosphorylation; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 24183675
DOI: 10.1016/j.tips.2013.10.001 -
The Journal of Neuroscience : the... Aug 2022Chemotherapy-induced peripheral neuropathy (CIPN) affects ∼68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life....
Chemotherapy-induced peripheral neuropathy (CIPN) affects ∼68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca activity of the large population of dorsal root ganglia (DRG) neurons For the latter, we used a genetically-encoded Ca indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca activity in DRG neurons, increased number of Ca transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)-3,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)-3,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted. Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persists several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Using GCaMP Ca imaging in live animals over 1800 neurons/dorsal root ganglia (DRG) at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.
PubMed: 35772967
DOI: 10.1523/JNEUROSCI.1064-21.2022 -
British Journal of Pharmacology Jul 2017The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT and...
BACKGROUND AND PURPOSE
The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT and MT receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools.
EXPERIMENTAL APPROACH
We therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy.
KEY RESULTS
Among the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT and MT receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the G /cAMP and ERK pathway and β-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between G /cAMP signalling of the MT receptor initiated at the cell surface and neuronal mitochondria.
CONCLUSIONS AND IMPLICATIONS
We report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.
Topics: Animals; Carbocyanines; Cell Membrane Permeability; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Ethylamines; HEK293 Cells; Humans; Indoles; Ligands; Mice; Molecular Structure; Pyrroles; Receptors, Melatonin; Structure-Activity Relationship
PubMed: 28493341
DOI: 10.1111/bph.13856 -
Immunity Feb 2024Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by...
Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.
Topics: Protein Tyrosine Phosphatases; Signal Transduction; CD28 Antigens; Receptors, Immunologic
PubMed: 38354703
DOI: 10.1016/j.immuni.2024.01.007 -
Proceedings of the National Academy of... Jan 2023Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron...
Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.
Topics: Animals; Mice; Atrophy; Disease Models, Animal; Growth Hormone-Releasing Hormone; Motor Neurons; Muscular Atrophy, Spinal; Spinal Cord; Survival of Motor Neuron 1 Protein
PubMed: 36603028
DOI: 10.1073/pnas.2216814120 -
Scientific Reports Mar 2019Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent...
Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent on the system in which it is measured, especially being dependent on receptor expression level. The operational model (OM) of functional receptor agonism is a useful means for the determination of agonist functional efficacy using the maximal response to agonist and ratio of agonist functional potency to its equilibrium dissociation constant (K) at the active state of the receptor. However, the functional efficacy parameter τ is inter-dependent on two other parameters of OM; agonist's K and the highest response that could be evoked in the system by any stimulus (E). Thus, fitting of OM to functional response data is a tricky process. In this work we analyse pitfalls of fitting OM to experimental data and propose a rigorous fitting procedure where K and E are derived from half-efficient concentration of agonist and apparent maximal responses obtained from a series of functional response curves. Subsequently, OM with fixed K and E is fitted to functional response data to obtain τ. The procedure was verified at M and M muscarinic receptors fused with the G G-protein α-subunit. The procedure, however, is applicable to any receptor-effector system.
PubMed: 30874590
DOI: 10.1038/s41598-019-40993-w -
Molecules (Basel, Switzerland) Jun 2021We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding...
We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding affinity for the ligand-binding domain of EphA2 (Kd~130 nM), receptor activation in the cell required the synthesis of dimeric versions of such agent (namely 135H12). This was expected given that the natural ephrin ligands also need to be dimerized or clustered to elicit agonistic activity in cell. In the present report we investigated whether the agonistic activity of 135H11 could be enhanced by biotin conjugation followed by complex formation with streptavidin. Therefore, we measured the agonistic EphA2 activity of 135H11-biotin (147B5) at various agent/streptavidin ratios, side by side with 135H12, and a scrambled version of 147B5 in pancreatic- and breast-cancer cell lines. The (147B5)-streptavidin complexes (when = 2, 3, 4, but not when = 1) induced a strong receptor degradation effect in both cell lines compared to 135H12 or the (scrambled-147B5)-streptavidin complex as a control, indicating that multimerization of the targeting agent resulted in an increased ability to cause receptor clustering and internalization. Subsequently, we prepared an Alexa-Fluor-streptavidin conjugate to demonstrate that (147B5)-AF-streptavidin, but not the scrambled equivalent complex, concentrates in pancreatic and breast cancers in orthotopic nude-mouse models. Hence, we conclude that these novel targeting agents, with proper derivatization with imaging reagents or chemotherapy, can be used as diagnostics, and/or to deliver chemotherapy selectively to EphA2-expressing tumors.
Topics: Animals; Binding Sites; Biotin; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Ligands; Mice; Pancreatic Neoplasms; Protein Binding; Receptor, EphA2; Streptavidin
PubMed: 34204178
DOI: 10.3390/molecules26123687 -
Journal of Thrombosis and Haemostasis :... Oct 2005Coated-platelets, formerly known as COAT-platelets, represent a subpopulation of cells observed after dual agonist stimulation of platelets with collagen and thrombin.... (Review)
Review
Coated-platelets, formerly known as COAT-platelets, represent a subpopulation of cells observed after dual agonist stimulation of platelets with collagen and thrombin. This class of platelets retains on its surface high levels of several procoagulant proteins, including fibrinogen, von Willebrand factor, fibronectin, factor V and thrombospondin. Coated-platelets also express surface phosphatidylserine and strongly support prothrombinase activity. Retention of alpha-granule proteins on the surface of coated-platelets involves an unexpected derivatization of these proteins with serotonin and an interaction of serotonin-conjugated proteins with serotonin binding sites on fibrinogen and thrombospondin. This review will also detail experimental systems where coated-platelets are generated as a result of other agonist(s). Finally, the putative physiological consequences of coated-platelet formation will be discussed.
Topics: Blood Coagulation Factors; Blood Platelets; Humans; Phosphatidylserines; Platelet Activation; Serotonin; Thromboplastin
PubMed: 16194197
DOI: 10.1111/j.1538-7836.2005.01274.x -
The Journal of Physiology Nov 2016The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed in nociceptive neurons and its activation causes ongoing pain and inflammation; TRPA1 is...
KEY POINTS
The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed in nociceptive neurons and its activation causes ongoing pain and inflammation; TRPA1 is thought to play an important role in inflammation in the airways. TRPA1 is sensitised by repeated stimulation with chemical agonists in a calcium-free environment and this sensitisation is very long lasting following agonist removal. We show that agonist-induced sensitisation is independent of the agonist's binding site and is also independent of ion channel trafficking or of other typical signalling pathways. We find that sensitisation is intrinsic to the TRPA1 protein and is accompanied by a slowly developing shift in the voltage dependence of TRPA1 towards more negative membrane potentials. Agonist-induced sensitisation may provide an explanation for sensitisation following long-term exposure to harmful irritants and pollutants, particularly in the airways.
ABSTRACT
The TRPA1 ion channel is expressed in nociceptive (pain-sensitive) neurons and responds to a wide variety of chemical irritants, such as acrolein in smoke or isothiocyanates in mustard. Here we show that in the absence of extracellular calcium the current passing through TRPA1 gradually increases (sensitises) during prolonged application of agonists. Activation by an agonist is essential, because activation of TRPA1 by membrane depolarisation did not cause sensitisation. Sensitisation is independent of the site of action of the agonist, because covalent and non-covalent agonists were equally effective, and is long lasting following agonist removal. Mutating N-terminal cysteines, the target of covalent agonists, did not affect sensitisation by the non-covalent agonist carvacrol, which activates by binding to a different site. Sensitisation is unaffected by agents blocking ion channel trafficking or by block of signalling pathways involving ATP, protein kinase A or the formation of lipid rafts, and does not require ion flux through the channel. Examination of the voltage dependence of TRPA1 activation shows that sensitisation is accompanied by a slowly developing shift in the voltage dependence of TRPA1 towards more negative membrane potentials, and is therefore intrinsic to the TRPA1 channel. Sensitisation may play a role in exacerbating the pain caused by prolonged activation of TRPA1.
Topics: Animals; Calcium; Cells, Cultured; Cymenes; Female; Humans; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Monoterpenes; Neurons; Signal Transduction; Transient Receptor Potential Channels
PubMed: 27307078
DOI: 10.1113/JP272237