J. S. Souza, R. Conceição, K. C. Oliveira, R. Maciel, G. Giannocco
The thyroid gland is controlled by a feedback system, the hypothalamus-pituitary-thyroid axis, and produces thyroid hormone (TH), which plays a critical role in growth, development and cellular metabolism. Diseases of the thyroid are well defined clinically and biochemically and diseases affecting thyroid function can cause both clinical hypothyroidisms, the most common cause of thyroid dysfunction, occurs when there is a decrease in the production of thyroid hormones, and hyperthyroidism, when there is an increase in hormone production. Common systemic manifestations of hypothyroidism include fatigue, dry skin, weight gain, hair loss, cold intolerance, hoarseness and constipation. Patients affected by this condition present a number of central and peripheral signs in the nervous system that may be neurological manifestations that occur along with the systemic disease. The conversion of thyroid hormone in the target tissue is done by three distinct deiodinases: type I, type II and type III. Each deiodinase has a different function in order to maintain thyroid hormone homeostasis in the tissues. Other proteins important for thyroid state are the TH transporters. MCT8, OATP1C1 and LAT1 and 2 transporters regulate T4 and T3 flow in the cells. The action of THs depends on the interaction of several proteins that are specialized in the control of thyroid hormone homeostasis not only in the brain but also in various tissues. THs are important for the maturation of the brain from the intrauterine period and remain important to adulthood. When there is some disturbance in the control mechanisms for the state of thyroid hormone, the consequences to the tissues, especially the CNS, can range from mild damage to severe impairment in neuronal development.
{"title":"The hypothyroid brain","authors":"J. S. Souza, R. Conceição, K. C. Oliveira, R. Maciel, G. Giannocco","doi":"10.14800/RCI.1408","DOIUrl":"https://doi.org/10.14800/RCI.1408","url":null,"abstract":"The thyroid gland is controlled by a feedback system, the hypothalamus-pituitary-thyroid axis, and produces thyroid hormone (TH), which plays a critical role in growth, development and cellular metabolism. Diseases of the thyroid are well defined clinically and biochemically and diseases affecting thyroid function can cause both clinical hypothyroidisms, the most common cause of thyroid dysfunction, occurs when there is a decrease in the production of thyroid hormones, and hyperthyroidism, when there is an increase in hormone production. Common systemic manifestations of hypothyroidism include fatigue, dry skin, weight gain, hair loss, cold intolerance, hoarseness and constipation. Patients affected by this condition present a number of central and peripheral signs in the nervous system that may be neurological manifestations that occur along with the systemic disease. The conversion of thyroid hormone in the target tissue is done by three distinct deiodinases: type I, type II and type III. Each deiodinase has a different function in order to maintain thyroid hormone homeostasis in the tissues. Other proteins important for thyroid state are the TH transporters. MCT8, OATP1C1 and LAT1 and 2 transporters regulate T4 and T3 flow in the cells. The action of THs depends on the interaction of several proteins that are specialized in the control of thyroid hormone homeostasis not only in the brain but also in various tissues. THs are important for the maturation of the brain from the intrauterine period and remain important to adulthood. When there is some disturbance in the control mechanisms for the state of thyroid hormone, the consequences to the tissues, especially the CNS, can range from mild damage to severe impairment in neuronal development.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"205 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77468176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Chou, Ting-Chun Weng, C. Soong, Sindy Hu, F. Lieu, G. Idova, Paulus S. Wang, Shyi-Wu Wang
Acrolein is a small unsaturated aldehyde and can be found in a wide range of resources including all types of smoke and exhaust gases from gasoline engines. Although the toxicity and damage of acrolein have been recognized, the action mechanisms of acrolein, especially that of acrolein on the response of stresshormones are still unclear. The present study hypothesized that administration of acrolein altered the secretion of both adrenocorticotropin (ACTH) and corticosterone via the regulation of steroid biosynthetic pathway in rat zona fasciculata-reticularis (ZFR) cells. Both in vivo and in vitro approaches were uased. In the in vivo study, intraperitonal injection of acrolein (2 mg/ml/kg) once daily for 1 or 3 days resulted in a reduction of plasma levels of ACTH and corticosterone as well as the intracellular cAMP and ACTH-induced secretion of corticosterone. The protein expression of ACTH receptor (ACTHR) in rat ZFR cells was also reduced by 40-60% after treatment of acrolein for 1 day and 3 days, respectively. In the in vitro study, rat ZFR cells were prepared and chanllenged with ACTH (10 -9 M), forskolin (an adenylyl cyclase activitior, 10 -5 M), 8-Br-cAMP (a permeable synthetic cAMP, 5x10 -5 M), 25-OH-cholesterol (10 -5 M) ± trilostane (an inhibitor of 3β-hydroxysteroid dehydrogenase, 3β-HSD, 10 -5 M). The evoked release of corticosterone by ACTH, forskolin, 8-Br-cAMP and the induced release of pregnenolone in response to 25-OH-cholesterol plus triolostane were decreased. Since the accumulation of pregnenolone after blocking 3β-HSD by trilostane represents the activity of P450 scc, therate-limiting step of steroid biosynthesis, we suggest that not only the cAMP pathway was inhibited, but also the enzyme activity of P450 scc was attenuated following administration of acrolein. Although insignificant, the protein expression of steroidogenic acute regulatory protein (StAR) was decreased by 40% in ZFR cells after treatment of acrolein in vivo . Incubation of ZFR cells with acrolein (10 -9 ~10 -7 M) also decreased the in vitro release of corticosterone. These results suggest that administration of acrolein inhibited corticosterone production via the attenuation of cAMP pathway, StAR protein expression, and the enzyme activity of P450 scc. The attenuation of protein expression of ACTHR (also named melanocortin 2 receptor, MC2R) and reduced secrection of ACTH indicated that the hypothalamus-pituitary-adrenal (H-P-A) axis was also down- regulated by the administration of acrolein.
{"title":"Down regulation of acrolein on corticosterone secretion in male rats","authors":"J. Chou, Ting-Chun Weng, C. Soong, Sindy Hu, F. Lieu, G. Idova, Paulus S. Wang, Shyi-Wu Wang","doi":"10.14800/RCI.1401","DOIUrl":"https://doi.org/10.14800/RCI.1401","url":null,"abstract":"Acrolein is a small unsaturated aldehyde and can be found in a wide range of resources including all types of smoke and exhaust gases from gasoline engines. Although the toxicity and damage of acrolein have been recognized, the action mechanisms of acrolein, especially that of acrolein on the response of stresshormones are still unclear. The present study hypothesized that administration of acrolein altered the secretion of both adrenocorticotropin (ACTH) and corticosterone via the regulation of steroid biosynthetic pathway in rat zona fasciculata-reticularis (ZFR) cells. Both in vivo and in vitro approaches were uased. In the in vivo study, intraperitonal injection of acrolein (2 mg/ml/kg) once daily for 1 or 3 days resulted in a reduction of plasma levels of ACTH and corticosterone as well as the intracellular cAMP and ACTH-induced secretion of corticosterone. The protein expression of ACTH receptor (ACTHR) in rat ZFR cells was also reduced by 40-60% after treatment of acrolein for 1 day and 3 days, respectively. In the in vitro study, rat ZFR cells were prepared and chanllenged with ACTH (10 -9 M), forskolin (an adenylyl cyclase activitior, 10 -5 M), 8-Br-cAMP (a permeable synthetic cAMP, 5x10 -5 M), 25-OH-cholesterol (10 -5 M) ± trilostane (an inhibitor of 3β-hydroxysteroid dehydrogenase, 3β-HSD, 10 -5 M). The evoked release of corticosterone by ACTH, forskolin, 8-Br-cAMP and the induced release of pregnenolone in response to 25-OH-cholesterol plus triolostane were decreased. Since the accumulation of pregnenolone after blocking 3β-HSD by trilostane represents the activity of P450 scc, therate-limiting step of steroid biosynthesis, we suggest that not only the cAMP pathway was inhibited, but also the enzyme activity of P450 scc was attenuated following administration of acrolein. Although insignificant, the protein expression of steroidogenic acute regulatory protein (StAR) was decreased by 40% in ZFR cells after treatment of acrolein in vivo . Incubation of ZFR cells with acrolein (10 -9 ~10 -7 M) also decreased the in vitro release of corticosterone. These results suggest that administration of acrolein inhibited corticosterone production via the attenuation of cAMP pathway, StAR protein expression, and the enzyme activity of P450 scc. The attenuation of protein expression of ACTHR (also named melanocortin 2 receptor, MC2R) and reduced secrection of ACTH indicated that the hypothalamus-pituitary-adrenal (H-P-A) axis was also down- regulated by the administration of acrolein.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"130 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76860543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protein surface recognition by fluorescent molecular sensors poses an immense challenge in supramolecular recognition chemistry owing to the immense difficulty of selectively targeting these large, relatively flat and non-contiguous domains. The fact that protein surfaces can exhibit different charges, topologies, and posttranslational modifications that can be found in other proteins in the mixture is an additional factor that complicates targeting and therefore, sensing specific protein surface modifications. A recent report, however, shows that the difficulty of sensing changes that occur on the surface of specific proteins could be circumvented by attaching a relatively non-specific synthetic receptor to a specific protein binder. The latter brings the receptor near the target protein and enhances its affinity toward its surface. Modifying the synthetic receptor with an environmentally sensitive fluorescent reporter along with suitable recognition elements enables such systems to target specific regions on protein surfaces and consequently, track modifications that result from conformational changes or binding interactions.
{"title":"Protein surface recognition with targeted fluorescent molecular probes","authors":"D. Margulies, Yael Nissinkorn, Leila Motiei","doi":"10.14800/RCI.1381","DOIUrl":"https://doi.org/10.14800/RCI.1381","url":null,"abstract":"Protein surface recognition by fluorescent molecular sensors poses an immense challenge in supramolecular recognition chemistry owing to the immense difficulty of selectively targeting these large, relatively flat and non-contiguous domains. The fact that protein surfaces can exhibit different charges, topologies, and posttranslational modifications that can be found in other proteins in the mixture is an additional factor that complicates targeting and therefore, sensing specific protein surface modifications. A recent report, however, shows that the difficulty of sensing changes that occur on the surface of specific proteins could be circumvented by attaching a relatively non-specific synthetic receptor to a specific protein binder. The latter brings the receptor near the target protein and enhances its affinity toward its surface. Modifying the synthetic receptor with an environmentally sensitive fluorescent reporter along with suitable recognition elements enables such systems to target specific regions on protein surfaces and consequently, track modifications that result from conformational changes or binding interactions.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78996378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cavernosal nerve injury is a common complication after radical prostatectomy and causes erectile dysfunction (ED). Our recent publication established that pioglitazone (PGZ) improves cavernosal nerve function after crush injury in the rat model by both neural protection and neuroregeneration. This result is clinically significant for the many men who undergo treatment for localized prostate cancer. A better understanding of the effects of PGZ on pelvic ganglion neurons after cavernosal nerve injury is warranted. In this Research Highlight, we discuss the implications of our investigation from a molecular and clinical perspective.
{"title":"Pioglitazone improves pelvic ganglion neuronal survival","authors":"D. Heidenberg, K. DeLay, E. G. Katz, W. Hellstrom","doi":"10.14800/RCI.1371","DOIUrl":"https://doi.org/10.14800/RCI.1371","url":null,"abstract":"Cavernosal nerve injury is a common complication after radical prostatectomy and causes erectile dysfunction (ED). Our recent publication established that pioglitazone (PGZ) improves cavernosal nerve function after crush injury in the rat model by both neural protection and neuroregeneration. This result is clinically significant for the many men who undergo treatment for localized prostate cancer. A better understanding of the effects of PGZ on pelvic ganglion neurons after cavernosal nerve injury is warranted. In this Research Highlight, we discuss the implications of our investigation from a molecular and clinical perspective.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"94 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80384120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A wide variety of receptors that function on the cell surface are regulated, at least in part, through intracellular membrane trafficking including endocytosis, recycling and subsequent degradation. Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) are essential molecules for the final step of intracellular membrane trafficking, i.e. fusion of transport vesicles with the target membrane. SNAREs on two opposing membranes form a trans -SNARE complex consisting of a four-helical bundle and drive a membrane fusion. The resultant cis -SNARE complex is disassembled through a process mediated by NSF and SNAPs. Cells contain families of SNAREs, and the interaction of cognate SNAREs at least contributes to the specificity of membrane fusion. The SNARE complex formation and dissociation are modulated by many SNARE-associated proteins at multiple steps including tethering, assembly and disassembly. Diverse molecular mechanisms, such as scaffolding, phosphorylation and ubiquitylation of SNARE proteins, and phosphoinositide production, are utilized for the modulation. In this review, we summarize recent progress in understanding the role of SNARE-associated proteins required for the endocytic recycling and degradation of epidermal growth factor receptor, transferrin receptor and integrins. We also discuss the physiological and pathological relevance of SNAREs and SNARE-associated proteins in the receptor trafficking.
{"title":"SNARE-associated proteins and receptor trafficking","authors":"H. Inoue, K. Tani, M. Tagaya","doi":"10.14800/RCI.1377","DOIUrl":"https://doi.org/10.14800/RCI.1377","url":null,"abstract":"A wide variety of receptors that function on the cell surface are regulated, at least in part, through intracellular membrane trafficking including endocytosis, recycling and subsequent degradation. Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) are essential molecules for the final step of intracellular membrane trafficking, i.e. fusion of transport vesicles with the target membrane. SNAREs on two opposing membranes form a trans -SNARE complex consisting of a four-helical bundle and drive a membrane fusion. The resultant cis -SNARE complex is disassembled through a process mediated by NSF and SNAPs. Cells contain families of SNAREs, and the interaction of cognate SNAREs at least contributes to the specificity of membrane fusion. The SNARE complex formation and dissociation are modulated by many SNARE-associated proteins at multiple steps including tethering, assembly and disassembly. Diverse molecular mechanisms, such as scaffolding, phosphorylation and ubiquitylation of SNARE proteins, and phosphoinositide production, are utilized for the modulation. In this review, we summarize recent progress in understanding the role of SNARE-associated proteins required for the endocytic recycling and degradation of epidermal growth factor receptor, transferrin receptor and integrins. We also discuss the physiological and pathological relevance of SNAREs and SNARE-associated proteins in the receptor trafficking.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89348660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The fundamental oncology-related research is required for a deeper understanding of the molecular mechanisms associated with the normal and/or abnormal protein functions, which are closely related with structure and dynamics of the macromolecules involved in these process. The most common origin of oncogenic events is related to missense mutations. Mutation-induced structural effects promoted by oncogenic mutations in receptor tyrosine kinases (RTKs), are not yet fully characterized. Computational biology completes and enriches experimental data, producing a novel vision of molecular mechanisms governing RTKs activity. In series of our papers, we studied the structural and dynamical features of native and mutated RTKs from III family (KIT and CSF-1R), yielding a detailed description of their mechanisms of activation, ligand-depend for the native proteins and constitutive for the distinct mutants. The mechanisms of RTKs activation are described in terms of allosteric regulation between coupled regulating fragments of the protein, juxta-membrane region (JMR) and activation (A-) loop. As some mutations promote resistance to the clinically-used drugs, we analyzed the affinity of imatinib to these therapeutic targets. The computationally-obtained ( in silico ) data were correlated with in vivo and in vitro observations, thus validating our numerically-based accounts. Going forward, clinical validation of cancer-related models and simulations are cornerstones key of translation of in silico data into biomedical research, at clinical and pharmacological levels.
{"title":"How missense mutations in receptors tyrosine kinases impact constitutive activity and alternate drug sensitivity: insights from molecular dynamics simulations","authors":"Isaure Chauvot de Beauchêne, L. Tchertanov","doi":"10.14800/RCI.1372","DOIUrl":"https://doi.org/10.14800/RCI.1372","url":null,"abstract":"The fundamental oncology-related research is required for a deeper understanding of the molecular mechanisms associated with the normal and/or abnormal protein functions, which are closely related with structure and dynamics of the macromolecules involved in these process. The most common origin of oncogenic events is related to missense mutations. Mutation-induced structural effects promoted by oncogenic mutations in receptor tyrosine kinases (RTKs), are not yet fully characterized. Computational biology completes and enriches experimental data, producing a novel vision of molecular mechanisms governing RTKs activity. In series of our papers, we studied the structural and dynamical features of native and mutated RTKs from III family (KIT and CSF-1R), yielding a detailed description of their mechanisms of activation, ligand-depend for the native proteins and constitutive for the distinct mutants. The mechanisms of RTKs activation are described in terms of allosteric regulation between coupled regulating fragments of the protein, juxta-membrane region (JMR) and activation (A-) loop. As some mutations promote resistance to the clinically-used drugs, we analyzed the affinity of imatinib to these therapeutic targets. The computationally-obtained ( in silico ) data were correlated with in vivo and in vitro observations, thus validating our numerically-based accounts. Going forward, clinical validation of cancer-related models and simulations are cornerstones key of translation of in silico data into biomedical research, at clinical and pharmacological levels.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77558748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Coronary computed tomography angiography (CCTA) was performed to further identify the abnormality, which revealed the enlargement of the opening in approximately 3cm and diffusely dilated of RCA. The distribution of RCA could be showed graphically by the volume rendering technique (VRT) (Fig 3), which was travelling tortuously into the LV. A saccular aneurysm was found in size of about 12cm × 12cm and located in its proximal portion (Fig 4). Another giant fusiform aneurysm could be found next to the fistula. The fistula was about 2cm in diameter. Right atrium and ventricle were crushed obviously. Pericardial effusion was observed. The LCA was normal.
{"title":"Right coronary artery with multiple giant aneurysms fistulizing into left ventricle","authors":"J. Lu, Heshui Shi","doi":"10.14800/RCI.1361","DOIUrl":"https://doi.org/10.14800/RCI.1361","url":null,"abstract":"Coronary computed tomography angiography (CCTA) was performed to further identify the abnormality, which revealed the enlargement of the opening in approximately 3cm and diffusely dilated of RCA. The distribution of RCA could be showed graphically by the volume rendering technique (VRT) (Fig 3), which was travelling tortuously into the LV. A saccular aneurysm was found in size of about 12cm × 12cm and located in its proximal portion (Fig 4). Another giant fusiform aneurysm could be found next to the fistula. The fistula was about 2cm in diameter. Right atrium and ventricle were crushed obviously. Pericardial effusion was observed. The LCA was normal.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82039088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disorder characterized by successive heterotopic bone formation, for which at present there is no therapy. Mutations in the bone morphogenetic protein (BMP) type I receptor Activin receptor-like kinase 2 (ACVR1/ALK2) are the main trigger for FOP and inflammation is thought to be the secondary hit. The single nucleotide mutation at position 617 in the cDNA ALK2 sequence, which is found in 98% of FOP patients, results in a R206H change in the intracellular juxtamembrane region of ALK2. Previous studies had revealed that this mutation perturbs the interaction with the negative regulator FKBP12, thereby sensitising cells expressing this mutant receptor to BMPs, which are potent inducers of cartilage and bone formation. Recently, however, a twist in the underlying mechanism of FOP was revealed. Mutant ALK2 was found to respond to Activin-A, whereas wild type ALK2 function is inhibited by Activin-A. The latter cytokine is induced locally upon tissue damage and inflammation. Moreover, therapeutic targeting of Activin-A was found to inhibit heterotopic ossification in a mutant ALK2 knock-in mouse model that is highly reminiscent to human FOP. This review will focus on these latest surprising findings and discuss the implication for treatment of FOP patients.
{"title":"Promiscuous signaling of ligands via mutant ALK2 in fibrodysplasia ossificans progressiva","authors":"D. J. J. Gorter, G. Sánchez-Duffhues, P. Dijke","doi":"10.14800/RCI.1356","DOIUrl":"https://doi.org/10.14800/RCI.1356","url":null,"abstract":"Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disorder characterized by successive heterotopic bone formation, for which at present there is no therapy. Mutations in the bone morphogenetic protein (BMP) type I receptor Activin receptor-like kinase 2 (ACVR1/ALK2) are the main trigger for FOP and inflammation is thought to be the secondary hit. The single nucleotide mutation at position 617 in the cDNA ALK2 sequence, which is found in 98% of FOP patients, results in a R206H change in the intracellular juxtamembrane region of ALK2. Previous studies had revealed that this mutation perturbs the interaction with the negative regulator FKBP12, thereby sensitising cells expressing this mutant receptor to BMPs, which are potent inducers of cartilage and bone formation. Recently, however, a twist in the underlying mechanism of FOP was revealed. Mutant ALK2 was found to respond to Activin-A, whereas wild type ALK2 function is inhibited by Activin-A. The latter cytokine is induced locally upon tissue damage and inflammation. Moreover, therapeutic targeting of Activin-A was found to inhibit heterotopic ossification in a mutant ALK2 knock-in mouse model that is highly reminiscent to human FOP. This review will focus on these latest surprising findings and discuss the implication for treatment of FOP patients.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82418325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Kaimori, M. Hatanaka, Satoko Yamamoto, N. Ichimaru, S. Takahara, Y. Isaka, H. Rakugi
Hypertension is one of the most life-threatening health problems in the modern world. Particularly, salt-sensitive hypertension is often associated with cardiovascular disease and defects in the circadian rhythm of the blood pressure. To date, the effects of angiotensin receptor blocker (ARB) against salt sensitivity and the blood pressure’s circadian rhythm have been obscure. A strong ARB, azilsartan, was previously reported to improve the circadian rhythm of blood pressure in hypertensive patients. In a recently published study, we investigated the mechanism by which azilsartan brought about this reaction. We speculated that azilsartan modulated sodium transporters located in the renal tubules because the circadian rhythm of blood pressure is linked to salt handling in the kidney. We discovered that one sodium transporter, NHE3 protein, in the proximal tubules was greatly attenuated in the kidneys of 5/6 nephrectomized mice that had been treated with azilsartan, although the expression of other sodium transporter proteins remained unchanged. The genetic expression of NHE3, however, was not changed by azilsartan. In a subsequent in vitro study using OKP cells, we found that NHE3 protein reduction was induced by enhanced protein degradation by proteasomes, not lysosomes, leading to enhanced sodium excretion. It is suggested that diminished salt sensitivity in the 5/6 nephrectomized mice treated with azilsartan was due to a change in sodium handling induced by the reduction of NHE3 protein in the proximal tubules. These mechanisms underlying the decreased salt sensitivity by azilsartan treatment may lead to totally new drug discoveries.
{"title":"New mechanism leading to alleviation of salt-sensitive hypertension by a powerful angiotensin receptor blocker, azilsartan","authors":"J. Kaimori, M. Hatanaka, Satoko Yamamoto, N. Ichimaru, S. Takahara, Y. Isaka, H. Rakugi","doi":"10.14800/RCI.1352","DOIUrl":"https://doi.org/10.14800/RCI.1352","url":null,"abstract":"Hypertension is one of the most life-threatening health problems in the modern world. Particularly, salt-sensitive hypertension is often associated with cardiovascular disease and defects in the circadian rhythm of the blood pressure. To date, the effects of angiotensin receptor blocker (ARB) against salt sensitivity and the blood pressure’s circadian rhythm have been obscure. A strong ARB, azilsartan, was previously reported to improve the circadian rhythm of blood pressure in hypertensive patients. In a recently published study, we investigated the mechanism by which azilsartan brought about this reaction. We speculated that azilsartan modulated sodium transporters located in the renal tubules because the circadian rhythm of blood pressure is linked to salt handling in the kidney. We discovered that one sodium transporter, NHE3 protein, in the proximal tubules was greatly attenuated in the kidneys of 5/6 nephrectomized mice that had been treated with azilsartan, although the expression of other sodium transporter proteins remained unchanged. The genetic expression of NHE3, however, was not changed by azilsartan. In a subsequent in vitro study using OKP cells, we found that NHE3 protein reduction was induced by enhanced protein degradation by proteasomes, not lysosomes, leading to enhanced sodium excretion. It is suggested that diminished salt sensitivity in the 5/6 nephrectomized mice treated with azilsartan was due to a change in sodium handling induced by the reduction of NHE3 protein in the proximal tubules. These mechanisms underlying the decreased salt sensitivity by azilsartan treatment may lead to totally new drug discoveries.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77565998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo , PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction.
{"title":"Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis","authors":"M. Mawhin, J. Fabre","doi":"10.14800/RCI.1343","DOIUrl":"https://doi.org/10.14800/RCI.1343","url":null,"abstract":"Aspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo , PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91218470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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