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Orphan receptors have unknown endogenous ligands, are expressed in different tissues, and participate in various diseases such as diabetes, hypertension and cancer. We studied the expression profiles of GPR21, GPR39, GPR135 and GPR153 orphan receptors in several tumour tissues. Cervical, breast, skin, prostate, and astrocytoma tissues were analysed for orphan receptor gene expression using Real time PCR analysis. GPR39 is over-expressed in cervical and prostate cancer tissues, and GPR21 and GPR135 receptors are significantly decreased in cervical, breast, skin, prostate, and astrocytoma tissues, when compared with healthy human fibroblasts. In conclusion, GPR21 and GPR135 receptor gene expression is reduced in cancerous tissues. GPR39 may have a role in the development and evolution of cervical and prostate cancer. These data suggest these receptors may be alternative molecules for new diagnostic approaches, and the design of novel therapeutics against oncological pathologies.

Cancer is a deadly disease and, globally, represents the second leading cause of death in the world. Although it is a disease where several factors can help its development, virus induced infections have been associated with different types of neoplasms. However, in bacterial infections, their participation is not known for certain. Among the proposed approaches to oncogenesis risks in different infections are microRNAs (miRNAs). These are small molecules composed of RNA with a length of 22 nucleotides capable of regulating gene expression by directing protein complexes that suppress the untranslated region of mRNA. These miRNAs and other recently described, such as small RNAs (sRNAs), are deregulated in the development of cancer, becoming promising biomarkers. Thus, resulting in a study possibility, searching for new tools with diagnostic and therapeutic approaches to multiple oncological diseases, as miRNAs and sRNAs are main players of gene expression and host–infectious agent interaction. Moreover, sRNAs with limited complementarity are similar to eukaryotic miRNAs in their ability to modulate the activity and stability of multiple mRNAs. Here, we will describe the regulatory RNAs from viruses that have been associated with cancer and how sRNAs in bacteria can be related to this disease.

Cardiovascular complications are the main cause of mortality in patients with diabetes, these have been associated with changes in function and expression of receptors coupled to G proteins (GPCR), which include orphan receptors which some of them tend to modify in diabetes, although others are not known, such as GPR135. For this reason, the objective of this work was to study the expression of the orphan receptor GPR135 in brain, heart, kidney, aorta, lung, spleen and liver of diabetic rats, as well as its function by the administration of siRNA (small interfering RNA) and curves to isoproterenol. Our results showed that GPR135 is expressed in all tissues analyzed and its expression is modified due to diabetes, we also observed that the responses to isoproterenol increase in diabetic rats administered with siRNA. Therefore, we conclude that the orphan receptor GPR135 is expressed in different tissues and its expression tends to be modified due to diabetes, besides that it is functional and that it seems to be coupled to Gi/o protein which has negative chronotropic and inotropic effects, therefore, we do not rule out that it participates in the cardiovascular complications associated with diabetes.

Hypertension (HBP) is a chronic disease characterized by increased blood pressure, which despite several treatments maintains a high morbi-mortality, which suggests that there are other mechanisms involved in this pathology, within which the orphan receptors could be candidates for the treatment of the HBP; these receptors are called orphan receptors because their ligand is unknown. These receptors have been suggested to participate in some pathologies because they are associated with various systems such as GPR88, which has been linked to the dopaminergic system, and GPR124 with angiogenesis, suggesting that these receptors could take part in HBP. Hence, the aim of this work was to study the expression of orphan receptors GPR88 and GPR124 in various tissues of normotensive and hypertensive rats. We used Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR) of 6-8 and 10-12 weeks of age and we determined systolic blood pressure (SBP), heart rate, as well as mRNA of GPR88 and GPR124 receptors by reverse transcription polymerase chain reaction (RT-PCR) in the aorta, heart, kidney, and brain. Our results showed that GPR88 and GPR124 were expressed in all analyzed tissues, but their expression is dependent on the age and development of HBP because their expression tends to be modified as HBP is established. Therefore, we conclude that GPR88 and GPR124 receptors may be involved in the development or maintenance of high blood pressure.

Diabetes and hypertension can coexist and exacerbate each other. In the early stages of diabetes, there is a decreased vascular response of the sympathetic nervous system (SNS), probably due to lower expression of α1-adrenoceptors; however, it is unclear how diabetes in advanced stages changes the functionality of the SNS, especially the expression of α1-adrenoceptors. Thus, the aim of this work was to analyse the functional response to phenylephrine, a selective α1-adrenoceptor agonist, and the expression of α1-adrenoceptors in chronic diabetes and hypertension. Male SHR and WKY rats aged 10–12 weeks were administered either streptozotocin (60 mg/kg i.p.) or a vehicle (control group). Eight weeks after administration, dose-response curves to phenylephrine were generated and the gene and protein expression of α1-adrenoceptor subtypes (α1A-, α1B- and α1D-adrenoceptors) in the heart and aorta were measured. The response to phenylephrine was diminished in hypertensive rats and in normotensive diabetic rats. The coexistence of both diabetes and hypertension produced an even smaller response to phenylephrine than that observed for each condition separately. In the heart and aorta of diabetic rats, no changes in α1A-, α1B- or α1D-adrenoceptor mRNA expression were observed; however, protein expression was increased, mainly for the α1D-adrenoceptor. Hypertension increased mRNA and protein expression of α1-adrenoceptors in a tissue-dependent manner. The coexistence of both diabetes and hypertension produced differences in the regulation of mRNA and protein expression (increase or decrease) in both the heart and aorta. In conclusion, diabetes, hypertension and the coexistence of both pathologies impairs the in vivo response to phenylephrine. However, the differences in α1A-, α1B- and α1D-adrenoceptor expression cannot explain the reduced response to the agonist. This should be further explored in future experiments.

Metabolic syndrome (MS) is a clinical condition, constituted by alterations that lead to the onset of type II diabetes and cardiovascular disease. It has been reported that orphan G-protein-coupled receptor 82 (GPR82) participates in metabolic processes. The aim of this study was to evaluate the function of GPR82 in MS using a small interfering RNA (siRNA) against this receptor. We used Wistar rats of 10–12 weeks of age fed with a high-fructose solution (70%) for 9 weeks to induce MS. Subsequently, the rats were treated with an intrajugular dose of an siRNA against GPR82 and the effects were evaluated on day 3 and 7 after administration. On day 3 the siRNA had a transient effect on decreasing blood pressure and triglycerides and increasing high-density lipoprotein cholesterol, which recovered to the MS control on day 7. Decreased gene expressions of GPR82 mRNA in the aorta and heart were observed on day 3; moreover, decreased gene expression was maintained in the aorta on day 7. Therefore, we conclude that the orphan receptor GPR82 participates in the development of MS induced by fructose and the silencing of this receptor could ameliorate metabolic components.

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT1 and AT2 receptors. For that reason, the aim of this work was to study the gene and protein expression of AT1 and AT2 receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60 mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT1 receptors than normotensive rats while the AT2 expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT1 and AT2 receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT1 and AT2 receptors. However, the overexpression of AT2 could be associated with the reduction in the response to Ang II in the early stage of diabetes.

Diabetes mellitus is a chronic degenerative disease characterized by high blood glucose levels as a result of problems in the action or insulin secretion. Although there are many treatments for this pathology, it has been associated with a high mortality rate. For this reason, it is important to try to identify new pathways that could be involved in diabetic complications. Recently, a new class of receptors has been reported, called orphan receptors because the associated ligand and signaling pathways are unknown, these receptors have been associated with certain pathologies. Therefore, the aim of this work was to study the expression of the orphan receptors GPR22 and GPR162 in heart, aorta, brain and kidney of diabetic rats.We used Wistar male rats with 10-12 weeks of age. Diabetes was induced by a single dose of streptozotocin (60 mg/kg i.p.). After four weeks, the tissue was obtained and the expression of the mRNA was measured by RT-PCR.Our results showed that the orphan receptors are expressed in a different way in heart, kidney, brain and aorta of diabetic and non-diabetic rats.We conclude that orphan receptors could be involved in the development of diabetes complications.