Olfactory receptors in neural regeneration in the central nervous system

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.

The role of α- and β-adrenergic receptors in the spasmolytic effects on rat ileum of Petroselinum crispum Latifolum(parsley)

Objective:To investigate Petroselinum crispum Latifolum(parsley) for treating stomach and intestinal disorders in Iran.Methods:An 80%ethanol extract was prepared from parsley seeds, and its antispasmodic activity assessed by measuring contractions of isolated ilea induced by 60 mM potassium chloride(KG).A piece of ileum from an adult male Wistar rat was dissected and mounted in an organ bath containing Tyrode’s solution,and ileum contractions were recorded by an isotonic transducer under one gram resting tension.The effect of parsley extract was measured in the presence of two antagonists’ of a - and(5-adrenoceptors.Results:These experiments showed that parsley extract inhibited the response to 60 mM KC1 in a concentration-dependent manner(P【0.01,n=7).The spasmolytic effect of parsley extract was unaffected by 1μM phentolamine or 1μM propranolol.Conclusions:This study shows that parsley seed extract is a relaxant of isolated rat ileum and the relaxation effect of extract does not involved adrenergic receptors.

B2 adrenergic receptors and morphological changes of the enteric nervous system in colorectal adenocarcinoma

To study the morphology of the enteric nervous system and the expression of beta-2 adrenergic (B2A) receptors in primary colorectal cancer.METHODSIn this study, we included forty-eight patients with primary colorectal cancer and nine patients for control tissue from the excision of a colonic segment for benign conditions. We determined the clinicopathological features and evaluated the immunohistochemical expression pattern of B2A receptors as well as the morphological changes of the enteric nervous system (ENS). In order to assess statistical differences, we used the student t-test for comparing the means of two groups and one-way analysis of variance with Bonferroni’s post hoc analysis for comparing the means of more than two groups. Correlations were assessed using the Pearson’s correlation coefficient.RESULTSB2A receptors were significantly associated with tumor grading, tumor size, tumor invasion, lymph node metastasis (P < 0.05), while there were no statistically significant associations with gender, CRC location and gross appearance (P > 0.05). We observed, on one hand, a decrease of the relative area for both Auerbach and Meissner plexuses with the increase of the tumor grading, and on the other hand, an increase of the relative area of other nervous elements not in the Meissner plexus or in the Auerbach plexus with the tumor grading. For G1 tumors we found that epithelial B2A area showed an inverse correlation with the Auerbach plexus areas [r(14) = -0.531, P < 0.05], while for G2 tumors, epithelial B2A areas showed an indirect variation with both the Auerbach plexus areas [r(14) = -0.453, P < 0.05] and the Meissner areas [r(14) = -0.825, P < 0.01]. For G3 tumors, the inverse dependence increased for both Auerbach [r(14) = -0.587, P < 0.05] and Meissner [r(14) = -0.934, P < 0.05] plexuses.CONCLUSIONB2A receptors play an important role in colorectal carcinogenesis and can be utilized as prognostic factors. Furthermore, study of the ENS in colorectal cancer may lead to targeted molecular therapies.

Clinical value of detecting autoantibodies against β1-, β2-, and α1-adrenergic receptors in carvedilol treatment of patients with heart failure

Objective To determine the possible association of anti-β1-adrenergic receptors(anti-β1-AR), anti-β2-AR and anti-α1-AR with carvedilol treatment in patients with heart failure(HF). Methods A total of 267 HF patients were prospectively enrolled. Blood samples were measured by an enzyme-linked immunosorbent assay. All of the patients received carvedilol for their HF. Each patient was followed up for six months and their cardiac function was measured. Results The final analysis encompassed 137 patients comprising 65 patients with three autoantibodies(positive group) and 72 patients without all three autoantibodies but with one or two autoantibodies(negative group). The frequency and geometric mean titer of anti-β1-AR, anti-β2-AR, and anti-α1-AR were significantly lower in the group without all three autoantibodies after six months of carvedilol treatment(all P < 0.01;from 100% to 57%, 50%, and 49%, respectively;and from 1: 118, 1: 138, and 1: 130 to 1: 72, 1: 61, and 1: 67, respectively). Furthermore, 28 patients in the positive group demonstrated complete ablation of autoantibodies. In addition, left ventricular remodelling and function was significantly improved by the use of carvedilol combined with the standard treatment regime for six months in the positive group(P < 0.01) when compared to the negative group(P < 0.05). Conclusions Carvedilol treatment significantly decreases frequency and geometric mean titer in patients with all three autoantibodies, even up to complete ablation, and significantly improved cardiac function and remodelling. The effect of carvedilol is probably correlated to the presence of all three autoantibodies.

β_(2) and α_(2) adrenergic receptors mediate the proneurogenic in vitro effects of norquetiapine

Positive modulation of adult hippocampal neurogenesis may contribute to the therapeutic effects of clinically relevant antidepressant drugs,including atypical antipsychotics.Quetiapine,an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants,promotes adult hippocampal neurogenesis in preclinical studies.Norquetiapine,the key active metabolite of quetiapine in humans,has a distinctive receptor profile than the parent compound.The drug is indeed a high affinity norepinephrine transporter inhibitor and such activity has been proposed to contribute to its antidepressant effect.At present,no information is available on the effects of norquetiapine on adult neurogenesis.We extensively investigated the activity of quetiapine and norquetiapine on adult murine neural stem/progenitor cells and their progeny.Additionally,selective antagonists for β_(2)/α_(2) adrenergic receptors allowed us to evaluate if these receptors could mediate quetiapine and norquetiapine effects.We demonstrated that both drugs elicit in vitro proneurogenic effects but also that norquetiapine had distinctive properties which may depend on its ability to inhibit norepinephrine transporter and involve β_(2)/α_(2) adrenergic receptors.Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees(IACUC)at University of Piemonte Orientale,Italy(approval No.1033/2015PR)on September 29,2015.

Changes of pulmonary α_1-and β-adrenergic receptors after endotoxininduced acute lung injury in rats

Changes of pulmonary α1-and βadrenergic receptors (α1- ARs and β-ARs) after endotoxin-induced lung injury were dynamically observed with radioligand binding assay and the pulmonary rnicrovascular permeability and histopathology were also studied in rats to investigate the relationship between changes of pu1monary ARs and acute lung injury. It was found that the contents of both α1-ARs and β-ARs were significantly decreased after endotoxin-induced acute lung injury. On the basis of these findings, the authors inferred that the down regulation of β-ARs might be one of the factors to increase pulmonary microvascular permeability and that of α1-ARs seems to be a protective reaction. This inference might serve as the theoretical basis to treat pulmonary edema with α1-antagonists and β-agonists clinically.

Experimental study on alteration of adrenergic receptors activity in neuronal membranes protein of cerebral cortex following brain trau ma in rats

Objective:To definethecourseof changestakenbyα 1 andβadrenergicreceptors(AR)activityaftertraumatic braininjury(TBI)andexploretheapproachforsecondarybraininjury(SBI)management.Methods:Theneuronalmem-braneproteinof cortexwereextractedfromtheratssubjectto traumaticbraininjury,andthechangesofα 1 -andβ-ARac-tivitiesintheneuronalmembraneswereexaminedby radioligandbindingassay(RLBA).Results:α 1 -andβ-ARactivities underwentobviouschanges,reachingtheirpeakvaluesat24h afterTBI.α 1 -ARbindingdensity(B max )reducedby22.6%whiletheligandaffinityincreasedby66.7%,andforβ-AR,however,B max increasedby116.9%andtheligandaffinityre-ducedby50.7%.Theirantagonistscouldcounteractthechangesofα 1 -andβ-ARactivity.Con clu sion:Thepatternsof changesvariesbetweenα 1 -andβ-ARactivityafterTBI, suggestingtheirdifferentrolesintheneuronalmembranesafter braintrauma,andtimelyadministrationof ARantagonistsispotentiallybeneficialinTBImanagement.

Changes of pulmonary beta-adrenergic receptors and their relationship with membranous phospholipid metabolism in endotoxin-induced lung injury in rats

The changes of beta-adrenergic receptors (AARs) in lung tissue in endotoxin-induced acute lung injury was investigated with radioligand bindig assay in rats. The lipid fluidity and phospholipid content of the cellular membrane of lung tissue were measured with fluorescent polarization and high performance liquid chromatography respectively. The findings were as follows:1- Four hours after endotoxin injection, there was a 47% decrease of the maximal binding capacity of fyARsas compared with the control.2. Endotoxin was able to decrease the lipid fluidity and phospholipid content of the pulmonary cellular membrane markedly and at the same time. There was an elevated activity of phospholipase A2 in the pulmonary tissueThese findings suggest that the decrease of the binding capacity of &ARs results in a decrease of the PAR mediated functions, which plays a ro1e in the pathogensis of endotoxin-induced acute lung injury and the activation of phospholipase A2 which is an important factor to reduce the phospholipid content of cell membrane and subsequently to decrease its lipid fluidity, can result in a reduction of the lateral diffusion and rotatory movement of β-ARs and to decrease the chances of β-ARs to bind with the ligands.

Interactive Effects of Zinc and Zilpaterol Hydrochloride on Bovine <i>β</i>-Adrenergic Receptors

The objective of this study was to determine if the addition of zinc (Zn) in combination with zilpaterol HCL (ZH) affected the interaction of ZH with the beta2-adrenergic receptor (β-AR) by altering cAMP production, gene expression, and protein abundance in cultured skeletal muscle cells. Cultures of muscle bovine satellite cells were established and treated at 120 h with: 1) 0 μM Zn/zilpaterol hydrochloride (ZH;CON);2) 0 μM Zn/10 μM ZH (ZH);3) 1 μM Zn from Zn chloride/0 μM ZH (Zn);4) 1 μM Zn from Zn chloride/10 μM ZH (ZN/ZH) in differentiation media for an additional 0, 6, 24, 48 and 96 h. Protein and mRNA were isolated and quantified at 24 and 96 h, and cAMP was measured at 0, 6, 24, 48 and 96 h. At 0, 24, 48 and 96 h, no differences (P > 0.05) were detected in cAMP production. At 6 h, Zn cells had the greatest concentration of cAMP (P < 0.05) compared to ZH treatments. No differences (P > 0.05) were detected in mRNA abundance at 24 h. At 96 h, 0 μM Zn/10 μM ZH cells had an increased abundance of myosin heavy chain (MHC)-I mRNA (P < 0.05) compared to CON. Furthermore, ZH had a greater abundance of MHC-IIX mRNA (P < 0.05) and a tendency for a greater abundance of IGF-1 mRNA (P < 0.15) compared to CON and ZN/ZH. No differences (P > 0.05) were detected in the protein abundance of β1AR and the β2AR. These results indicated Zn and ZH in combination did not have an additive effect on β2-AR function as indicated by cAMP concentrations.

Correlation of beta－receptors in human pathological brain tissue and in peripheral blood lymphocytes

Beta-adrenergic receptors in the brain are involved in modulating cerebral blood flow (CBF) and cerebral energy metabolism (CEM). Because of the difficult availability of brain tissue samples, investigation of the relevant beta-receptor of brain is limited. In the present study, the density of beta-receptors in brain tissues and in circulating lymphocytes was measured by the method of radio-ligand receptor binding (RLBA), in brain injury or brain tumor and a correlation analysis was performed. Our results show that there is linear correlation between the beta-receptors in brain tissue and in peripheral blood lymphocytes (r= 0. 811 , P<0. 01) in cases of increased permeability of bloodbrain barrier during brain injury or brain tumor.

No functional β_3-adrenergic receptors expressed in rat skeletal muscle cells

目的：研究原代培养的大鼠骨骼肌细胞中是否存在功能性β３肾上腺素受体（β３ＡＲ）．方法：利用柱层析方法测定异丙肾上腺素（Ｉｓｏ），β３ＡＲ激动剂ＣＧＰ１２１７７Ａ和β３ＡＲ拮抗剂ＳＲ５９２３０Ａ对培养骨骼肌细胞环磷腺苷（ｃＡＭＰ）生成作用．结果：Ｉｓｏ剂量依赖性刺激骨骼肌细胞ｃＡＭＰ的生成，ＥＣ５０为１５１ｎｍｏｌ·Ｌ－１．普萘洛尔０．１μｍｏｌ·Ｌ－１抑制Ｉｓｏ刺激的ｃＡＭＰ的生成，ＫＢ值为３４７ｎｍｏｌ·Ｌ－１．ＣＧＰ１２１７７Ａ无刺激ｃＡＭＰ生成作用，但可抑制Ｉｓｏ的作用．ＳＲ５９２３０Ａ１０ｎｍｏｌ·Ｌ－１不能抑制Ｉｓｏ刺激ｃＡＭＰ的产生．

Purification of β-adrenergic receptors from Beijing duck erythrocyte plasma membranes and their reconstitution with Gs and adenylate cyclase on asolectin liposomes

Catecholamines such as adrenaline, norepinephrine and isoproterenol regulate a wide variety of physiological responses via their specific binding to adrenergic receptors located in the plasma membrane. Adrenergic receptors have been divided into two major types, α and β. Binding of ligands to β-adrenergic receptors (β-AR) first triggers the activation of stimulatory GTP-binding protein (Gs). The activated Gs then interacts

Correlation Analysis between Visceral Manifestation Theories on Xuanfa and Effect of Adrenergic Receptors

Chinese visceral manifestation theory states that lung dominates qi,regulates breathing,and governs Xuanfa（dispersing）and Sujiang（descending）.Clarifying this theory with modern physiological and pathological knowledge has been considered as an important part of complementary and alternative medicine therapy.Previous studies found that most Xuanfa drugs contained pharmacodynamic ingredients related to adrenergic receptors（ARs）signal transduction.The association of Xuanfa,with the control of breath movement,nutrient transfer,spreading heat to regulate temperature,and helping the heart control blood circulation,coincides with the physiological function of organs dominated by ARs-regulated sympathetic postganglionic fibers.Therefore,we hypothesize that Xuanfa is closely related to ARs-regulated signal transduction.By modern biological knowledge,we tried to evaluate and expound the correlation between the molecular mechanisms of modern physiology or pathology and Xuanfa or Sujiang theory.Ultimately,the research and development of modern drugs should fully expect the guidance from Chinese visceral manifestation theory,and the application of this principle will guide the prevention and clinical treatment of a variety of refractory diseases caused by a change in environment,climate,or lifestyle.

Effect of transmembrane Ca^(2+) gradient on ligand binding of reconstituted β-adrenergic receptors

It is well known that, under physiological conditions, the cytosolic free Ca2+ in most cells is around 10-7—10-6 mol/L, whereas the extracellular Ca2+ concentration is about 10-3 mol/L. This results in a 1 000—10 000-fold transmembrane Ca2+ gradient. The maintenance of such a concentration gradient has been proved to be of vital importance in cell function. Although a transmembrance Ca2+ gradient exists across the plasma membrance, little attention has

THE DISTRIBUTION OF BETA-ADRENERGIC RECEPTORS IN GUINEA PIG LUNGS AND THEIR CHANGES IN EXPERIMENTAL ALLERGIC ASTHMA

In this paper, the distribution of pulmonary beta-adrenergic receptors (beta-receptors) innormal and experimental allergic asthmatic guinea pigs was determined using autoradiograph-ic method. The results showed that the distribution of beta-receptors in the lung sections waswidespread. There was a significant decrease of beta-receptor density in several tissue struc-tures of asthmatic guinea pig lungs compared with the controls, a 23.73% decrease in beta-recep-tor binding sites in bronchiolar smooth muscles and a 18.65% decrease in bronchial smoothmuscles; a 23 .53%. a 14.23% and a 17. 16% decrease in bronchiolar epithelium, in bronchialepithelium and in alveolar epithelium respectively. The results indicated that the beta-recep-tor decrease in smooth muscles in experimental asthmatic guinea pig lungs might be one ofthe important factors which made the tension of smooth muscles increase. The relationshipbetween the beta-receptor decrease of other sites and bronchial asthma needs to be studiedfurther.

FKBP12.6 Knockout Increases Ryanodine Receptors Open Probability During β-adrenergic Stimulation in Mice Cardiac Myocytes

FK506 binding protein 12.6 (FKBP12.6) is the protein in the ryanodine receptor complex, but its function is controversial in different reported work. Some conclude that FKBP12.

Mediating effect of dopamine D3 receptors on Jak2 and GABAAα1 expression in mouse brains induced by cocaine

Background Cocaine addiction may involve complex neuroadaptations, including many changes of genes expression. Dopamine D3 receptors play an important role in cocaine addiction; however, its role in cocaine induced gene expression change is poorly understood. To identify the changes in gene expression induced by repeated cocaine exposure through D3 dopamine receptors, we compared the expression of four molecules： Janus kinase 2 （Jak2）, g-aminobutanoic acid receptor subunit alpha 1 （GABAAα1）, glutamate receptor AMPA3 alpha 3 （GluR 3） and stromal cell derived factor 1 （SDF1）. These four have been implicated in mediating the actions of cocaine in the nucleus accumbens （NAc） and caudoputamen （CPu） in mice after acute and repeated cocaine exposure. Methods For the acute and repeated injections, the mice were divided into four groups： 30 mg/kg cocaine, nafadotride 0.5 mg/kg ＋ cocaine 30 mg/kg, nafadotride 0.5 mg/kg, and saline as the basal group. The expression of Jak2, GABAAα1, GluR 3 and SDF1 were assayed by Western blot, quantitative real-time RT-PCR and immunohistochemistry. Results Twenty-four hours after seven consecutive days of repeated cocaine exposure, the expression of GABAAα1 decreased in cocaine group compared with basal line and further decreased in the cocaine ＋ nafadotride group and remained at basal level in the nafadotride group. Similarly, the Jak2 expression decreased in cocaine group compared with base line. However, the levels of Jak2 increased in cocaine ＋ nafadotride group compared with cocaine group, while remained at basal level in nafadotride group. Conclusions GABAAα1 and Jak2 may be involved in chronic cocaine induced neuroadaptations. D3 dopamine receptors play an important role in the expression of these genes.

β_(2)-肾上腺素能受体通过β-抑制蛋白/细胞外调节蛋白激酶通路在病毒性心肌炎中的机制研究

目的:探究β_(2)-肾上腺素能受体(β_(2)-AR)通过β-抑制蛋白(β-arrestin)/细胞外调节蛋白激酶(ERK1/2)通路在病毒性心肌炎(VMC)小鼠心肌损伤中的可能作用机制。方法:将40只小鼠随机分为:对照组、VMC组、抑制β_(2)-AR组及抑制β-arrestin组,每组10只。超声心动图检测小鼠Tie指数、射血分数(EF)及左室短轴缩短率(FS)。HE染色检测心肌组织病理结构;Tunel试剂盒检测心肌凋亡水平;免疫荧光染色检测心肌组织β_(2)-AR、β-arrestin、ERK1/2蛋白水平;ELISA试剂盒检测血清肌酸激酶(CK)、天冬氨酸氨基转移酶(AST)含量。结果:与对照组比较,VMC组小鼠Tie指数增加,EF、FS减少(均P<0.05),小鼠心肌组织结构疏松紊乱、炎性细胞大量浸润,心肌细胞凋亡增加,心肌组织β_(2)-AR、β-arrestin及ERK1/2表达增加,血清CK与AST含量增加(均P<0.05);与VMC组比较,抑制β_(2)-AR组小鼠Tie指数减少,EF、FS增加(均P<0.05),小鼠心肌组织损伤改善,心肌细胞凋亡减少,心肌组织β_(2)-AR、β-arrestin及ERK1/2表达减少。与VMC组比较,抑制β-arrestin组小鼠心肌组织β-arrestin及ERK1/2表达减少,血清CK与AST含量减少(均P<0.05)。结论:抑制β_(2)-AR可通过下调β-arrestin/ERK1/2通路改善VMC小鼠心功能异常及心肌损伤。

The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells

AIM: The existence and properties of alpha-fetoprotein (AFP) receptor on the surface of NIH 3T3 cells and the effects of AFP on cellular signal transduction pathway were investigated. METHODS: The effect of AFP on the proliferation of NIH 3T3 cells was measured by incorporation of 3H-TdR. Receptor-binding assay of 125I-AFP was performed to detect the properties of AFP receptor in NIH 3T3 cells. The influences of AFP on the [cAMP]i and the activities of protein kinase A (PKA) were determined. Western blot was used to detect the change of K-ras P21 protein expression. RESULTS: The proliferation of NIH 3T3 cells treated with 0-80 mg/L of AFP was significantly enhanced. The Scatchard analysis indicated that there were two classes of binding sites with KD of 2.722 x 10(-9)M (Bmax=12810 sites per cell) and 8.931 x 10(-8)M (Bmax=119700 sites per cell) respectively. In the presence of AFP (20 mg/L), the content of cAMP and activities of PKA were significantly elevated . The level of K-ras P21 protein was upregulated by AFP at the concentration of 20 mg/L. The monoclonal antibody against AFP could reverse the effects of AFP on the cAMP content, PKA activity and the expression of K-ras p21 gene. CONCLUSION: The effect of AFP on the cell proliferation was achieved by binding its receptor to trigger the signal transduction pathway of cAMP-PKA and alter the expression of K- ras p21 gene.

多溴二苯醚类化合物干扰人雌激素受体alpha活性机理的理论研究

基于分子对接方法探讨了多溴二苯醚(PBDEs)类化合物与人雌激素受体α亚型间的分子作用机理.对多溴二苯醚类化合物是否具有拟雌激素功能的研究得出:可通过对接打分值和化合物结构特征来推测PBDEs母体化合物是否具有拟雌激素活性;对HO-PBDEs,与氨基酸残基GLU53和/或ARG394形成氢键可能是影响其拟雌激素活性的重要因素;对MeO-PBDEs,疏水MeO-位于结合腔的疏水中部有利于拟雌激素活性.从结构及构象分析得出,邻位疏水基(Br-、MeO-)有利于PBDEs类化合物的拟雌激素活性.同时对多溴二苯醚类化合物是否具有抗雌激素功能的结合特征研究发现,表现出抗雌激素活性的部分PBDEs类化合物伸进通常被雌激素受体拮抗剂雷洛昔芬和4-羟基它莫西芬的烷基胺侧链占据的通道,而大多数未表现出抗雌激素活性的PBDEs类化合物的结合模式类似雌激素受体激动剂17β-雌二醇,位于结合腔,没有伸进通道.本研究从化合物结构及化合物在受体内结合的构象特征上解释化合物活性不同的原因,以期能够利用构象分析得到的结果进行筛选.