Activation of calcium-sensing receptors is associated with apoptosis in a model of simulated cardiomyocytes ischemia/reperfusion

Objective： Calcium-sensing receptors （CaSRs） are G-protein coupled receptors which maintain systemic calcium homeostasis and participate in hormone secretion, activation of ion channels, cell apoptosis, proliferation, and differentiation. Previous studies have shown that CaSRs induce apoptosis in isolated adult rat heart and in normal neonatal rat cardiomyocytes by G-protein-PLC-IP3 signaling transduction. However, little knowledge is presently available concerning the role of CaSRs in the apoptosis induced by ischemia and reperfusion in neonatal cardiomyocytes. Methods： Primary neonatal rat ventricular cardiomyocytes were incubated in ischemiamimetic solution for 2 h, and then re-incubated in normal culture medium for 24 h to establish a model of simu- lated ischemia/reperfusion （I/R）. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase- mediated dUTP nick end labeling （TUNEL）. The expression of CaSRs mRNA was detected by real-time reverse transcription polymerase chain reaction （RT-PCR）. In addition, the expressions of caspase-3 and Bcl-2 were analyzed by western blot. Results： The simulated I/R enhanced the expression of CaSRs and cardiomyocyte apoptosis. GdCl3, a specific activator of CaSRs, further increased the expression of CaSRs and cardiomyocyte apoptosis, along with up-regulation of caspase-3 and down-regulation of Bcl-2. Conclusion： CaSRs are associated with UR injury and apoptosis in neonatal rat ventricular cardiomyocytes via suppressing Bcl-2 and promoting caspase-3 expression.

Phenytoin-Induced Elevation of the Intracellular Calcium Concentration by Stimulation of Calcium-Sensing Receptors in Gingival Fibroblasts

Background:The mechanism concerning gingival overgrowth as a side effect of phenytoin, a therapeutic drug for epilepsy has been still unclear. As one of mechanisms, by measuring the intracellular calcium concentration ([Ca2+]i) of the gingival fibroblasts, it has been advocated that there is relationship between gingival overgrowth and phenytoin-induced alterations in the [Ca2+]i in gingival fibroblasts. To confirm that phenytoin elevates the [Ca2+]i, and if so, to find out its mode of action. Methods: The [Ca2+]i was measured with the Ca2+-sensitive fluorescent dye fura-2/AM. Cells were soaked in a flexiperm chamber and perfused by a saline. Drugs at appropriate concentrations were added to the perfusate. Results: Phenytoin concentration-dependently elevated the [Ca2+]i. NPS2390, a calcium-sensing receptor (CaSR) blocker, significantly suppressed the phenytoin-induced [Ca2+]i elevation. U73122, a phospholipase C (PLC) inhibitor, inihibited the phenytoin-induced [Ca2+]i elevation. TMB-8, a blocker of inositol triphophate (IP3) receptors in ER, significantly depressed the phenytoin-induced [Ca2+]i elevation. m-3M3FBS, a PLC activator, enhanced the phenytoin-induced [Ca2+]i elevation. From the findings obtained, it is discussed as follows: The Ca2+-free saline and NPS2390, a CaSR antagonist, inhibited the phenytoin-induced [Ca2+]i rise;These results indicate that CaSRs exist in gingival fibroblasts and that CaSRs are involved in the phenytoin-induced [Ca2+]i rise;U73122 and TMB-8 depressed the phenytoin-induced [Ca2+]i elevation and furthermore, m-3M3FBS enhanced the phenytoin-induced [Ca2+]i elevation, showing that the Ca2+ release from the ER is involved in the phenytoin-induced [Ca2+]i elevation. Conclusion: We have concluded that phenytoin elevates the [Ca2+]i by activating CaSRs and enhancing the Ca2+ release from the Ca2+ stores in gingival fibroblasts.

Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice

BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.

Novel Role of Calcium-Sensitive Receptors in Chronic Hypoxia-Induced Proliferation of Pulmonary Vein Smooth Muscle Cells

Objective:Vascular remodeling due to chronic hypoxia(CH)occurs not only in the pulmonary arteries but also in the pulmonary veins.Pulmonary vascular remodeling arises from the proliferation of pulmonary vascular myocytes.However,the mechanism by which CH induces the proliferation of pulmonary vein smooth muscle cells(PVSMCs)is unknown.This study aimed to investigate the mechanism by which CH affects the proliferation of PVSMCs.Methods:PVSMCs were isolated from rat distal pulmonary veins and exposed to CH(4%O2,60h),and the expression of the calcium-sensitive receptor(CaSR)was detected by Western blotting and immunofluorescence.MTT assay was used to detect the proliferation viability of the cells,and the changes in the intracellular calcium concentration were detected by laser confocal scanning technique.Results:CaSR expression was present in rat distal PVSMCs,and CaSR protein expression was upregulated under hypoxia.The positive regulator spermine not only enhanced CH-induced CaSR upregulation but also enhanced CH-induced increase in cell viability and calcium ion concentration.The negative CaSR regulator NPS2143 not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced cell viability and calcium ion concentration.Conclusion:CaSR-mediated hyperproliferation is a novel pathogenic mechanism for the development of proliferation in distal PVSMCs under CH conditions.

Melanocortin 3,5 receptors immunohistochemical expression in colonic mucosa of inflammatory bowel disease patients:A matter of disease activity?

BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.

Role of bitter contributors and bitter taste receptors:a comprehensive review of their sources,functions and future development

Bitterness,one of the 5“basic tastes”,is usually undesired by humans.However,abundant literature reported that bitter fruits and vegetables have beneficial health effects due to their bitter contributors.This review provided an updated overview of the main bitter contributors of typical bitter fruits and vegetables and their health benefits.The main bitter contributors,including phenolics,terpenoids,alkaloids,amino acids,nucleosides and purines,were summarized.The bioactivities and wide range of beneficial effects of them on anti-cancers,anti-inflammations,anti-microbes,neuroprotection,inhibiting chronic and acute injury in organs,as well as regulating behavior performance and metabolism were reported.Furthermore,not only did the bitter taste receptors(taste receptor type 2 family,T2Rs)show taste effects,but extra-oral T2Rs could also be activated by binding with bitter components,regulating physiological activities via modulating hormone secretion,immunity,metabolism,and cell proliferation.This review provided a new perspective on exploring and explaining the nutrition of bitter foods,revealing the relationship between the functions of bitter contributors from food and T2Rs.Future trends may focus on revealing the possibility of T2Rs being targets for the treatment of diseases,exploring the mechanism of T2Rs mediating the bioactivities,and making bitter foods more acceptable without getting rid of bitter contributors.

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.

Immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation

Proton-activated G protein-coupled receptors(GPCRs),initially discovered by Ludwig in 2003,are widely distributed in various tissues.These receptors have been found to modulate the immune system in several inflammatory diseases,including inflammatory bowel disease,atopic dermatitis,and asthma.Proton-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular pH.This detection triggers downstream signaling pathways within the cells,ultimately influencing the function of immune cells.In this review,we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.

Intricate roles of estrogen and estrogen receptors in digestive system cancers:a systematic review

Gender disparities are evident across different types of digestive system cancers,which are typically characterized by a lower incidence and mortality rate in females compared to males.This finding suggests a potential protective role of female steroid hormones,particularly estrogen,in the development of these cancers.Estrogen is a well-known sex hormone that not only regulates the reproductive system but also exerts diverse effects on non-reproductive organs mediated through interactions with estrogen receptors(ERs),including the classic(ERαand ERβ)and non-traditional ERs[G protein-coupled estrogen receptor(GPER)].Recent advances have contributed to our comprehension of the mechanisms underlying ERs in digestive system cancers.In this comprehensive review we summarize the current understanding of the intricate roles played by estrogen and ERs in the major types of digestive system cancers,including hepatocellular,pancreatic,esophageal,gastric,and colorectal carcinoma.Furthermore,we discuss the potential molecular mechanisms underlying ERα,ERβ,and GPER effects,and propose perspectives on innovative therapies and preventive measures targeting the pathways regulated by estrogen and ERs.The roles of estrogen and ERs in digestive system cancers are complicated and depend on the cell type and tissue involved.Additionally,deciphering the intricate roles of estrogen,ERs,and the associated signaling pathways may guide the discovery of novel and tailored therapeutic and preventive strategies for digestive system cancers,eventually improving the care and clinical outcomes for the substantial number of individuals worldwide affected by these malignancies.

Exploring the vital role of microglial membrane receptors in Alzheimer’s disease pathogenesis: a comprehensive review

Neurodegenerative diseases constitute a broad category of diseases caused by the degeneration of the neurons.They are mainly manifested by the gradual loss of neuron structure and function and eventually can cause death or loss of neurons.As the global population ages rapidly,increased people are being diagnosed with neurodegenerative diseases.It has been established that the onset of Alzheimer’s disease(AD)is closely linked with increasing age and its major pathological features include amyloid-beta plaques(Aβ),Tau hyperphosphorylation,Neurofibrillary tangles(NFTs),neuronal death as well as synaptic loss.The involvement of microglia is crucial in the pathogenesis and progression of AD and exhibits a dual role.For instance,in the early stage of AD,microglia surface membrane proteins or receptors can participate in immunophagocytosis,and anti-inflammatory functions and act as a physical barrier after recognizing various ligands such as Aβand NFTs.However,in the later stage of the disease,membrane receptors on the surface of microglia can cause its activation to release a substantial quantity of pro-inflammatory factors.Which can amplify the neuroinflammatory response.The rapid decline of normal immune phagocytosis can result in the continuous accumulation of abnormal proteins,leading to neuronal dysfunction and destruction of the formed physical barrier as well as the neurovascular microenvironment.It can also increase the transformation of microglia from anti-inflammatory phenotype M2 to pro-inflammatory phenotype M1,induce severe neuronal injury or apoptosis,and aggravate the progression of AD.Due to few articles have focused on the AD-related membrane protein receptors on microglia,thus in this paper,we have reviewed several representative microglial membrane proteins or receptors about their specific roles and functions implicated in AD,and expect that there will be more in-depth research and scientific research results in the treatment of AD by targeted regulation of microglia membrane protein receptors in the future.

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Characterization of Domeless receptors and the role of Bd Domeless3 in anti-symbiont-like virus defense in Bactrocera dorsalis

The Janus kinase/signal transducers and activators of transcription(JAK/STAT)signaling pathway play a pivotal role in innate immunity.Among invertebrates,Domeless receptors serve as the key upstream regulators of this pathway.In our study on Bactrocera dorsalis,we identified three cytokine receptors:BdDomeless1,BdDomeless2,and BdDomeless3.Each receptor encompasses five fibronectin-type-III-like(FN III)extracellular domains and a transmembrane domain.Furthermore,these receptors exhibit the increased responsiveness to diverse pathogenic challenges.Notably,only BdDomeless3 is upregulated during symbiont-like viral infections.Moreover,silencing BdDomeless3 enhanced the infectivity of Bactrocera dorsalis cripavirus(BdCV)and B.dorsalis picorna-like virus(BdPLV),underscoring BdDomeless3’s crucial role in antiviral defense of B.dorsalis.Following the suppression of Domeless3 expression,six antimicrobial peptide genes displayed decreased expression,potentially correlating with the rise in viral infectivity.To our knowledge,this is the first study identifying cytokine receptors associated with the JAK/STAT pathway in tephritid flies,shedding light on the immune mechanisms of B.dorsalis.

The Role of Toll-Like Receptors and Nuclear Factor κB p65 Protein in the Pathogenesis of Otitis Media

The role of Toll-like receptor 4 (TLR4) and nuclear factor κB p65 (NF-κB p65) proteins in the pathogenesis of otitis media is explored. In recent years, the incidence of otitis media has been rising globally, becoming a significant threat to human health. More and more studies have found that Toll-like receptor 4 (TLR4), as a member of the Toll-like receptor family, can promote the generation of inflammatory factors and is closely related to the body’s immune response and inflammatory response. Nuclear factor-κB p65 (NF-κB p65) is a nuclear transcription factor that can interact with various cytokines, growth factors, and apoptotic factors, participating in processes such as oxidative stress, apoptosis, and inflammation in the body [1]. This article elaborates on the structure, function, and signaling pathways of TLR4 and NF-κB p65 proteins in the pathogenesis of otitis media, aiming to provide more precise targets and better therapeutic efficacy for the diagnosis and treatment of otitis media. The role of inflammation in disease.

Toll-like receptors 2 polymorphism is associated with psoriasis: A case-control study in the northern Chinese population

Background:Psoriasis is a disease caused by genetics and immune system dysfunction,affecting the skin and joints.Toll-like receptors(TLRs)play an important role in triggering the innate immune response and controlling adaptive immunity.The role of TLR2 in the progression of psoriasis is not well understood.Methods:A case-control study was conducted on a northern Chinese Han population,consisting of psoriasis patients and healthy control subjects.Genotyping was performed using the tetra-primer amplification refractory mutation system-polymerase chain reaction(ARMS-PCR),and allele and genotype frequencies of four SNPs in TLR2 were analyzed in 270 psoriasis patients and 246 healthy controls.Results:Four TLR2 SNPs(rs11938228,rs4696480,rs3804099,rs5743699)were genotyped and found to be in linkage disequilibrium.The genotype distributions of rs11938228 and rs4696480 in two groups were in Hardy-Weinberg equilibrium and statistically significant except for the overdominance model.The haplotypes ATTC and ATCC were found to be protective against psoriasis.Conclusion:Our study found a correlation between TLR2 genetic variations and the likelihood of psoriasis in northern China.

N-acetylcysteine and zinc sulphate abate di-2-ethylhexyl phthalate-mediated reproductive dysfunction in rats:Focus on oxidative and sex hormone receptors mechanisms

Objective:To investigate the potential of N-acetylcysteine(NAC)and zinc sulphate(ZnSO_(4))in mitigating reproductive dysfunction caused by di-2-ethylhexyl phthalate(DEHP)in rats and to understand the underlying mechanisms,specifically oxidative stress and sex hormone receptor activity.Methods:Thirty-five male Wistar rats were randomly divided into five equal groups(n=7 per group).Group 1 was administered 0.5 mL of distilled water and served as the control group.Group 2 was given only DEHP(750 mg/kg/day),while group 3,4 and 5 were given DEHP(750 mg/kg/day)plus NAC(100 mg/kg/day),DEHP(750 mg/kg/day)plus ZnSO_(4)(0.5 mg/kg/day),and DEHP(750 mg/kg/day)plus NAC(100 mg/kg/day)as well as ZnSO_(4)(0.5 mg/kg/day),respectively.All treatments lasted for 21 days.Samples were obtained after the rats were sacrificed,and hormones levels in the serum and markers of oxidative stress in the testicles were analyzed using the enzyme-linked immunosorbent assay.The amount of androgen receptors in the testicles was determined by immunohistochemistry,and the susceptibility of testosterone and DEHP to bind to androgen receptor and 5α-reductase was determined by molecular docking studies.Results:DEHP decreased reproductive hormones,testicular antioxidant enzymes,increased malondialdehyde levels,and negatively impacted histology of the pituitary and testes.NAC or ZnSO_(4) treatment showed a marked improvement in testicular antioxidant status and hormone levels,as well as a positive effect on the histology of the pituitary and testes.The combination of both treatments appeared to be more effective.The affinity of DEHP to bind to androgen receptors may lead to disruption of androgen receptor signaling,which can further result in dysfunction of hormones related to androgen.However,NAC is more likely to form stronger binding interactions with follicle stimulating hormone and luteinizing hormone receptors,as well as gonadotropin-releasing hormone receptors,when compared to DEHP.Conclusions:The possibility that NAC and ZnSO_(4) could downregulate DEHP-induced sex hormone changes is suggested by their potential to reduce toxicity.

Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development

Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Calcium-sensing receptor in colorectal inflammation and cancer:Current insights and future perspectives

The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the Ca SR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitisassociated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.

Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression?

Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and intercellular Ca2＋ signaling and gliotransmitters release via the Aβ/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （calcium-sensing receptor） signaling. Recently, it was suggested that the NMDAR （N-methyl-D-aspartate receptor） inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.