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.

C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

P2Y1 receptor in Alzheimer’s disease

Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.

Targeting the adenosine A2A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease

Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors,called A1 and A2A receptors.The adenosine A2A receptor(A2AR)antagonists have been clinically pursued for the last 2 decades,leading to final approval of the istradefylline,an A2AR antagonist,for the treatment of OFF-Parkinson's disease(PD)patients.The approval paves the way to develop novel therapeutic methods for A2AR antagonists to address 2 major unmet medical needs in PD and traumatic brain injury(TBI),namely neuroprotection or improving cognition.In this review,we first consider the evidence for aberrantly increased adenosine signaling in PD and TBI and the sufficiency of the increased A2AR signaling to trigger neurotoxicity and cognitive impairment.We further discuss the increasing preclinical data on the reversal of cognitive deficits in PD and TBI by A2AR antagonists through control of degenerative proteins and synaptotoxicity,and on protection against TBI and PD pathologies by A2AR antagonists through control of neuroinflammation.Moreover,we provide the supporting evidence from multiple human prospective epidemiological studies which revealed an inverse relation between the consumption of caffeine and the risk of developing PD and cognitive decline in aging population and Alzheimer's disease patients.Collectively,the convergence of clinical,epidemiological and experimental evidence supports the validity of A2AR as a new therapeutic target and facilitates the design of A2AR antagonists in clinical trials for disease-modifying and cognitive benefit in PD and TBI patients.

Adenosine A_(2A)receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult

During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.

Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.

Erythropoietin-induced hepatocyte receptor A2 regulates effect of pyroptosis on gastrointestinal colorectal cancer occurrence and metastasis resistance

Erythropoietin-induced hepatocyte receptor A2(EphA2)is a receptor tyrosine kinase that plays a key role in the development and progression of a variety of tumors.This article reviews the expression of EphA2 in gastrointestinal(GI)colorectal cancer(CRC)and its regulation of pyroptosis.Pyroptosis is a form of programmed cell death that plays an important role in tumor suppression.Studies have shown that EphA2 regulates pyrodeath through various signaling pathways,affecting the occurrence,development and metastasis of GI CRC.The overexpression of EphA2 is closely related to the aggressiveness and metastasis of GI CRC,and the inhibition of EphA2 can induce pyrodeath and improve the sensitivity of cancer cells to treatment.In addition,EphA2 regulates intercellular communication and the microenvironment through interactions with other cytokines and receptors,further influencing cancer progression.The role of EphA2 in GI CRC and its underlying mechanisms provide us with new perspectives and potential therapeutic targets,which have important implications for future cancer treatment.

Role of triggering receptor expressed on myeloid cells 1/2 in secondary injury after cerebral hemorrhage

Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.

Nuclear receptors and pathogenesis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.

Electroacupuncture improves neuropathic pain Adenosine, adenosine 5'-triphosphate disodium and their receptors perhaps change simultaneously

Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 （P2X3） receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.

Electronic Structure of some A3 Adenosine-Receptor Antagonist——A Structure Activity Relationship

DFT quantum chemical computations have been carried out at the B3LYP/6-31G (d) level. Full geometry optimization has been performed and equilibrium geometries for a new series of phenyl thiazoles have been located. Ground state electronic properties, charge density distributions, dipole moments and its components have been calculated and reported. Effect of substituents on the geometry and on the polarization of the studied series of compounds are analyzed and discussed. Some structural features have been pinpointed to underline the affinity and selectivity of the studied compounds as adenosine A3-receptor antagonists. Results of the present work indicate that activity towards A3 receptor sites is directly correlated with both of the polarity and the co-planarity of the thiazole.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

Electroacupuncture-induced neuroprotection against focal cerebral ischemia in the rat is mediated by adenosine A1 receptors

The activation of adenosine A1 receptors is important for protecting against ischemic brain injury and pretreatment with electroacupuncture has been shown to mitigate ischemic brain insult. The aim of this study was to test whether the adenosine A1 receptor mediates electroacupuncture pretreatment-induced neuroprotection against ischemic brain injury. We first performed 30 minutes of electroacupuncture pretreatment at the Baihui acupoint（GV20）, delivered with a current of 1 mA, a frequency of 2/15 Hz, and a depth of 1 mm. High-performance liquid chromatography found that adenosine triphosphate and adenosine levels peaked in the cerebral cortex at 15 minutes and 120 minutes after electroacupuncture pretreatment, respectively. We further examined the effect of 15 or 120 minutes electroacupuncture treatment on ischemic brain injury in a rat middle cerebral artery-occlusion model. We found that at 24 hours reperfusion,120 minutes after electroacupuncture pretreatment, but not for 15 minutes, significantly reduced behavioral deficits and infarct volumes. Last, we demonstrated that the protective effect gained by 120 minutes after electroacupuncture treatment before ischemic injury was abolished by pretreatment with the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine（1 mg/kg, intraperitoneally）. Our results suggest that pretreatment with electroacupuncture at the Baihui acupoint elicits protection against transient cerebral ischemia via action at adenosine A1 receptors.

Long-term adenosine A1 receptor activation-induced sortilin expression promotes α-synuclein upregulation in dopaminergic neurons

Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases.However,the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains unclear.In this study,rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine(CPA)for five weeks.The mobility of rats was evaluated by forced swimming test,while their cognitive capabilities were evaluated by Y-maze test.Expression of sortilin,α-synuclein,p-JUN,and c-JUN proteins in the substantia nigra were detected by western blot analysis.In addition,immunofluorescence staining of sortilin andα-synuclein was performed to detect expression in the substantia nigra.The results showed that,compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(5 mg/kg)+CPA co-treated rats,motor and memory abilities were reduced,surface expression of sortin andα-synuclein in dopaminergic neurons was reduced,and total sortilin and totalα-synuclein were increased in CPA-treated rats.MN9D cells were incubated with 500 nM CPA alone or in combination with 10μM SP600125(JNK inhibitor)for 48 hours.Quantitative real-time polymerase chain reaction analysis of sortilin andα-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone,but the combination of CPA and SP600125 could inhibit this expression.Predictions made using Jasper,PROMO,and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents.A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this prediction.After sortilin expression was inhibited by sh-SORT1,expression of p-JUN and c-JUN was detected by western blot analysis.Long-term adenosine A1 receptor activation levels upregulatedα-synuclein expression at the post-transcriptional level by affecting sortilin expression.The online tool Raptor-X-Binding and Discovery Studio 4.5 prediction software predicted that sortilin can bind toα-synuclein.Co-immunoprecipitation revealed an interaction between sortilin andα-synuclein in MN9D cells.Our findings indicate that suppression of prolonged adenosine A1 receptor activation potently inhibited sortilin expression andα-synuclein accumulation,and dramatically improved host cognition and kineticism.This study was approved by the University Committee of Animal Care and Supply at the University of Saskatchewan(approval No.AUP#20070090)in March 2007 and the Animals Ethics Committee of University of South China(approval No.LL0387-USC)in June 2017.

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.

Attenuation of gastric mucosal inflammation induced by aspirin through activation of A_(2A) adenosine receptor in rats

AIM： To determine whether a specific adenosine A2A receptor agonist （ATL-146e） can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines. METHODS： Gastric lesions were produced by oral gavage of aspirin （200 mg/kg） and HCI （0.15 mol/L, 8.0 mL/kg）. 4-{3-[6-Amino-9-（5-ethylcarbamoyl-3,4- dihydroxy-tetrahydro-furan-2-yl）-9H-purin-2-yl]-prop-2- ynyl}-cyclohexanecarboxylic acid methyl ester （ATL-146e, 2.5-5μg/kg, IP） was injected 30 min before the administration of aspirin. Tissue myeloperoxidase （MPO） concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 （PGE2） production and gastric secretion. RESULTS： Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions （ulcer index） in control rats was 29.8±7.75 mm and was reduced to 3.8±1.42 mm alter pretreatment with 5.0 g/kg ATL-146e （P〈 0.01）. The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e. CONCLUSION： The specific adenosine A2A receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

Pretreatment with adenosine and adenosine A1 receptor agonist protects against intestinal ischemia-reperfusion injury in rat

AIM： To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury. METHODS： Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N^6-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl- 1,3-clipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase,malondialdehyde, and reduced glutathione levels were measured. RESULTS： Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist. CONCLUSION： The data suggest that adenosine and A1 receptor stimulation attenuate ischemic intestinal injury via decreasing oxidative stress, lowering neutrophil infiltration, and increasing reduced glutathione content.

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.

The gene expression of adenosine receptors in the processes of contrast induced nephropathy in mouse kidney

Objective: Contrast induced nephropathy (CIN) is the third leading cause of hospital acquired renal failure. The mechanism of CIN is not fully understood. The objectives of this study were to investigate the expression changes of the four subtypes of adenosine receptors (A1AR, A2AAR, A2BAR, and A3AR) following administration of contrast media in mice. Methods: C57BL/6J mice were randomized into treatment and control groups. Iodixanol (IDX) was administered to two treatment groups through retroorbital injection at two different dosages, 0.75 gI/kg and 2.75 gI/kg. Phosphate buffered saline (PBS) was given to the control group. Mice kidneys were harvested at day 3 and day 7 after Iodixanol administration. Kidney injuries and function were evaluated according to Hematoxylin and eosin stain, Ki67 protein expression, and TUNEL assay of paraffin embedded kidney sections, and plasma creatinine assay. RNA and protein were extracted from the kidney specimens. A1AR, A2AAR, A2BAR, and A3AR RNA and protein level of the samples were assessed using qRT-PCR and Western blotting, with GAPDH as an endogenous control. Results: H&E staining showed no significant histopathology injuries after Iodixanol administration. No evidence of kidney injury and functional impairment was found. However, there was an increased number of A1AR, A2AAR, A2BAR, and A3AR RNA transcripts detected in the kidney 3 days after Iodixanol injection. The RNA levels in all the four subtypes of adenosine receptors were increased 2-3 fold in the day 3 specimens and back to normal at day 7. Western blot demonstrated that A1AR, A2AAR, and A3AR expression increased 1.5 to 2 fold at day 3 and day 7 following Iodixanol injection. A2BAR baseline expression was low in normal physiological conditions and no significant change was detected by Western blot. Conclusions: Iodixanol significantly increases adenosine receptors gene expression in mice. This suggests that adenosine receptors may play a role in the development of CIN.

<i>Cordyceps sinensis</i>Acts As an Adenosine A₃Receptor Agonist on Mouse Melanoma and Lung Carcinoma Cells, and Human Fibrosarcoma and Colon Carcinoma Cells

Cordyceps sinensis, a parasitic fungus on the larva of Lapidoptera, has been used as a traditional Chinese medicine. We previously reported that the growth of B16-BL6 mouse melanoma (B16-BL6) cells and mouse Lewis lung carcinoma (LLC) cells was inhibited by cordycepin (3’-deoxyadenosine), an ingredient of Cordyceps sinensis, and its effect was antagonized by MRS1191, a selective adenosine A3 receptor (A3-R) antagonist although adenosine (up to 100 μM) had no effect on the growth of B16-BL6 and LLC cells. In this study, we investigated whether water extracts of Cordyceps sinensis (WECS) inhibit the growth of B16-BL6 cells, LLC cells, HT1080 human fibrosarcoma (HT1080) cells and CW-2 human colon carcinoma (CW-2) cells via their A3-R. As a result, the growth of all cell lines were potently inhibited by WECS (10 μg/mL) and the inhibitory effect of WECS was significantly antagonized by MRS1191 (1 μM). Furthermore, WECS included 2.34% w/w cordycepin and 0.12% w/w adenosine as components according to the HPLC- ECD system. In conclusion, WECS inhibited the proliferation of four cancer cell lines by stimulation of A3-R and the main component in WECS with anticancer action might be cordycepin instead of adenosine.