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.

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.

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.

Augmentative effect of tetrandrine on pentobarbital hypnosis mediated by 5-HT_(1A) and 5-HT_(2A/2C) receptors in mice

It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to serotonergic system. The present study was undertaken to investigate the interaction of tetrandrine and different 5-HT receptors on pentobarbital-induced sleep by using the loss-of-righting reflex method. The results showed that augmentative effect of tetrandrine on pentobarbital hypnosis in mice were potentiated by the p-MPPI （5-HT1A receptor antagonist） （1 mg/kg, i.p.） and ketanserin （5-HT2A/2C receptor antagonist） （1.5 mg/kg, i.p.）, respectively. Pretreatment with either 8-OH-DPAT （5-HT1A receptor agonist） （0.1 mg/kg, s.c.） or DOI （5-HT2A/2C receptor agonist） （0.2 mg/kg, i.p.） significantly decreased pentobarbital-induced sleep time, and tetrandrine （60 mg/kg, i.g.） significantly reversed this effect. These results suggest that both the 5-HTLA and 5-HT2A/2C subfamily may be involved in the potentiating mechanism of tetrandrine＇s effects on pantobarbital hypnosis.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Leukocyte immunoglobulin-like receptor B2:A promising biomarker for colorectal cancer

According to the latest global cancer statistics,colorectal cancer(CRC)has emerged as the third most prevalent malignant tumor across the globe.In recent decades,the medical field has implemented several levels of CRC screening tests,encompassing fecal tests,endoscopic examinations,radiological examinations and blood tests.Previous studies have shown that leukocyte immunoglobulin-like receptor B2(LILRB2)is involved in inhibiting immune cell function,immune evasion,and promoting tumor progression in acute myeloid leukemia and nonsmall cell lung cancer.However,its interaction with CRC has not been reported yet.Recently,a study published in the World Journal of Gastroenterology revealed that LILRB2 and its ligand,angiopoietin-like protein 2,are markedly overexpressed in CRC.This overexpression is closely linked to tumor progression and is indicative of a poor prognosis.The study highlights the potential of utilizing the concentration of LILRB2 in serum as a promising biomarker for tumors.However,there is still room for discussion regarding the data processing and analysis in this research.

Divergent expression of bacterial wall sensing toll-like receptors 2 and 4 in colorectal cancer

To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed. RESULTSNormal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours. CONCLUSIONTumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.

Expression of HER2 and bradykinin B_1 receptors in precursor lesions of gallbladder carcinoma

AIM： To determine the expression of HER2 and bradykinin B1 receptors （B1R） in the two pathogenic models of gallbladder cancer： the metaplasia dysplasia carcino ma and the adenoma carcinoma pathways.METHODS： Receptor proteins were visualized by immunohistochemistry on 5-μm sections of paraffin-embedded tissue. Expression of both receptors was studied in biopsy samples from 92 patients （6 males and 86 females; age ranging from 28 to 86 years, mean 56 years）. High HER2 expression in specimens was additionally investigated by fluorescence in situ hybridization. Cell proliferation in each sample was assessed by using the Ki-67 proliferation marker.RESULTS： HER2 receptor protein was absent in adenomas and in normal gallbladder epithelium. On the contrary, there was intense staining for HER2 on the basolateral membrane of epithelial cells of intestinal metaplasia （22/24; 91.7%） and carcinoma in situ （9/10; 90%）, the lesions that displayed a significantly high proliferation index. Protein up-regulation of HER2 in the epithelium with metaplasia or carcinoma in s/tu was not accompanied by HER2 gene amplification. A similar result was observed in invasive carcinomas （0/12）. The B1R distribution pattern mirrored that of HER2 except that B1R was additionally observed in the adenomas. The B1R appeared either as cytoplasmic dots or labeling on the apical cell membrane of the cells composing the epithelia with intestinal metaplasia （24/24; 100%） and carcinoma in situ （10/10; 100%） and in the epithelial cells of adenomas. In contrast, both HER2 （4/12; 33%） and B1R （1/12; 8.3%） showed a low expression in inva- sive gallbladder carcinomas.CONCLUSION： The up-regulation of HER2 and B1R in precursor lesions of gallbladder carcinoma suggests cross-talk between these two receptors that may be of importance in the modulation of cell proliferation in gallbladder carcinogenesis,

Down-regulation of pancreatic transcription factors and incretin receptors in type 2 diabetes

Type 2 diabetes is one of the most prevalent and serious metabolic diseases.Under diabetic conditions,chronic hyperglycemia and subsequent induction of oxidative stress deteriorate pancreaticβ-cell function,which leads to the aggravation of type 2 diabetes.Although such phenomena are well known as glucose toxicity,its molecular mechanism remains unclear.In this review article,we describe the possible molecular mechanism forβ-cell dysfunction found in type 2 diabetes,focusing on(1)oxidative stress,(2)pancreatic transcription factors(PDX-1 and MafA)and(3)incretin receptors(GLP-1 and GIP receptors).Under such conditions,nuclear expression levels of PDX-1 and MafA are decreased,which leads to suppression of insulin biosynthesis and secretion.In addition,expression levels of GLP-1 and GIP receptors are decreased,which likely contributes to the impaired incretin effects found in diabetes.Taken together,it is likely that downregulation of pancreatic transcription factors(PDX-1and MafA)and down-regulation of incretin receptors(GLP-1 and GIP receptors)explain,at least in part,the molecular mechanism forβ-cell dysfunction found in type 2 diabetes.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Role of P2X_7 receptors in the development of diabetic retinopathy

The P2X7 receptor is one of the members of the family of purinoceptors which are ligand-gated membrane ion channels activated by extracellular adenosine 5'-triphosphate. A unique feature of the P2X7 receptor is that its activation can result in the formation of large plasma membrane pores that allow not only the flux of ions but also of hydrophilic molecules of up to 900 Da. Recent studies indicate that P2X7-mediated signaling can trigger apoptotic cell death after ischemia and during the course of certain neurodegenerative disorders. Expression of the P2X7 receptor has been demonstrated in most types of cells in the retina. This purinoceptor mediates the contraction of pericytes and regulates the spatial and temporal dynamics of the vasomotor response through cell-to-cell electrotonic transmission within the microvascular networks. Of potential clinical significance, investigators have found that diabetes markedly boosts the vulnerability of retinal microvessels to the lethal effect of P2X7 receptor activation. This purinergic vasotoxicity may result in reduced retinal blood flow and disrupted vascular function in the diabetic retina. With recent reports indicating an association between P2X7 receptor activation and inflammatory cytokine expression in the retina, this receptor may also exacerbate the development of diabetic retinopathy by a mechanism involving inflammation.

Influence of berberine on protein tyrosine kinase of erythrocyte insulin receptors from type 2 diabetes mellitus

Objective： Bererine has been used to treat type 2 diabetes mellitus in Chinese traditional medicine because of its hypoglycemic effect. In this report, we compared the intrinsic tyrosine kinase activities of erythrocyte insulin receptors from type 2 diabetes mellitus with or without stimulation by berberine in vitro. Methods- Preparations containing insulin receptors were obtained from soluble human erythrocytes, and the insulin receptors were partially purified by affinity chromatography. The tyrosine kinase activity was measured by the exogenous substrate phosphorylation. Results： Both the membrane tyrosine kinase activity and the purified receptor tyrosine kinase activity from diabetics decreased significantly compared with those of normal individuals （reduced by 67.4% and 47.2%, respectively）. After incubation with berbefine, there is a statistical difference in the activity of membrane tyrosine kinase for diabetic patients （ a 150% increase）. Berefine had no effect on the tyrosine kinase activity of purified insulin receptors. Conclusion： We concluded from these results that berbefine was able to improve the insulin sensitivity by increasing the protein tyrosine kinase activity of membrane-bound insulin receptors from type 2 diabetes mellitus.

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.

Central CB2 receptors in inflammation-driven neurodegeneration： dysregulation and therapeutic potential

In recent times there has been an intensification of interest in the pathological role of neuroinflammation in neurodegenerative disease. Neuroprotective strategies to slow, halt or reverse neuro- degeneration have not proven fruitful clinically, and the notion of a multi-hit hypothesis in the progression of neurodegenerative disease has steered focus towards other contributory pathological factors, particularly neuroinflammation. Neuroinflammation is believed to sustain the neurodegenerative pathology, forming a cy- clical and self-sustaining pathological process, with dying neurons activating microglia, which, once activated, can release several fac- tors that kill further neurons （reviewed in Blandini, 2013）.

The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity:A Meta-Analysis

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

Origin and genomic characteristics of SARS-CoV-2 and its interaction with angiotensin converting enzyme type 2 receptors, focusing on the gastrointestinal tract

The emergence of coronavirus disease-2019 induced by a newly identified bcoronavirus, namely severe acute respiratory syndrome coronavirus 2(SARSCoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2(ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract(GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system(RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.

H_1 and H_2 receptors in the locus ceruleus are involved in the intracere-broventricular histamine-induced carotid sinus baroreceptor reflex reset-ting in rats

Objective To investigate the role of H1 and H2 receptors in the locus ceruleus （LC） in carotid sinus baroreceptor reflex （CSR） resetting induced by intracerebroventricular （i.c.v.） injection of histamine （HA）. Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure （ISP） was altered in a stepwise manner in vivo. ISP-mean arterial pressure （MAP） relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H1 or H2 receptors selective antagonist, chlorpheniramine （CHL） or cimetidine （CIM） into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA （100 ng in 5 μl） significantly shifted the ISP-MAP relationship curve upwards （P 〈 0.05） and obviously decreased the value of the reflex parameters such as MAP range and maximum gain （P 〈 0.05）, but increased the threshold pressure, saturation pressure and ISP at maximum gain （P 〈 0.05）. The pretreatment with CHL （0.5 μg in 1 μl） or CIM （1.5 μg in 1 μl） into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL （P 〈 0.05）. Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly （P 〉 0.05）. Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H1 and H2 receptors activities in the LC, especially by H1 receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.

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.

Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway

Objective This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients.Methods Through various techniques,such as Argonaute immunoprecipitation,luciferase assays,and ChIP,this study confirmed the positive effects of androgen receptor(AR)on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models.Results The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level,which in turn required changes in miRNA-23a-3p.Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR.Conclusion This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.