β-Receptor blocker enhances the anabolic effect of PTH after osteoporotic fracture

The autonomic nervous system plays a crucial role in regulating bone metabolism,with sympathetic activation stimulating bone resorption and inhibiting bone formation.We found that fractures lead to increased sympathetic tone,enhanced osteoclast resorption,decreased osteoblast formation,and thus hastened systemic bone loss in ovariectomized(OVX)mice.However,the combined administration of parathyroid hormone(PTH)and theβ-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice.The effect of this treatment is superior to that of treatment with PTH or propranolol alone.In vitro,the sympathetic neurotransmitter norepinephrine(NE)suppressed PTH-induced osteoblast differentiation and mineralization,which was rescued by propranolol.Moreover,NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation,whereas these effects were reversed by propranolol.Furthermore,PTH increased the expression of the circadian clock gene Bmal1,which was inhibited by NE-βAR signaling.Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTHstimulated osteoblast differentiation.Taken together,these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

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.

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.

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.

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.

Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.

Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke

Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Pan-TRK positive uterine sarcoma in immunohistochemistry without neurotrophic tyrosine receptor kinase gene fusions:A case report

BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.

Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

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.

Effect of angiotensin Ⅱ type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

AIM： To investigate the effect of angiotensin II type 1 receptor blocker （ARB） and angiotensin converting enzyme inhibitor （ACEI） on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS： Forty Sprague-Dawley rats were divided into 4 groups： control, diabetes mellitus （DM）, candesartan- treated DM, and enalapril-treated DM （each group, n---10）. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/（kg · d）] and enalapril [ACEI, 10 mg/（kg · d）] were administered to rats orally for 4Wko Vascular endothelial growth factor （VEGF） and angiotensin II （Ang II） concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor （ATIR） levels were assessed at week 4 by Western blotting. RESULTS： Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control （P=0.04 and 0.005, respectively）. Vitreous ATIR increased significantly in DM compared to the other three groups （P〈0.007）. Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control （P〈0.001 and P=0.005, respectively）. No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION： Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

Effects of angiotensin-converting enzyme inhibitor and angiotensin Ⅱ receptor blocker on one-year outcomes of patients with atrial fibrillation: insights from a multicenter registry study in China

Objective To evaluate the effect of angiotensin-converting enzyme inhibitor(ACEI)/angiotensin Ⅱ receptor blocker(ARB)therapy on the prognosis of patients with atrial fibrillation(AF).Methods A total of 1,991 AF patients from the AF registry were divided into two groups according to whether they were treated with ACEI/ARB at recruitment.Baseline characteristics were carefully collected and analyzed.Logistic regression was utilized to identify the predictors of ACEI/ARB therapy.The primary endpoint was all-cause mortality,while the secondary endpoints included cardiovascular mortality,stroke and major adverse events(MAEs)during the one-year follow-up period.Univariable and multivariable Cox regression were performed to identify the association between ACEI/ARB therapy and the one-year outcomes.Results In total,759 AF patients(38.1%)were treated with ACEI/ARB.Compared with AF patients without ACEI/ARB therapy,patients treated with ACEI/ARB tended to be older and had a higher rate of permanent AF,hypertension,diabetes mellitus,heart failure(HF),left ventricular ejection fraction(LVEF)<40%,coronary artery disease(CAD),prior myocardial infarction(MI),left ventricular hypertrophy,tobacco use and concomitant medications(all P<0.05).Hypertension,HF,LVEF<40%,CAD,prior MI and tobacco use were determined to be predictors of ACEI/ARB treatment.Multivariable analysis showed that ACEI/ARB therapy was associated with a significantly lower risk of one-year all-cause mortality[hazard ratio(HR)(95%CI):0.682(0.527-0.882),P=0.003],cardiovascular mortality[HR(95%CI):0.713(0.514-0.988),P=0.042]and MAEs[HR(95%CI):0.698(0.568-0.859),P=0.001].The association between ACEI/ARB therapy and reduced mortality was consistent in the subgroup analysis.Conclusions In patients with AF,ACEI/ARB was related to significantly reduced one-year all-cause mortality,cardiovascular mortality and MAEs despite the high burden of cardiovascular comorbidities.

Role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cryoballoon ablation outcomes for paroxysmal atrial fibrillation

BACKGROUND Cryoballoon ablation(CBA)is recommended for patients with paroxysmal atrial fibrillation(AF)refractory to antiarrhythmic drugs.However,only 80%of patients benefit from initial CBA.There is growing evidence that pretreatment with angiotensin-converting enzyme inhibitors(ACEIs)and angiotensin receptor blockers(ARBs)decreases the recurrence of AF postablation,particularly in nonparoxysmal AF undergoing radiofrequency ablation.The role of ACEIs and ARBs in patients with paroxysmal AF in CBA remains unknown.We decided to investigate the role of ACEIs and ARBs in preventing the recurrence of atrial arrhythmia(AA)following CBA for paroxysmal AF.AIM To investigate the role of ACEIs and ARBs in preventing recurrence of AA following CBA for paroxysmal AF.METHODS We followed 103 patients(age 60.6±9.1 years,29%women)with paroxysmal AF undergoing CBA 1-year post procedure.Recurrence was assessed by documented AA on electrocardiogram or any form of long-term cardiac rhythm monitoring.A multivariable Cox proportional hazard model was used to assess if ACEI or ARB treatment predicted the risk of AA recurrence.RESULTS After a 1-year follow-up,19(18.4%)participants developed recurrence of AA.Use of ACEI or ARB therapy was noted in the study population.Patients on ACEI/ARB had a greater prevalence of hypertension and coronary artery disease.On a multivariate model adjusted for baseline demographics and risk factors for AF,ACEI or ARB therapy did not prevent recurrence of AA following CBA(P=0.72).Similarly,on Kaplan–Meier analysis pretreatment with ACEI/ARB did not predict the time to first recurrence of AA(P=0.2173).CONCLUSION In our study population,preablation treatment with an ACEI or ARB had no influence on the recurrence of AA following CBA for paroxysmal AF.

Hyperkalemia of Angiotensin-converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Hemodialysis: A Meta-analysis

The safety of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) used in hemodialysis (HD) patients was evaluated.Medline,Embase,the Cochrane Library,some databases of clinical trial registries,grey literatures,other reference lists of eligible articles and review articles for the randomized clinical trials (RCTs) on comparison of ACEIs/ARBs or placebo in HD patients were retrieved.RCTs reporting the risk of hyperkalemia by using ACEIs/ARBs in HD patients were selected.Eight articles met the eligibility criteria and were subjected to meta-analysis by using the Cochrane Collaboration’s RevMan 4.2 software package.The results showed that there was no significant difference in hyperkalemia in HD patients between ACEIs or ARBs group and control group (ACEIs vs.control:RD=0.03,95% CI=-0.13?0.18,Z=0.34,P=0.73;ARBs vs.control:RD=-0.02,95% CI=-0.07?0.03,Z=0.75,P=0.45).However,there was no significant difference in the serum potassium between ACEIs or ARBs group and control group in HD patients (ACEIs vs.control:WMD=0.10,95% CI=0.06?0.15,Z=4.64,P<0.00001;ARBs vs.control:WMD=-0.24,95% CI=-0.37--0.11,Z=3.58,P=0.0003).The use of ACEIs or ARBs could not cause an increased risk of hyperkalemia in HD patients,however the serum potassium could be increased with use of ACEIs in HD patients.Therefore the serum potassium concentration should still be closely monitored when ACEIs are taken during the maintenance HD.

Potential protective role of ACE-inhibitors and AT1 receptor blockers against levodopa-induced dyskinesias:a retrospective case-control study

Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.

Angiotensin receptor blocker neprilysin inhibitors

Heart failure(HF)is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with,or eject,blood.It is a multifaceted clinical condition that affects up to 2%of the population in the developed world,and is linked to significant morbidity and mortality;it is therefore considered a major concern for public health.Regarding the mechanism of HF,three neurohumoral factors-the reninangiotensin-aldosterone system,the sympathetic nervous system,and natriuretic peptides—are related to the pathology of chronic HF(CHF),and the targets of treatment.Angiotensin receptor blocker and neprilysin inhibitor(angiotensinreceptor neprilysin inhibitor),namely sacubitril/valsartan(SAC/VAL),has been introduced as a treatment for CHF.SAC/VAL is an efficacious,safe,and costeffective therapy that improves quality of life and longevity in patients with HF with reduced ejection fraction(HFrEF),and reduces hospital admissions.An inhospital initiation strategy offers a potential new avenue to improve the clinical uptake of SAC/VAL.In the last five years,SAC/VAL has been established as a cornerstone component of comprehensive disease-modifying medical therapy in the management of chronic HFrEF.On the other hand,further work,with carefully designed and controlled preclinical studies,is necessary for understanding the molecular mechanisms,effects,and confirmation of issues such as long-term safety in both human and animal models.

Recent advances and future directions in preclinical research of argininevasopressin(AVP) receptor blocker conivaptan in the context of stroke

Stroke is a major cause of mortality and permanent disability.The onset of stroke is followed by life-threatening pathophysiological responses including brain edema,elevation of intracranial pressure,disruption of blood-brain barrier（BBB）,brain infarct and permanent tissue damage.Brain edema develops due to accumulation of water in intracellular and extracellular compartments of the brain,

Effects of chronic peripheral pretreatment with an angiotensin II type-1 receptor blocker on apoptosis-related molecules in rats with cerebral ischemia/reperfusion injury

Chronic systemic treatment with blockers of angiotensin II type-1 （AT1） receptors inhibits ischemia-induced apoptosis and reduces ischemic neuronal damage. However, the molecular mechanisms of AT1 receptor blockers in modulating neuronal apoptosis remain poorly understood. Pretreatment with irbesartan significantly suppressed cell apoptosis at 1-7 days following cerebral ischemia/reperfusion, increased levels of brain-derived neurotrophic factor, and elevated the ratios of Bcl-2/Bax and phosphorylated cyclic adenosine monophosphate response element-binding protein （pCREB）/CREB in the ischemic cortex at 1 day after reperfusion, as well as suppressing caspase-3 activation. Cerebral ischemia increased the mRNA expression of AT1 and AT2 receptors in the ischemic cortex, whereas irbesartan blocked this increase in AT1 expression but potentiated the expression of AT2. Therefore, this AT1 receptor blocker was neuroprotective by increasing the ratios of Bcl-2/Bax and pCREB/CREB, increasing brain-derived neurotrophic factor levels, inhibiting caspase-3 activation, and modulating AT receptor expression.

Effects of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors on COVID-19

BACKGROUND The World Health Organization reported that 28637952 people worldwide had been infected with severe acute respiratory syndrome coronavirus 2,the causative agent of coronavirus disease 2019(COVID-19),by September 13.AIM The aim was to investigate whether long-term use of renin-angiotensin-aldosterone system(RAAS)inhibitors for the treatment of hypertension aggravates the performance of COVID-19 patients with hypertension.METHODS This was a retrospective analysis of lung computed tomography(CT)data and laboratory values of COVID-19 patients with hypertension who were admitted to Huoshenshan Hospital,Wuhan,Hubei Province,between February 18 and March 31,2020.Patients were divided into two groups.Group A included 19 people who were long-term users of RAAS inhibitors for hypertension;and group B included 28 people who were randomly selected from the database and matched with group A by age,sex,basic diseases,and long-term use of other antihypertensive drugs.All patients underwent a series of CT and laboratory tests.We compared the most severe CT images of the two groups and the laboratory examination results within 2 d of the corresponding CT images.RESULTS The time until the most severe CT images from the onset of COVID-19 was 30.37±14.25 d group A and 26.50±11.97 d in group B.The difference between the two groups was not significant(t=1.01,P=0.32).There were no significant differences in blood laboratory values,C-reactive protein,markers of cardiac injury,liver function,or kidney function between the two groups.There was no significant difference in the appearance of the CT images between the two groups.The semiquantitative scores of each involved lobe were 11.84±5.88 in group A and 10.36±6.04 group B.The difference was not significantly different(t=0.84,P=0.41).CONCLUSION Chest CT is an important imaging tool to monitor the characteristics of COVID-19 and the degree of lung injury.Chronic use of RAAS inhibitors is not related to the severity of COVID-19,and it does not worsen the clinical process.