Rationale: Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. Methods: We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Conclusions: Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.

BACKGROUND:After acute coronary syndrome (ACS), inflammation aids healing but may harm the heart. Interleukin (IL)-18 and IL-1β are pivotal proinflammatory cytokines released during pyroptosis, a process that initiates and sustains inflammation. This study aimed to evaluate the levels of circulating IL-18 and IL-1β during the progression of ACS and to determine their association with subsequent clinical events in ACS patients. HYPOTHESIS:Circulating levels of IL-18 and IL-1β are associated with subsequent clinical events in ACS patients. METHODS:Employing immunoassays, we examined plasma levels of IL-1β and IL-18 in 159 ACS patients and matched them with 159 healthy controls. The primary composite endpoint included recurrent unstable angina, myocardial infarction, heart failure exacerbation, stroke, or cardiovascular death. RESULTS:ACS patients exhibited a significant increase in plasma IL-18 levels, measuring 6.36 [4.46-9.88] × 102 pg/mL, in contrast to the control group with levels at 4.04 [3.21-4.94] × 102 pg/mL (p < 0.001). Conversely, plasma levels of IL-1β remained unchanged compared to the control group. Following a 25-month follow-up, IL-18 levels exceeding the median remained an important prognostic factor for adverse clinical events in ACS patients (hazard ratio = 2.37, 95% confidence interval: 1.14-4.91, p = 0.021). Besides, IL-18 displayed a nonlinear association with adverse clinical events (p nonlinear = 0.044). Subgroup analysis revealed that the correlation between IL-18 and the risk of adverse clinical events was not significantly affected by factors such as age, sex, history of diabetes, smoking, Gensini score, or ACS type (all p interaction >0.05). CONCLUSION:IL-18 appears to hold potential as a predictive marker for anticipating clinical outcomes in patients with ACS.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aβ and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aβ, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aβ: β-amyloid, GABA: gamma-aminobutyric acid.

BACKGROUND:Prior research underscores the significant impact of remnant cholesterol (RC) on stroke occurrence due to its proatherogenic and proinflammatory traits. This study aims to explore diverse risks of new-onset stroke associated with RC, considering distinct inflammation levels in the middle-aged and senior population in China. METHODS:We analyzed 6509 participants from the China Health and Retirement Longitudinal Study (CHARLS) across four waves (2011-2018). We employed a multivariable Cox proportional hazards regression model, incorporated restricted cubic spline techniques, and conducted sensitivity analyses to evaluate the association among RC, high-sensitivity C-reactive protein (hsCRP), and the risk of new-onset stroke. RESULTS:Over 7 years, 540 new-onset strokes occurred. Individuals in the highest quartile of RC levels exhibited a heightened risk of new-onset stroke, with a multivariable-adjusted hazard ratio (HR) peaking at 1.50 (95% confidence interval 1.12-2.00, P for trend = 0.021), showing a non-linear correlation (P nonlinearity = 0.049). High hsCRP alone had an adjusted HR of 1.10 (95% CI 0.87-1.39), compared to 1.40 (95% CI 1.00-1.96) for high RC alone. Additionally, concurrent high RC and hsCRP showed an adjusted HR of 1.43 (95% CI 1.05-1.96). Consistency persisted across various hsCRP thresholds, after adjusting for additional parameters, or excluding chronic diseases in the primary model, reinforcing result robustness. CONCLUSION:Our findings reveal a substantial and non-linear association between higher baseline RC levels and an elevated risk of new-onset stroke. Moreover, elevated levels of both RC and hsCRP jointly pose the highest risk for new-onset stroke, surpassing the risk associated with each factor individually.

目的 了解黄连解毒汤加减方对阿尔茨海默病(AD)模型小鼠学习记忆功能的影响并探索相关机制.方法 4月龄5×FAD小鼠分别灌胃给予黄连解毒汤加减方、黄连解毒汤原方治疗3个月,采用水迷宫等行为学方法检测小鼠学习记忆功能,采用膜片钳等电生理学方法检测神经元及突触功能,采用免疫印迹、免疫组化及电镜等检测小鼠脑内Aβ沉积及神经血管单元变化情况.结果 与模型组相比,黄连解毒汤加减方治疗能提高5×FAD小鼠的学习记忆功能,改善海马及皮层区突触结构及功能,减少Aβ沉积和星形胶质细胞增殖,上调ZO-1/Occludin等紧密连接蛋白表达,下调IL-1β、TNF-α等炎性因子及RAGE/NF-κB等信号分子表达,改善微血管超微结构;且加减方作用优于原方.结论 黄连解毒汤加减方可能通过抑制5×FAD小鼠脑内Aβ沉积、RAGE/NF-κB通路介导的神经炎症,改善神经血管单元损伤,从而改善AD模型小鼠的学习记忆功能.

Alzheimer’s disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson’s disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg−1·d−1, i.g.) for 3 months. At the end of treatment, retinal function and structure were assessed, cognitive function was evaluated in Morris water maze test. We showed that 4-month-old 5×FAD mice displayed distinct structural and functional deficits in the retinas, which were significantly ameliorated by Sal B treatment. In contrast, untreated, 4-month-old 5×FAD mice did not exhibit cognitive impairment compared to wild-type mice. In SH-SY5Y-APP751 cells, we demonstrated that Sal B (10 μM) significantly decreased BACE1 expression and sorting into the Golgi apparatus, thereby reducing Aβ generation by inhibiting the β-cleavage of APP. Moreover, we found that Sal B effectively attenuated microglial activation and the associated inflammatory cytokine release induced by Aβ plaque deposition in the retinas of 5×FAD mice. Taken together, our results demonstrate that functional impairments in the retina occur before cognitive decline, suggesting that the retina is a valuable reference for early diagnosis of AD. Sal B ameliorates retinal deficits by regulating APP processing and Aβ generation in early AD, which is a potential therapeutic intervention for early AD treatment.

The prognosis of patients with nonvalvular atrial fibrillation (NVAF) with a low CHA2DS2-VASc score (0-1) following a stroke is not well studied. In this investigation, stroke risk factors and prognostic markers in low-risk NVAF patients who are nonetheless at risk for stroke were examined.From January 2012 to January 2022, we retrospectively assessed atrial fibrillation (AF) patients at Xiamen University's Zhongshan Hospital for ischemic stroke. Along with a control group of patients with CHA2DS2-VASc scores of 0-1 who weren't suffering from a stroke, patients with CHA2DS2-VASc scores of 0-1 at the time of stroke were included in the study. Using multivariate logistic regression, independent risk factors were identified. To assess the cumulative occurrences of in-hospital mortality in patients with NVAF-related stroke, the Kaplan-Meier method was used.The study included 156 out of 3.237 inpatients with AF-related stroke who had CHA2DS2-VASc ratings of 0-1. Left atrial diameter (LAD) (odds ratio [OR]: 1.858, 95% confidence interval (CI) 1.136-3.036, P = 0.013), D-dimer (OR: 2.569, 95% CI 1.274-5.179, P = 0.008), and NT-proBNP (OR: 4.558, 95% CI 2.060-10.087, P = 0.000) were found to be independent risk factors for stroke in NVAF patients with a low CHA2DS2-VASc score. During hospitalization, nine patients with NVAF-related stroke died. In patients with NVAF-related stroke, NT-proBNP (hazard ratio: 3.504, 95% CI 1.079-11.379, P = 0.037) was an indicator of mortality risk.Patients with NVAF and CHA2DS2-VASc scores of 0-1 had independent risk factors for stroke in the form of LAD, D-dimer, and NT-proBNP. Notably, in low-risk NVAF patients with stroke, NT-proBNP was discovered to be a potent predictor of in-hospital death.

Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson’s disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

阿尔茨海默病(AD),即老年性痴呆,是一种起病隐匿、进行性发展的神经系统退行性疾病,尽早诊断与治疗有利于延缓疾病进程.AD的病因及病理机制复杂,其中特异性细胞毒性病理改变及应激/炎症反应、脑微血管病变及代谢失衡、神经微环路兴奋/抑制失衡等因素导致退行性改变进行性发展,尤其值得关注.我们认为上述病理改变在微观层面具有中医"虚痰瘀毒"特征,其中"浊毒损络"可作为AD的核心病机和治疗的关键切入点,且在AD早期就存在"浊毒损络"核心病机.AD疾病进程中,嗅觉、视觉等外周感觉功能异常早于认知功能障碍,上述外周感觉功能异常可作为AD早期病理进程的重要预警指标.我们探索了开心散加味优化方、黄连解毒汤加减方等经典名方及其有效成分早期干预对AD模型认知功能及视觉、嗅觉等功能的影响,并探索了相关机制,希望为中医药治疗早期AD提供现代生物医学依据.

The prognosis of patients with nonvalvular atrial fibrillation (NVAF) with a low CHA2DS2-VASc score (0-1) following a stroke is not well studied. In this investigation, stroke risk factors and prognostic markers in low-risk NVAF patients who are nonetheless at risk for stroke were examined.From January 2012 to January 2022, we retrospectively assessed atrial fibrillation (AF) patients at Xiamen University's Zhongshan Hospital for ischemic stroke. Along with a control group of patients with CHA2DS2-VASc scores of 0-1 who weren't suffering from a stroke, patients with CHA2DS2-VASc scores of 0-1 at the time of stroke were included in the study. Using multivariate logistic regression, independent risk factors were identified. To assess the cumulative occurrences of in-hospital mortality in patients with NVAF-related stroke, the Kaplan-Meier method was used.The study included 156 out of 3.237 inpatients with AF-related stroke who had CHA2DS2-VASc ratings of 0-1. Left atrial diameter (LAD) (odds ratio [OR]: 1.858, 95% confidence interval (CI) 1.136-3.036, P = 0.013), D-dimer (OR: 2.569, 95% CI 1.274-5.179, P = 0.008), and NT-proBNP (OR: 4.558, 95% CI 2.060-10.087, P = 0.000) were found to be independent risk factors for stroke in NVAF patients with a low CHA2DS2-VASc score. During hospitalization, nine patients with NVAF-related stroke died. In patients with NVAF-related stroke, NT-proBNP (hazard ratio: 3.504, 95% CI 1.079-11.379, P = 0.037) was an indicator of mortality risk.Patients with NVAF and CHA2DS2-VASc scores of 0-1 had independent risk factors for stroke in the form of LAD, D-dimer, and NT-proBNP. Notably, in low-risk NVAF patients with stroke, NT-proBNP was discovered to be a potent predictor of in-hospital death.

BACKGROUND Spontaneous coronary artery dissection (SCAD) is a frequent cause of acute coronary syndrome in young to middle-aged women with few or no traditional cardiovascular risk factors. Chest pain is the most frequently described presenting symptom, but syncope is extremely rare. Herein, we report on a 16-year-old girl who presented with an episode of syncope occurring during a race. Despite significantly elevated troponin level, the diagnosis of the left main coronary artery SCAD with cardiogenic shock was delayed. CASE SUMMARY A 16-year-old girl presented with an episode of syncope. Myocardial injury markers were positive. Echocardiography showed a mildly reduced left ventricular ejection fraction (50%). Although initially stable, she later experienced recurrent chest pain accompanying precordial ST segment elevation with dynamic changes and developed cardiogenic shock, necessitating emergent revascularization. Coronary angiography demonstrated almost total occlusion at the ostium and proximal segment of the left main trunk coronary artery (LMT). Intravascular ultrasound confirmed a false lumen with prominent dissection in the LMT. Percutaneous coronary intervention assisted by intra-aortic balloon pump was conducted in the LMT. A 3.5 mm × 24 mm everolimus-eluting stent was deployed to the focal lesions of the LMT. A postprocedural electrocardiogram showed alleviation of the precordial ST-segment elevation. The diagnosis of SCAD was confirmed. Transthoracic echocardiography showed an improved left ventricular ejection fraction (57%). The patient was asymptomatic during the 24-mo. follow-up period. CONCLUSION SCAD should always be considered in the differential diagnosis of acute coronary syndrome presentations in low-risk patients, regardless of age.

Background:The role of soluble interleukin-1 receptor type 2 (sIL-1R2) in acute myocardial infarction (AMI) remains undocumented.In the present study, we aimed to evaluate the possible associations of sIL-1R2 with left ventricular (LV) function, remodeling and future clinical events in the setting of AMI.Methods: Circulating sIL-1R2 levels were quantified after percutaneous coronary intervention (PCI) on day 1 of hospital admission for 204 AMI patients, and upon enrollment of 204 healthy controls.Echocardiography was conducted in the acute phase and at 12-month follow-up.Adverse clinical events were registered after 12 months.Results: Circulating sIL-1R2 levels were significantly higher in AMI patients than in healthy controls (medians respectively 6652.81 pg/mL, 3799.13 pg/mL, p < 0.0001).AMI patients with sIL-1R2 levels less than the median had a larger proportion of worsened LV ejection fraction [a decrease in LV ejection fraction (LVEF) of more than 10% units] and reduced LVEF (a final LVEF <50%).After multivariate adjustment, sIL-1R2 levels less than the median were associated with an increased risk of worsened LVEF [odds ratio (OR): 3.7, 95% confidence interval (CI): 1.6-8.5, p = 0.002] and reduced LVEF at 12 months (OR: 2.1, 95% CI: 1.1-4.3,p = 0.035).Moreover, low sIL-1R2 levels were associated with an increased risk of having an adverse clinical event during the first 12 months after AMI [hazard ratio (HR): 2.5, 95% CI: 1.0-6.1,p = 0.039].Conclusions: Low levels of circulating sIL-1R2 were associated with impaired recovery of LV function and adverse clinical outcomes in AMI patients.These findings might contribute to understanding the important role of sIL-1R2 in postinfarction inflammation.

Older adults (≥65 years of age) bear a significant burden of severe disease and mortality associated with influenza, despite relatively high annual vaccination coverage and substantial pre-existing immunity to influenza. To test the hypothesis that host factors, including age and sex, play a role in determining the effect of repeated vaccination and levels of pre-existing humoral immunity to influenza, we evaluated pre- and post-vaccination strain-specific hemagglutination inhibition (HAI) titers in adults over 75 years of age who received a high-dose influenza vaccine in at least four out of six influenza seasons. Pre-vaccination titers, rather than host factors and repeated vaccination were significantly associated with post-vaccination HAI titer outcomes, and displayed an age-by-sex interaction. Pre-vaccination titers to H1N1 remained constant with age. Titers to H3N2 and influenza B viruses decreased substantially with age in males, whereas titers in females remained constant with age. Our findings highlight the importance of pre-existing immunity in this highly vaccinated older adult population and suggest that older males are particularly vulnerable to reduced pre-existing humoral immunity to influenza.

目的:探讨中性粒细胞与淋巴细胞计数比值(NLR)对行经皮冠脉介入治疗(PCI)的急性冠脉综合征(ACS)患者主要不良心血管事件(MACE)的预测价值.方法:选择在我院行PCI的ACS患者125例,根据GRACE评分(GRS)患者被分为低危组(GRS≤108分,38例)、中危组(109分≤GRS≤140分,46例)、高危组(GRS＞140分,41例).比较不同危险分层组血清C反应蛋白(CRP)、心肌肌钙蛋白T(cTnT)和血浆N末端脑钠肽前体(NT-proBNP)水平及NLR值.根据住院期间和出院后1年内MACE发生情况,患者被分为MACE组(94例)和非MACE组(31例),比较两组GRS、NLR值及CRP水平.采用ROC曲线评价NLR对患者MACE的预测价值.结果:随着ACS的危险分层的上升,NLR值[1.80 (0.76)比2.68 (1.33)比3.82(3.25)]显著升高(P均=0.001).与非MACE组比较,MACE组GRS [114.0(37.5)分比162.0 (52.0)分]、NLR值[2.4(1.5)比3.9(4.8)]和CRP [3.5 (6.9) mg/L比12.2 (40.8) mg/L]水平均显著升高(P均=0.001).ROC曲线分析NLR、GRS、GRS+ NLR对发生MACE的预测价值,其曲线下面积(AUC)分别为:0.810 (95％CI:0.722～0.897)、0.837 (95％CI:0.756～0.917)、0.849 (95％CI:0.774～0.925).结论:NLR作为一项简便易获取的常规检验指标,联合GRACE评分可更加准确地预测PCI术后ACS患者的预后,具有重要临床价值.

Ginsenoside Rb1 has been demonstrated to protect dopaminergic (DA) neurons from death in vitro. However, the neuroprotective effects and underlying mechanism of Rb1 in treating Parkinson's disease (PD) remain uncharacterized. Here we explored the effects of Rb1 on the glutamatergic systems in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results demonstrate that Rb1 treatment ameliorates motor deficits, prevents DA neuron death, and suppresses alpha-synuclein expression and astrogliosis in the MPTP mouse model of PD. Rb1 attenuates glutamate excitotoxicity by upregulating glutamate transporter expression and function, and modulating the nigrostriatal and cortico-nigral glutamatergic transmission pathways. Furthermore, Rb1 increases glutamate transporter expression via nuclear translocation of nuclear factor-kappa B, regulates glutamate receptor expression and promotes synaptic protein expression. These results indicate that Rb1 suppresses glutamate excitotoxicity and modulate synaptic transmission to improve the impairments in motor functions of the MPTP model of PD, suggesting that Rb1 may serve as a potential therapeutic agent for PD. Supported by the National Key Research and Development Program of China (No. 2016YFC1305903), the National Natural Science Foundation of China (No. 81373999, No. 81774377 and No. 81704130), the Natural Science Foundation of Fujian Province of China (No. 2017J05139), the Natural Science Foundation of Guangdong Province of China (No. 2017A030310643) and the China Postdoctoral Science Foundation (No. 2016M590598).

Chronic neuropathic pain can cause serious physical as well as emotional harm to the patients. The analgesics currently commonly used in clinic have their limitations because of their side effects. Traditional Chinese Medicines have their own characteristics and advantages in treating pain, however, most of their underlying mechanisms are unclear and the majority of the researches mainly focused on the peripheral analgesic mechanisms. Sinomenine is the most important effective ingredient of Caulis Sinomenii in pain treatment, here, the central analgesic mechanisms of sinomenine in chronic neuropathic pain are explored. NMDA receptors in the spinal dorsal horn are critically involved in central sensitization and maintenance of neuropathic pain. Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase and is involved in regulating NMDA receptor function. In this study, neuropathic pain was induced by ligation of the left L5 and L6 spinal nerves in rats. Nerve injury significantly increased the protein levels of calpain, CDK5 and P25 in the dorsal spinal cord ipsilateral to spinal nerve ligation (SNL) and induced hyperalgesia and allodynia in rats. The amplitude of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) and the NMDA-EPSC to AMPA-EPSC ratio in spinal lamina II neurons were significantly increased after nerve injury. Intrathecal application of sinomenine significantly reduced pain hypersensitivity and attenuated the increase in NMDA-EPSCs of dorsal horn neurons in nerve-injured rats. The expressions of calpain, CDK5 and P25 at the spinal level were also significantly inhibited after sinomenine treatment. Furthermore, sinomenine could significantly inhibit the voltage-gated calcium currents, especially the N- and P/Q-type currents in the dorsal horn neurons of the spinal cord and the dorsal root ganglion (DRG) neurons. Our data indicate that intrathecal application of sinomenine could inhibit the voltage-gated calcium channel function in spinal cord and DRG, which contributes to modulating the NMDA receptor function and chronic neuropathic pain through the calpain and p25 of CDK5 pathway. Supported by the National Key Research and Development Program of China (No. 2016YFC1305903) and the National Natural Science Foundation of China (No. 81373999 and No. 81774377).

Depression is a common and serious mental illness which negatively affects people's feelings. Panax ginseng is widely used in treating the neurological disorders in the Far East, previously its active ingredients, including ginsenoside Rg1 and Rb1, have been demonstrated to ameliorate depression while the underlying mechanism is unclear. In the present study, we first explored the effects of ginsenoside Rg1 and Rb1 on chronic unpredictable mild stress (CUMS) induced depressive-like behaviors in mice, the results showed that ginsenoside Rg1 and Rb1 could reduce the immobility time in forced swimming and tail suspension tests. We further studied their effects on the glutamatergic synaptic transmission using molecular biological and electrophysiological approaches, the results demonstrated that both ginsenoside Rg1 and Rb1 could promote glutamate release in mouse prefrontal cortex and improve glutamatergic synaptic transmission by increasing the expression and function of glutamate receptors in the CUMS mouse model. The underlying mechanism is involved in ginsenoside Rg1 and Rb1 regulating the phosphorylation of NMDAR1 receptor via mTOR-Akt-NF-kappa B signaling pathway. These results indicate that ginsenoside Rg1 and Rb1 may serve as the potential agents against depression. Supported by the National Key Research and Development Program of China (No. 2016YFC1305903) and the grants from National Natural Science Foundation of China (No. 81373999 and No. 81774377).

Background: Sarcopenia is an important geriatric syndrome. Despite the clinical significance of sarcopenia, the molecular pathways underlying it remain elusive. Here we explored the promotive effects of ucOC in proliferation and differentiation processes in C2C12 myoblasts, decreased IL-6 production in C2C12 myotubes as well as the possible signalling pathways involved. Methods: The effects of exogenous ucOC on C2C12 myoblasts proliferation were assessed using CCK8 and immunohistological staining assays. The levels of Akt, phosphorylated- Akt (p-Akt), P38, and phosphorylated-P38 (p-P38) were measured by Western Blotting. The effects of ucOC on myoblast differentiation were quantified by morphological analysis. A silencing experiment was conducted in which the expression of GPRC6A in C2C12 myoblasts was modified. The expression of GPRC6A, myosin heavy chain (MyHC) and the related ERK1/2 signalling pathway in C2C12 myoblasts were monitored by qRT-PCR and Western Blotting. IL-6 production in C2C12 myotubes were detected using the method of ELISA. Results: We showed that treatment with exogenous ucOC stimulated the priming of C2C12 myoblasts proliferation. Inhibition of Akt phosphorylation by wortmannin or inhibition of P38 MAPK phosphorylation by SB203580 decreased C2C12 cell proliferation. Wortmannin also reduced P38 MAPK phosphorylation, whereas SB203580 did not affect Akt activation. Besides, ucOC promoted C2C12 myoblast differentiation. Inhibition of ERK1/2 phosphorylation with U0126 decreased C2C12 cell differentiation. Furthermore, ucOC played a role of anti-inflammation and decreased IL-6 production in isolated C2C12 myotubes. Finally, GPRC6A expression was substantially increased after ucOC treatment of C2C12 cells. GPRC6A silencing inhibited Akt, P38 MAPK phosphorylation in C2C12 cells, and ERK1/2 phosphorylation in C2C12 myotubes; GPRC6A silencing also decreased cell proliferation, decreased cell differentiation, and increased IL-6 expression. Conclusions: The present data suggest that ucOC induces myoblast proliferation, enhances myogenic differentiation and decreased IL-6 production via a mechanism involving GPRC6A. We believe that our data support the idea that ucOC plays a major role in sarcopenia by promoting myoblast cellular function and anti-inflammatory property.

Background/Aims: Sarcopenia is characterized by an age-related decline in skeletal muscle plus low muscle strength and/or physical performance. Despite the clinical significance of sarcopenia, the molecular pathways underlying sarcopenia remain elusive. The recent demonstration that undercarboxylated osteocalcin (ucOC) favours muscle function related to insulin sensitivity and glucose metabolism raises the question of whether this hormone may also regulate muscle mass. The present study explored the promotive effects of ucOC in proliferation and differentiation processes of C2C12 myoblasts as well as the possible signalling pathways involved. Methods: The effects of exogenous ucOC on C2C12 myoblasts proliferation were assessed using CCK8 and immunohistological staining assays. C2C12 cells were pretreated with PI3K/Akt or P38 MAPK inhibitors to investigate the possible involvement of the PI3K/Akt and P38 MAPK pathways in proliferation. The levels of Akt, phosphorylated-Akt (p-Akt), P38, and phosphorylated-P38 (p-P38) were measured by Western Blotting. The effects of ucOC on myoblast differentiation were quantified by morphological analysis. A silencing experiment was conducted in which the expression of GPRC6A in C2C12 myoblasts was modified. The expression of GPRC6A, myosin heavy chain (MyHC) and the related ERK1/2 signalling pathway in C2C12 myoblasts were monitored by qRT-PCR and Western Blotting. Results: We showed that treatment with exogenous ucOC stimulated the priming of C2C12 myoblasts proliferation. Inhibition of Akt phosphorylation by wortmannin or inhibition of P38 MAPK phosphorylation by SB203580 decreased C2C12 cell proliferation. Wortmannin also reduced P38 MAPK phosphorylation, whereas SB203580 did not affect Akt activation. Furthermore, ucOC promoted C2C12 myoblast differentiation. Inhibition of ERK1/2 phosphorylation with U0126 decreased C2C12 cell differentiation. Finally, GPRC6A expression was substantially increased after ucOC treatment of C2C12 cells. GPRC6A silencing inhibited Akt, P38 MAPK phosphorylation in C2C12 cells, and ERK1/2 phosphorylation in C2C12 myotubes; GPRC6A silencing also decreased cell proliferation, decreased cell differentiation, and downregulated MyHC expression. Conclusions: The present data suggest that ucOC induces myoblast proliferation via sequential activation of the PI3K/Akt and p38 MAPK pathways in C2C12 myoblast cells. Moreover, ucOC enhances myogenic differentiation via a mechanism involving GPRC6A-ERK1/2 signalling.

老年人常常多病共存，导致多重用药（ polyphar-macy）。目前，多重用药尚无公认定义。欧洲强调药物数目，定义老年人每天用药数目>5种为多重用药。美国强调临床不需要/不必要药物，指老年人应用比临床需要更多的药物或药物方案中含有潜在不恰当用药（potentially inappropriate medication，PIM）。多重用药常常导致药物不良反应（ adverse drug reaction， ADR）、医药费用、住院率和病死率的增加［1，2］。