Modulation of the vitamin D/vitamin D receptor system in osteoporosis pathogenesis: insights and therapeutic approaches.

Osteoporosis is a prevalent bone disorder characterized by low bone mineral density (BMD) and deteriorated bone microarchitecture, leading to an increased risk of fractures. Vitamin D (VD), an essential nutrient for skeletal health, plays a vital role in maintaining bone homeostasis. The biological effects of VD are primarily mediated through the vitamin D receptor (VDR), a nuclear receptor that regulates the transcription of target genes involved in calcium and phosphate metabolism, bone mineralization, and bone remodeling. In this review article, we conduct a thorough literature search of the PubMed and EMBASE databases, spanning from January 2000 to September 2023. Utilizing the keywords "vitamin D," "vitamin D receptor," "osteoporosis," and "therapy," we aim to provide an exhaustive overview of the role of the VD/VDR system in osteoporosis pathogenesis, highlighting the most recent findings in this field. We explore the molecular mechanisms underlying VDR's effects on bone cells, including osteoblasts and osteoclasts, and discuss the impact of VDR polymorphisms on BMD and fracture risk. Additionally, we examine the interplay between VDR and other factors, such as hormonal regulation, genetic variants, and epigenetic modifications, that contribute to osteoporosis susceptibility. The therapeutic implications of targeting the VDR pathway for osteoporosis management are also discussed. By bringing together these diverse aspects, this review enhances our understanding of the VD/VDR system's critical role in the pathogenesis of osteoporosis and highlights its significance as a potential therapeutic target.

Exosomes derived from M2-type microglia ameliorate oxygen-glucose deprivation/reoxygenation-induced HT22 cell injury by regulating miR-124-3p/NCOA4-mediated ferroptosis.

Background: Although it has been reported that miRNA carried by M2 microglial exosomes protects neurons from ischemia-reperfusion brain injury, the mechanism of action remains poorly understood. This study aimed to explore the miRNA signaling pathway by which M2-type microglia-derived exosomes (M2-exosomes) ameliorate oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cytotoxicity in HT22 cells. Methods: BV2 microglia were induced by M2 polarization. Then, M2-exosomes were identified via transmission electron microscopy and special biomarker detection and co-cultured with HT22 cells. Cell proliferation was evaluated using the Cell Counting Kit-8 (CCK-8) assay. Intracellular concentrations of reactive oxygen species (ROS), Fe2+, glutathione (GSH), and malondialdehyde (MDA) were determined using dichlorofluorescein fluorescence and biochemical determination. miR-124-3p levels were determined using qRT-PCR, and protein expressions were examined via western blotting. Results: OGD/R suppressed the proliferation and induced the accumulation of Fe2+, ROS, and MDA and reduction of GSH in mouse HT22 cells, suggesting ferroptosis of HT22 cells. OGD/R-induced changes in the above mentioned indexes was ameliorated by M2-exosomes but restored by the exosome inhibitor GW4869. M2-exosomes with (mimic-exo) or without miR-124-3p (inhibitor-exo) promoted and suppressed proliferation and ferroptosis-associated indexes of HT22 cells, respectively. Moreover, mimic-exo and inhibitor-exo inhibited and enhanced NCOA4 expression in HT22 cells, respectively. NCOA4 overexpression reversed the protective effects of miR-124-3p mimic-exo in OGD/R-conditioned cells. NCOA4 was targeted and regulated by miR-124-3p. Conclusions: M2-exosome protects HT22 cells against OGD/R-induced ferroptosis injury by transferring miR-124-3p and NCOA4 into HT22 cells, with the latter being a target gene for miR-124-3p.

PINCH1 knockout aggravates myocardial infarction in mice via mediating the NF-κB signaling pathway.

Myocardial infarction (MI), the leading cause of death among patients with cardiovascular diseases, is characterized by acute cardiac muscle injury due to severe impairment of the coronary blood supply, which may lead to cardiogenic shock and cardiac arrest. Particularly interesting new cysteine histidine rich 1 (PINCH1) protein, a key component of the integrin signaling pathway, interacts with several proteins and serves a vital role in numerous cellular processes, including cytoskeleton remodeling, cell proliferation and cell migration. To investigate the role of PINCH1 in heart injury in the present study, PINCH1 was knocked out in the myocardial tissue of mice (age, 18 weeks) to induce MI. In addition, cell viability, migration and apoptosis, as well as the expression levels of NF-κB-associated proteins were determined in murine HL1 cardiomyocytes with a conditional PINCH1 shRNA using Cell Counting Kit-8, Transwell, flow cytometry and western blot assays, respectively. Furthermore, the cardiac expansion and myocardial fibrosis in PINCH1 knockout mice was investigated in vivo by performing morphological and histological examinations. Additionally, the murine ventricular myocardial ultrastructure was evaluated using an electron microscope, and the cardiomyocyte apoptotic rate and expression levels of NF-κB-related proteins were determined using TUNEL and western blot assays, respectively. The results showed that the apoptotic rate in the in vivo PINCH1 knockdown group was significantly increased. In addition, the protein expression levels of NF-κB signaling pathway-related proteins, including NF-κB, myeloid differentiation factor 88, TNF-α and caspase-3, were significantly increased in the in vivo PINCH1 knockdown group compared with the wild-type group, but the protein expression of MMP2 and MMP9 were the opposite. Overall, the in vitro and in vivo results revealed that PINCH1 knockout in mice significantly aggravated MI via the NF-κB signaling pathway.

MicroRNA-379-5p targets MAP3K2 to reduce autophagy and alleviate neuronal injury following cerebral ischemia via the JNK/c-Jun signaling pathway.

MicroRNAs (miRNAs) are abundant in neurons and play key roles in the function and development of the nervous system. This study focuses on the function of miR-379-5p in neurological function recovery during ischemic stroke. The expression of miR-379-5p in the serum of patients with ischemic stroke was determined. Human cerebral cortical neuron cells (HCN-2) were subjected to oxygen/glucose deprivation (OGD) to mimic an ischemic stroke in vitro, whereas mice subjected to middle cerebral artery occlusion (MCAO) were used as an animal model. The serum of patients with ischemic stroke and OGD-treated HCN-2 cells displayed a poor expression of miR-379-5p. Upregulation of miR-379-5p reduced the OGD-induced cell damage and decreased the expression of the autophagy marker protein Beclin1 in cells. Rapamycin, an autophagy activator, blocked the protective functions of miR-379-5p. Further, miR-379-5p directly bound to MAP3K2. MAP3K2 activated the JNK/c-Jun signaling pathway and suppressed the neuroprotective events mediated by miR-379-5p. The in vitro results were reproduced in vivo, where upregulation of miR-379-5p reduced neurological impairment and infarct size in MCAO-induced mice. This study suggested that miR-379-5p showed a neuroprotective effect on ischemic stroke and reduced autophagy of neurons through the suppression of MAP3K2 and the JNK/c-Jun axis.

Ibrutinib ameliorates cerebral ischemia/reperfusion injury through autophagy activation and PI3K/Akt/mTOR signaling pathway in diabetic mice.

Bruton's tyrosine kinase (BTK) is involved in the diabetogenic process and cerebral ischemic injury. However, it remained unclear whether BTK inhibition has remedial effects on ischemia/reperfusion (I/R) injury complicated with diabetes. We aim to investigate the regulatory role and potential mechanism of ibrutinib, a selective inhibitor of BTK, in cerebral I/R injured diabetic mice. The cytotoxicity and cell vitality tests were performed to evaluate the toxic and protective effects of ibrutinib at different incubating concentrations on normal PC12 cells or which were exposed to high glucose for 24 h, followed by hypoxia and reoxygenation (H/R), respectively. Streptozotocin (STZ) stimulation-induced diabetic mice were subjected to 1 h ischemia and then reperfusion. Then the diabetic mice received different dosages of ibrutinib or vehicle immediately and 24 h after the middle cerebral artery occlusion (MCAO). The behavioral, histopathological, and molecular biological tests were then performed to demonstrate the neuroprotective effects and mechanism in I/R injured diabetic mice. Consequently, Ibrutinib improved the decreased cell viability and attenuated oxidative stress in the high glucose incubated PC12 cells which subjected to H/R injury. In the I/R injured diabetic mice, ibrutinib reduced the cerebral infarct volume, improved neurological deficits, ameliorated pathological changes, and improved autophagy in a slightly dose-dependent manner. Furthermore, the expression of PI3K/AKT/mTOR pathway-related proteins were significantly upregulated by ibrutinib treatment. In summary, our finding collectively demonstrated that Ibrutinib could effectively ameliorate cerebral ischemia/reperfusion injury via ameliorating inflammatory response, oxidative stress, and improving autophagy through PI3K/Akt/mTOR signaling pathway in diabetic mice.

Years of Life Lost Due to Premature Death and Their Trends in People With Selected Neurological Disorders in Shanghai, China, 1995-2018: A Population-Based Study.

Background: Neurological disorders are the leading cause of long-term disability and the second leading cause of death in the world. We aimed to characterize the long-term trends in mortality and disease burden of selected neurological disorders and quantitatively analyze the contributions of demographic and non-demographic factors on the mortality of selected neurological disorders in Shanghai, China, 1995-2018. Methods: Mortality data were derived from the Vital Statistics System of Pudong New Area, Shanghai, China, during 1995-2018. Temporal trends for the mortality rates and burden of selected neurological disorders were analyzed by Joinpoint Regression Program. Years of life lost (YLL) was used to analyze the burden of disease. The increasing mortality rates related to demographic and non-demographic factors were estimated by the decomposition method. Results: A total of 4432 deaths from selected neurological disorders occurred during 1995-2018, accounting for 0.98% of total deaths. The crude mortality rates (CMR) and age-standardized mortality rates (ASMRW) of neurological disorders were 7.14/105 person-years and 4.08/105 person-years, respectively. Extrapyramidal and movement disorders, other degenerative diseases of the nervous system, and episodic and paroxysmal disorders were the three leading causes of mortality and YLL of selected neurological disorders. The CMR, ASMRW, and rate of YLL for deaths from selected neurological disorders showed significantly increasing trends in males, females, and the total population during 1995-2018 (all P < 0.001). The contribution rates of increased values of CMR related to demographic factors were more evident than non-demographic factors. Conclusion: The mortality rate and rate of YLL for death from selected neurological disorders increased significantly during 1995-2018 in Pudong New Area, Shanghai. The demographic factors, particularly aging, might be related to an increase in the mortality of neurological disorders. More effective prevention strategies are needed to prevent the aging-related death and burden from neurological disorders in the future.

The protective effects of curcumin in cerebral ischemia and reperfusion injury through PKC-θ signaling.

Ischemic stroke is a common cerebrovascular disease with the main cause considered to be cerebral ischemia and reperfusion (I/R), which exerts irreparable injury on nerve cells. Thus, the development of neuroprotective drugs is an urgent concern. Curcumin, a known antioxidant, has been found to have neuroprotective effects. To determine the protective mechanism of curcumin in ischemic stroke, oxygen and glucose deprivation/reoxygenation (OGD/R) was used to treat PC12 cells to mimic the cerebral I/R cell model. Curcumin (20 µM) was applied to OGD/R PC12 cells, followed by Ca2+ concentration, transepithelial electrical resistance (TEER), and cell permeability measurements. The results showed that OGD/R injury induced a decrease in TEER and increases in Ca2+ concentration and cell permeability. In contrast, curcumin alleviated these effects. The protein kinase C θ (PKC-θ) was associated with the protective function of curcumin in the OGD/R cell model. Moreover, the middle cerebral artery occlusion and reperfusion model (MCAO/R) was applied to simulate the I/R rat model. Our results demonstrated that curcumin could reverse the MCAO/R-induced increase in Ca2+ concentration and blood-brain barrier (BBB) disruption. Our study demonstrates the mechanisms by which curcumin exhibited a protective function against cerebral I/R through PKC-θ signaling by reducing BBB dysfunction.

AntagomiR-29b inhibits vascular and valvular calcification and improves heart function in rats.

We aimed to investigate the role of the miR-29b and its effect on TGF-ß3 pathway in vascular and valvular calcification in a rat model of calcific aortic valve diseases (CAVD). A rat model of CAVD was established by administration of warfarin plus vitamin K. The expression levels of miR-29b, osteogenic markers and other genes were determined by qRT-PCR, Western blot and/or immunofluorescence and immunohistochemistry. The calcium content and alkaline phosphatase (ALP) activity were measured. The calcium content, ALP activity and osteogenic markers levels in calcified aorta and aortic valve were augmented compared to controls. The expression of miR-29b, p-Smad3, and Wnt3 and ß-catenin was significantly up-regulated, whereas TGF-ß3 was markedly down-regulated. However, compared with the CAVD model group, the calcium content and ALP activity in rats treated with antagomiR-29b were significantly decreased, and antagomiR-29b administration reversed the effects of CAVD model on the expression of miR-29b and osteogenic markers. Inhibition of miR-29b in CAVD rats prevented from vascular and valvular calcification and induced TGF-ß3 expression, suggesting that the miR-29b/TGF-ß3 axis may play a regulatory role in the pathogenesis of vascular and valvular calcification and could play a significant role in the treatment of CAVD and other cardiovascular diseases.

Improved Early Recognition of Coronavirus Disease-2019 (COVID-19): Single-Center Data from a Shanghai Screening Hospital.

BACKGROUND: In December 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV) was reported in Wuhan, Hubei province, China, which has subsequently affected more than 200 countries worldwide including Europe, North America, Oceania, Africa and other places. The number of infected people is rapidly increasing, while the diagnostic method of COVID-19 is only by nucleic acid testing. OBJECTIVE: To explain the epidemiological characteristics, clinical features, imaging manifestations and to judge diagnostic value of COVID-19 by analyzing the clinical data of COVID-19 suspected and confirmed patients in a non-outbreak, Shanghai, China. To clarify the early epidemiology and clinical characteristics about COVID-19. METHODS: Cross-sectional, single-center case reports of the 86 patients screened at Zhoupu Hospital in Pudong New District, Shanghai, China, from January 23 to February 16, 2020. Epidemiology, demography, clinical, laboratory and chest CTs were collected and analyzed. The screened patients were divided into COVID-19 and non-COVID-19 based on nucleic acid test results. RESULTS: Of the 86 screened patients, 11 were confirmed (12.8%) by nucleic acid testing (mean age 40.73 ± 11.32, 5 males). No significant differences were found in clinical symptoms including fever, cough, dyspnea, sore throat, and fatigue (P > 0.05). No statistical difference was observed in plasma C-reactive protein (CRP) between the two groups (COVID-19 and non-COVID-19 ) of patients (P = 0.402), while the white blood cell count and lymphocyte count of the confirmed patients were slightly lower than those of the suspected patients (P < 0.05). Some non-COVID-19 chest CTs also showed subpleural lesions, such as ground-glass opacities (GGO) combined with bronchiectasis; or halo nodules distributed under the pleura with focal GGO; consolidation of subpleural distribution or combined with air bronchi sign and vascular bundle sign, etc. CONCLUSION: The early clinical manifestations and imaging findings of COVID-19 are not characteristic in non-outbreak areas. Etiological testing should be performed as early as possible for clinically suspected patients.

Autophagy and inflammation in ischemic stroke.

Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role in the survival of nerve cells and the recovery of neural tissue after ischemia. Many studies have found an interaction between autophagy and inflammation in the pathogenesis of ischemic stroke. This study outlines recent advances regarding the role of autophagy in the post-stroke inflammatory response as follows. (1) Autophagy inhibits inflammatory responses caused by ischemic stimulation through mTOR, the AMPK pathway, and inhibition of inflammasome activation. (2) Activation of inflammation triggers the formation of autophagosomes, and the upregulation of autophagy levels is marked by a significant increase in the autophagy-forming markers LC3-II and Beclin-1. Lipopolysaccharide stimulates microglia and inhibits ULK1 activity by direct phosphorylation of p38 MAPK, reducing the flux and autophagy level, thereby inducing inflammatory activity. (3) By blocking the activation of autophagy, the activation of inflammasomes can alleviate cerebral ischemic injury. Autophagy can also regulate the phenotypic alternation of microglia through the nuclear factor-κB pathway, which is beneficial to the recovery of neural tissue after ischemia. Studies have shown that some drugs such as resveratrol can exert neuroprotective effects by regulating the autophagy-inflammatory pathway. These studies suggest that the autophagy-inflammatory pathway may provide a new direction for the treatment of ischemic stroke.

Ischemic Postconditioning Alleviates Cerebral Ischemia-Reperfusion Injury Through Activating Autophagy During Early Reperfusion in Rats.

This study aimed to investigate whether ischemic postconditioning (IpostC) alleviates cerebral ischemia/reperfusion (I/R) injury involved in autophagy. Adult Sprague-Dawley rats were divided into five groups: sham (sham surgery), I/R (middle cerebral artery occlusion [MCAO] for 100 min, then reperfusion), IpostC (MCAO for 100 min, reperfusion for 10 min, MCAO for 10 min, then reperfusion), IpostC+3MA (3-methyladenine, an autophagy inhibitor, administered 30 min before first reperfusion), and IpostC+Veh (vehicle control for IpostC+3MA group). Infarct volume was measured using cresyl violet staining. Autophagy-related proteins were detected by western blot and immunohistochemistry. Autophagosomes, autophagolysosomes, and mitochondrial damage were identified by transmission electron microscopy. Cortical cell apoptosis was detected by the TUNEL assay. Neurologic function was assessed using the modified Neurologic Severity Score. IpostC improved neurological function and reduced infarct volume after I/R (P < 0.05). These effects of IpostC were inhibited by 3MA (P < 0.05). Autophagosome formation was increased in the I/R and IpostC+Veh groups (P < 0.05), but not in the IpostC+3MA group. The I/R group showed enhanced LC3-II/LC3-I ratio, p62, and Cathepsin B levels and decreased LAMP-2 level (all P < 0.05 vs. sham), indicating dysfunction of autophagic clearance. IpostC reduced p62 and Cathepsin B levels and increased the LC3-II/LC3-I ratio, and nuclear translocation of transcription factor EB (all P < 0.05); these effects of IpostC were reversed by 3MA, suggesting IpostC enhanced autophagic flux. Furthermore, IpostC attenuated I/R-induced mitochondrial translocation of Bax and mitochondrial cytochrome-c release (all P < 0.05); 3MA inhibited these effects of IpostC (P < 0.05). In conclusion, IpostC may alleviate cerebral I/R injury by activating autophagy during early reperfusion.

Curcumin attenuates cerebral ischemia injury in Sprague-Dawley rats and PC12 cells by suppressing overactivated autophagy.

The present study assessed whether the protective effects of curcumin against cerebral ischemia injury were due to the suppression of overactivated autophagy. Curcumin is a well-known natural polyphenolic compound that effectively counteracts oxidation, inflammation, and various types of cancer. Several studies have demonstrated the protective effects of curcumin against ischemia-reperfusion injury in tissues from the lungs, cardiomyocytes, and liver. The present study employed brain injury models induced by middle cerebral artery occlusion (MCAO) in rats and PC12 oxygen-glucose-deprived (OGD) cells. Infarct area, neurological score, lactate dehydrogenase (LDH) activity, autophagy expression, cell apoptosis, and mRNA and protein expressions of caspase-3 were determined following curcumin supplementation. Compared to MCAO rats, curcumin-treated MCAO rats exhibited substantial reductions in neurological score, infarct area, and LDH activity. MCAO also increased LC3 II/I protein expression and decreased p62 protein expression, but curcumin supplementation significantly reversed these altered protein expressions. Caspase-3 protein expression increased by 46.2% in the MCAO group, but curcumin supplementation significantly reduced this expression. Similarly, apoptosis increased by 33.1% in OGD cells, but curcumin supplementation significantly reduced apoptosis to 21.6% and 9.3% at doses of 100 and 200 mg/kg, respectively. The mRNA and protein expressions of caspase-3 exhibited substantial increases in OGD cells but these expressions were significantly decreased following curcumin supplementation. Taken together, the present results indicate that curcumin represents a natural bioactive substance that can protect against cerebral ischemia via the suppression of overactivated autophagy.

Mir-29b promotes human aortic valve interstitial cell calcification via inhibiting TGF-ß3 through activation of wnt3/ß-catenin/Smad3 signaling.

Herein, we hypothesized that pro-osteogenic MicroRNAs (miRs) could play functional roles in the calcification of the aortic valve and aimed to explore the functional role of miR-29b in the osteoblastic differentiation of human aortic valve interstitial cells (hAVICs) and the underlying molecular mechanism. Osteoblastic differentiation of hAVICs isolated from human calcific aortic valve leaflets obtained intraoperatively was induced with an osteogenic medium. Alizarin red S staining was used to evaluate calcium deposition. The protein levels of osteogenic markers and other proteins were evaluated using western blotting and/or immunofluorescence while qRT-PCR was applied for miR and mRNA determination. Bioinformatics and luciferase reporter assay were used to identify the possible interaction between miR-29b and TGF-ß3. Calcium deposition and the number of calcification nodules were pointedly and progressively increased in hAVICs during osteogenic differentiation. The levels of osteogenic and calcification markers were equally increased, thus confirming the mineralization of hAVICs. The expression of miR-29b was significantly increased during osteoblastic differentiation. Furthermore, the osteoblastic differentiation of hAVICs was significantly inhibited by the miR-29b inhibition. TGF-ß3 was markedly downregulated while Smad3, Runx2, wnt3, and ß-catenin were significantly upregulated during osteogenic induction at both the mRNA and protein levels. These effects were systematically induced by miR-29b overexpression while the inhibition of miR-29b showed the inverse trends. Moreover, TGF-ß3 was a direct target of miR-29b. Inhibition of miR-29b hinders valvular calcification through the upregulation of the TGF-ß3 via inhibition of wnt/ß-catenin and RUNX2/Smad3 signaling pathways.

Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells.

Our previous findings have demonstrated that autophagy regulation can alleviate the decline of learning and memory by eliminating deposition of extracellular beta-amyloid peptide (Aß) in the brain after stroke, but the exact mechanism is unclear. It is presumed that the regulation of beta-site APP-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in metabolism of Aß, would be a key site. Neuro-2a/amyloid precursor protein 695 (APP695) cell models of cerebral ischemia were established by oxygen-glucose deprivation to investigate the effects of Rapamycin (an autophagy inducer) or 3-methyladenine (an autophagy inhibitor) on the expression of BACE1. Either oxygen-glucose deprivation or Rapamycin down-regulated the expression of BACE1 while 3-methyladenine up-regulated BACE1 expression. These results confirm that oxygen-glucose deprivation down-regulates BACE1 expression in Neuro-2a/APP695 cells through the introduction of autophagy.

Autophagy: a double-edged sword for neuronal survival after cerebral ischemia.

Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether activation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.

Clinical profile of Parkinson's disease in the Gumei community of Minhang district, Shanghai.

OBJECTIVE: We examined the demographic and clinical profiles of Parkinson's disease in Shanghai, China, to assist in disease management and provide comparative data on Parkinson's disease prevalence, phenotype, and progression among different regions and ethnic groups. METHODS: A door-to-door survey and follow-up clinical examinations identified 180 community-dwelling Han-Chinese Parkinson's disease patients (104 males, 76 females). RESULTS: The average age at onset was 65.16 ± 9.60 years. The most common initial symptom was tremor (112 patients, 62.22%), followed by rigidity (38, 21.11%), bradykinesia (28, 15.56%) and tremor plus rigidity (2, 1.11%). Tremor as the initial symptom usually began in a single limb (83.04% of patients). The average duration from onset to mild Parkinson's disease (Hoehn-Yahr phase 1-2) was 52.74 ± 45.64 months. Progression from mild to moderate/severe Parkinson's disease (phase ≥ 3) was significantly slower (87.07 ± 58.72 months; p<0.001), except for patients presenting initially with bradykinesia (53.83 ± 24.49 months). Most patients (149/180, 82.78%) took levodopa with or without other drugs. The Hamilton Anxiety Scale revealed symptoms of clinical anxiety in 35 patients, and the Hamilton Depression Scale revealed depressive symptoms in 88 patients. The depressed or anxious subgroup (123 patients) demonstrated a significantly younger age at onset (55.54 ± 7.68 years) compared with the overall mean (p<0.05). CONCLUSION: Unilateral limb tremor was the most common initial symptom, and motor function deteriorated slowly over ≅4-9 years. Earlier-onset patients experience greater psychiatric dysfunction.

Ghrelin suppresses Purkinje neuron P-type Ca(2+) channels via growth hormone secretagogue type 1a receptor, the ßγ subunits of Go-protein, and protein kinase a pathway.

Although ghrelin receptors have been demonstrated to be widely expressed in the central nervous system and peripheral tissues of mammals, it is still unknown whether ghrelin functions in cerebellar Purkinje neurons. In this study, we identified a novel functional role for ghrelin in modulating P-type Ca(2+) channel (P-type channel) currents (IBa) as well as action-potential firing in rat Purkinje neurons. Our results show that ghrelin at 0.1µM reversibly decreased IBa by ~32.3%. This effect was growth hormone secretagogue receptor 1a (GHS-R1a)-dependent and was associated with a hyperpolarizing shift in the voltage-dependence of inactivation. Intracellular application of GDP-ß-S and pretreatment with pertussis toxin abolished the inhibitory effects of ghrelin. Dialysis of cells with the peptide QEHA (but not the scrambled peptide SKEE), and a selective antibody raised against the G-protein αo subunit both blocked the ghrelin-induced response. Ghrelin markedly increased protein kinase A (PKA) activity, and intracellular application of PKI 5-24 as well as pretreatment of the cells with the PKA inhibitor KT-5720 abolished ghrelin-induced IBa decrease, while inhibition of PKC had no such effects. At the cellular level, ghrelin induced a significant increase in action-potential firing, and blockade of GHS-R1a by BIM-28163 abolished the ghrelin-induced hyperexcitability. In summary, these results suggest that ghrelin markedly decreases IBa via the activation of GHS-R1a, which is coupled sequentially to the activities of Go-protein ßγ subunits and the downstream PKA pathway. This could contribute to its physiological functions, including the spontaneous firing of action potentials in cerebellar Purkinje neurons.

Clinical profile of Parkinson's disease in the Gumei community of Minhang district, Shanghai

OBJECTIVE: We examined the demographic and clinical profiles of Parkinson's disease in Shanghai, China, to assist in disease management and provide comparative data on Parkinson's disease prevalence, phenotype, and progression among different regions and ethnic groups. METHODS: A door-to-door survey and follow-up clinical examinations identified 180 community-dwelling Han-Chinese Parkinson's disease patients (104 males, 76 females). RESULTS: The average age at onset was 65.16±9.60 years. The most common initial symptom was tremor (112 patients, 62.22%), followed by rigidity (38, 21.11%), bradykinesia (28, 15.56%) and tremor plus rigidity (2, 1.11%). Tremor as the initial symptom usually began in a single limb (83.04% of patients). The average duration from onset to mild Parkinson's disease (Hoehn-Yahr phase 1-2) was 52.74±45.64 months. Progression from mild to moderate/severe Parkinson's disease (phase≥3) was significantly slower (87.07±58.72 months; p<0.001), except for patients presenting initially with bradykinesia (53.83±24.49 months). Most patients (149/180, 82.78%) took levodopa with or without other drugs. The Hamilton Anxiety Scale revealed symptoms of clinical anxiety in 35 patients, and the Hamilton Depression Scale revealed depressive symptoms in 88 patients. The depressed or anxious subgroup (123 patients) demonstrated a significantly younger age at onset (55.54±7.68 years) compared with the overall mean (p<0.05). CONCLUSION: Unilateral limb tremor was the most common initial symptom, and motor function deteriorated slowly over ≅4−9 years. Earlier-onset patients experience greater psychiatric dysfunction. .

Mitophagy in ischaemia/reperfusion induced cerebral injury.

Mitochondrial autophagy (Mitophagy), the specific autophagic elimination of mitochondria, has been related with several forms of degenerative disease and mitochondrial dysfunction. It is involved in multiple cellular processes. In addition to one of its established key roles in the maintenance of normal cellular phenotype and function, there is growing interest in the concept that targeted modulation of mitophagy may reduce cerebral ischaemia/reperfusion injury. Induction of mitophagy results in selective clearance of damaged mitochondria in cells. In response to stress such as ischaemia/reperfusion, prosurvival and prodeath pathways are concomitantly activated in neuronal cells.

Inhibition of L-type Ca(2+) channels by curcumin requires a novel protein kinase-theta isoform in rat hippocampal neurons.

Curcumin, a major active compound of Curcuma longa, has been reported to have potent neuroprotective activities. However to date, the relevant mechanisms still remain unclear. In this study, we report that curcumin selectively inhibits L-type Ca(2+) channel currents in cultured rat hippocampal neurons. Whole-cell currents were recorded using 10mM barium as a charge carrier. Curcumin reversibly inhibited high-voltage-gated Ca(2+) channel (HVGCC) currents (IBa) in a concentration-dependent manner but had no apparent effects on the cells treated with nifedipine, a specific L-type Ca(2+) channel blocker. Curcumin did not markedly affect the activation of L-type Ca(2+) channels while significantly shifted the inactivation curve in the hyperpolarizing direction. Pretreatment of cells with the classical and novel PKC antagonists GF109203X and calphostin C completely abolished curcumin-induced IBa inhibition, whereas the classical PKC antagonist Gö6976 or inhibition of PKA activity elicited no such effects. Moreover, the curcumin-induced IBa response was abolished by intracellular application of the PKC-θ inhibitory peptide PKC-θ-IP or by siRNA knockdown of PKC-θ in cultured rat hippocampal neurons. In these neurons, novel isoforms of PKC including delta (PKC-δ), epsilon (PKC-ɛ) and theta (PKC-θ), but not eta (PKC-η), were endogenously expressed. Taken together, these results suggest that curcumin selectively inhibits IBavia a novel PKC-θ-dependent pathway, which could contribute to its neuroprotective effects in rat hippocampal neurons.