Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson's disease mouse model through activating GHS-R1a/D2R heterodimers.

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 µM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.

"Sibling" battle or harmony: crosstalk between nesfatin-1 and ghrelin.

Ghrelin was first identified as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) in 1999, with the function of stimulating the release of growth hormone (GH), while nesfatin-1 was identified in 2006. Both peptides are secreted by the same kind of endocrine cells, X/A-like cells in the stomach. Compared with ghrelin, nesfatin-1 exerts opposite effects on energy metabolism, glucose metabolism, gastrointestinal functions and regulation of blood pressure, but exerts similar effects on anti-inflammation and neuroprotection. Up to now, nesfatin-1 remains as an orphan ligand because its receptor has not been identified. Several studies have shown the effects of nesfatin-1 are dependent on the receptor of ghrelin. We herein compare the effects of nesfatin-1 and ghrelin in several aspects and explore the possibility of their interactions.

The Functions of TRIM56 in Antiviral Innate Immunity and Tumorigenesis.

As a member of the TRIM (tripartite motif) protein family, TRIM56 can function as an E3 ubiquitin ligase. In addition, TRIM56 has been shown to possess deubiquitinase activity and the ability to bind RNA. This adds to the complexity of the regulatory mechanism of TRIM56. TRIM56 was initially found to be able to regulate the innate immune response. In recent years, its role in direct antiviral and tumor development has also attracted the interest of researchers, but there is no systematic review on TRIM56. Here, we first summarize the structural features and expression of TRIM56. Then, we review the functions of TRIM56 in TLR and cGAS-STING pathways of innate immune response, the mechanisms and structural specificity of TRIM56 against different types of viruses, and the dual roles of TRIM56 in tumorigenesis. Finally, we discuss the future research directions regarding TRIM56.

The Biological Behaviors of Neural Stem Cell Affected by Microenvironment from Host Organotypic Brain Slices under Different Conditions.

Therapeutic strategies based on neural stem cells (NSCs) transplantation bring new hope for neural degenerative disorders, while the biological behaviors of NSCs after being grafted that were affected by the host tissue are still largely unknown. In this study, we engrafted NSCs that were isolated from a rat embryonic cerebral cortex onto organotypic brain slices to examine the interaction between grafts and the host tissue both in normal and pathological conditions, including oxygen-glucose deprivation (OGD) and traumatic injury. Our data showed that the survival and differentiation of NSCs were strongly influenced by the microenvironment of the host tissue. Enhanced neuronal differentiation was observed in normal conditions, while significantly more glial differentiation was observed in injured brain slices. The process growth of grafted NSCs was guided by the cytoarchitecture of host brain slices and showed the distinct difference between the cerebral cortex, corpus callosum and striatum. These findings provided a powerful resource for unraveling how the host environment determines the fate of grafted NSCs, and raise the prospect of NSCs transplantation therapy for neurological diseases.

Role of Mitophagy in neurodegenerative Diseases and potential tagarts for Therapy.

Mitochondria dysfunction has been defined as one of the hallmarks of aging-related diseases as is characterized by the destroyed integrity, abnormal distribution and size, insufficient ATP supply, increased ROS production, and subsequently damage and oxidize the proteins, lipids and nucleic acid. Mitophagy, an efficient way of removing damaged or defective mitochondria by autophagy, plays a pivotal role in maintaining the mitochondrial quantity and quality control enabling the degradation of unwanted mitochondria, and thus rescues cellular homeostasis in response to stress. Accumulating evidence demonstrates that impaired mitophagy has been associated with many neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) in a variety of patients and disease models with neural death, oxidative stress and disturbed metabolism, either as the cause or consequence. These findings suggest that modulation of mitophagy may be considered as a valid therapeutic strategy in neurodegenerative diseases. In this review, we summarize recent findings on the mechanisms of mitophagy and its role in neurodegenerative diseases, with a particular focus on mitochondrial proteins acting as receptors that mediate mitophagy in these diseases.

Longitudinal clinical and radiographic evaluation reveals interleukin-6 as an indicator of persistent pulmonary injury in COVID-19.

Rationale: Previous studies of coronavirus disease 2019 (COVID-19) were mainly focused on cross-sectional analysis. In this study, we sought to evaluate the dynamic changes of immunological and radiographic features, and the association with the outcome of pulmonary lesions in COVID-19 patients. Methods: Peripheral blood samples and radiographic data were collected longitudinally for up to 8 weeks from 158 laboratory-confirmed COVID-19 patients. The chest computed tomography (CT) scans were scored based on a semi-quantification assessment according to the extent of pulmonary abnormalities; the temporal change of the immunological and radiographic features was analyzed. Results: Compared with mild and moderate patients, severe patients had significantly decreased counts of lymphocytes, CD4+ T cells, CD8+ T cells, and CD19+ B cells but dramatically elevated counts of neutrophils and levels of interleukin (IL)-6. Sequential monitoring showed a sustained increase in lymphocytes counts and significantly decreased levels of IL-6 in severe patients during the disease course. Notably, patients with persistent pulmonary lesions (CT score ≥ 5 in week 8) showed high levels of IL-6 during the follow-up period, compared with those with recovery lesions (CT score < 5 in week 8). More importantly, the peak expression of IL-6 prior to the aggravated lung injury was mainly found in patients with persistent lesions, and multivariate analysis showed that IL-6 level upon admission was an independent factor associated with the persistent pulmonary injury. Conclusion: Prolonged elevation of IL-6 is associated with persistent pulmonary lesions in COVID-19 patients. Sequential monitoring and timely intervention of IL-6 may favor the clinical management of COVID-19.

Identification and molecular analysis of cashmere goat lncRNAs reveal their integrated regulatory network and potential roles in secondary hair follicle.

Long non-coding RNAs (lncRNAs) is a class of eukaryotic transcripts with length of more than 200 bp. They contribute to the regulation of gene expressions involved in multiple processes including the skin cell proliferation, differentiation, and reconstruction of the secondary hair follicles (SHFs). In this study, firstly, we identified 16 putative lncRNAs from SHFs of cashmere goat based on the EST sequences from NCBI database. Secondly, we investigated their transcriptional pattern in SHFs of cashmere goat, and constructed their ceRNA regulatory networks. The RT-qPCR results showed four lncRNAs (lncRNA-475074, -052149, -052140, and -051789) were significantly up-regulated, and nine lncRNAs (lncRNA-711032, -475083, -475070, -052139, -052127, -052037, -051903, -051847, and -051804) were significantly down-regulatd in anagen SHFs of cashmere goat. CeRNA networks analysis revealed complex interactional relationship among lncRNAs, miRNAs and mRNAs. Further, the KEGG pathway enrichment was performed for the potential target genes of the identified lncRNAs based on bioinformatics technique, and the results indicated that differentially expressed lncRNAs directly or indirectly might regulate potential target genes. Our results from this study will provide a significant information for further exploring the functions and possible mechanisms of the identified lncRNAs in SHFs of cashmere goat.

Ghrelin promotes midbrain neural stem cells differentiation to dopaminergic neurons through Wnt/ß-catenin pathway.

Ghrelin plays a neuroprotective role in the process of dopaminergic (DAergic) neurons degeneration in Parkinson's disease (PD). However, it still largely unknown whether ghrelin could affect the midbrain neural stem cells (mbNSCs) from which DAergic neurons are originated. In the present study, we observed that ghrelin enhanced mbNSCs proliferation, and promoted neuronal differentiation especially DAergic neuron differentiation both in vitro and ex vivo. The messenger RNA levels of Wnt1, Wnt3a, and glial cell line-derived neurotrophic factor were increased in response to the ghrelin treatment. Results showed that Wnt/ß-catenin pathway was relevant to this DAergic neuron differentiation induced by ghrelin. Our finding gave a new evidence that ghrelin may enable clinical therapies for PD by its neurogenesis role.

Association of orthostatic hypotension with Parkinson's disease: a meta-analysis.

OBJECTIVE: Orthostatic hypotension (OH) is a common non-motor sign of Parkinson's disease (PD). Several epidemiological studies have estimated the association between OH and PD with controversial results. Here, a meta-analysis was conducted to evaluate the association between them. METHODS: PubMed, Embase, Web of Science, CNKI (Chinese National Knowledge Infrastructure), VIP (Database of Chinese Scientific and Technical Periodicals), and Wanfang databases were searched for eligible publications from October 2003 to December 2017. Prevalence numbers from studies were pooled using a non-linear random-effects meta-analysis. Random effect model was used to calculate the pooled odds ratio (OR) with 95% confidence intervals (CIs) from individual studies. Publication bias was estimated by Egger's test, Begg's test, and the funnel plot. RESULTS: Nineteen studies involving 1620 PD patients and 898 healthy controls were included in this meta-analysis. The pooled estimate of the prevalence of OH in PD was 27.7% compared with 7.9% of that in control. The pooled OR of OH with PD was 4.343 (95% CI 3.323-5.676) with a low heterogeneity (I2 = 12.5%, Pheterogeneity = 0.301). CONCLUSION: In the present meta-analysis, the pooled OR of OH with PD was 4.343 (95% CI 3.323-5.676) with a low heterogeneity, which showed a significant association between OH and increased risk of PD.

LncRNA-000133 from secondary hair follicle of Cashmere goat: identification, regulatory network and its effects on inductive property of dermal papilla cells.

Long noncoding RNAs (lncRNAs), a class of non-protein conding RNAs > 200 nt in length, were thought to play critical roles in regulating the expression of protein-coding genes. Here, we identified and characterized a novel lncRNA-000133 from the secondary hair follicle (SHF) of cashmere goat with its ceRNA network analysis, as well as, its potential effects on inductive property of dermal papilla cells were evaluated through overexpression analysis. Expression analysis indicated that lncRNA-000133 had a significantly higher expression at anagen than that at telogen in SHF of Cashmere goat, suggesting that lncRNA-000133 might be involved in the reconstruction of SHF with the formation and growth of cashmere fiber. Taken together with methylation analysis, we showed that 5' regulatory region methylation of the lncRNA-000133 gene might be involved in its expression suppression in SHF of Cashmere goat. The ceRNA regulatory network showed that a rich and complex regulatory relationship between lncRNA-000133 and related miRNAs with their target genes. The overexpression of lncRNA-000133 led to a significant increasing in the relative expression of ET-1, SCF, ALP and LEF1 in dermal papilla cells suggesting that lncRNA-000133 appears to contribute the inductive property of dermal papilla cells.

Neural stem cell-derived factors inhibit the growth and invasion of U87 stem-like cells in vitro.

Glioma is one of the most common and aggressive tumors in the brain. Significant attention has been paid to the potential use of neural stem/progenitor cells (NSCs/NPCs) as delivery vehicles to cure gliomas. However, whether the NSCs/NPCs or the factors they produced could make a contribution still remains to be seen. In this study, we focused on the inhibitory effects of the factors produced by NSCs/NPCs on the biological behavior of the glioma stem-like cell in vitro. The human glioma cell line U87 was selected and the U87 stem-like cells were addressed. After being cultured in the NSC condition medium (NSC-CM), the viability and proliferation of U87 stem-like cells were significantly reduced. The invasion of U87 stem-like cells and the migration of U87 cells were also significantly decreased. However, no significant change was observed in regard to the astrocytic differentiation of U87 stem-like cells. These indicated that NSCs/NPCs produced some factors and had an inhibitory effect on the growth and invasion but not the terminal differentiation of U87 stem-like cells. It is worth paying attention to NSCs/NPCs as a high-potential candidate for glioma treatment.

Iron Pathophysiology in Parkinson Diseases.

The key molecular events that provoke Parkinson's disease (PD) are not fully understood. Iron deposit was found in the substantia nigra pars compacta (SNpc) of PD patients and animal models, where dopaminergic neurons degeneration occurred selectively. The mechanisms involved in disturbed iron metabolism remain unknown, however, considerable evidence indicates that iron transporters dysregulation, activation of L-type voltage-gated calcium channel (LTCC) and ATP-sensitive potassium (KATP) channels, as well as N-methyl-D-aspartate (NMDA) receptors (NMDARs) contribute to this process. There is emerging evidence on the structural links and functional modulations between iron and α-synuclein, and the key player in PD which aggregates in Lewy bodies. Iron is believed to modulate α-synuclein synthesis, post-translational modification, and aggregation. Furthermore, glia, especially activated astroglia and microglia, are involved in iron deposit in PD. Glial contributions were largely dependent on the factors they released, e.g., neurotrophic factors, pro-inflammatory factors, lactoferrin, and those undetermined. Therefore, iron chelation using iron chelators, the extracts from many natural foods with iron chelating properties, may be an effective therapy for prevention and treatment of the disease.

Comparison of Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium by simultaneous determination of multi-components with single reference standard method and chemometric analysis.

INTRODUCTION: Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium, two morphologically similar herbal medicines derived from Artemisia genus. Although the two Artemisia herbs have been used as medicines for a long time in China, the study of their phytochemical and bioactive composition is limited. OBJECTIVE: To comprehensively compare and evaluate the composition of Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium, and find the chemical makers for quality evaluation of the two Artemisia herbal medicines. METHODOLOGY: Eight compounds including six phenolic acids and two flavonoids were assayed by a single reference standard for simultaneous determination of multi-components method using 3-caffeoylquinic acid as the reference standard. The quantitative data were further analysed by chemometric approaches to compare and distinguish the two herbal medicines. RESULTS: The credibility and feasibility of the single reference standard for simultaneous determination of the multi-components method were carefully validated. The validated method was applied to analyse 16 batches of Artemisiae argyi Folium and 10 batches of Artemisiae lavandulaefoliae Folium samples. The quantitative results showed that 3,5-di-O-caffeoylquinic acid was the most abundant constituent, and the contents of flavonoids were notably different between the two herbal medicines. The chemometric analysis results indicated the two flavonoids, jaceosidin and eupatilin could be used as chemical markers for quality evaluation of the two herbal medicines. CONCLUSION: The single reference standard for simultaneous determination of the multi-components method coupled with chemometrics analysis could be a well-acceptable strategy to compare and evaluate the quality of Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium.

Association of the rs1611115 polymorphism in DBH gene with Parkinson's disease: a meta-analysis.

A meta-analysis was performed to assess the association between the dopamine beta-hydroxylase (DBH) rs1611115 genetic polymorphism and Parkinson's disease (PD). A comprehensive search was conducted to identify all case-control or cohort studies. The fixed or random effect-pooled measure was selected on the basis of a homogeneity test among studies. Heterogeneity among studies was evaluated using the I2. We performed sensitivity analyses to evaluate the robustness of the results. Publication bias was estimated using Egger's linear regression test. Five case-control studies corresponded to the inclusion criteria comprising 3926 patients and 3542 controls which were included in the present meta-analysis. Our meta-analysis showed no significant association between DBH rs1611115 genetic polymorphism and risk of PD in the codominant (REM, OR = 1.017, 95%CI = 0.854-1.210), dominant (REM, OR = 0.989, 95%CI = 0.826-1.185), and recessive (REM, OR = 1.007, 95%CI = 0.657-1.542) models. Moreover, in the subgroup analysis based on region (Asia and Europe), no significant associations were observed in Asia or Europe. This meta-analysis suggests that the DBH rs1611115 genetic polymorphism might not be associated with PD.

[Quality evaluation of Artemisiae Argyi Folium based on fingerprint analysis and quantitative analysis of multicomponents].

Artemisiae Argyi Folium, the dried leaves of Artemisia argyi, has been widely used in traditional Chinese and folk medicines for treatment of hemorrhage, pain, and skin itch. Phytochemical studies indicated that volatile oil, organic acid and flavonoids were the main bioactive components in Artemisiae Argyi Folium. Compared to the volatile compounds, the research of nonvolatile compounds in Artemisiae Argyi Folium are limited. In the present study, an accurate and reliable fingerprint approach was developed using HPLC for quality control of Artemisiae Argyi Folium. A total of 10 common peaks were marked，and the similarity of all the Artemisiae Argyi Folium samples was above 0.940. The established fingerprint method could be used for quality control of Artemisiae Argyi Folium. Furthermore, an HPLC method was applied for simultaneous determination of seven bioactive compounds including five organic acids and two flavonoids in Artemisiae Argyi Folium and Artemisiae Lavandulaefoliae Folium samples. Moreover, chemometrics methods such as hierarchical clustering analysis and principal component analysis were performed to compare and discriminate the Artemisiae Argyi Folium and Artemisiae Lavandulaefoliae Folium based on the quantitative data of analytes. The results indicated that simultaneous quantification of multicomponents coupled with chemometrics analysis could be a well-acceptable strategy to identify and evaluate the quality of Artemisiae Argyi Folium.

Influence of sodium nitroprusside on expressions of FBXL5 and IRP2 in SH-SY5Y cells.

Iron accumulation in the brain is associated with the pathogenesis of Parkinson's disease (PD). Misexpression of some iron transport and storage proteins is related to iron dyshomeostasis. Iron regulatory proteins (IRPs) including IRP1 and IRP2 are cytosolic proteins that play important roles in maintaining cellular iron homeostasis. F-box and leucine-rich repeat protein 5 (FBXL5) is involved in the regulation of iron metabolism by degrading IRP2 through the ubiquitin-proteasome system. Nitric oxide (NO) enhances the binding activity of IRP1, but its effect on IRP2 is ambiguous. Therefore, in the present study, we aim to determine whether sodium nitroprusside (SNP), a NO donor, regulates FBXL5 and IRP2 expression in cultured SH-SY5Y cells. MTT assay revealed that treatment of SNP attenuated the cell viability in a dose-dependent manner. Flow cytometry test showed that 100 and 300 µmol/L SNP administration significantly reduced the mitochondrial membrane potential by 45% and 60%, respectively. Moreover, Western blotting analysis demonstrated that 300 µmol/L SNP significantly increased FBXL5 expression by about 39%, whereas the expression of IRP2 was decreased by 46%, correspondingly. These findings provide evidence that SNP could induce mitochondrial dysfunction, enhance FBXL5 expression and decrease IRP2 expression in SH-SY5Y cells.

[Research on topographic factors of ecology suitability regionalization of Bupleuri Radix in Hebei province].

To study the correlation between the content of saikosaponins ingredient of Bupleuri Radix and topographic factors, we researched the ecology suitability regionalization of topographic of Bupleuri Radix from Hebei province to provide a scientific basis for selecting artificial planting. Based on 43 samples of Bupleuri Radix from Hebei province, the variation of the content of saikosaponins in different conditions of topographic factors and the influence of slope, altitude and aspect were comprehensively analyzed by SPSS 21.0. Then we studied topographic factors of ecology suitability regionalization of Bupleuri Radix on the basis of the relationship between the saikosaponins and topographic factors by ArcGIS. The most suitable conditions of topographic for cultivation of saikosaponins are as follows：altitude 600 m above, slope 4.00-5.50 degrees, aspect to the sun. In Hebei province, it is suitable for growth of Bupleuri Radix in the Taihang Mountains and the Yanshan Mountains where the content of saikosaponins is higher.

[An overview on autophagy in neural stem cells].

Neural stem cells (NSCs) offer great promise for the treatment of multiple neurodegenerative diseases. However, the survival and differentiation rates of grafted cells in the host brain need to be enhanced. In this regard, understanding of the underlying mechanism of NSCs survival and death is of great importance for the implications of stem cell-based therapeutic application in the treatments of neurological disorders. Autophagy is a conserved proteolytic mechanism required for maintaining cellular homeostasis, which can affect NSCs fate through regulating their biological behaviors, such as survival and proliferation. In this mini-review, we will summarize the effects of autophagy on NSCs fate including survival, apoptosis, proliferation and differentiation, as well as the underlying mechanisms.

[Advances in the association of ATP-sensitive potassium channels and Parkinson's disease].

ATP-sensitive potassium channels (KATP), as an inward rectifying potassium channel, are widely distributed in many types of tissues. KATP are activated by the depletion of ATP level and the increase in oxidative stress in cells. The activity of KATP couples cell metabolism with electrical activity and results in membrane hyperpolarization. KATP are ubiquitously distributed in the brain, including substantia nigra, hippocampus, hypothalamus, cerebral cortex, dorsal nucleus of vagus and glial cells, and participate in neuronal excitability, mitochondria homeostasis and neurotransmitter release. Accumulating lines of evidence suggest that KATP are the major contributing factors in the pathogenesis of Parkinson's disease (PD). This review discussed the association of KATP with the pathogenic processes of PD by focusing on the roles of KATP on the degeneration of dopaminergic neurons, the functions of mitochondria, the firing pattern of dopaminergic neurons in the substantia nigra, the α-synuclein secretion from striatum, and the microglia activation.

De novo transcriptome analysis of mulberry (Morus L.) under drought stress using RNA-seq technology.

A large-scale RNA sequencing (RNA-seq) of mulberry (Morus L.) was carried out between two samples in regular and drought stress condition. In this research, de novo assembly was performed, and totally 54736 contigs were obtained from the reads, including the scaffolded regions. 1051 genes were identified that were significantly differently expressed between the two samples. As determined by Gene Ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes pathway mapping, 10110 GO terms and 247 pathways were assigned and then analyzed. Thousands of SSR markers produced in this study will enable genetic linkage mapping construction and gene-based association studies. Seven unique genes showing different expression level in control and drought stress groups were subsequently analyzed and identified by real-time PCR. For lack of mulberry whole genome information, transcriptome and de novo analysis from the two samples will provide important and useful information for later research and help genetic breeding of mulberry.