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.