Autophagy in ischemic stroke: role of circular RNAs

Stroke, a central nervous system (CNS) injury, is responsible for the second leading cause of death in the world, bringing a great burden on the world. Stroke is normally divided into ischemic and hemorrhagic stroke, among which ischemic stroke takes up 87% proportion. Accumulating evidence has denoted a rather pivotal role for autophagy in the pathogenesis of ischemic stroke, which is activated in neuronal cells, glial cells, and endothelial cells. Besides, circular RNAs (circRNAs), a novel type of epigenetic regulation, are highly expressed in the CNS and are involved in the process of CNS diseases, which is regarded as an important molecular mechanism in ischemic stroke. Meanwhile, circRNA and autophagy have a significant correlation. The intracellular signaling pathways regulating autophagy can either restrain or activate autophagy. However, under the circumstances of ischemic stroke, the precise communication between circRNA and stroke is largely unknown. This review aims to provide a summary of the relationship between circRNA, autophagy, and ischemic stroke, as well as the current research advancements in understanding how circRNA regulates autophagy in the context of stroke

Specific detection and deletion of the sigma-1 receptor widely expressed in neurons and glial cells in vivo

The chaperon protein sigma-1 receptor (S1R) has been discovered over 40 years ago. Recent pharmacological studies using S1R exogenous ligands demonstrated a promising therapeutical potential of targeting the S1R in several neurological disorders. Although intensive in vitro studies have revealed S1Rs are mainly residing at the membrane of the endoplasmic reticulum (ER), the cell-specific in vivo expression pattern of S1Rs is still unclear, mainly because of the lack of a reliable detection method which also prevented a comprehensive functional analysis. Here, first, we identified a highly specific antibody using S1R knockout (KO) mice and established an immunohistochemical protocol involving a 1% sodium dodecyl sulphate (SDS) antigen retrieval step. Second, we characterized the S1R expression in the mouse brain and can demonstrate that the S1R is widely expressed: in principal neurons, interneurons and all glial cell types. In addition, unlike reported in previous studies, we showed that the S1R expression in astrocytes is not colocalized with the astrocytic cytoskeleton protein GFAP. Thus, our results raise concerns over previously reported S1R properties. Finally, we generated a Credependent S1R conditional KO mouse (S1R flox) to study cell-type-specific functions of the S1R. As a proof of concept, we successfully ablated S1R expressions in neurons or microglia employing neuronal and microglial Cre-expressing mice, respectively. In summary, we provide powerful tools to cell-specifically detect, delete and functionally characterize S1R in vivo

Early methodist experience: some prototypical accounts

A great many 20th century studies of 18th century Methodism concern John Wesley himself, and even those which promise to tell you about early Methodist beliefs and activities often turn out to be largely based on Wesley’s alone. Few have concerned themselves with the humble folk who followed him. Yet it is impossible properly to understand even why Wesley himself believed and behaved in the way he did without taking account of the minds and desires of his disciples

MiR-9 promotes microglial activation by targeting MCPIP1

Microglia participate in innate inflammatory responses within the central nervous system. The highly conserved microRNA-9 (miR-9) plays critical roles in neurogenesis as well as axonal extension. Its role in microglial inflammatory responses, however, remains poorly understood. Here we identify a unique role of miR-9 in mediating the microglial inflammatory response via distinct signalling pathways. MiR-9-mediated regulation of cellular activation involved downregulated expression of the target protein, monocyte chemotactic protein-induced protein 1 (MCPIP1) that is crucial for controlling inflammation. Results indicate that miR-9-mediated cellular activation involved signalling via the NF-kappa B pathway, but not the beta-catenin pathway

COMT, 5-HTR2A, and SLC6A4 mRNA Expressions in First-Episode Antipsychotic-Naïve Schizophrenia and Association With Treatment Outcomes

Background: Dopaminergic and serotonergic systems play crucial roles in the pathophysiology of schizophrenia and modulate response to antipsychotic treatment. However, previous studies of dopaminergic and serotonergic genes expression are sparse, and their results have been inconsistent. In this longitudinal study, we aim to investigate the expressions of Catechol-O-methyltransferase (COMT), serotonin 2A receptor (5-HTR2A), and serotonin transporter gene (SLC6A4) mRNA in first-episode antipsychotic-naïve schizophrenia and to test if these mRNA expressions are associated with cognitive deficits and treatment outcomes or not.Method: We measured COMT, 5-HTR2A, and SLC6A4 mRNA expressions in 45 drug-naive first-episode schizophrenia patients and 38 health controls at baseline, and repeated mRNA measurements in all patients at the 8-week follow up. Furthermore, we also assessed antipsychotic response and cognitive improvement after 8 weeks of risperidone monotherapy.Results: Patients were divided into responders (N = 20) and non-responders groups (N = 25) according to the Remission criteria of the Schizophrenia Working Group. Both patient groups have significantly higher COMT mRNA expression and lower SLC6A4 mRNA expression when compared with healthy controls. Interestingly, responder patients have significantly higher levels of COMT and 5-HTR2A mRNA expressions than non-responder patients at baseline. However, antipsychotic treatment has no significant effect on the expressions of COMT, 5-HTR2A, and SLC6A4 mRNA over 8-week follow up.Conclusion: Our findings suggest that dysregulated COMT and SLC6A4 mRNA expressions may implicate in the pathophysiology of schizophrenia, and that COMT and 5-HTR2A mRNA may be potential biomarkers to predict antipsychotic response

Morphine Induces Expression of Platelet-Derived Growth Factor in Human Brain Microvascular Endothelial Cells: Implication for Vascular Permeability

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Morphine, often abused by HIV-infected patients, is known to accelerate neuroinflammation associated with HIV-1 infection. Detailed molecular mechanisms of morphine action however, remain poorly understood. Platelet-derived growth factor (PDGF) has been implicated in a number of pathological conditions, primarily due to its potent mitogenic and permeability effects. Whether morphine exposure results in enhanced vascular permeability in brain endothelial cells, likely via induction of PDGF, remains to be established. In the present study, we demonstrated morphine-mediated induction of PDGF-BB in human brain microvascular endothelial cells, an effect that was abrogated by the opioid receptor antagonist-naltrexone. Pharmacological blockade (cell signaling) and loss-of-function (Egr-1) approaches demonstrated the role of mitogen-activated protein kinases (MAPKs), PI3K/Akt and the downstream transcription factor Egr-1 respectively, in morphine-mediated induction of PDGF-BB. Functional significance of increased PDGF-BB manifested as increased breach of the endothelial barrier as evidenced by decreased expression of the tight junction protein ZO-1 in an in vitro model system. Understanding the regulation of PDGF expression may provide insights into the development of potential therapeutic targets for intervention of morphine-mediated neuroinflammation

Transcriptome and UPLC-MS/MS reveal mechanisms of amino acid biosynthesis in sweet orange ‘Newhall’ after different rootstocks grafting

Sweet orange ‘Newhall’ (C. sinensis) is a popular fruit in high demand all over the world. Its peel and pulp are rich in a variety of nutrients and are widely used in catering, medicine, food and other industries. Grafting is commonly practiced in citrus production. Different rootstock types directly affect the fruit quality and nutritional flavor of citrus. However, the studies on citrus metabolites by grafting with different rootstocks are very limited, especially for amino acids (AAs). The preliminary test showed that there were significant differences in total amino acid content of two rootstocks (Poncirus trifoliata (CT) and C. junos Siebold ex Tanaka (CJ)) after grafting, and total amino acid content in the peel was higher than flesh. However, the molecular mechanism affecting amino acid differential accumulation remains unclear. Therefore, this study selected peel as the experimental material to reveal the amino acid components and differential accumulation mechanism of sweet orange ‘Newhall’ grafted with different rootstocks through combined transcriptome and metabolome analysis. Metabolome analysis identified 110 amino acids (AAs) and their derivatives in sweet orange ‘Newhall’ peels, with L-valine being the most abundant. L-asparagine was observed to be affected by both developmental periods and rootstock grafting. Weighted gene co-expression network analysis (WGCNA) combined with Redundancy Analysis (RDA) revealed eight hub structural genes and 41 transcription factors (TFs) that significantly influenced amino acid biosynthesis in sweet orange ‘Newhall’ peels. Our findings further highlight the significance of rootstock selection in enhancing the nutritional value of citrus fruits and might contribute to the development of functional citrus foods and nutritional amino acid supplements

Performance characteristics of 18F–fluorodeoxyglucose in non-infected hip replacement

PurposeThe aim of this study was to retrospectively analyze 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/ computed tomography (CT) images of non-infected hip arthroplasty patients and summarize findings that may be useful for clinical practice.Methods18F-FDG PET/CT images of non-infected hip arthroplasty patients were collected from September 2009 to August 2021. The region of interest was independently delineated by two physicians and maximum standardized uptake values (SUVmax) were recorded and compared. Serologic data were also collected and the correlation between SUVmax and serologic parameters was analyzed, while the images were classified based on the 18F-FDG uptake pattern in the images using the diagnostic criteria proposed by Reinartz et al. (9). The interval between hip replacement and PET/CT was classified by year and the characteristics of the two groups were compared. The images of patients who underwent PET/CT multiple times were analyzed dynamically.ResultsA total of 121 examinations were included; six patients underwent PET/CT twice and two patients had three scans. There were no significant correlations between SUVmax and serologic results. The interobserver agreement between the two physicians in the classification according to the criteria of Reinartz et al. (9) was 0.957 (P < 0.005). Although there was non-specific uptake in cases with an arthroplasty-to-PET/CT interval this was non-significant. Additionally, 18F-FDG showed potential utility for dynamic observation of the condition of the hip.ConclusionSUVmax provided information independent of serologic results, meanwhile 18F-FDG showed potential applicability to the dynamic monitoring of hip arthroplasty-related diseases. However, the presence of blood vessels and muscles affected image interpretation and the specificity of 18F-FDG was not optimal. A more specific radionuclide is needed to maximize the benefits of using PET/CT for the assessment of periprosthetic joint infection (PJI)

HIV-1 Tat Co-Operates with IFN-γ and TNF-α to Increase CXCL10 in Human Astrocytes

HIV-associated neurological disorders (HAND) are estimated to affect 60% of the HIV infected population. HIV-encephalitis (HIVE), the pathological correlate of the most severe form of HAND is often characterized by glial activation, cytokine/chemokine dysregulation, and neuronal damage and loss. However, the severity of HIVE correlates better with glial activation rather than viral load. One of the characteristic features of HIVE is the increased amount of the neurotoxic chemokine, CXCL10. This chemokine can be released from astroglia activated with the pro-inflammatory cytokines IFN-γ and TNF-α, in conjunction with HIV-1 Tat, all of which are elevated in HIVE. In an effort to understand the pathogenesis of HAND, this study was aimed at exploring the regulation of CXCL10 by cellular and viral factors during astrocyte activation. Specifically, the data herein demonstrate that the combined actions of HIV-1 Tat and the pro-inflammatory cytokines, IFN-γ and TNF-α, result in the induction of CXCL10 at both the RNA and protein level. Furthermore, CXCL10 induction was found to be regulated transcriptionally by the activation of the p38, Jnk, and Akt signaling pathways and their downstream transcription factors, NF-κB and STAT-1α. Since CXCL10 levels are linked to disease severity, understanding its regulation could aid in the development of therapeutic intervention strategies for HAND