Xi Zhang's research while affiliated with Xuanwu hospital and other places

Background Altered brain-derived neurotrophic factor (BDNF) concentrations have been detected in the central nervous system tissues and peripheral blood. These alterations are associated with a series of neurological disorders. Objective To investigate the potential causal relationships between genetically determined plasma BDNF levels and various neurological diseases using a two-sample Mendelian randomisation study. Methods We selected single nucleotide polymorphisms strongly related to plasma BDNF levels as instrumental variables. Within the Mendelian randomisation framework, we used summary-level statistics for exposure (plasma BDNF levels) and outcomes (neurological disorders). Results We observed suggestive evidence of a relation between higher plasma BDNF levels and less risk of nontraumatic intracranial haemorrhage (nITH) (odds ratio [OR] = 0.861, 95 % confidence interval [CI]: 0.774–0.958, P = 0.006, PFDR = 0.078), epilepsy (OR = 0.927, 95 % CI: 0.880–0.976, P = 0.004, PFDR = 0.078), focal epilepsy (OR = 0.928, 95 % CI: 0.874–0.986, P = 0.016, PFDR = 0.139), and non-lesional focal epilepsy (OR = 0.981, 95 % CI: 0.964–0.999, P = 0.041, PFDR = 0.267). Combined with the UK Biobank dataset, the association of plasma BDNF levels with nITH remained significant (OR = 0.88, 95 % CI: 0.81–0.96, P < 0.01). The combined analysis of three consortium datasets demonstrated a considerable impact of plasma BDNF on epilepsy (OR = 0.94, 95 % CI: 0.90–0.98, P < 0.01) and a suggestive impact on focal epilepsy (OR = 0.94, 95 % CI: 0.89–0.99, P = 0.02). However, there was no apparent correlation between plasma BDNF levels and other neurological disorders or related subtypes. Conclusions Our study supports a possible causal relationship between elevated plasma BDNF levels and a reduced risk of nITH, epilepsy, and focal epilepsy.

Background: Angiotensin II type 1 receptor (AT1R) is a key mediator of the rennin-angiotensin-aldosterone system (RAAS). Autoantibodies against AT1R (AT1-AA), as an activator of AT1R, was found in abdominal aortic aneurysm (AAA) related diseases, such as hypertension and atherosclerosis. However, the role of AT1-AA in AAA is still unclear. Methods: We used angiotensin II (AngII)-infused male ApoE -/- mice model of AAA. Ultrasonography measurement, histological assessment, western blot, qRT-PCR and RNA sequencing were used to assess the severity of AAA. Nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay, radio assay of receptors and homogeneous time resolved fluorescence (HTRF) were used to measure the activation feature of AT1R and the affinity of AT1R with AT1-AA or AngII. Results: AT1-AA increased the incidence of AAA (vehicle vs. AT1-AA: 47% vs. 81%; P<0.05), which can be attenuated by AT1R blocker Candesartan. Furthermore, AT1-AA greatly increased severity of AAA, due to augmenting the diameter of abdominal aorta and the degradation of elastin by enhancing the expression of MMP2/9 (matrix metalloproteinase) and the accumulation of inflammatory cells. And AT1-AA could induce phenotypic switch of smooth muscle cells. But AT1-AA does not increase the plasma level of AngII. Mechanically, AT1-AA enhanced AngII-induced recruitment of Gq, but not β-arrestin1/2. AT1-AA potentiated the AngII-mediated Gq-dependent inositol phosphate (EC50 shift=3.829 nM) and the activation of PKC and ERK1/2. The responses were abolished by AT1R blocker and Gq inhibitor. The affinity of AT1-AA for the AT1R in cells was calculated to be 75.49 ± 4.7 nM. AT1-AA cannot compete for the binding of AngII to AT1R. However, AT1-AA significantly potentiated the binding of AngII with AT1R allosterically (mean K D ± SEM: 34.11 ± 0.9765 nM at 0 nM AT1-AA vs. 25.63 ± 1.826 nM at 100 nM AT1-AA; p<0.05), without altering the maximum binding. Conclusion: AT1-AA, as an allosteric activator of AT1R, promotes AAA through increasing the affinity of AngII with AT1R and activating Gq biasedly.

Angiotensin II type 1 receptor (AT1R) is a promising therapeutic target for cardiovascular diseases. Compared with orthosteric ligands, allosteric modulators attract considerable attention for drug development due to their unique advantages of high selectivity and safety. However, no allosteric modulators of AT1R have been applied in clinical trials up to now. Except for the classical allosteric modulators of AT1R such as antibody, peptides and amino acids, cholesterol and biased allosteric modulators, there are non-classical allosteric modes including the ligand-independent allosteric mode, and allosteric mode of biased agonists and dimers. In addition, finding the allosteric pockets based on AT1R conformational change and interaction interface of dimers are the future of drug design. In this review, we summarize the different allosteric mode of AT1R, with a view to contribute to the development and utilization of drugs targeting AT1R allostery.

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in the human body and are responsible for accurately transmitting extracellular information to cells. Arrestin is an important member of the GPCR signaling pathway. The main function of arrestin is to assist receptor desensitization, endocytosis and signal transduction. In these processes, the recognition and binding of arrestin to phosphorylated GPCRs is fundamental. However, the mechanism by which arrestin recognizes phosphorylated GPCRs is not fully understood. The GPCR phosphorylation recognition “bar code model” and “flute” model describe the basic process of receptor phosphorylation recognition in terms of receptor phosphorylation sites, arrestin structural changes and downstream signaling. These two models suggest that GPCR phosphorylation recognition is a process involving multiple factors. This process can be described by a “QR code” model in which ligands, GPCRs, G protein-coupled receptor kinase, arrestin, and phosphorylation sites work together to determine the biological functions of phosphorylated receptors. Graphical Abstract

The large-conductance calcium-activated potassium (BK) channel is a critical regulator and potential therapeutic target of vascular tone and architecture, and abnormal expression or dysfunction of this channel is linked to many vascular diseases. Vascular remodelling is the early pathological basis of severe vascular diseases. Delaying the progression of vascular remodelling can reduce cardiovascular events, but the pathogenesis remains unclear. To clarify the role of BK channels in vascular remodelling, we use rats with BK channel α subunit knockout (BK α ‒/‒). The results show that BK α ‒/‒ rats have smaller inner and outer diameters, thickened aortic walls, increased fibrosis, and disordered elastic fibers of the aortas compared with WT rats. When the expression and function of BK α are inhibited in human umbilical arterial smooth muscle cells (HUASMCs), the expressions of matrix metalloproteinase 2 (MMP2), MMP9, and interleukin-6 are enhanced, while the expressions of smooth muscle cell contractile phenotype proteins are reduced. RNA sequencing, bioinformatics analysis and qPCR verification show that C1q/tumor necrosis factor-related protein 7 ( CTRP7) is the downstream target gene. Furthermore, except for that of MMPs, a similar pattern of IL-6, smooth muscle cell contractile phenotype proteins expression trend is observed after CTRP7 knockdown. Moreover, knockdown of both BK α and CTRP7 in HUASMCs activates PI3K/Akt signaling. Additionally, CTRP7 is expressed in vascular smooth muscle cells (VSMCs), and BK α deficiency activates the PI3K/Akt pathway by reducing CTRP7 level. Therefore, we first show that BK channel deficiency leads to vascular remodelling. The BK channel and CTRP7 may serve as potential targets for the treatment of cardiovascular diseases.

Aim: Intermittent hypoxia (IH) is the prominent feature of obstructive sleep apnea (OSA) pathophysiology, which is an in dependent risk factor of cardiovascular complications. The effects of IH on adipocyte metabolism were explored by high-throughput sequencing technology. Methods: Plasma was collected from OSA patients and control group to perform mRNA sequencing. 3T3-L1 cells were differentiated into adipocytes then subjected to a 5%–21% O2 hypoxic environment (IH) for 24 h. High-throughput sequencing method was used to determine differential mRNA and miRNA patterns in fat cells exposed to IH. We then performed Gene Ontology (GO) analysis, identified relevant KEGG pathways and miRNA-target-pathways. Results: Sequencing data showed that OSA affected the expression of 343 mRNAs in the plasma. At the same time, we found that IH affected the expression of 3034 mRNAs in the adipocytes. In addition, 68 differentially expressed mRNAs were overlapped in plasma from OSA patient and IH-induced adipocyte model. We observe that 68 differential genes could be connected to 49 reciprocally expressed miRNAs. We showed that IH significantly reduced the expression of miR-182-5p and miR-30c-2-3p. KEGG predicted that the function of expressed miR-182-5p and miR-30c-2-3p was enriched to AKT signaling pathway. Notably, IH activated PI3K/AKT pathway in fat cells. Conclusion: Our results demonstrated that IH might induce adipocyte metabolism by regulating miR-182-5p and miR-30c-2-3p.

Insular involvement in temporal lobe epilepsy (TLE) has gradually been recognized since the widespread use of stereoelectroencephalography (SEEG). However, the correlation between insular involvement and failed temporal lobe surgery remains unclear. In this study, we analyzed the surgical outcomes of TLE patients who underwent temporal and insular SEEG recordings and explored the predictors of failed anterior temporal lobectomy (ATL) in these patients with temporal seizures. Forty-one patients who underwent ATL for drug-resistant TLE were examined using temporal and insular SEEG recordings. The clinical characteristics, SEEG data, and postoperative seizure outcomes of these patients were analyzed, and multivariate analysis was used to identify the predictors of surgical outcome. In this series, the ictal temporal discharges invaded the insula in 39 (95.1%) patients. Twenty-three (56.1%) patients were seizure-free (Engel class I) after ATL with at least 1 year follow-up. Only temporal-insular spreading time (TIST) was an independent predictor of postoperative seizure-free outcomes (P = .035). By creating receiver operating characteristic curves for TIST, 400 milliseconds was identified as the cutoff for classification. All patients were classified into 2 groups (TIST ≤ 400 milliseconds and TIST > 400 milliseconds) based on the cutoff value; the difference in seizure-free rates between the 2 groups was significant (P = .001). The very early insular involvement in TLE may be associated with poorer seizure outcomes after ATL. Our findings may be helpful for estimating the appropriate operative procedures and will be valuable for evaluating the prognosis of TLE patients with temporal-insular SEEG recordings and temporal lobectomy.

Objectives Based on data for a large population of patients from a single center accumulated over 22 years, the present study aimed to reveal an overall profile of movement disorders (MDs) in terms of their demographic features and surgical treatment. Methods This study was conducted on 21,005 outpatients (2008–2019) and 5,126 inpatients (1998–2019) with MDs who underwent radiofrequency ablation (RFA) or deep-brain stimulation (DBS). Patients were categorized into those with Parkinson’s disease (PD), essential tremor (ET), dystonia, tics, or involuntary movements (IMs). The clinical data of these patients were analyzed retrospectively. Results PD accounted for the largest proportion (75.4%) among surgically treated MD patients, and was associated with the highest surgical rate (18.8%), followed by ET (proportion: 12.1%, surgical rate: 10.4%) and dystonia (proportion: 5.7%, surgical rate: 5.7%). The male:female ratio was higher in surgical patients than in outpatients (1.49 vs. 1.27, p < 0.001). The surgery ages in patients with PD, ET, dystonia, tics, or IMs was 62 (54–67), 61 (46–68), 40 (26–53), 21 (19–25), and 21 (17–28) years; and the duration of illness (DOI was 6 (4–10), 14 (9–20), 4 (2–10), 11 (7–17), and 17 (10–22) years, respectively. Between 1998 and 2019, the percentage of patients undergoing DBS among surgically treated MD patients increased from 0% to 85%, and the shift towards DBS in PD was larger than that shift for dystonia or ET. Conclusion PD is the most common MD that necessitates surgical treatment, followed by ET and dystonia. Surgical timing is individualized and varies among different types of MDs. DBS has become the dominant surgical modality for MDs.