Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Fiber-reinforced gelatin/ß-cyclodextrin hydrogels loaded with platelet-rich plasma-derived exosomes for diabetic wound healing.

Diabetic complications with high-glucose status (HGS) cause the dysregulated autophagy and excessive apoptosis of multiple-type cells, leading to the difficulty in wound self-healing. Herein, we firstly developed fiber-reinforced gelatin (GEL)/ß-cyclodextrin (ß-CD) therapeutic hydrogels by the modification of platelet-rich plasma exosomes (PRP-EXOs). The GEL fibers that were uniformly dispersed within the GEL/ß-CD hydrogels remarkably enhanced the compression strengths and viscoelasticity. The PRP-EXOs were encapsulated in the hydrogels via the covalent crosslinking between the PRP-EXOs and genipin. The diabetic rat models demonstrated that the GEL/ß-CD hydrogels and PRP-EXOs cooperatively promoted diabetic wound healing. On the one hand, the GEL/ß-CD hydrogels provided the biocompatible microenvironments and active components for cell adhesion, proliferation and skin tissue regeneration. On the other hand, the PRP-EXOs in the therapeutic hydrogels significantly activated the autophagy and inhibited the apoptosis of human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs). The activation of autophagy and inhibition of apoptosis in HUVECs and HSFs induced the blood vessel creation, collagen formation and re-epithelialization. Taken together, this work proved that the incorporation of PRP-EXOs in a wound dressing was an effective strategy to regulate autophagy and apoptosis, and provide a novel therapeutic platform for diabetic wound healing.

Nacre-mimetic cerium-doped nano-hydroxyapatite/chitosan layered composite scaffolds regulate bone regeneration via OPG/RANKL signaling pathway.

Autogenous bone grafting has long been considered the gold standard for treating critical bone defects. However, its use is plagued by numerous drawbacks, such as limited supply, donor site morbidity, and restricted use for giant-sized defects. For this reason, there is an increasing need for effective bone substitutes to treat these defects. Mollusk nacre is a natural structure with outstanding mechanical property due to its notable "brick-and-mortar" architecture. Inspired by the nacre architecture, our team designed and fabricated a nacre-mimetic cerium-doped layered nano-hydroxyapatite/chitosan layered composite scaffold (CeHA/CS). Hydroxyapatite can provide a certain strength to the material like a brick. And as a polymer material, chitosan can slow down the force when the material is impacted, like an adhesive. As seen in natural nacre, the combination of these inorganic and organic components results in remarkable tensile strength and fracture toughness. Cerium ions have been demonstrated exceptional anti-osteoclastogenesis capabilities. Our scaffold featured a distinct layered HA/CS composite structure with intervals ranging from 50 to 200 µm, which provided a conducive environment for human bone marrow mesenchymal stem cell (hBMSC) adhesion and proliferation, allowing for in situ growth of newly formed bone tissue. In vitro, Western-blot and qPCR analyses showed that the CeHA/CS layered composite scaffolds significantly promoted the osteogenic process by upregulating the expressions of osteogenic-related genes such as RUNX2, OCN, and COL1, while inhibiting osteoclast differentiation, as indicated by reduced TRAP-positive osteoclasts and decreased bone resorption. In vivo, calvarial defects in rats demonstrated that the layered CeHA/CS scaffolds significantly accelerated bone regeneration at the defect site, and immunofluorescence indicated a lowered RANKL/OPG ratio. Overall, our results demonstrate that CeHA/CS scaffolds offer a promising platform for bone regeneration in critical defect management, as they promote osteogenesis and inhibit osteoclast activation.

Identifying causal genes for migraine by integrating the proteome and transcriptome.

BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.

Langerhans cell histiocytosis misdiagnosed as thyroid malignancy: A case report.

BACKGROUND: The incidence of Langerhans cell histiocytosis (LCH) is low, and involvement of the thyroid is even rarer, which results in high missed diagnosis or misdiagnosis rates. CASE SUMMARY: We report a young woman with a thyroid nodule. Thyroid malignancy was suggested by fine needle aspiration, but she was eventually diagnosed with multisystem LCH, thus avoiding thyroidectomy. CONCLUSION: The clinical manifestations of LCH involving the thyroid are atypical, and the diagnosis depends on pathology. Surgery is the main method for treating primary thyroid LCH, while chemotherapy is the main treatment method for multisystem LCH.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

Human blood metabolites and lacunar stroke: A Mendelian randomization study.

BACKGROUND: Lacunar stroke accounts for a quarter of all strokes, but little is known about the underlying pathological mechanisms. Analysis of serum metabolites may allow better understanding of the underlying biological processes. Mendelian randomization (MR) can provide information on the causality of associations. AIMS: To identify causal relationships between serum metabolites and lacunar stroke. METHODS: We applied a two-sample MR analysis to evaluate relationships between 486 serum metabolites and lacunar stroke. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of the exposure on the outcome, while sensitivity analyses were performed using MR-Egger, weighted median, and MR-PRESSO to eliminate the pleiotropy. We also performed a metabolic pathway analysis to identify potential metabolic pathways. RESULTS: We identified 15 known (8 risk and 7 protective) and 14 unknown serum metabolites associated with lacunar stroke. Among the known risk metabolites, two were lipids (1-linoleoylglycerophosphoethanolamine and dihomo-linolenate (20:3n3 or n6)), five amino acids (kynurenine, isobutyrylcarnitine, aspartate, trans-4-hydroxyproline, and 3-methyl-2-oxovalerate), and one peptide (ADSGEGDFXAEGGGVR). The known protective metabolites included four lipids (4-androsten-3beta,17beta-diol disulfate 1, 1-palmitoleoylglycerophosphocholine, adrenate (22:4n6), and glycodeoxycholate), one amino acid (methionine), and two exogenous metabolites (homostachydrine and 2-methoxyacetaminophen sulfate). Metabolic pathway analysis identified several pathways that might be involved in the disease. CONCLUSION: We identified eight risk and seven protective human serum metabolites associated with lacunar stroke. Isobutyrylcarnitine was positively associated with an increased risk of lacunar stroke. In addition, 3-methyl-2-oxovalerate and aspartate may be involved in the disease pathogenesis through metabolic pathways.

Anti-apoptotic effect of HeidihuangWan in renal tubular epithelial cells via PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Heidihuang Wan (HDHW) is a classic Chinese herbal formula, which was first recorded in the "Suwen Bingji Qiyi Baoming Collection" written by Liu Wansu during the Jin Dynasty (1115-1234 AD). It is commonly used clinically for the treatment of kidney diseases and its curative effect is stable. Previous animal experiments have confirmed that HDHW can effectively improve renal fibrosis. However, the underlying pharmacological mechanism remains unclear. AIMS OF THIS STUDY: Renal tubular epithelial cell (RTEC) apoptosis is one of the main pathological features of renal fibrosis. This study aimed to observe the effect and underlying mechanism of HDHW on the apoptosis of RTECs to further explore the pathological mechanism of HDHW against renal fibrosis. MATERIALS AND METHODS: We examined the HDHW composition in rat serum. In vitro, we first screened out the optimal intervention concentration of HDHW on RTECs using the MTT assay. Hypoxia/reoxygenation was then used to induce apoptosis of RTECs (H/R-RTECs), which were divided into H/R-RTEC, astragaloside IV (positive control), HDHW, and RTECs groups. After 48 h of drug intervention, apoptosis of RTECs was detected using flow cytometry and protein expression was detected by western blotting. The 5/6 nephrectomy rat model was constructed and divided into the normal control, 5/6 nephrectomy, HDHW, and astragaloside IV groups. After 8 weeks of treatment, TUNEL staining was used to detect cell apoptosis, and western blotting was used to detect protein expression. RESULTS: HDHW downregulated the expression of pro-apoptotic proteins Bax and Caspase3, up-regulated the expression of anti-apoptotic protein Bcl-2, activated the PI3K/Akt/mTOR signaling pathway, and reversed the early apoptosis of RTECs, thereby resisting the apoptosis of RTECs. CONCLUSION: HDHW inhibits apoptosis of RTECs by modulating the PI3K/Akt/mTOR signaling pathway. This study provides experimental evidence for the anti-fibrotic effect of HDHW on the kidneys and partially elucidates its pharmacological mechanism of action.

Analysis of research hotspots in COVID-19 genomics based on citespace software: Bibliometric analysis.

Introduction: To analyze the current state, hotspots, and cutting-edge trends of genomics research on the outbreak of Corona Virus Disease 2019 (COVID-19) from 2019 to the present (March 2022). Methods: Statistical and visual analysis of COVID-19 genomics results published in the 2019-2022 Web of Science Core Collection Database (WOSCC) was performed using CiteSpace software, including data on countries, institutions, authors, journals, co-citations, keywords, etc. Results: A total of 9133 English literature were included. The number of publications has significantly increased in 2021, and it is expected that this upward trend will last into the future. The research hotspots of COVID-19 revolve around quarantine, biological management, angiotensin-converting enzyme-2, RNA-dependent RNA polymerase, etc. Research frontiers and trends focus on molecular docking, messenger RNA, functional receptor, etc. Conclusion: The last two years have seen a significant increase in research interest in the field of novel coronavirus pneumonia genomics.

Efficacy of astragalus in the treatment of radiation-induced lung injury based on traditional Chinese medicine: A systematic review and meta-analysis of 25 RCTs.

BACKGROUND: Astragalus (Hedysarum Multijugum Maxim., Huangqi) is a Chinese herbal medicine, and according to the theory of traditional Chinese medicine (TCM), Chinese medicinal preparations containing astragalus can be used clinically to treat radiation-induced lung injury (RILI). To systematically review the efficacy and safety of Chinese medicinal preparations containing astragalus in the prevention and treatment of RILI by means of meta-analysis. METHODS: A systematic literature on randomized controlled trials (RCTs) of prescriptions containing astragalus in the treatment of RILI by Pubmed, Embase, Web of Science, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, WANFANG Database. The retrieval time is from the establishment of the database to January 18, 2022. Meta-analysis, heterogeneity test and sensitivity analysis were performed on eligible RCTs using Revman 5.4 software and STATA 17.0 software, and a "funnel plot" was used to analyze potential publication bias. RESULTS: A total of 25 RCTs were included, including 1762 patients, and the most widely used drugs were heat-clearing and detoxifying, yin-nourishing and qi-nourishing. The prescriptions containing astragalus can significantly reduce the total incidence of RILI (P < .01), improve the total effective rate and cure rate of RILI (P < .01), improve the quality of life of patients, alleviate breathing difficulties and reduce the expression of inflammatory factors (P < .01), and no adverse reactions related to TCM treatment were reported. CONCLUSION: The traditional Chinese medicinal preparation containing astragalus can effectively alleviate the clinical symptoms of RILI, reduce the toxic side effects, and is safe to use in clinic.

Protective effects of Huang-Lian-Jie-Du Decoction on diabetic nephropathy through regulating AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling in db/db mice.

BACKGROUND: Diabetic nephropathy (DN) is a severe diabetic complication that is the principal cause of end-stage kidney disease worldwide. Huang-Lian-Jie-Du Decoction (HLJDD) is widely used to treat diabetes clinically. However, the nephroprotective effects and potential mechanism of action of HLJDD against DN have not yet been fully elucidated. PURPOSE: This study aimed to investigate the potential roles of HLJDD in DN and elucidate its mechanisms in db/db mice. METHODS: An integrated strategy of network pharmacology, pharmacodynamics, molecular biology, and metabolomics was used to reveal the mechanisms of HLJDD in the treatment of DN. First, network pharmacology was utilized to predict the possible pathways for DN using the absorbed ingredients of HLJDD in rat plasma in silico. Then, combined with histopathological examination, biochemical evaluation immunohistochemistry/immunofluorescence assay, western blot analysis, and UPLC-Q-Orbitrap HRMS/MS-based metabolomics approach were applied to evaluate the efficacy of HLJDD against DN and its underlying mechanisms in vivo. RESULTS: In silico, network pharmacology indicated that the AGEs/RAGE pathway was the most prominent pathway for HLJDD against DN. In vivo, HLJDD exerted protective effects against DN by ameliorating glycolipid metabolic disorders and kidney injury. Furthermore, we verified that HLJDD protected against DN by regulating the AGEs/RAGE/Akt/Nrf2 pathway for the first time. In addition, 22 potential biomarkers were identified in urine, including phenylalanine metabolism, tryptophan metabolism, glucose metabolism, and sphingolipid metabolism. CONCLUSION: These findings suggest that HLJDD ameliorates DN by regulating the AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling.

A Novel Scoring System for Predicting the Metastases of Posterior Right Recurrent Laryngeal Nerve Lymph Node Involvement in Patients With Papillary Thyroid Carcinoma by Preoperative Ultrasound.

Objective: Our goal was to investigate the correlation between papillary thyroid carcinoma (PTC) characteristics on ultrasonography and metastases of lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN). There is still no good method for clinicians to judge whether a patient needs LN-prRLN resection before surgery, and we also wanted to establish a new scoring system to determine whether patients with papillary thyroid carcinoma require LN-prRLN resection before surgery. Patients and Methods: There were 482 patients with right or bilateral PTC who underwent thyroid gland resection from December 2015 to December 2017 recruited as study subjects. The relationship between the PTC characteristics on ultrasonography and the metastases of LN-prRLN was analyzed by univariate and logistic regression analyses. Based on the risk factors identified in univariate and logistic regression analysis, a nomogram-based LN-prRLN prediction model was established. Result: LN-prRLN were removed from all patients, of which 79 had LN-prRLN metastasis, with a metastasis rate of 16.39%. Multivariate logistic regression analysis revealed that LN-prRLN metastasis was closely related to sex, age, blood supply, larger tumors (> 1 cm) and capsular invasion. A risk prediction model has been established and fully verified. The calibration curve used to evaluate the nomogram shows that the consistency index was 0.75 ± 0.065. Conclusion: Preoperative clinical data, such as sex, age, abundant blood supply, larger tumor (> 1 cm) and capsular invasion, are positively correlated with LN-prRLN metastasis. Our scoring system can help surgeons non-invasively determine which patients should undergo LN-prRLN resection before surgery. We recommend that LN-prRLN resection should be performed when the score is above 103.1.

Application of velocity vector imaging (VVI) in the evaluation of left ventricular myocardial contractile strain and dyssynchrony before and after stent implantation in patients with coronary heart disease.

BACKGROUND: Percutaneous coronary intervention (PCI) has become increasingly mature and has gradually become the main treatment for coronary heart disease (CHD). However, evaluation of myocardial reperfusion after PCI remains a major clinical challenge. This study aimed to explore the VVI technique in evaluating the effect, prognosis, and follow-up of CHD patients after percutaneous coronary intervention. We performed a quantitative analysis of left ventricular myocardial contractile strain and dyssynchrony before and after stent implantation in patients by VVI. METHODS: Thirty-five patients diagnosed with CHD who underwent percutaneous coronary stenting (PCI) in the Department of Cardiovascular Medicine, Affiliated Hospital of Jiangnan University from March 2019 to October 2020 were selected as the case group. Continuous dynamic two-dimensional images of the patient's left ventricle were analyzed using VVI at 1 day before PCI (group A), 7 days after PCI (group B), and 30 days after PCI (group C). The patients' left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricle ejection fraction (LVEF), peak longitudinal strain, and peak radial strain of myocardial contraction were measured. The VVI images of 35 healthy subjects who underwent physical examination in the outpatient department of our hospital from March 2019 to October 2020 were selected as controls. RESULTS: There were no significant differences in the LVEF, LVEDD, and LVESD between the case and control groups (P>0.05). The peak systolic longitudinal and radial strain values at 1 month after treatment were higher than those before treatment. The differences among myocardial segments were statistically significant, except for the apical septum, base anterior, apical anterior, and base inferior segments (P<0.05). The peak systolic longitudinal and radial strain values at 1 week after treatment were not significantly different from those at 1 month after treatment, except for the base anterior septum, mid anterior, posterior, and inferior myocardial segments (P>0.05). CONCLUSIONS: VVI technology can comprehensively and objectively evaluate the overall and local myocardial function of the left ventricle, thereby providing a novel method for the clinical treatment of CHD as well as the evaluation of curative effect and prognosis.

Danggui-Shaoyao-San improves cognitive impairment through inhibiting O-GlcNAc-modification of estrogen α receptor in female db/db mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to show therapeutic effect on dementia. AIM OF THE STUDY: The present study aims to investigate whether DSS treatment could alleviate diabetes-induced cognitive dysfunction, and explores its neuroprotective mechanism on db/db mice. MATERIALS AND METHODS: The female db/db mice were randomly divided into model group, DSS low-dose group and DSS high-dose group. Homologous female db/m mice were used as the control group. DSS was intragastric administrated for 15 weeks. Glucose tolerance, insulin tolerance, blood glucose and blood lipid levels were measured. Morris water maze was used to measure spatial learning and memory ability in mice. Nissl staining and Tunel staining were used to measure the changes of brain neurons, and ELISA kits were used to measure levels of inflammatory mediators (PGE2, TXB2 and LTB4). The kits detected oxidative stress (MDA, SOD, CAT, GSH-PX), nitrosative stress (NO, iNOS, TNOS) and glucose metabolism (LDH, PK, HK) levels. Western blot and immunofluorescence detected neurotrophic factors (PSD95, BDNF, NGF and SYN), apoptosis (Bcl-2, Bax, Bcl-xl, Caspase-3) and changes of ERα, O-GlcNAc, OGT, OGA levels. RESULTS: Morris water maze results showed that DSS could improve the learning and memory abilities of female db/db mice. Nissl staining showed that DSS could relieve hippocampal neurons damage of db/db mice. In addition, the serological tests showed that DSS could improve the impaired glucose tolerance and insulin resistance, while reduce hyperlipemia in db/db mice. Besides, DSS treatment increased the activities of SOD, GSH-PX, and CAT, and reduced MDA, NO, iNOs, tNOS, PGE2, TXB2 and LTB4 levels. Western blot and immunofluorescence results of PSD95, BDNF, NGF, and SYN showed that DSS could improve the expressions of neurotrophic factors. Meanwhile, Tunel staning and Western blot (Bcl-2, Bax, Bcl-xl, Caspase-3) results indicated that DSS could reduce neuronal apoptosis. Finally, Western blot (ERα, O-GlcNAc, OGA, and OGT) and immunofluorescence (ERα and O-GlcNAc) results indicated that DSS could increase the levels of ERα and OGA, decrease the levels of O-GlcNAc and OGT. CONCLUSION: DSS alleviate DE might be related to improve the abnormal O-GlcNAc-modification of ERα.

Coronary Heart Disease and Depression or Anxiety: A Bibliometric Analysis.

This study aimed to conduct a bibliometric analysis of published studies on the association between coronary heart disease (CHD) and depression or anxiety. The study also aimed to identify leading authors, institutions, and countries to determine research hotspots and obtain some hints from the speculated future frontiers. Publications about CHD and depression or anxiety between 2004 and 2020 were collected from the Web of Science Core Collection (WOSCC) database. Bibliographic information, such as authorship, country, citation frequency, and interactive visualization, was generated using VOSviewer1.6.16 and CiteSpace5.6.R5. In total, 8,073 articles were identified in the WOSCC database. The United States (2,953 publications), Duke University and Harvard University (214 publications), Psychosomatic Medicine (297 publications), and Denollet Johan. (99 publications) were the most productive country, institutions, journal, and author, respectively. The three hotspots of the research were "The relationship between depression and CHD," "depression and myocardial infarction," and "The characteristic of women suffering depression after MI." The four future research frontiers are predicted to be "treating depression in CHD patients with multimorbidity," "psychometric properties of instruments for assessing depression and anxiety in CHD patients," "depression or anxiety in post-PCI patients," and "other mental diseases in CHD patients." Bibliometric analysis of the association between CHD and depressive disorders might identify new directions for future research.

The Anatomical and Clinical Significance of the Superior Laryngeal Nerve.

OBJECTIVE: This study summarizes the anatomical features of the superior laryngeal nerve in Chinese to enable the rapid location of the superior laryngeal nerve during an operation. STUDY DESIGN: Retrospective analysis of anatomical data. SETTING: Hangzhou First People's Hospital Affiliated to Nanjing Medical University. METHODS: A total of 71 embalmed human cadavers (132 heminecks) were examined over 3 months. The length and diameter of the internal and external branches of the superior laryngeal nerve and their relationships with different landmarks were recorded. RESULTS: The total length of the internal branch of the superior laryngeal nerve was 23.4 ± 6.9 mm. The length of the external branch of the superior laryngeal nerve was 47.7 ± 11.0 mm. Considering the midpoint of the lower edge of the thyroid cartilage as the starting point and using that edge as a horizontal line, when the entry point is above that line, the external branch of the superior laryngeal nerve can be found within 41.1 mm and at an angle of 57.2°. When the entry point is below the lower edge of the thyroid cartilage, the external branch of the superior laryngeal nerve can be found within 34.0 mm and at an angle of 36.5°. CONCLUSION: The superior laryngeal nerve in Chinese people has distinct anatomical characteristics. This article provides a new method of quickly locating the external branch of the superior laryngeal nerve during the operation, which can reduce the probability of damaging the external branch of the superior laryngeal nerve.

Explore of the beneficial effects of Huang-Lian-Jie-Du Decoction on diabetic encephalopathy in db/db mice by UPLC-Q-Orbitrap HRMS/MS based untargeted metabolomics analysis.

Diabetic encephalopathy (DE) is a severe diabetic complication with cognitive dysfunction. Huang-Lian-Jie-Du Decoction (HLJDD), a famous traditional Chinese formula, is effective for the treatment of diabetes mellitus and Alzheimer's disease in clinical practices, however, the therapeutic effects and the underlying mechanisms of HLJDD on DE is unclear yet. With this purpose, behavior test, brain histological and biochemical analysis were estimated to assess the beneficial effects of HLJDD on DE. Plasma samples were collected for metabolomics analysis based on UPLC-Q-Orbitrap HRMS/MS and chemometric analysis. As a result, morris water maze test revealed that HLJDD could effectively improve the learning and memory abilities in db/db mice. Brain histological and biochemical analysis indicated that HLJDD could protect against neurodegeneration and oxidative stress in db/db mice. Meanwhile, a total of 21 potential biomarkers with significant differences were identified between Model group and Control group using untargeted metabolomics strategy. Among them, 11 metabolites showed a trend towards the normal levels after HLJDD intervention. These metabolites principally involved in glycerophospholipid metabolism, fatty acid ß-oxidation, linoleic acid metabolism, glucose metabolism and glutathione metabolism based on the metabolic pathway analysis, which were regulated in DE model mice after HLJDD intervention. Generally, the results demonstrated that HLJDD had beneficial effects on DE, which could be mediated via ameliorating the metabolic disorders.

Quercetin ameliorates diabetic encephalopathy through SIRT1/ER stress pathway in db/db mice.

Studies have shown that diabetes is an important risk factor for cognitive dysfunction, also called diabetic encephalopathy (DE). Quercetin has been reported to be effective in improving cognitive dysfunction in DE. But its detailed mechanism is still ambiguous. In this study, we used db/db mice to investigate whether quercetin could activate SIRT1 and inhibit ER pathways to improve DE. Behavioral tests (Morris water maze and new objects) showed that quercetin (70 mg/kg) can effectively improve the learning and memory ability in db/db mice. OGTT and ITT tests indicated that quercetin could alleviate impaired glucose tolerance and insulin resistance in db/db mice. Western blot analysis and Nissl staining showed that quercetin can improve the expression of nerve and synapse-associated proteins (PSD93, PSD95, NGF and BDNF) and inhibit neurodegeneration. Meanwhile, quercetin up-regulates SIRT1 protein expression and inhibits the expression of ER signaling pathway-related proteins (PERK, IRE-1α, ATF6, eIF2α, BIP and PDI). In addition, oxidative stress levels were significantly reduced after quercetin treatment. In conclusion, current experimental results indicated that SIRT1/ER stress is a promising mechanism involved in quercetin-treated diabetic encephalopathy.

Quercetin protects against diabetic encephalopathy via SIRT1/NLRP3 pathway in db/db mice.

Epidemiological studies have found that diabetes and cognitive dysfunction are closely related. Quercetin has been certified with the effect on improving diabetes mellitus (DM) and cognitive impairment. However, the effect and related mechanism of quercetin on diabetic encephalopathy (DE) are still ambiguous. In this study, we used the db/db mice (diabetic model) to discover whether quercetin could improve DE through the Sirtuin1/NLRP3 (NOD-, LRR- and pyrin domain-containing 3) pathway. Behavioural results (Morris water maze and new object recognition tests) showed that quercetin (70 mg/kg) improved the learning and memory. Furthermore, quercetin alleviated insulin resistance and the level of fasting blood glucose. Besides, Western blot analysis also showed that quercetin increased the protein expressions of nerve- and synapse-related protein, including postsynapticdensity 93 (PSD93), postsynapticdensity 95 (PSD95), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of db/db mice. Quercetin also increased the protein expression of SIRT1 and decreased the expression of NLRP3 inflammation-related proteins, including NLRP3, the adaptor protein ASC and cleaved Caspase-1, the pro-inflammatory cytokines IL-1ß and IL-18. In conclusion, the present results indicate that the SIRT1/NLRP3 pathway may be a crucial mechanism for the neuroprotective effect of quercetin against DE.