Publications by authors named "Tian Zhou"

231 Publications

IL-17 signaling induces iNOS+ microglia activation in retinal vascular diseases.

Glia 2021 Jul 21. Epub 2021 Jul 21.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China.

Activation of microglia and inflammation-mediated vascular damages are suggested to play a decisive role in the pathogenesis of various retinopathies. The inducible nitric oxide synthase (iNOS) was required for activated microglia-mediated injuries. However, the induction mechanism of microglia activation during retinal vascular diseases is still elusive. Here we showed that IL-17 induced microglia activation with high expression of iNOS and promoted the development of retinal vascular diseases. IL-17-dependent activation of the STAT3-iNOS pathway was essentially required for microglia activation, which promoted endothelial cell growth and accelerated vascular leakage and leukostasis via IL-6 in vitro and in vivo. Taken together, our data provide novel mechanistic insights on microglia activation-mediated retinopathy, unveil the specific role of IL-17 on microglia, and define novel therapeutic targets for treating retinal vascular diseases.
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http://dx.doi.org/10.1002/glia.24063DOI Listing
July 2021

YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury.

Oxid Med Cell Longev 2021 22;2021:6617345. Epub 2021 Jun 22.

Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Hepatic ischemia-reperfusion injury (IRI) is the most common cause of liver damage leading to surgical failures in hepatectomy and liver transplantation. Extensive inflammatory reactions and oxidative responses are reported to be the major processes exacerbating IRI. The involvement of Yes-associated protein (YAP) in either process has been suggested, but the role and mechanism of YAP in IRI remain unclear. In this study, we constructed hepatocyte-specific YAP knockout (YAP-HKO) mice and induced a hepatic IRI model. Surprisingly, the amount of serum EVs decreased in YAP-HKO compared to WT mice during hepatic IRI. Then, we found that the activation of YAP increased EV secretion through F-actin by increasing membrane formation, while inhibiting the fusion of multivesicular body (MVB) and lysosomes in hepatocytes. Further, to explore the essential elements of YAP-induced EVs, we applied mass spectrometry and noticed CD47 was among the top targets highly expressed on hepatocyte-derived EVs. Thus, we enriched CD47 EVs by microbeads and applied the isolated CD47 EVs on IRI mice. We found ameliorated IRI symptoms after CD47 EV treatment in these mice, and CD47 EVs bound to CD172 on the surface of dendritic cells (DCs), which inhibited DC activation and the cascade of inflammatory responses. Our data showed that CD47-enriched EVs were released in a YAP-dependent manner by hepatocytes, which could inhibit DC activation and contribute to the amelioration of hepatic IRI. CD47 EVs could be a potential strategy for treating hepatic IRI.
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http://dx.doi.org/10.1155/2021/6617345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241504PMC
June 2021

Traditional Chinese Medicine Xihuang Wan Inhibited Lewis Lung Carcinoma in a Syngeneic Model, Equivalent to Cytotoxic Chemotherapy, by Altering Multiple Signaling Pathways.

In Vivo 2021 Jul-Aug;35(4):2005-2014

Department of Oncology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P.R. China;

Background/aim: Xihuang Wan (XHW), a traditional Chinese medicine (TCM), has been used in China for a variety of cancers including lung cancer. The present study evaluated the efficacy of XHW on a Lewis lung mouse model and explored the potential mechanism via transcriptomics.

Materials And Methods: The mice were randomized into 6 groups: 1) untreated control (n=10); 2) low-dose XHW; 3) medium-dose XHW; 4) high-dose XHW; 5) cisplatin; and 6) untreated blank (n=4). Lewis lung carcinoma (LLC) cells were injected subcutaneously except for the 4 mice in the blank group. The body weight and tumor length and width were measured every 3 days. RNA-sequencing was performed on tumors in the high-dose XHW group and the control group.

Results: XHW inhibited the growth of LLC in a syngeneic mouse model, without toxicity, with equivalent efficacy to cisplatin. RNA-sequencing demonstrated that many signaling pathways were involved in XHW-mediated inhibition of LLC, including tumor necrosis factor, estrogen, cyclic guanosine 3', 5'-monophosphate-protein kinase G, apelin and the peroxisome proliferator-activated receptor signaling pathways.

Conclusion: XHW inhibited LLC carcinoma through different pathways and shows clinical promise for patients who cannot tolerate platinum-based drugs.
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http://dx.doi.org/10.21873/invivo.12469DOI Listing
June 2021

Fabrication and Characterization of Collagen/PVA Dual-Layer Membranes for Periodontal Bone Regeneration.

Front Bioeng Biotechnol 2021 9;9:630977. Epub 2021 Jun 9.

National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China.

Guided tissue regeneration (GTR) is a promising treatment for periodontal tissue defects, which generally uses a membrane to build a mechanical barrier from the gingival epithelium and hold space for the periodontal regeneration especially the tooth-supporting bone. However, existing membranes possess insufficient mechanical properties and limited bioactivity for periodontal bone regenerate. Herein, fish collagen and polyvinyl alcohol (Col/PVA) dual-layer membrane were developed via a combined freezing/thawing and layer coating method. This dual-layer membrane had a clear but contact boundary line between collagen and PVA layers, which were both hydrophilic. The dual membrane had an elongation at break of 193 ± 27% and would undergo an degradation duration of more than 17 days. Further cell experiments showed that compared with the PVA layer, the collagen layer not only presented good cytocompatibility with rat bone marrow-derived mesenchymal stem cells (BMSCs), but also promoted the osteogenic genes (RUNX2, ALP, OCN, and COL1) and protein (ALP) expression of BMSCs. Hence, the currently developed dual-layer membranes could be used as a stable barrier with a stable degradation rate and selectively favor the bone tissue to repopulate the periodontal defect. The membranes could meet the challenges encountered by GTR for superior defect repair, demonstrating great potential in clinical applications.
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http://dx.doi.org/10.3389/fbioe.2021.630977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219956PMC
June 2021

Analysis of psychological status and effect of psychological intervention in quarantined population during the epidemic of SARS-CoV-2.

Medicine (Baltimore) 2021 May;100(19):e25951

Beijing Rehabilitation Hospital Affiliated to Capital Medical University.

Abstract: During outbreaks of the coronavirus disease 2019 (COVID-19), many countries adopted quarantine to slow the spread of the virus of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Quarantine will cause isolation from families, friends, and the public, which consequently leads to serious psychological pressure with potentially long-lasting effects on the quarantined population. Experience of specific practices to improve the psychological status of the mandatory quarantined population was limited. The aim of this study was to investigate the psychological impact of mandatory quarantine, and evaluate the effect of psychological intervention on the quarantined population.We conducted a prospective cohort study to assess and manage the psychological status of a mandatory quarantined population in Beijing, China. A total of 638 individuals completed 2 questionnaires and were enrolled in this study, of which 372 participants accepted designed psychological intervention while other 266 participants refused it. The SCL-90 questionnaire was used to evaluate the psychological status and its change before and after the intervention. The differences of SCL-90 factor scores between participants and the national norm group were assessed by 2 samples t test. While the SCL-90 factor scores before and after intervention were compared with 2 paired samples t test.Compared with the Chinese norms of SCL-90, the participants had higher SCL-90 factor scores in most items of the SCL-90 inventory. The SCL-90 factor scores of participants with psychological intervention significantly decreased in somatization, obsessive-compulsive, depression, anxiety, phobic anxiety, paranoid ideation, and psychoticism. In contrast, most factor scores of the SCL-90 inventory changed little without statistical significance in participants without psychological intervention.Psychological problems should be emphasized in the quarantined individuals and professional psychological intervention was a feasible approach to improve the psychological status of the mandatory quarantined population in the epidemic of SARS-CoV-2.
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http://dx.doi.org/10.1097/MD.0000000000025951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133182PMC
May 2021

Water-soluble brown carbon in atmospheric aerosols along the transport pathway of Asian dust: Optical properties, chemical compositions, and potential sources.

Sci Total Environ 2021 Oct 24;789:147971. Epub 2021 May 24.

Key Laboratory for Semi-Arid Climate Change of the Ministry of Education, College of Atmospheric Sciences, Lanzhou University, Lanzhou 730000, China; Institute of Surface-Earth System Science, School of Earth System Science, Tianjin University, Tianjin 300072, China. Electronic address:

As an important type of light-absorbing aerosol, brown carbon (BrC) has the potential to affect the atmospheric photochemistry and Earth's energy budget. A comprehensive field campaign was carried out along the transport pathway of Asian dust during the spring of 2016, including a desert site (Erenhot), a rural site (Zhangbei), and an urban site (Jinan), in northern China. Optical properties, bulk chemical compositions, and potential sources of water-soluble brown carbon (WS-BrC) were investigated in atmospheric total suspended particulate (TSP) samples. Samples from Zhangbei had higher mass absorption efficiency at 365 nm (MAE, 1.32 ± 0.34 m g) than those from Jinan (1.00 ± 0.23 m g) and Erenhot (0.84 ± 0.30 m g). Compere to the non-dust samples, elevated water-soluble organic carbon (WSOC) concentrations and MAE values of dust samples from Erenhot are related to the input of high molecular weight organic compounds and biogenic matter from the Gobi Desert, while lower values from Zhangbei and Jinan are attributed to the dilution effect caused by strong northwesterly winds. Based on fluorescence excitation-emission matrix spectra and parallel factor analysis, two humic-like (C1 and C2) and two protein-like (C3 and C4) substances were identified. Together, C1 and C2 accounted for ~64% of total fluorescence intensity at the highly polluted urban Jinan site; C3 represented ~45% at the rural Zhangbei site where local biomass burning affects; and C4 contributed ~24% in the desert region (Erenhot) due to dust-sourced biogenic substances. The relative absorptive forcing of WS-BrC compared to black carbon at 300-400 nm was about 31.3%, 13.9%, and 9.2% during non-dust periods at Erenhot, Zhangbei, and Jinan, respectively, highlighting that WS-BrC may significantly affect the radiative balance of Earth's climate system and should be included in radiative forcing models.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147971DOI Listing
October 2021

Increasing LRP4 diminishes neuromuscular deficits in a mouse model of Duchenne muscular dystrophy.

Hum Mol Genet 2021 May 13. Epub 2021 May 13.

School of Life Science, Nanchang University, Nanchang, Jiangxi, China.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Futhermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD.
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http://dx.doi.org/10.1093/hmg/ddab135DOI Listing
May 2021

Activation of macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling by hyperglycemia aggravates the complexity of coronary atherosclerosis: An in vivo and in vitro study.

FASEB J 2021 05;35(5):e21609

Department of Cardiology, Xuanwu Hospital, Capital Medical University, National Clinical Research Centre for Geriatric Diseases, Beijing, China.

Our purpose was to study the effect of hyperglycemia on macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling and its correlation with coronary atherosclerosis. A total of 135 patients with coronary heart disease (CHD) were divided into a stable CHD (SCHD) group (n = 30) and an acute myocardial infarction (AMI) group (n = 105) [nondiabetes mellitus (non-DM)-AMI, n = 60; DM-AMI, n = 45] from January to September 2020. The SYNTAX score and metabolic and inflammatory markers were quantified and compared. THP-1 cell studies and an animal study of coronary intimal hyperplasia were also carried out. We found that the DM-AMI group showed a higher SYNTAX score than the non-DM-AMI group (P < .05). The DM-AMI group showed the highest expression levels of TANK-binding kinase 1 (TBK1), hypoxia-inducible factor 1α (HIF-1α), and interleukin (IL)-17 and the lowest expression level of IL-10, followed by the non-DM-AMI group and the SCHD group (P < .05). THP-1 cell studies showed that BAY87-2243 (a HIF-1α inhibitor) reversed the increase in IL-17 and decrease in IL-10 expression induced by hyperglycemia. Amlexanox (a TBK1 inhibitor) reversed the increase in HIF-1α expression induced by hyperglycemia. Amlexanox treatment resulted in lower coronary artery intimal hyperplasia and a larger lumen area in a diabetic swine model. We conclude that hyperglycemia might aggravate the complexity of coronary atherosclerosis through activation of TBK1-HIF-1α-mediated IL-17/IL-10 signaling. Thus, TBK1 may be a novel drug therapy target for CHD complicated with DM.
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http://dx.doi.org/10.1096/fj.202100086RRDOI Listing
May 2021

Bovine lactoferrin inhibits alveolar bone destruction in an orthodontic rat model with periodontitis.

Ann Anat 2021 Sep 22;237:151744. Epub 2021 Apr 22.

College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China; Department of Orthodontics, the Affiliated Stomatological Hospital of Guangxi Medical University, Nanning, Guangxi, China. Electronic address:

Objective: We aimed to evaluate the effect of bovine lactoferrin (bLF) on alveolar bone destruction and remodelling under orthodontic force (OF) in periodontitis-affected rats.

Material And Methods: After establishing the periodontitis-affected rat model with lipopolysaccharides (LPS), the left maxillary first molars were moved orthodontically under a force of 0.2N. Based on saline or bLF gavage, 54 Sprague-Dawley (SD) rats were randomized into 5 groups: A (blank), P1 (LPS+OF+bLF), P2 (LPS+OF+saline), C1 (OF+bLF), and C2 (OF+saline). Animals were evaluated using micro-computed tomography (micro-CT) followed by haematoxylin and eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining, and the LF level was determined using ELISA in the gingival crevicular fluid (GCF) of the experimental teeth. Immunohistochemistry helped to detect expression changes in RANKL, OPG and COX-2.

Results: Micro-CT results indicated that compared with group P2, trabecular number (Tb.N) and trabecular thickness (Tb.Th) in group P1 were higher and bone surface/bone volume (BS/BV) was lower on day 14, while trabecular separation (Tb.Sp) decreased significantly on Day 5 and Day 14 after bLF gavage (P<0.05). This was supported by changes in H&E and TRAP staining. bLF down-regulated RANKL level at both timepoints and up-regulated OPG level on Day 14 in periodontitis rats (P<0.05). The significant changes mentioned above were not observed between group C1 and C2 (P>0.05). No significant change in COX-2 levels were observed in any group (P>0.05). The lactoferrin level in GCF increased significantly after bLF gavage (P<0.05).

Conclusion: Bovine lactoferrin inhibited LPS-induced bone destruction, but the bone healing effect was independent of orthodontic aseptic inflammatory bone remodelling.
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http://dx.doi.org/10.1016/j.aanat.2021.151744DOI Listing
September 2021

Next-Generation Sequencing Reveals That Oxidative Phosphorylation Might Be a Key Pathway Differently Expressed in the Third and Fourth Stages Larvae of .

Iran J Parasitol 2020 Oct-Dec;15(4):587-595

School of Medicine, Huzhou University, Huzhou Cent Hosp, 759 Er Huan Rd, Huzhou, Zhejiang, China.

Background: When develops from the third and fourth stage, it needs to change its host from the middle host, snail to the final host, rat. However, the mechanism involved in this change remains unclear.

Methods: The transcriptome differences of the third and fourth stages of were explored by next-generation Illumina Hiseq/Miseq sequencing in China, in 2018.

Results: Overall, 137 956 488 clean reads and 20 406 213 373 clean bases of the two stages larvae were produced. Based on the queries against the Gene Ontology (GO), NCBI non-redundant protein sequences (Nr), Swissprot, and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, 14 204 differentially expressed genes (DEGs) were predicted. GO enrichment analysis revealed 5660 DEGs with the top s categories as followings: biological process (GO:0008150, related to 5345 DEGs), cellular component (GO:0005575, related to 5297 DEGs), molecular function (GO:0003674, related to 5290 DEGs). In KEGG enrichment analysis, 116 genes were related to oxidative phosphorylation and 49 genes involved in the glycolytic process.

Conclusion: Metabolism changes, especially oxidative phosphorylation and glycolysis, might play a key role in infection of its final rat host. Many other pathways might also contribute to the transcriptome changes between these two life stages. Overall, additional studies are needed for further details.
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http://dx.doi.org/10.18502/ijpa.v15i4.4869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039486PMC
April 2021

Lévy walk dynamics in mixed potentials from the perspective of random walk theory.

Phys Rev E 2021 Mar;103(3-1):032151

School of Mathematics and Statistics, Gansu Key Laboratory of Applied Mathematics and Complex Systems, Lanzhou University, Lanzhou 730000, People's Republic of China.

Lévy walk process is one of the most effective models to describe superdiffusion, which underlies some important movement patterns and has been widely observed in micro- and macrodynamics. From the perspective of random walk theory, here we investigate the dynamics of Lévy walks under the influences of the constant force field and the one combined with harmonic potential. Utilizing Hermite polynomial approximation to deal with the spatiotemporally coupled analysis challenges, some striking features are detected, including non-Gaussian stationary distribution, faster diffusion, still strongly anomalous diffusion, etc.
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http://dx.doi.org/10.1103/PhysRevE.103.032151DOI Listing
March 2021

Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation.

Cell Death Dis 2021 04 14;12(4):403. Epub 2021 Apr 14.

School of Life Sciences, Nanchang University, Nanchang, 330031, China.

The genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1-LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.
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http://dx.doi.org/10.1038/s41419-021-03687-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047019PMC
April 2021

Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas.

Front Pharmacol 2021 24;12:565748. Epub 2021 Mar 24.

Science and Technology Innovation Center, Shandong First Medical University, Jinan, China.

Oxidative stress and oxidative damage are the common pathophysiological characteristics in pituitary adenomas (PAs), which have been confirmed with many omics studies in PA tissues and cell/animal experimental studies. Nuclear factor erythroid 2 45-related factor 2 (Nrf2), the core of oxidative stress response, is an oxidative stress sensor. Nrf2 is synthesized and regulated by multiple factors, including Keap1, ERK1/2, ERK5, JNK1/2, 38 MAPK, PKC, PI3K/AKT, and ER stress, in the cytoplasm. Under the oxidative stress status, Nrf2 quickly translocates from cytoplasm into the nucleus and binds to antioxidant response element /electrophile responsive element to initiate the expressions of antioxidant genes, phases I and II metabolizing enzymes, phase III detoxifying genes, chaperone/stress response genes, and ubiquitination/proteasomal degradation proteins. Many Nrf2 or Keap1 inhibitors have been reported as potential anticancer agents for different cancers. However, Nrf2 inhibitors have not been studied as potential anticancer agents for PAs. We recommend the emphasis on in-depth studies of Nrf2 signaling and potential therapeutic agents targeting Nrf2 signaling pathways as new therapeutic strategies for PAs. Also, the use of Nrf2 inhibitors targeting Nrf2 signaling in combination with ERK inhibitors plus p38 activators or JNK activators targeting MAPK signaling pathways, or drugs targeting mitochondrial dysfunction pathway might produce better anti-tumor effects on PAs. This perspective article reviews the advances in oxidative stress and Nrf2-mediated oxidative stress response signaling pathways in pituitary tumorigenesis, and the potential of targeting Nrf2 signaling pathways as a new therapeutic strategy for PAs.
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http://dx.doi.org/10.3389/fphar.2021.565748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024532PMC
March 2021

A specific RIP3 subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China;

Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis-FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.
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http://dx.doi.org/10.1073/pnas.2023290118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980367PMC
March 2021

methylation and serum IFN-a1 level among patients with discoid and systemic lupus erythematosus and healthy individuals.

J Transl Autoimmun 2021 1;4:100092. Epub 2021 Mar 1.

Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.

Lupus erythematosus (LE) is an autoimmune disease that can be divided into two types. The cutaneous lupus erythematosus (CLE), such as discoid LE (DLE), affects only the skin. While the systemic lupus erythematosus (SLE) affects the hematopoietic, renal, and other systems. We previously found that methylation could be a biomarker for SLE. Here, we detect the methylation by high-resolution melting-quantitative polymerase chain reaction (HRM-qPCR) assay. The positive percentages of SLE, DLE and healthy controls (HC) are 96.00%, 27.45%, 2.00%, if the curve of 25% methylation was used as the threshold of SLE. And we determined the serum IFN-a1 level by enzyme-linked immunosorbent assay (ELISA) in SLE, DLE and HC. The serum concentration of IFN-a1 in patients with SLE was significantly higher than in the DLE (12.63 ​± ​6.38 ​pg/mL vs 7.99 ​± ​2.28 ​pg/mL,  ​< ​0.05) and HC (12.63 ​± ​6.38 ​pg/mL vs 7.17 ​± ​1.86 ​pg/mL,  ​< ​0.05). But the expression level of IFN-a1 in serum was not significantly different between DLE and HC (7.99 ​± ​2.28 ​pg/mL vs 7.17 ​± ​1.86 ​pg/mL, P ​= ​0.5365). This suggests that methylation of and serum concentration of IFN-a1 may be used as biomarkers to distinguish DLE from SLE.
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http://dx.doi.org/10.1016/j.jtauto.2021.100092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972957PMC
March 2021

The anti-breast cancer property of physcion via oxidative stress-mediated mitochondrial apoptosis and immune response.

Pharm Biol 2021 Dec;59(1):303-310

Department of Translational Medicine Research Institute, First Hospital, Jilin University, Changchun, Jilin, China.

Context: Physcion (Phy) exerts several pharmacological effects including anti-inflammatory, antioxidant, and antitumor properties.

Objective: This study investigates the cytotoxicity and its underlying mechanisms of Phy on breast cancer.

Materials And Methods: Human breast cancer cell MCF-7 was treated with 5-400 µM Phy for 24 h, MCF-7-xenografted BALB/c nude mice and immunosuppressive mice model induced by cyclophosphamide were intraperitoneally injected with 0.1 mL/mouse normal saline (control group) and 30 mg/kg Phy every other day for 14 or 28 days, and pathological examination, ELISA and western blot were employed to investigate the Phy anti-breast cancer property and .

Results: In MCF-7 cells, Phy 24 h treatment significantly reduced the cell viability at dose of 50-400 µM and 24 h, with an IC of 203.1 µM, and 200 µM Phy induced 56.9, 46.9, 36.9, and 46.9% increment on LDH and caspase-3, -8 and -9. In MCF-7-xenograft tumour nude mice and immunosuppressive mice, 30 mg/kg Phy treatment inhibited tumour growth from the 8th day, and reduced Bcl-2 and Bcl-xL >50%, HO-1 and SOD-1 > 70% in tumour tissues of immunosuppressive mice. In addition, Phy reduced nuclear factor erythroid 2-related factor 2 > 30% and its downstream proteins, and enhanced the phosphorylation of nuclear factor-kappa B > 110% and inhibitor of NF-кB α > 80% in the tumour tissues of BALB/c mice.

Discussion And Conclusions: This research demonstrated that Phy has an anti-breast cancer property via the modulation of oxidative stress-mediated mitochondrial apoptosis and immune response, which provides a scientific basis for further research on its clinical applications.
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http://dx.doi.org/10.1080/13880209.2021.1889002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971271PMC
December 2021

Challenges and advances in clinical applications of mesenchymal stromal cells.

J Hematol Oncol 2021 02 12;14(1):24. Epub 2021 Feb 12.

Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.

Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
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http://dx.doi.org/10.1186/s13045-021-01037-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880217PMC
February 2021

Expression, Activity, and Regulation of Phosphorylating Enzymes in Tissues and Cells Relevant to HIV-1 Sexual Transmission.

AIDS Res Hum Retroviruses 2021 Mar 9. Epub 2021 Mar 9.

Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.

Phosphorylating enzymes (PEs) are responsible for activating nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) such as tenofovir (TFV) and are critical for their conversion to obtain intracellular antiviral activity. However, there are limited data available regarding the expression of PEs and their activity in the female genital tract. This work compared the messenger RNA (mRNA) expression levels of PEs in human female genital tissue, immune cells, and animal models that are commonly used in human immunodeficiency virus (HIV) research. Furthermore, the effect of contraceptive hormones and proinflammatory cytokines on tenofovir diphosphate (TFV-DP) formation and efficacy in human vaginal, epithelial, and immune cells was also evaluated. We found that human vaginal and ectocervical tissues had similar mRNA expression for seven PEs tested. Polymerase chain reaction results revealed that creatine kinase brain (CKB), mitochondrial creatine kinase 1 (CKMT1), mitochondrial creatine kinase 2 (CKMT2), adenylate kinase AK3L1 (AK4), and nucleoside diphosphate kinase 1 (NME1) exhibited a 10- to 10,000-fold higher expression level in a vaginal epithelial cell line, VK2, compared with CD4 T cells ( < .05). Medroxyprogesterone acetate (MPA)/progesterone (P4) and IL-1β/IL-8 treatment resulted in altered TFV-DP levels in VK2 and PM1 cells. MPA and P4 at concentrations above 0.1 μM, as well as IL-1β and IL-8 at concentrations above 10 ng/mL, significantly decreased HIV-1 inhibition in PM1 cells when 1 μM TFV was added. However, this observed effect of hormones and cytokines was abrogated when TFV concentration was raised to 1 mM. These results elucidate the role of PEs in TFV metabolism and provide information regarding differences in PE tissue expression for animal models commonly used in HIV testing. This information can be applied to better understand and interpret data obtained using these models.
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http://dx.doi.org/10.1089/AID.2020.0250DOI Listing
March 2021

Comparative analyses of hypothalamus transcriptomes reveal fertility-, growth-, and immune-related genes and signal pathways in different ploidy cyprinid fish.

Genomics 2021 Mar 21;113(2):595-605. Epub 2021 Jan 21.

State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Engineering Research Center of Polyploid Fish Reproduction and Breeding of the State Education Ministry, Hunan Normal University, Changsha 410081, Hunan, PR China. Electronic address:

Triploid crucian carp (TCC) is obtained by hybridization of female diploid red crucian carp (Carassius auratus red var., RCC) and male allotetraploid hybrids. In this study, high-throughput sequencing was used to conduct the transcriptome analysis of the female hypothalamus of diploid RCC, diploid common carp (Cyprinus carpio L., CC) and TCC. The key functional expression genes of the hypothalamus were obtained through functional gene annotation and differential gene expression screening. A total of 71.56 G data and 47,572 genes were obtained through sequencing and genome mapping, respectively. The Fuzzy Analysis Clustering assigned the differentially expressed genes (DEGs) into eight groups, two of which, overdominance expression (6005, 12.62%) and underdominance expression (3849, 8.09%) in TCC were further studied. KEGG enrichment analysis showed that the DEGs in overdominance were mainly enriched in four pathways. The expression of several fertility-related genes was lower levels in TCC, whereas the expression of several growth-related genes and immune-related genes was higher levels in TCC. Besides, 15 DEGs were verified by quantitative real-time PCR (qPCR). The present study can provide a reference for breeding sterility, fast-growth, and disease-resistant varieties by distant hybridization.
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http://dx.doi.org/10.1016/j.ygeno.2021.01.004DOI Listing
March 2021

Unexpected Role of Nonimmune Cells: Amateur Phagocytes.

DNA Cell Biol 2021 Feb 13;40(2):157-171. Epub 2021 Jan 13.

Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China.

Effective and efficient efferocytosis of dead cells and associated cellular debris are critical to tissue homeostasis and healing of injured tissues. This important task was previously thought to be restricted to professional phagocytes (PPs). However, accumulating evidence has revealed another type of phagocyte, the amateur phagocyte (AP), which can also participate in efferocytosis. APs are non-myeloid progenitor/nonimmune cells that include differentiated cells (e.g., epithelial cells, fibroblasts, and endothelial cells [ECs]) and stem cells (e.g., neuronal progenitor cells and mesenchymal cells) and can be found throughout the human body. Studies have shown that APs have two prominent roles: identifying and removing dead cells presumably before PPs reach the site of injury and assisting PPs in the removal of cell corpses and the resolution of inflamed tissue. With respect to the engulfment and degradation of dead cells, APs are slower and less efficient than PPs. However, APs are fundamental to preventing the spread of inflammation over a large area. In this review, we present the diversity and characteristics of healthy and non-neoplastic APs in mammals. We also propose a hypothetical mechanism of the efferocytosis of immunoglobulin G (IgG)-opsonized myelin debris by ECs (APs). Furthermore, the ingestion and clearance of dead cells can induce proinflammatory or anti-inflammatory cytokine production, endothelial activation, and cellular fate transition, which contribute to the progression of disease. An understanding of the role of APs is necessary to develop effective intervention strategies, including potential molecular targets for clinical diagnosis and drug development, for inflammation-related diseases.
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http://dx.doi.org/10.1089/dna.2020.5647DOI Listing
February 2021

SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression.

Nat Commun 2021 01 8;12(1):135. Epub 2021 Jan 8.

Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200001, China.

Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter. NF-kB binds the disease protective allele in a sequence-specific manner, increasing expression of this immunoregulatory microRNA. Finally, CRISPR activation-based modulation of this enhancer in the PBMCs of SLE patients attenuates type I interferon pathway activation by increasing miR-146a expression. Our work provides a strategy to define non-coding RNA functional regulatory elements using disease-associated variants and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.
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http://dx.doi.org/10.1038/s41467-020-20460-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794586PMC
January 2021

Microfluidic preparation of PLGA composite microspheres with mesoporous silica nanoparticles for finely manipulated drug release.

Int J Pharm 2021 Jan 13;593:120173. Epub 2020 Dec 13.

Shanghai Key Laboratory of Multiphase Materials Chemical Engineering, Department of Product Engineering, School of Chemical Engineering, East China University of Science and Technology, No. 130 Mei Long Road, Shanghai 200237, PR China. Electronic address:

The current study explored the feasibility of a microfluidic preparation of PLGA composite microspheres with mesoporous silica nanoparticles (MSNs) to finely manipulate the drug release behaviors of the microspheres. MSNs were synthesized via a hydrothermal method, and PLGA microspheres loaded with MSNs (PLGA-MSNs) were prepared using a capillary-based three-phase microfluidic device. Drug loading and release behaviors using rhodamine B (RB) as a water-soluble model drug were investigated and compared with those of PLGA microspheres. MSNs with an average particle size of 119 nm, a specific surface area of 902.5 cm/g, and a pore size of approximately 5 nm were obtained. The mean diameter of PLGA-MSNs was 56 μm (CV = 4.91%). A sustained release duration of encapsulated RB from PLGA-MSNs for 4 months was achieved without any observable burst release. PLGA microspheres with monodispersion could also allow for a similar release duration of encapsulated RB but encountered a burst release in the mid-term of the studied duration. PLGA-MSNs had a denser outer PLGA layer and a more centralized hollow hole than PLGA microspheres without MSNs. Hence, the incorporation of MSNs into PLGA microspheres via microfluidics could be an efficient strategy to finely tune the drug release behavior of PLGA microspheres.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120173DOI Listing
January 2021

Intranasal administration of white tea alleviates the olfactory function deficit induced by chronic unpredictable mild stress.

Pharm Biol 2020 Dec;58(1):1221-1228

School of Life Science, East China Normal University, Shanghai, China.

Context: White tea [ (L) O.Ktze. (Theaceae)] is popular in Asia, but its benefits on olfactory injury are unknown.

Objective: The present study explores the effects of white tea on the olfactory injury caused by chronic unpredictable mild stress (CUMS).

Materials And Methods: C57BL/6J mice (WT) were exposed to CUMS. CUMS mice (CU) were intranasally treated with white tea extract [low tea (LT), 20 mg/kg; high tea (HT), 40 mg/kg] and fluoxetine (CF, 20 mg/kg) for 7 days. Several behavioural tests were conducted to assess depression and olfactory function. The transmission electron microscope (TEM) and semi-quantitative reverse transcription PCR were performed separately to observe the changes of related structures and genes transcription level.

Results: The depressive behaviours of the LT and HT mice were reversed. The latency time of the buried food pellet test decreased from 280 s (CU) to 130 s (HT), while the olfactory sensitivity and olfactory avoidance test showed that the olfactory behaviours disorder of LT and HT mice were alleviated. The white tea increased the A values of the cortisol treated cells from 0.15 to 1.4. Reduced mitochondrial and synaptic damage in the olfactory bulb (OB), enhanced expression of the brain-derived neurotrophic factor (BDNF) and olfactory marker protein (OMP) were observed in the LT and HT mice.

Conclusions And Discussion: White tea has the potential in curing the olfactory deficiency related to chronic stress. It lays the foundation for the development of new and reliable drug to improve olfactory.
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http://dx.doi.org/10.1080/13880209.2020.1855213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875552PMC
December 2020

Adenosine Triphosphate-Induced Rapid Liquid-Liquid Phase Separation of a Model IgG1 mAb.

Authors:
Zhou Tian Feng Qian

Mol Pharm 2021 01 12;18(1):267-274. Epub 2020 Dec 12.

School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.

Adenosine triphosphate (ATP) is amphiphilic in nature and has the characteristics of a hydrotrope because of the charged triphosphate moiety and the large aromatic ring located on each end of its structure. Previous studies revealed that ATP can effectively maintain the solubility and prevent liquid-liquid phase separation (LLPS) of some biological proteins. In this study, we assessed the impact of ATP on the stability of a model therapeutic IgG1 antibody (MA1) to evaluate its potential application in protein formulation design. In our system, ATP promotes rapid LLPS of MA1 and we demonstrate that the ATP-MA1 static interaction drives phase separation of MA1. The attractive protein-protein interaction increased exclusively in the presence of ATP but not in the presence of other ATP analogues, such as adenosine diphosphate, adenosine monophosphate, and adenine. Through an intrinsic fluorescence quenching study, we revealed that ATP bound to MA1 electrostatically and formed static interactions; furthermore, such static ATP-MA1 interactions significantly altered the surface property of the protein and the protein-protein interactions and subsequently induced LLPS of MA1. This ATP-induced LLPS could be effectively eliminated by Mg, which chelated with ATP and thus negated ATP-MA1 static interaction. Our results revealed the unique molecular mechanism of ATP-induced rapid LLPS of MA1.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00905DOI Listing
January 2021

Efficacy and safety of complementary and alternative medicine therapy for gastroparesis: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Nov;99(47):e23294

Dongfang hospital Beijing University of Chinese Medicine, No.6 Community 1 Fangxingyuan, Fengtai District.

Background: Gastroparesis affects the quality of life of many patients, but there is no effective treatment. Now, complementary and alternative medicine originated from China is gradually accepted by the world because of its unique treatment principles and relatively safe treatment methods. However, at present, there is still a lack of more definitive clinical application evidence for the treatment of gastroparesis with complementary and alternative medicine to confirm the safety and efficacy of complementary and alternative medicine in the treatment of gastroparesis caused by various causes. More comprehensive and stronger evidence-based medicine evidence is needed.

Methods: We will retrieve literatures using Medline, Embase, the Cochrane Library database, Web of science, CNKI, VIP, CBM, and WanFang. We will look for RCTs or CCTs on the use of complementary and alternative medicine in the treatment of gastroparesis, and extract relevant data into the excel sheet. The whole retrieval and data extraction process were carried out by 2 researchers independently. Then we will use meta-analysis to make statistical analysis of all the results and make a systematic review of all the included literatures.

Results: All results and safety data were analyzed for a comprehensive evaluation and/or descriptive analysis of the efficacy and safety of complementary and alternative therapies for gastroparesis.

Conclusion: This study will provide more comprehensive clinical evidence for the treatment of gastroparesis with complementary and alternative therapies.

Registration: The research has been registered and approved on the INPLASY.COM website. The registration number is INPLASY2020100033.
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http://dx.doi.org/10.1097/MD.0000000000023294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676567PMC
November 2020

Modeling stochastic gene expression: From Markov to non-Markov models.

Math Biosci Eng 2020 08;17(5):5304-5325

Key Laboratory of Computational Mathematics, Guangdong Province, and School of Mathematics, Sun Yat-sen University, Guangzhou 510275, China.

Gene expression is an inherently noisy process due to low copy numbers of mRNA or protein. The involved reaction events may happen in a Markov fashion but also in a non-Markov manner, depending on waiting-time distributions for the occurrence of reaction events. In recent years, many mechanistic models of stochastic gene expression have been developed to forecast fluctuations in mRNA or protein levels. Here we discus commonalities between these models as well as their extensions from Markov to non-Markov models, focusing on the contributions of noisy sources to the protein level. We derive a useful formula for the protein noise quantified by the ratio of the variance over the squared mean. This formula, expressed in terms of the frequencies of the probabilistic events, can be used in the fast evaluation of fluctuations in the protein abundance. Although the detail of the formula may vary from gene to gene, it highlights sources of the protein noise, which can be decomposed into two parts: spontaneous fluctuations resulting from the birth and death of the protein and forced fluctuations originated from switching between the promoter states.
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http://dx.doi.org/10.3934/mbe.2020287DOI Listing
August 2020

Metformin Ameliorates Lipopolysaccharide-Induced Depressive-Like Behaviors and Abnormal Glutamatergic Transmission.

Biology (Basel) 2020 Oct 26;9(11). Epub 2020 Oct 26.

Laboratory of Synaptic Development and Plasticity, Institute of Life Science, Nanchang University, Nanchang 330031, China.

Metformin, a first-line drug for type 2 diabetes mellitus (T2DM), has been found to reduce depressive symptoms in patients with comorbid depression and other diseases. However, it is largely unclear how metformin ameliorates depressive-like behaviors. Here, we used lipopolysaccharide (LPS) to induce depressive-like behaviors in mice and found that LPS-treated mice exhibited increased immobility in the forced swimming test (FST) and tail suspension test (TST), as well as increased glutamatergic transmission. Furthermore, metformin administration in the LPS-treated mice ameliorated depressive-like behaviors and elevated glutamatergic transmission. Our results suggest that metformin has antidepressant effects and can correct abnormal glutamatergic transmission, providing an insight into the underlying mechanism by which metformin acts against depression.
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http://dx.doi.org/10.3390/biology9110359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692296PMC
October 2020

Determination of the molecular mechanism by which macrophages and γδ-T cells contribute to ZOL-induced ONJ.

Aging (Albany NY) 2020 10 25;12(20):20743-20752. Epub 2020 Oct 25.

Department of Orthopedics, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200336, China.

Objective: This study aims to explore the molecular mechanism of macrophages and γδ-T cells in the ZOL drug-induced osteonecrosis of jaws based on the IFN-γ involved osteoblast differentiation signaling pathway.

Results: The number and apoptotic rate of CD11b+Gr1hi cells and γδ-T cells in the ONJ group were significantly higher. The TNF-α, IL-1β, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were significantly higher in the ONJ group. The expression of CTSK and FGFR3 was lower in the ONJ group, but was higher in the NF-κB and ERBB2IP group.

Conclusion: The proliferation of macrophages and γδ-T cells promote the inflammation in ZOL-induced jaw necrosis.

Methods: A total of 20 patients with osteonecrosis of the jaw from January 2016 to March 2018 were collected and assigned into the observation group, while 20 healthy subjects were assigned into the control group. Furthermore, 40 SD rats were selected and assigned into observation group, while 10 non-treatment SD rats were selected and assigned as controls. The distribution and proportion of CD11b+Gr1hi cells and γδ-T cells in the necrotic tissues of the jaw were analyzed. Then, the TNF-α, IL-1β, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were measured. Afterwards, the expression of CTSK, FGFR3, NF-κB and ERBB2IP in the necrotic tissues of the jaw in the animal models were analyzed.
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http://dx.doi.org/10.18632/aging.104006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655157PMC
October 2020

22q11.2 deletion syndrome and schizophrenia.

Acta Biochim Biophys Sin (Shanghai) 2020 Dec;52(11):1181-1190

School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.

22q11.2 deletion is a common microdeletion that causes an array of developmental defects including 22q11.2 deletion syndrome (22q11DS) or DiGeorge syndrome and velocardiofacial syndrome. About 30% of patients with 22q11.2 deletion develop schizophrenia. Mice with deletion of the ortholog region in mouse chromosome 16qA13 exhibit schizophrenia-like abnormal behaviors. It is suggested that the genes deleted in 22q11DS are involved in the pathogenesis of schizophrenia. Among these genes, COMT, ZDHHC8, DGCR8, and PRODH have been identified as schizophrenia susceptibility genes. And DGCR2 is also found to be associated with schizophrenia. In this review, we focused on these five genes and reviewed their functions in the brain and the potential pathophysiological mechanisms in schizophrenia, which will give us a deeper understanding of the pathology of schizophrenia.
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http://dx.doi.org/10.1093/abbs/gmaa113DOI Listing
December 2020