Publications by authors named "Bei Zhang"

707 Publications

Efficacy and safety of PD-L1 inhibitors versus PD-1 inhibitors in first-line treatment with chemotherapy for extensive-stage small-cell lung cancer.

Cancer Immunol Immunother 2021 Jul 23. Epub 2021 Jul 23.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Objectives: Programmed cell death-ligand 1 inhibitors plus chemotherapy (PD-L1 + Chemo) have achieved substantial progress in extensive-stage small-cell lung cancer (ES-SCLC). However, evidence about programmed cell death 1 inhibitors plus chemotherapy (PD-1 + Chemo) in SCLC is relatively lacking. Whether PD-1 inhibitors differ from PD-L1 inhibitors in their clinical outcomes remains controversial.

Materials And Methods: We performed a meta-analysis to compare efficacy and safety of PD-L1 + Chemo vs PD-1 + Chemo in ES-SCLC by searching PubMed, Embase, the Cochrane Library, and major oncology conferences. We examined overall survival (OS) as the primary outcome. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs).

Results: We included four randomized trials (IMpower133, CASPIAN, KEYNOTE-604, and EA5161) with a total of 1553 patients. Direct comparison showed that PD-L1 + Chemo (PFS: hazard ratio [HR] 0.79; OS: HR 0.75) and PD-1 + Chemo (PFS: HR 0.72; OS: HR 0.77) significantly prolonged survival time compared with chemotherapy alone. But PD-L1 + Chemo (relative risk [RR]: 1.07) and PD-1 + Chemo (RR: 1.13) were not superior to chemotherapy alone in terms of ORR. Indirect comparison showed no significant difference in clinical efficacy between PD-L1 + Chemo and PD-1 + Chemo (OS: HR 0.99; PFS: HR 1.10; ORR: RR 0.95). We further stratified patients according to subgroups in terms of OS. In the subgroup of patients with brain metastasis, PD-L1 + Chemo tended to prolong OS (HR: 0.61, 0.28 to 1.32). There were no significant differences between PD-L1 + Chemo and PD-1 + Chemo regarding safety analyses. However, PD-L1 + Chemo exhibited a better safety profile in reducing the risk of treatment discontinuation due to AEs (RR: 0.43, 0.19 to 0.95) and pneumonia (pneumonia of any grade, RR: 0.59, 0.24 to 1.42; pneumonia of grade ≥ 3, RR: 0.37, 0.10 to 1.39).

Conclusions: PD-L1 + Chemo and PD-1 + Chemo provided a significant survival benefit relative to chemotherapy alone for ES-SCLC. The efficacy and safety of PD-L1 + Chemo and PD-1 + Chemo were similar based on current evidence.
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http://dx.doi.org/10.1007/s00262-021-03017-zDOI Listing
July 2021

Displacement current distribution on a high dielectric constant helmet and its effect on RF field at 10.5 T (447 MHz).

Magn Reson Med 2021 Jul 17. Epub 2021 Jul 17.

Center for NMR Research, Departments of Neurosurgery and Radiology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA.

Purpose: Investigating the designs and effects of high dielectric constant (HDC) materials in the shape of a conformal helmet on the enhancement of RF field and reduction of specific absorption rate at 10.5 T for human brain studies.

Methods: A continuous and a segmented four-piece HDC helmet fit to a human head inside an eight-channel fractionated-dipole array were constructed and studied with a phantom and a human head model using computer electromagnetic simulations. The simulated transmit efficiency and receive sensitivity were experimentally validated using a phantom with identical electric properties and helmet-coil configurations of the computer model. The temporal and spatial distributions of displacement currents on the HDC helmets were analyzed.

Results: Using the continuous HDC helmet, simulation results in the human head model demonstrated an average transmit efficiency enhancement of 66%. A propagating displacement current was induced on the continuous helmet, leading to an inhomogeneous RF field enhancement in the brain. Using the segmented four-piece helmet design to reduce this effect, an average 55% and 57% enhancement in the transmit efficiency and SNR was achieved in human head, respectively, along with 8% and 28% reductions in average and maximum local specific absorption rate.

Conclusion: The HDC helmets enhanced the transmit efficiency and SNR of the dipole array coil in the human head at 10.5 T. The segmentation of the helmet to disrupt the continuity of circumscribing displacement currents in the helmet produced a more uniform distribution of the transmit field and lower specific absorption rate in the human head compared with the continuous helmet design.
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http://dx.doi.org/10.1002/mrm.28923DOI Listing
July 2021

MiR-125b inhibits cardiomyocyte apoptosis by targeting BAK1 in heart failure.

Mol Med 2021 Jul 8;27(1):72. Epub 2021 Jul 8.

Department of Ultrasound Medicine, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People's Republic of China.

Background: Although miR-125b plays a crucial role in many human cancers. However, its function in heart failure (HF) remains unclear. Our study aimed to investigate its involvement in heart failure.

Methods: In this study, the mouse HF model was successfully constructed through transverse aortic constriction (TAC) operation. Changes in mRNA and protein levels in isolated myocytes and heart tissues were examined using qRT-PCR, Western blot and Immunohistochemical staining and immunofluorescent staining. Changes in cardiac functions were examined using ultrasound. Interactions between miR-125b and BAK1 was analyzed using the luciferase reporter assay. Cardiomyocyte apoptosis was evaluated using the TUNEL staining.

Results: We found that miR-125b expression was significantly downregulated in myocardial tissues of HF mice. Moreover, miR-125b upregulation in HF mice injected with agomir-125b efficiently ameliorated cardiac function. Further, miR-125b upregulation significantly decreased the protein levels of apoptosis-related makers c-caspase 3 and Bax, while increased Bcl-2 expression. In addition, BAK1 was identified as a direct target of miR-125b. As expected, BAK1 overexpression observably reversed the effect of agomir-125b on cardiac function and on the expression of apoptosis-related makers in the heart tissues of HF mice.

Conclusions: Taken together, miR-125b overexpression efficiently attenuated cardiac function injury of HF mice by targeting BAK1 through inhibiting cardiomyocyte apoptosis, suggesting that miR-125b/BAK1 axis might be a potential target for the diagnosis or treatment of HF.
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http://dx.doi.org/10.1186/s10020-021-00328-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268255PMC
July 2021

TIM-3: An update on immunotherapy.

Int Immunopharmacol 2021 Jul 2;99:107933. Epub 2021 Jul 2.

Department of Laboratory Medicine, The Third People's Hospital of Qingdao, Qingdao, Shandong 266071, China. Electronic address:

T cell immunoglobulin and mucin domain 3 (TIM-3) was originally found to be expressed on the surface of Th1 cells, acting as a negative regulator and binding to the ligand galectin-9 to mediate Th1 cell the apoptosis. Recent studies have shown that TIM-3 is also expressed on other immune cells, such as macrophages, dendritic cells, and monocytes. In addition, TIM-3 ligands also include Psdter, High Mobility Group Box 1 (HMGB1) and Carcinoembryonic antigen associated cell adhesion molecules (Ceacam-1), which have different effects upon biding to different ligands on immune cells. Studies have shown that TIM-3 plays an important role in autoimmune diseases, chronic viral infections and tumors. A large amount of experimental data supports TIM-3 as an immune checkpoint, and targeting TIM-3 is a promising treatment method in current immunotherapy, especially the new combination of other immune checkpoint blockers. In this review, we summarize the role of TIM-3 in different diseases and its possible signaling pathway mechanisms, providing new insights for better breakthrough immunotherapy.
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http://dx.doi.org/10.1016/j.intimp.2021.107933DOI Listing
July 2021

Engage in Exploration: Pathology Gross Laboratory in the COVID-Era.

Acad Pathol 2021 Jan-Dec;8:23742895211002843. Epub 2021 Mar 25.

Department of Pathology and Laboratory Medicine, The Robert Larner, M.D. College of Medicine at the University of Vermont, Burlington, VT, USA.

The outbreak of Covid-19 has changed education, including the mechanism of delivery of gross pathology laboratories. Herein, we describe how we revised our preclinical gross pathology lab to a flipped model to fit with COVID-19 regulations. A series of short, session objective-driven videos are made available online. Students are expected to watch the videos before coming to the hands-on lab. Groups of 2 students enter the gross lab on a timed basis and rotate through a series of stations. At each station, students examine gross pathology specimens while answering questions designed to apply the clinical correlation of pathophysiology and heighten observational skills. One or 2 pathologists are available throughout the lab session to address the questions from the students. The design of this laboratory exercise maintains appropriate distancing and hygiene in the time of COVID-19. The laboratory rooms are mapped to set up an appropriate number of timed stations. Flow-through of the rooms is unidirectional. Comparing with the traditional show-and-tell of teaching gross pathology, the renovated flipped model is genuinely student-centered and focuses on active learning. Holding the specimen in their hands, students learn from discovery as they are completely engaged by exploring the specimen and deriving answers themselves. The flipped learning gross pathology method has been very well received and evaluated highly by both faculty and students.
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http://dx.doi.org/10.1177/23742895211002843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994920PMC
March 2021

Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation.

iScience 2021 Jun 19;24(6):102554. Epub 2021 May 19.

Internal Medicine Research Unit, Pfizer Inc, 1 Portland St, Cambridge, MA 02139, USA.

Growth differentiation factor 15 (GDF15) causes anorexia and weight loss in animal models, and higher circulating levels are associated with cachexia and reduced survival in cancer and other chronic diseases such as sepsis. To investigate the role of sepsis-induced GDF15, we examined whether GDF15 neutralization via a validated and highly potent monoclonal antibody, mAB2, modulates lipopolysaccharide (LPS)-induced anorexia, weight loss, and mortality in rodents. LPS injection transiently increased circulating GDF15 in wild-type mice, decreased food intake and body weight, and increased illness behavior and mortality at a high dose. GDF15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. Similarly, in GDF15 knockout mice, the LPS effect on appetite and survival was comparable with that observed in wild-type controls. Therefore, effective inhibition of circulating active GDF15 via an antibody or via gene knockout demonstrated that survival in the LPS acute inflammation model was independent of GDF15.
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http://dx.doi.org/10.1016/j.isci.2021.102554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215224PMC
June 2021

Design, synthesis and biological evaluation of novel pyrazolopyrimidone derivatives as potent PDE1 inhibitors.

Bioorg Chem 2021 Jun 18;114:105104. Epub 2021 Jun 18.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.

Phosphodiesterase-1 (PDE1) is a promising drug target closely related to central and peripheral diseases. With the assistance of molecular docking and dynamics simulations, we designed and synthesized a novel series of pyrazolopyrimidone derivatives as effective and metabolically stable inhibitors against PDE1. Most compounds have good inhibitory activities against PDE1 at the concentration of 20 nM. Compound 2j with the IC of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t of 28.5 min), indicating that compound 2j can be used as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1.
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http://dx.doi.org/10.1016/j.bioorg.2021.105104DOI Listing
June 2021

Circulating tumor DNA reveals genetic traits of patients with intraductal carcinoma of the prostate.

BJU Int 2021 Jun 29. Epub 2021 Jun 29.

Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 610041, Chengdu, China.

Objectives: To investigate the genetic alterations of prostate cancer (PCa) patients with and without intraductal carcinoma of the prostate (IDC-P).

Materials And Methods: We performed targeted sequencing of plasma cell-free DNA on 161 patients of prostate adenocarcinoma (PAC) with IDC-P and 84 cases without IDC-P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients' survival outcomes was also explored.

Results: Totally, we identified 29.8% (48/161) and 21.4% (18/84) patients with and without IDC-P harbored genomic alterations in DNA repair pathway, respectively (P=0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC-P carriers compared to IDC-P non-carries (11.8% [19/161] vs. 2.4% [2/84], P=0.024). Germline BRCA2 and somatic CDK12 defects were specifically identified in IDC-P carriers relative to PAC (BRCA2: 8.7% [14/161] vs. 0% and CDK12: 6.8% [11/161] vs. 1.2% [1/84]). Patients with IDC-P had a distinct AR pathway alteration, characterized by an enrichment of NCOR2 mutations against patients with pure PAC (21.1% [34/161] vs. 6.0% [5/84], P=0.004). Increased AR alterations were detected in patients harbouring tumors with IDC-P proportion≥10% versus cohort with IDC-P proportion<10% (6.4% [5/78] vs. 18.1% [15/83], P=0.045). For IDC-P carries, TP53 mutation was associated with shorter castration-resistant free survival (median 10.9-Mo vs. 28.9-Mo, P=0.026), and BRCA2 alteration was related to rapid PSA progression for those receiving abiraterone treatment (median 9.1-Mo vs 11.9-Mo, P=0.036).

Conclusion: Our findings provide genomic evidence explaining the aggressive phenotype of tumors with IDC-P, highlighting the potential therapeutic strategies for this patient population.
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http://dx.doi.org/10.1111/bju.15530DOI Listing
June 2021

Clinical application of the 2011 IFCPC colposcope terminology.

BMC Womens Health 2021 06 24;21(1):257. Epub 2021 Jun 24.

Department of Obstetrics and Gynecology, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, No.16766, Jingshi Road, Jinan, 250014, Shandong Province, China.

Background: Colposcopy offers an accurate way to the diagnose of cervical precancerous lesions. However, the diagnostic accuracy of colposcopy is unsatisfied. This study was to evaluate colposcopic accuracy according to the 2011 International Federation of Cervical Pathology and Colposcopy (IFCPC) terminology.

Methods: A retrospective cohort study was performed in 1,838 patients who underwent colposcopy in Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University from October 2013 to April 2018. Using conization or cervical biopsy pathology as the gold standard, the agreement between colposcopic diagnosis and pathologic diagnosis was calculated, and correlations between variables were analyzed.

Results: As an authoritative and widely used terminology for colposcopy diagnosis, the 2011 IFCPC terminology has certain clinical practicality and diagnostic accuracy. However, some signs such as mosaic, punctation, sharp border, inner border sign and ridge sign had high specificity but unsatisfactory sensitivity, which limited the diagnostic value. Therefore, we discussed the Lugol's staining, a very common sign in colposcopy, and analyzed the diagnostic significance of bright yellow staining in low-grade squamous intraepithelial lesion (LSIL) and mustard yellow staining in high-grade squamous intraepithelial lesion (HSIL). The results showed that mustard yellow may be a valuable indicator in the diagnosis of HSIL.

Conclusion: The 2011 IFCPC colposcope terminology has standardized interpretations of the colposcopic findings and improved the accuracy of colposcopy diagnosis. The aceto-white epithelium still has important diagnostic value; however, the value of a few signs is needed to be discussed and new signs are expected to be discovered. Although the significance of Lugol's staining was diminishing, mustard yellow might be a valuable indicator for the diagnosis of HSIL.
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http://dx.doi.org/10.1186/s12905-021-01395-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223298PMC
June 2021

Intravital Whole-Process Monitoring Thermo-Chemotherapy Via 2D Silicon Nanoplatform: A Macro Guidance and Long-Term Microscopic Precise Imaging Strategy.

Adv Sci (Weinh) 2021 Jun 24:e2101242. Epub 2021 Jun 24.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.

Tumor angiogenesis is a complex process that is unamenable to intravital whole-process monitoring, especially on microscopic assessment of tumor microvessel and quantifying microvascular hemodynamics before and after the nanotherapeutics, which hinder the understanding of nanotheranostics outcomes in tumor treatment. Herein, a new photoacoustic (PA) imaging-optical coherence tomography angiography (OCTA)-laser speckle (LS) multimodal imaging strategy is first proposed, which is not only able to precisely macro guide the thermo-chemotherapy of tumor by monitoring blood oxygen saturation (SaO ) and hemoglobin content (HbT), but also capable of long-term microscopic investigating the microvessel morphology (microvascular density) and hemodynamics changes (relative blood flow) before and after the nanotherapeutics in vivo. Moreover, to realize the tumor thermo-chemotherapy treatment based on this novel multimodal imaging strategy, a 2D 5-fluorouracil silicon nanosheets (5-Fu-Si NSs) therapeutic agent is designed. Furthermore, 2D high-resolution tumor microvascular images in different stage display that tendency of the thermo-chemotherapy effect is closely associated with tumor angiogenesis. Taken together, the investigations establish the fundamental base in theory and technology for further tailoring the novel specific diagnosis and treatment strategy in tumor. More importantly, this technique will be beneficial to evaluate the tumor microvascular response to nanotherapeutics at microscale.
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http://dx.doi.org/10.1002/advs.202101242DOI Listing
June 2021

Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis.

J Med Chem 2021 Jul 18;64(13):9537-9549. Epub 2021 Jun 18.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit led to lead , which exhibited an IC value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-β-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00862DOI Listing
July 2021

Cortical Pathways or Mechanism in the Face Inversion Effect in Patients with First-Episode Schizophrenia.

Neuropsychiatr Dis Treat 2021 10;17:1893-1906. Epub 2021 Jun 10.

Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, 510370, People's Republic of China.

Objective: Impaired face perception is considered as a hallmark of social disability in schizophrenia. It is widely believed that inverted faces and upright faces are processed by distinct mechanisms. Previous studies have identified that individuals with schizophrenia display poorer face processing than controls. However, the mechanisms underlying the face inversion effect (FIE) in patients with first-episode schizophrenia (FSZ) remain unclear.

Methods: We designed an fMRI task to investigate the FIE mechanism in patients with schizophrenia. Thirty-four patients with FSZ and thirty-five healthy controls (CON) underwent task-related fMRI scanning, clinical assessment, anhedonia experience examination, and social function and cognitive function evaluation.

Results: The patients with FSZ exhibited distinct functional activity regarding upright and inverted face processing within the cortical face and non-face network. These results suggest that the differences in quantitative processing might mediate the FIE in schizophrenia. Compared with controls, affected patients showed impairments in processing both upright and inverted faces; and for these patients with FSZ, upright face processing was associated with more severe and broader impairment than inverted face processing. Reduced response in the left middle occipital gyrus for upright face processing was related to poorer performance of social function outcomes evaluated using the Personal and Social Performance Scale.

Conclusion: Our data suggested that patients with FSZ exhibited similar performance in processing inverted faces and upright faces, but were less efficient than controls; and for these patients, inverted faces are processed less efficiently than upright faces. We also provided a clue that the mechanism under abnormal FIE might be related to an aberrant activation of non-face-selective areas instead of abnormal activation of face-specific areas in patients with schizophrenia. Finally, our study indicated that the neural pathway for upright recognition might be relevant in determining the functional outcomes of this devastating disorder.
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http://dx.doi.org/10.2147/NDT.S302584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203188PMC
June 2021

SARS-CoV-2 NSP12 protein is not an IFN-β antagonist.

J Virol 2021 Jun 16:JVI0074721. Epub 2021 Jun 16.

State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is bringing an unprecedented health crisis to the world. To date, our understanding of the interaction between SARS-CoV-2 and host innate immunity is still limited. Previous studies reported that SARS-CoV-2 non-structural protein 12 (NSP12) was able to suppress interferon-β (IFN-β) activation in IFN-β promoter luciferase reporter assays, which provided insights into the pathogenesis of COVID-19. In this study, we demonstrated that IFN-β promoter mediated luciferase activity was reduced during co-expression of NSP12. However, we could show NSP12 did not affect IRF3 or NF-κB activation. Moreover, IFN-β production induced by Sendai virus (SeV) infection or other stimulus was not affected by NSP12 at mRNA or protein level. Additionally, type I IFN signaling pathway was not affected by NSP12, as demonstrated by the expression of interferon stimulated genes (ISGs). Further experiments revealed that different experiment systems, including protein tags and plasmid backbones, could affect the readouts of IFN-β promoter luciferase assays. In conclusion, unlike previously reported, our study showed SARS-CoV-2 NSP12 protein is not an IFN-β antagonist. It also rings the alarm on the general usage of luciferase reporter assays in studying SARS-CoV-2. Previous studies investigated the interaction between SARS-CoV-2 viral proteins and interferon signaling, and proposed that several SARS-CoV-2 viral proteins, including NSP12, could suppress IFN-β activation. However, most of these results were generated from IFN-β promoter luciferase reporter assay, and have not been validated functionally. In our study, we found that although NSP12 could suppress IFN-β promoter luciferase activity, it showed no inhibitory effect on IFN-β production or it downstream signaling. Further study revealed that contradictory results could generated from different experiment systems. On one hand, we demonstrated that SARS-CoV-2 NSP12 could not suppress IFN-β signaling. On the other hand, our study suggests that cautions need to be taken with the interpretation of SARS-CoV-2 related luciferase assays.
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http://dx.doi.org/10.1128/JVI.00747-21DOI Listing
June 2021

Efficient whole-cell biosynthesis of l-gulose by coupling mannitol-1-dehydrogenase with NADH oxidase.

Enzyme Microb Technol 2021 Aug 7;148:109815. Epub 2021 May 7.

Department of Biochemistry, College of Life Sciences and Technology, China Pharmaceutical University, 639 Longmian Ave, Nanjing 211198, PR China. Electronic address:

L-Gulose is a rare aldohexose to serve as a building block for anticancer drug bleomycin and nucleoside-based antivirals. However, preparative inaccessibility and high cost have hindered its pharmaceutical application. Despite a regio- and stereo-selective enzymatic synthesis of l-gulose from d-sorbitol using a variant of NAD-dependent mannitol-1-dehydrogenase from Apium graveolens (mMDH) was explored, low efficiency and productivity caused by NADH accumulation or insufficient amount of NAD limited the practical utility of this process. In this study, a stable and efficient NADH oxidase from Bacillus cereus (bcNOX) was found to be more compatible with mMDH to recycle NAD in E. coli cells for l-gulose biosynthesis. After a systematic optimization of the whole-cell system, efficient biosynthesis of l-gulose was achieved. Starting with 70 g/L of readily available and cheap d-sorbitol resulted in a volumetric productivity of 5.5 g/L/d. This whole-cell approach enables practical, efficient and environmentally friendly biosynthesis of l-gulose and exhibits the potential of becoming a biocatalytic strategy for various enzymatic oxidative transformations.
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http://dx.doi.org/10.1016/j.enzmictec.2021.109815DOI Listing
August 2021

Optimal cumulative cisplatin dose during concurrent chemoradiotherapy among children and adolescents with locoregionally advanced nasopharyngeal carcinoma: A real-world data study.

Radiother Oncol 2021 Aug 8;161:83-91. Epub 2021 Jun 8.

VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address:

Purpose: To identify an optimal cumulative cisplatin dose along with concurrent chemoradiotherapy (CC-CCD) for children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC) using real-world data.

Materials And Methods: Using an NPC-specific database at our center, 157 patients younger than 19 years old with non-disseminated CALANPC and receiving neoadjuvant chemotherapy (NAC) plus cisplatin-based concurrent chemoradiotherapy (CCRT) were enrolled. Confounding factors were controlled by conducting propensity score matching analysis. Primary endpoints include disease-free survival (DFS) and distant metastasis-free survival (DMFS).

Results: The optimal threshold for CC-CCD with respect to DFS was 160 mg/m based on recursive partitioning analyses (RPA). Therefore, a uniform threshold of 160 mg/m (≥160 vs. <160 mg/m) was selected to classify patients between high and low CC-CCD groups for survival analysis. Patients receiving low CC-CCD showed a significant decrease in 5-year DFS (76.6% vs 91.3%; P = 0.006) and DMFS (81.3% vs 93.5%; P = 0.009) compared to those receiving high CC-CCD. Multivariate analyses indicated that high CC-CCD as an favorable prognostic influence for DFS (P = 0.007) and DMFS (P = 0.008). Further matched analysis identified 65 pairs in both high and low CC-CCD groups. In the matched cohort, high CC-CCD was still identified as a favorable factor for prognosis in DFS (HR, 0.23; 95% CI, 0.08-0.70; P = 0.010) and DMFS (HR, 0.23; 95% CI, 0.06-0.82; P = 0.023).

Conclusion: CC-CCD exerts significant treatment effects and 160 mg/m CC-CCD may be adequate to provide antitumor effects for CALANPC receiving NAC plus CCRT.
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http://dx.doi.org/10.1016/j.radonc.2021.06.003DOI Listing
August 2021

Correlations between apparent diffusion coefficient values of WB-DWI and clinical parameters in multiple myeloma.

BMC Med Imaging 2021 Jun 8;21(1):98. Epub 2021 Jun 8.

Shenzhen Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, China.

Background: Whole-body diffusion-weighted imaging (WB-DWI) is a method for evaluating bone marrow infiltration in multiple myeloma (MM). This study seeks to elucidate the correlation between the apparent diffusion coefficient (ADC) value and some selected clinical parameters.

Methods: A total of 101 Chinese patients with MM who had undergone WB-DWI from May 2017 to May 2019 were enrolled in this study. The ADC values of the MM lesions and the clinical parameters were quantified at the first (baseline) visit and after four-course induction chemotherapy. Multiple linear regression and logistic analyses were carried out to find the implicit inherent relationships within the patients' data.

Results: The paired Wilcoxon test showed that the ADC values at the baseline visit (ADC) were significantly lower than the values after four-course induction chemotherapy (ADC) (p < 0.001), including different therapeutic responses. The Revised International Staging System (RISS) stage, type of MM, and β2-microglobulin (β2-MG) were predictors of clinically significant increases or decreases in the ADC values (p < 0.05). Multiple linear regression showed that the ADC was negatively associated with β2-MG (p < 0.001) and immunoglobulin heavy chain gene rearrangement (p = 0.012), while the RISS Stage III (p = 0.001), type IgG λ (p = 0.005), and albumin were negatively associated with ADC (p = 0.010). The impacts of the therapeutic response were associated with ADC and immunoglobulin heavy chain gene rearrangement (p < 0.001).

Conclusion: The ADC values of WB-DWI may be associated with clinical parameters of MM including the fluorescence in situ hybridization result, and may be useful in the prognosis of patients with MM.

Trial Registration: ChiCTR2000029587.
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http://dx.doi.org/10.1186/s12880-021-00631-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186136PMC
June 2021

The Abnormal Functional Connectivity in the Locus Coeruleus-Norepinephrine System Associated With Anxiety Symptom in Chronic Insomnia Disorder.

Front Neurosci 2021 21;15:678465. Epub 2021 May 21.

Department of Neurology, The Third Affiliated Hospital of Anhui Medical University, Heifei, China.

Background: Mental syndromes such as anxiety and depression are common comorbidities in patients with chronic insomnia disorder (CID). The locus coeruleus noradrenergic (LC-NE) system is considered to be crucial for modulation of emotion and sleep/wake cycle. LC-NE system is also a critical mediator of the stress-induced anxiety. However, whether the LC-NE system contributes to the underlying mechanism linking insomnia and these comorbidities remain unclear. This study aimed to investigate the LC-NE system alterations in patients with insomnia and its relationship with depression and anxiety symptoms.

Materials And Methods: Seventy patients with CID and 63 matched good sleep control (GSC) subjects were recruited and underwent resting-state functional MRI scan. LC-NE functional network was constructed by using seed-based functional connectivity (FC) analysis. The alterations in LC-NE FC network in patients with CID and their clinical significance was explored.

Results: Compared with GSC group, the CID group showed decreased left LC-NE FC in the left inferior frontal gyrus, while they had increased LC-NE FC in the left supramarginal gyrus and the left middle occipital gyrus (MOG). For the right LC-NE FC network, decreased FC was found in left dorsal anterior cingulate cortex (dACC). Interesting, the increased LC-NE FC was located in sensory cortex, while decreased LC-NE FC was located in frontal control cortex. In addition, the FC between the left LC and left MOG was associated with the duration of the disease, while abnormal FC between right LC and left dACC was associated with the anxiety scores in patients with CID.

Conclusion: The present study found abnormal LC-NE functional network in patients with CID, and the altered LC-NE function in dACC was associated with anxiety symptoms in CID. The present study substantially extended our understanding of the neuropathological basis of CID and provided the potential treatment target for CID patients who also had anxiety.
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http://dx.doi.org/10.3389/fnins.2021.678465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175797PMC
May 2021

A Retrospective Analysis on Clinical Practice-Based Approaches Using Zolpidem and Lorazepam in Disorders of Consciousness.

Brain Sci 2021 May 29;11(6). Epub 2021 May 29.

Department of Physical Medicine and Rehabilitation, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

This is a retrospective study to investigate the results of using zolpidem and lorazepam in persons with disorders of consciousness (DoC) and to provide practical information for clinical application and further studies. The cohort included 146 patients (11 hemorrhagic stroke, 87 traumatic brain injury (TBI), 48 anoxic brain injury (ABI)) admitted to a specialized DoC rehabilitation program. A positive trial indicated a patient responded to either zolpidem or lorazepam with prominent functional improvements necessitating routine use of the medication. Non-responders had equivocal or negative (i.e., went to sleep) responses. Eleven patients with a stroke who had either medication were all non-responders. Of the remaining 135 patients, 95 received at least one medication trial. The overall positive rate was 11.6% (11/95), with 6.3% (5/79) for zolpidem and 14.0% (6/43) for lorazepam. Among TBI patients, the positive rate of the zolpidem trial (10.2%, 5/49) was slightly higher than that of the lorazepam trial (6.9%, 2/29; > 0.05). Among ABI patients, the positive rate of the lorazepam trial (28.6%, 4/14) was significantly higher than that of the zolpidem trial (0%, 0/30; = 0.007). Following a positive trial, most patients were continued on the medications on a regular basis before eventual discontinuation. Our results suggested the etiology of DoC, considering traumatic vs. anoxic injuries, may serve in guiding the clinical application of these medications in the treatment of DoC and in future prospective studies. We advocate for screening all patients with DoC using zolpidem and/or lorazepam.
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http://dx.doi.org/10.3390/brainsci11060726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226545PMC
May 2021

Many Faces of the Hidden Souls: Medical and Neurological Complications and Comorbidities in Disorders of Consciousness.

Brain Sci 2021 May 10;11(5). Epub 2021 May 10.

Department of Physical Medicine and Rehabilitation, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Early and goal-directed management of complications and comorbidities is imperative to facilitate neurorecovery and to optimize outcomes of disorders of consciousness (DoC). This is the first large retrospective cohort study on the primary medical and neurological complications and comorbidities in persons with DoC. A total of 146 patients admitted to a specialized inpatient DoC rehabilitation program from 1 January 2014 to 31 October 2018 were included. The incidences of those conditions since their initial brain injuries were reviewed per documentation. They were categorized into reversible causes of DoC, confounders and mimics, and other medical/neurological conditions. The common complications and comorbidities included pneumonia (73.3%), pain (75.3%), pressure ulcers (70.5%), oral and limb apraxia (67.1%), urinary tract infection (69.2%), and 4-limb spasticity (52.7%). Reversible causes of DoC occurred very commonly. Conditions that may confound the diagnosis of DoC occurred at surprisingly high rates. Conditions that may be a source of pain occurred not infrequently. Among those that may diminish or confound the level of consciousness, 4.8 ± 2.0 conditions were identified per patient. In conclusion, high rates of various complications and comorbidities occurred in persons with DoC. Correcting reversible causes, identifying confounders and mimics, and managing general consequences need to be seriously considered in clinical practice.
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http://dx.doi.org/10.3390/brainsci11050608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151666PMC
May 2021

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-β Associated Neurodegenerative Pathways and Glial Signatures in a Mouse Model of Alzheimer's Disease: A Targeted Transcriptome Analysis.

Front Immunol 2021 11;12:628156. Epub 2021 May 11.

Sanders-Brown Center on Aging, Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States.

Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer's disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 () is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells' inflammatory response. At the same time, myeloid deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.
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http://dx.doi.org/10.3389/fimmu.2021.628156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144303PMC
May 2021

Hybrid Poly(AMPS-CS)-Au Microneedle Arrays to Enrich Metabolites from Skin for Early Disease Diagnosis.

Adv Healthc Mater 2021 May 24:e2100764. Epub 2021 May 24.

School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, P. R. China.

Recently, some metabolites in skin interstitial fluid (SIF) have become emerging re×sources for early disease diagnosis. However, their low level in SIF and difficulty to sampling are the biggest obstacle to further potential application. Here, a swellable microneedle array patch (MNAP) with high mechanical strength is presented, and the rapid enrichment of positively charged metabolites is achieved. The MNAP is fabricated by poly (chondroitin sulfate-acrylamido-2-methylpropane sulfonic acid)-gold nanoparticles (GNPs) composites via a micro-molding. The negatively charged copolymer hydrogel not only enrich positively charged metabolites, but also provide swellable capacity. The in situ synthesis of GNPs in the process of copolymerization make the GNPs cross-link to the hydrogel, which further enhance the MNAP mechanical strength and enrichment efficiency for positively charged metabolites. By using the MNAP, around 5 mg SIF in 10 min from the high fat/cholecalciferol/methimazole-induced atherogenesis rat is extracted and 23 metabolites including 13 quaternary ammonium cationic compounds can be detected and quantified by using a LC-QTOF-MS. Dysregulated L-carnitine and choline metabolism are discovered a week earlier in the SIF than in the serum, achieving early diagnosis of the metabolism syndrome disease. This MNAP also helps users complete home sampling for early disease diagnosis and monitoring.
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http://dx.doi.org/10.1002/adhm.202100764DOI Listing
May 2021

Clinical values of serum NGAL combined with NT-proBNP in the early prognosis of type 1 cardiorenal syndrome.

Am J Transl Res 2021 15;13(4):3363-3368. Epub 2021 Apr 15.

Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University Nanchang, Jiangxi Province, China.

Background: Cardiorenal syndrome (CRS) is a condition that defines disorders of the heart and kidneys whereby "acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other". Early diagnosis of its biomarkers has a significant impact on the treatment and prognosis of the CRS. Elevated serum NGAL and NT-proBNP levels are independent risk factors for predicting heart and kidney disease. Therefore, we proposed early detection of type 1 CRS using serum NGAL in combination with NT-proBNP.

Objective: This study intended to investigate the clinical value of serum NGAL in combination with NT-proBNP in the early diagnosis of type 1 CRS.

Methods: In this paper, 80 patients with type 1 CRS and 80 healthy controls admitted to our hospital from January 2019 to August 2020 were retrospectively included, and the predictive value of single index and combined indices for predicting CRS were judged by calculating the correlation between serum NGAL, NT-proBNP and the creatinine levels and plotting receiver operating characteristic (ROC) curves.

Results: There was no difference in baseline data between the control and patient groups. Serum NGAL and NT-proBNP in the patient group were significantly higher than those in the control group, and were positively correlated with changes in blood creatinine. The ROC curves showed that serum NGAL and NT-proBNP independently had a high predictive value for CRS, and the combination of the two had a better predictive value.

Conclusion: Serum NGAL in combination with NT-proBNP is of high clinical value for the early diagnosis of type 1 CRS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129259PMC
April 2021

Acute inflammatory profiles differ with sex and age after spinal cord injury.

J Neuroinflammation 2021 May 13;18(1):113. Epub 2021 May 13.

Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.

Background: Sex and age are emerging as influential variables that affect spinal cord injury (SCI) recovery. Despite a changing demographic towards older age at the time of SCI, the effects of sex or age on inflammation remain to be elucidated. This study determined the sex- and age-dependency of the innate immune response acutely after SCI.

Methods: Male and female mice of ages 4- and 14-month-old received T9 contusion SCI and the proportion of microglia, monocyte-derived macrophages (MDM), and neutrophils surrounding the lesion were determined at 3- and 7-day post-injury (DPI) using flow cytometry. Cell counts of microglia and MDMs were obtained using immunohistochemistry to verify flow cytometry results at 3-DPI. Microglia and MDMs were separately isolated using fluorescence-activated cell sorting (FACS) at 3-day post-injury (DPI) to assess RNA expression of 27 genes associated with activation, redox, and debris metabolism/clearance.

Results: Flow cytometry revealed that being female and older at the time of injury significantly increased MDMs relative to other phagocytes, specifically increasing the ratio of MDMs to microglia at 3-DPI. Cell counts using immunohistochemistry revealed that male mice have more total microglia within SCI lesions that can account for a lower MDM/microglia ratio. With NanoString analyses of 27 genes, only 1 was differentially expressed between sexes in MDMs; specifically, complement protein C1qa was increased in males. No genes were affected by age in MDMs. Only 2 genes were differentially regulated in microglia between sexes after controlling for false discovery rate, specifically CYBB (NOX2) as a reactive oxygen species (ROS)-associated marker as well as MRC1 (CD206), a gene associated with reparative phenotypes. Both genes were increased in female microglia. No microglial genes were differentially regulated between ages. Differences between microglia and MDMs were found in 26 of 27 genes analyzed, all expressed higher in MDMs with three exceptions. Specifically, C1qa, cPLA2, and CD86 were expressed higher in microglia.

Conclusions: These findings indicate that inflammatory responses to SCI are sex-dependent at both the level of cellular recruitment and gene expression.
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http://dx.doi.org/10.1186/s12974-021-02161-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120918PMC
May 2021

Prognostic value of CCR2 as an immune indicator in lung adenocarcinoma: A study based on tumor-infiltrating immune cell analysis.

Cancer Med 2021 Jun 4;10(12):4150-4163. Epub 2021 May 4.

Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China.

Background: Prognostic indicators in lung adenocarcinoma (LUAD) have been seeking under database analysis, and remarkable advance is on the way.

Methods: This study calculated the scores of stromal and immune components of the tumor microenvironment (TME) in 551 LUAD samples using the ESTIMATE algorithm on The Cancer Genome Atlas (TCGA) database. R package ''limma'' was used to selected differentially expressed genes (DEG). We have analyzed the DEGs by means of Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichments. The protein-protein network, univariate Cox analysis, and Lasso regression analysis were performed to selected survival-related genes. Gene Set Enrichment Analysis (GSEA) represented the enriched pathway of CC chemokine receptor 2 (CCR2). The ratios of immune cells in the TME of each LUAD sample were obtained using the R package "limma" and CIBERSORT algorithm in R 4.0.2.

Results: The ImmuneScore was positively correlated with prognosis regarding survival rate, T classification of TNM stages, and clinicopathological staging characteristics. GO and KEGG enrichments showed DEGs were associated with immune-related activities. Three genes of LUAD were selected from the PPI network and Cox proportional hazards regression analysis. CCR2 was the most survival correlated gene by Lasso regression analysis. GSEA results showed that C2 kegg gene sets in the CCR2 high-expression group were mainly enriched in the B cell or T cell receptor signaling pathway and natural killer cell-mediated cytotoxicity. Correlation of CCR2 expression with prognosis was conducted, implicating a positive correlation with the prognosis of survival rate and M classification, negative correlation with the prognosis of T and N classifications. The correlation between CCR2 and tumor-infiltrating immune cells (TICs) was analyzed, and 14 kinds of TICs were found closely correlated with CCR2 expression through difference analysis.

Conclusion: Therefore, CCR2 has prognostic value as an immune indicator in LUAD.
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http://dx.doi.org/10.1002/cam4.3931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209599PMC
June 2021

Risk factors for urinary retention after urogynecologic surgery: A retrospective cohort study and prediction model.

Neurourol Urodyn 2021 Jun 23;40(5):1182-1191. Epub 2021 Apr 23.

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.

Aims: Postoperative urinary retention (POUR) is a common complication of urogynecological surgery. Our study aimed to identify demographic and perioperative risk factors to construct a prediction model for POUR in urogynecology.

Methods: Our retrospective cohort study reviewed all patients undergoing pelvic reconstructive surgeries at our tertiary care center (Jan 1, 2013-May 1, 2019). Demographic, pre-, intra- and postoperative variables were collected from medical records. The primary outcome, POUR, was defined as (1) early POUR (E-POUR), failing initial trial of void or; (2) late POUR (L-POUR), requiring an indwelling catheter or intermittent catheterization on discharge. Risk factors were identified through univariate and multivariate logistic regression analyses. A clinical prediction model was constructed with the most significant and clinically relevant risk factors.

Results: In 501 women, 182 (36.3%) had E-POUR and 61 of these women (12.2% of the entire cohort) had L-POUR. Multivariate logistic regression revealed preoperative postvoid residual (PVR) over 200 ml (odds ratio [OR]: 3.17; p = 0.026), voiding dysfunction symptoms extracted from validated questionnaires (OR: 3.00; p = 0.030), and number of concomitant procedures (OR: 1.30 per procedure; p = 0.021) as significant predictors of E-POUR; preoperative PVR more than 200 ml (OR: 4.07; p = 0.011) and antiincontinence procedure with (OR: 3.34; p = 0.023) and without (OR: 2.64; p = 0.019) concomitant prolapse repair as significant predictors of L-POUR. A prediction model (area under the curve: 0.70) was developed for E-POUR.

Conclusions: Elevated preoperative PVR is the most significant risk factor for POUR. Alongside other risk factors, our prediction model for POUR can be used for patient counseling and surgical planning in urogynecologic surgery.
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http://dx.doi.org/10.1002/nau.24676DOI Listing
June 2021

Maternal exposure to low doses of bisphenol A affects learning and memory in male rat offspring with abnormal -methyl-d-aspartate receptors in the hippocampus.

Toxicol Ind Health 2021 Jun 21;37(6):303-313. Epub 2021 Apr 21.

Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China.

Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been reported to induce learning and memory deficits. However, the mechanisms have not been fully elucidated. Growing evidence has suggested that -methyl-d-aspartate receptors (NMDARs) are involved in cognitive impairments. In this study, BPA was administered to female Sprague-Dawley rats (six per dose group) at concentrations of 0 (control), 4, 40, and 400 μg/kg·body weight/day from gestation day 1 through lactation day 21. Spatial learning was evaluated using the Morris water maze on postnatal day 22. Expression levels of NMDARs were determined using real-time polymerase chain reaction and Western blot. The results showed that male offspring exposed to BPA exhibited increased latency in reaching the platform and reduced time in the target quadrant, and the number of crossing the platform was less, as compared with the control group. The mRNA and protein expression levels of NMDARs in the hippocampus were significantly downregulated when compared with the control group of male offspring. The data showed that maternal exposure to BPA at low dosage can cause cognitive deficits in male rat offspring, probably due to a decrease in NMDARs in the hippocampus.
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http://dx.doi.org/10.1177/0748233720984624DOI Listing
June 2021

Anti-inflammatory effects of FS48, the first potassium channel inhibitor from the salivary glands of the flea Xenopsylla cheopis.

J Biol Chem 2021 Jan-Jun;296:100670. Epub 2021 Apr 15.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Electronic address:

The voltage-gated potassium (Kv) 1.3 channel plays a crucial role in the immune responsiveness of T-lymphocytes and macrophages, presenting a potential target for treatment of immune- and inflammation related-diseases. FS48, a protein from the rodent flea Xenopsylla cheopis, shares the three disulfide bond feature of scorpion toxins. However, its three-dimensional structure and biological function are still unclear. In the present study, the structure of FS48 was evaluated by circular dichroism and homology modeling. We also described its in vitro ion channel activity using patch clamp recording and investigated its anti-inflammatory activity in LPS-induced Raw 264.7 macrophage cells and carrageenan-induced paw edema in mice. FS48 was found to adopt a common αββ structure and contain an atypical dyad motif. It dose-dependently exhibited the Kv1.3 channel in Raw 264.7 and HEK 293T cells, and its ability to block the channel pore was demonstrated by the kinetics of activation and competition binding with tetraethylammonium. FS48 also downregulated the secretion of proinflammatory molecules NO, IL-1β, TNF-α, and IL-6 by Raw 264.7 cells in a manner dependent on Kv1.3 channel blockage and the subsequent inactivation of the MAPK/NF-κB pathways. Finally, we observed that FS48 inhibited the paw edema formation, tissue myeloperoxidase activity, and inflammatory cell infiltrations in carrageenan-treated mice. We therefore conclude that FS48 identified from the flea saliva is a novel potassium channel inhibitor displaying anti-inflammatory activity. This discovery will promote understanding of the bloodsucking mechanism of the flea and provide a new template molecule for the design of Kv1.3 channel blockers.
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http://dx.doi.org/10.1016/j.jbc.2021.100670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131326PMC
April 2021

Association of HMOX-1 with sporadic Alzheimer's disease in southern Han Chinese.

Eur J Neurol 2021 Apr 17. Epub 2021 Apr 17.

Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.

Background And Purpose: The aim of this study was to discover the associations between HMOX-1 and Alzheimer's disease (AD).

Methods: A total of 500 AD patients and 500 healthy controls were recruited in this study. Polymer chain reaction was used.

Results: There was a statistically significant difference between AD patients and controls in both the dominant and recessive models of HMOX-1 rs2071746 after adjustment for age, gender and education (dominant model: p = 0.047, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.00-1.78, adjusted; recessive model: p = 0.049, OR 1.34, 95% CI 1.00-1.80, adjusted). There was also a trend for an association between the dominant model and late-onset AD after adjustment for age, gender and education (dominant model: p = 0.084, OR 1.37, 95% CI 0.96-1.95, adjusted).

Conclusions: We found an association between the dominant and recessive models of HMOX1 rs2071746 and AD.
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http://dx.doi.org/10.1111/ene.14870DOI Listing
April 2021

Comprehensive Identification and Alternative Splicing of Microexons in .

Front Genet 2021 30;12:642602. Epub 2021 Mar 30.

RNA Institute, State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Science, Wuhan University, Wuhan, China.

Interrupted exons in the pre-mRNA transcripts are ligated together through RNA splicing, which plays a critical role in the regulation of gene expression. Exons with a length ≤ 30 nt are defined as microexons that are unique in identification. However, microexons, especially those shorter than 8 nt, have not been well studied in many organisms due to difficulties in mapping short segments from sequencing reads. Here, we analyzed mRNA-seq data from a variety of samples with a newly developed bioinformatic tool, ce-TopHat. In addition to the Flybase annotated, 465 new microexons were identified. Differentially alternatively spliced (AS) microexons were investigated between the tissues (head, body, and gonad) and genders. Most of the AS microexons were found in the head and two AS microexons were identified in the sex-determination pathway gene .
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http://dx.doi.org/10.3389/fgene.2021.642602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042270PMC
March 2021

Effect of rt-PA intravenous thrombolysis on the prognosis of patients with minor ischemic stroke.

Neurol Res 2021 Apr 13:1-6. Epub 2021 Apr 13.

Department of Neurology, Qi-Lu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Shandong, China.

Aims: The evidence of rt-PA intravenous thrombolysis in patients with minor ischemic stroke (MIS) is still controversial. This study aims to investigate the effect of rt-PA intravenous thrombolysis on the prognosis of patients with MIS.:We continuously enrolled and analyzed patients with MIS admitted into our hospital within 24 h after symptom onset between January 2016 and December 2018, including 96 patients received intravenous thrombolysis within 4.5 h after symptom onset and 84 patients not received intravenous thrombolysis. A favorable long-term outcome was a 90-day mRS score of 0-1. Good short-term outcome was a 7-day NIHSS score of 0 or less than NIHSS onset.: There were no statistical differences between two groups of patients' age, gender, history of hypertension, coronary heart disease, atrial fibrillation, smoking, drinking, and baseline NIHSS score. Patients with history of stroke (22.62% vs. 10.42%, < 0.05) and diabetes (46.43% vs. 22.92%, = 0.01) were higher in group of non-thrombolysis. The difference of NIHSS score after 7 days was statistically different between the two groups ( < 0.05), while there was no significant difference in 90-day mRS score. Logistic regression analysis indicated that the prognosis of patients was correlated with neutrophil ratio and CRP at admission.: Patients with MIS received intravenous thrombolysis may be associated with earlier neurological improvement, but might has no significant effect on long-term prognosis. The level of neutrophil ratio and CRP at admission are risk factors determining the prognosis, which requires further research.
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http://dx.doi.org/10.1080/01616412.2021.1908672DOI Listing
April 2021
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