Publications by authors named "Huimin Yan"

149 Publications

Broad phenotypic alterations and potential dysfunction of lymphocytes in individuals clinically recovered from COVID-19.

J Mol Cell Biol 2021 Mar 5. Epub 2021 Mar 5.

Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells (PBMCs) of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor (HD) cohort. We found that CD8+ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ+), Tc2 (IL-4+), and Tc17 (IL-17A+) cell frequencies. The CD4+ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4+ T cells in the CR cohort showed lower PD-1 expression and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+), and circulating follicular helper T (CXCR5+PD-1+) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM-CD20hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3-HLA-DR- lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B, and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4‒11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that SARS-CoV-2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.
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http://dx.doi.org/10.1093/jmcb/mjab014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989217PMC
March 2021

Characteristics of T-cell responses in COVID-19 patients with prolonged SARS-CoV-2 positivity - a cohort study.

Clin Transl Immunology 2021 4;10(3):e1259. Epub 2021 Mar 4.

Shanghai Public Health Clinical Center Fudan University Shanghai China.

Objective: SARS-CoV-2 has caused a worldwide pandemic of COVID-19. The existence of prolonged SARS-CoV-2 positivity (PP) has further increased the burden on the health system. Since T cells are vital for viral control, we aimed to evaluate the characteristics of T-cell responses associated with PP.

Methods: We established a PP cohort and two age- and sex-matched control cohorts: a regular clinical recovery (CR) cohort and a healthy donor (HD) cohort. The mean time for RNA negativity conversion in the PP cohort was markedly longer than that in the CR cohort (66.2 vs 25.3 days), while the time from illness onset to sampling was not significantly different. T-cell responses in the PP cohort were assayed, analysed and compared with those in the CR and HD cohorts by flow cytometry and ELISpot analysis of peripheral blood mononuclear cells.

Results: Compared with the CR cohort, the proliferation, activation and functional potential of CD8 and CD4 T cells in the PP cohort were not significantly different. However, the frequencies and counts of Teff and Tem in CD8 but not in CD4 T cells of the PP cohort were prominently lower. Moreover, a weaker SARS-CoV-2 N protein-specific IFN-γ T-cell response and a higher frequency of Tregs were detected in the PP cohort.

Conclusion: Suppressed CD8 T-cell differentiation is associated with PP and may be an indicator for the prediction of prolonged SARS-CoV-2 positivity in COVID-19 patients. The association between suppressed CD8 T-cell differentiation and elevated Tregs warrants studies in the future.
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http://dx.doi.org/10.1002/cti2.1259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932004PMC
March 2021

Alterations in Phenotypes and Responses of T Cells Within 6 Months of Recovery from COVID-19: A Cohort Study.

Virol Sin 2021 Feb 9. Epub 2021 Feb 9.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, CAS, Wuhan, 430071, China.

The COVID-19 pandemic, caused by the SARS-CoV-2 infection, is a global health crisis. While many patients have clinically recovered, little is known about long-term alterations in T cell responses of COVID-19 convalescents. In this study, T cell responses in peripheral blood mononuclear cells of a long-time COVID-19 clinically recovered (20-26 weeks) cohort (LCR) were measured via flow cytometry and ELISpot. The T cell responses of LCR were comparatively analyzed against an age and sex matched short-time clinically recovered (4-9 weeks) cohort (SCR) and a healthy donor cohort (HD). All volunteers were recruited from Wuhan Jinyintan Hospital, China. Phenotypic analysis showed that activation marker PD-1 expressing on CD4 T cells of LCR was still significantly lower than that of HD. Functional analysis indicated that frequencies of Tc2, Th2 and Th17 in LCR were comparable to those of HD, but Tc17 was higher than that of HD. In LCR, compared to the HD, there were fewer IFN-γ producing T cells but more IL-2 secreting T cells. In addition, the circulating Tfh cells in LCR were still slightly lower compared to HD, though the subsets composition had recovered. Remarkably, SARS-CoV-2 specific T cell responses in LCR were comparable to that of SCR. Collectively, T cell responses experienced long-term alterations in phenotype and functional potential of LCR cohort. However, after clinical recovery, SARS-CoV-2 specific T cell responses could be sustained at least for six months, which may be helpful in resisting re-infection.
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http://dx.doi.org/10.1007/s12250-021-00348-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871951PMC
February 2021

Corrigendum: Phenotypic, Transcriptomic, and Metabolomic Signatures of Root-Specifically Overexpressed in Rice.

Front Plant Sci 2020 19;11:641990. Epub 2021 Jan 19.

Henan Key Laboratory of Rice Biology, Collaborative Innovation Center of Henan Grain Crops, Henan Agricultural University, Zhengzhou, China.

[This corrects the article DOI: 10.3389/fpls.2020.575304.].
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http://dx.doi.org/10.3389/fpls.2020.641990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851706PMC
January 2021

Phenotypic, Transcriptomic, and Metabolomic Signatures of Root-Specifically Overexpressed in Rice.

Front Plant Sci 2020 23;11:575304. Epub 2020 Nov 23.

Henan Key Laboratory of Rice Biology, Collaborative Innovation Center of Henan Grain Crops, Henan Agricultural University, Zhengzhou, China.

Cytokinins are crucial signaling molecules that regulate plant growth and development. irreversibly degrades nucleobase cytokinins by encoding cytokinin oxidase/dehydrogenase to control grain production in rice. In this study, was specifically overexpressed in roots using promoter to investigate the effects of root-source cytokinins on the growth of rice. overexpressed (OE) rice showed retarded growth with lower cytokinin levels and biomass production. Shoot-specific transcriptome analysis between OE rice and wild type (WT) revealed differentially expressed genes (DEGs) associated with cell division, cell wall structure, phytohormone signaling, and assimilation and catabolism. Metabolome analysis indicated that a majority of differential primary metabolites, such as amino acids and organic acids, increased, while lipids decreased in OE rice. Integration of transcriptomic and metabolomic data showed that several DEGs and differential metabolites were related to glycolysis and tricarboxylic acid cycle (TCA). To conclude, reduced cytokinin levels via root-specific overexpression of resulted in developmental defects, which confirmed the importance of root-source cytokinins in plant growth and morphogenesis.
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http://dx.doi.org/10.3389/fpls.2020.575304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719687PMC
November 2020

China's agricultural GHG emission efficiency: regional disparity and spatial dynamic evolution.

Environ Geochem Health 2020 Oct 29. Epub 2020 Oct 29.

School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen, China.

Improving China's agricultural greenhouse gases (GHG) emission efficiency has become an important way to cope with climate change in an ecologically-and ethically responsible manner. In this paper, we use a global slacks-based inefficiency model to evaluate the agricultural greenhouse gases (GHG) emission efficiency levels in China during 2000-2015. The regional disparity of China's GHG emission efficiency is examined by using a Dagum Gini coefficient. A spatial Markov chain technique is also employed to investigate the spatial dynamic evolution of agricultural GHG emission efficiency. The results show that: (1) China's agricultural GHG emission efficiency increased steadily during the study period; a certain gap in efficiency among provinces and regions also exists. (2) Between-group disparity is the main source of the overall regional disparities in China's agricultural GHG emission efficiency. The disparities between regions are on the rise, while the disparities within regions are relatively stable. (3) China's agricultural GHG emission efficiency demonstrates significant spatial dependence. This study provides policy implications for the sustainable development of China's agricultural sector.
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http://dx.doi.org/10.1007/s10653-020-00744-7DOI Listing
October 2020

TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8 T cells.

Immunology 2020 Dec 12;161(4):325-344. Epub 2020 Oct 12.

Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.

The liver is an immune-privileged organ with a tolerogenic environment for maintaining liver homeostasis. This hepatic tolerance limits the intrahepatic CD8 T-cell response for eliminating infections. The tolerant microenvironment in the liver is orchestrated by liver-specific immunoregulatory cells that can be functionally regulated by pathogen-associated molecular patterns (PAMPs). Here, we report that flagellin, a key PAMP of gut bacteria, modulates the intrahepatic CD8 T-cell response by activating the TLR5 signalling pathway of hepatocytes. We found that mice treated with Salmonella-derived recombinant flagellin (SF) by hydrodynamic injection had a significantly elevated IFN-γ production by the intrahepatic lymphocytes in 7 days after injection. This was correlated with a reduced immune suppressive effect of primary mouse hepatocytes (PMHs) in comparison with that of PMHs from mock-injected control mice. In vitro co-culture of SF-treated PMHs with splenocytes revealed that hepatocyte-induced immune suppression is alleviated through activation of the TLR5 but not the NLRC4 signalling pathway, leading to improved activation and function of CD8 T cells during anti-CD3 stimulation or antigen-specific activation. In an acute HBV replication mouse model established by co-administration of SF together with an HBV-replicating plasmid by hydrodynamic injection, SF significantly enhanced the intrahepatic HBV-specific CD8 T-cell response against HBV surface antigen. Our results clearly showed that flagellin plays a role in modulating the intrahepatic CD8 T-cell response by activating the TLR5 pathway in PMHs, which suggests a potential role for gut bacteria in regulating liver immunity.
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http://dx.doi.org/10.1111/imm.13251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692256PMC
December 2020

Longitudinal Characteristics of T Cell Responses in Asymptomatic SARS-CoV-2 Infection.

Virol Sin 2020 12 21;35(6):838-841. Epub 2020 Aug 21.

Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, 430023, China.

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http://dx.doi.org/10.1007/s12250-020-00277-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441833PMC
December 2020

Clinical research on minimally invasive internal fixation for the treatment of anterior ring injury in tile C pelvic fracture.

Medicine (Baltimore) 2020 Jul;99(30):e20652

Department of Orthopaedic Surgery, Tianjin Hospital, Tianjin, China.

The aim of this study is to explore the clinical outcome and indications in treating anterior ring injury of Tile C pelvic fracture with minimally invasive internal fixation.We retrospectively reviewed 18 patients (aged 25-62, 34.2 ± 7.4) with 26 pelvic anterior ring injuries of Tile C pelvic fracture treated with minimally invasive internal fixation in our hospital were from January 2012 to August 2016. Two cases were pubic symphysis diastasis, 15 were anterior ring fracture (7 were bilateral), and 1 was vertical displacement of pubic symphysis associated with pubic ramus fracture. According to Tile classification, 8, 4, and 6 cases were types C1, C2, and C3, respectively. All patients accepted the operation of pelvic fractures on both rings, while the anterior ring injuries were treated with minimally invasive internal fixation. The period from injury to operation was 5 to 32 days (11.2 ± 3.7). Four patients had pubic symphysis diastasis or pelvic anterior ring fracture medial obturator foramen reduced with modified Pfannenstiel incision and fixed with cannulated screws, 14 patients (22 fractures) had a fractured lateral obturator foramen reduced with modified Pfannenstiel incision associated with small iliac crest incision and fixed with locking reconstruction plates. Clinical data, such as operation time, intraoperative bleeding, Matta standard to assess the reduction quality of fracture, and complications, were collected and analyzed.The operation time ranged from 30 to 65 minutes (42.8 ± 18.7), and the intraoperative bleeding volume was 30 to 150 mL (66.5 ± 22.8). All cases were continuously followed-up for 16 to 42 months (30.2 ± 4.6). All fractures were healed between 3 and 9 months postoperatively (4.9 ± 2.7 months). According to the Matta standard assessment, 18, 7, and 1 cases were excellent, good, and fair, respectively, with a 96.2% (25/26) rate of satisfaction. Neither reduction loss, fixation failure, nor infection occurred; complications included 1 patient with fatal liquefaction, 1 patient had lateral femoral cutaneous nerve injury, and 1 patient complained of discomfort in the inguinal area due to fixation stimulation.Minimally invasive internal fixation for pelvic anterior ring injury in Tile C pelvic fracture has the advantages of less damage, safer manipulation, less complications, and good prognosis.
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http://dx.doi.org/10.1097/MD.0000000000020652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386985PMC
July 2020

Genetic immunization against hepatitis B virus with calcium phosphate nanoparticles in vitro and in vivo.

Acta Biomater 2020 07 25;110:254-265. Epub 2020 Apr 25.

Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Universitaetsstr. 5-7, 45117 Essen, Germany. Electronic address:

Calcium phosphate nanoparticles were loaded with plasmid DNA and toll-like receptor ligands (TLR), i.e. CpG or flagellin, to activate antigen-presenting cells (APCs) like dendritic cells (DCs). The functionalized nanoparticles were studied in vitro on HeLa, C2C12 and BHK-21 cell lines, focusing on the expression of two specific proteins. EGFP-DNA, encoding for enhanced green fluorescent protein (EGFP), was used as a model plasmid to optimize the transfection efficiency in vitro by fluorescence microscopy and flow cytometry. Calcium phosphate nanoparticles loaded with TLR ligands and plasmid DNA encoding for the hepatitis B virus surface antigen (pHBsAg) were evaluated by in vitro and in vivo immunization experiments to identify a possible candidate for a prophylactic hepatitis B virus (HBV) vaccine. The nanoparticles induced a strong expression of HBsAg in the three cell lines. In splenocytes, the expression of the co-stimulatory molecules CD80 and CD86 was enhanced. After intramuscular injection in mice, the nanoparticles induced the expression of HBsAg, the antigen-specific T cell response, and the antigen-specific antibody response (IgG1). STATEMENT OF SIGNIFICANCE: Hepatitis B is one of the most frequent viral infections worldwide. For preventive immunization, nanoparticles can be used which carry both an adjuvant (a stimulatory molecule) and DNA encoding for a viral antigen. After administration of such nanoparticles to cells, they are taken up by cells where the DNA is transcribed into the viral antigen (a protein). This viral antigen is inducing a virus-specific immune response. This was shown both by in vitro cell culture as well as by an extensive in vivo study in mice.
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http://dx.doi.org/10.1016/j.actbio.2020.04.021DOI Listing
July 2020

Aberrant expression of miR-21 in patients with inflammatory bowel disease: A protocol for systematic review and meta analysis.

Medicine (Baltimore) 2020 Apr;99(17):e19693

Department of Laboratory Medicine, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China.

Background: microRNAs have drawn more attention due to their function on the inflammatory process. The association between microRNA-21 (miR-21) expression and risk of inflammatory bowel diseases (IBD) remain inconclusive. This study was aimed to acquire a more exact estimation of this relationship.

Methods: Relevant studies were identified through searching PubMed, Embase, Wanfang, and China National Knowledge Infrastructure database. Pooled standardized mean difference and 95% confidence intervals were calculated using a random-effect model. Publication bias test, sensitivity analysis and subgroup analysis were carried out.

Results: A total of 20 relevant articles comprising 540 patients with ulcerative colitis (UC), 459 patients with Crohn disease (CD) and 511 non-IBD controls were included in this analysis. The expression of miR-21 was significantly increased in colon tissue of both UC and CD patients compared with non-IBD controls. However, there were no significant differences between patients with UC and CD. Moreover, increased miR-21 expression was associated with disease activity status in UC patients, but not in CD patients.

Conclusions: This meta-analysis demonstrates that the higher miR-21 expression in colon tissue is positively associated with the development of UC and CD, and miR-21 might serve as a disease marker of IBD.
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http://dx.doi.org/10.1097/MD.0000000000019693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220677PMC
April 2020

Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma.

Biomed Res Int 2020 14;2020:6527192. Epub 2020 Mar 14.

Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China.

Methods: The percentages of MDSCs, IFN--producing CD4 and CD8 T cells in the peripheral blood of HCC patients, chronic hepatitis B (CHB) patients, and healthy controls (HC) were determined by flow cytometry. The serum concentrations of IL-10 and TNF- were determined by ELISA. The association of the percentages of MDSCs with tumor burden, liver function parameters, systemic inflammation-related indexes, and IFN--producing T cells was assessed.

Results: The percentages of MDSCs and PMN-MDSCs were significantly higher in HCC patients than those in CHB patients and HC. The level of MDSCs was correlated with indirect bilirubin and prealbumin, as well as systemic inflammation response index, monocyte/lymphocyte ratio, and monocyte counts. The frequency of IFN--producing CD8 T cells of HCC patients was lower than that of HC. However, there was no relationship between MDSCs and IFN--producing CD8 T cells. The level of IL-10 in HCC patients was significantly higher than that in CHB patients.

Conclusion: MDSCs seem to play an important role in the process leading from chronic HBV infection to HCC. Early inhibiting these cells could affect tumor progression.
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http://dx.doi.org/10.1155/2020/6527192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097855PMC
December 2020

Immunoglobulin A Targeting on the N-Terminal Moiety of Viral Phosphoprotein Prevents Measles Virus from Evading Interferon-β Signaling.

ACS Infect Dis 2020 05 11;6(5):844-856. Epub 2020 Mar 11.

The Joint Laboratory for Translational Precision Medicine, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, China.

Immunoglobulin A (IgA) can inhibit intracellular viral replication during its transport across the epithelial cells. We find a monoclonal IgA antibody 7F1-IgA against the N-terminal moiety of the phosphoprotein (PNT) of measles virus (MV), which inhibits the intracellular replication of MV in Caco-2 cells but not in interferon-deficient Vero-pIgR cells. Transcytosis of 7F1-IgA across the MV-infected Caco-2 cells enhances the production of interferon-β (IFN-β) and the expression of IFN-stimulated genes, rendering Caco-2 cells with higher antiviral immunity. 7F1-IgA specifically interacts with MV phosphoprotein inside the MV-infected Caco-2 cell and prevents MV phosphoprotein from inhibiting the phosphorylation of JAK1 and STAT1. The intraepithelial interaction between 7F1-IgA and the viral phosphoprotein results in an earlier and stronger phosphorylation of JAK1 and STAT1 and, consequently, a more efficient nuclear translocation of STAT1 for the activation of the type I interferon pathway. Thus, IgA against phosphoprotein prevents a virus from evading type I IFN signaling and confers host epithelial cells efficient innate antiviral immunity, which potentiates a new antiviral target and an antiviral strategy.
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http://dx.doi.org/10.1021/acsinfecdis.9b00427DOI Listing
May 2020

The Characteristics of Intestinal-Barrier Damage in Rats With IgA Nephropathy.

Am J Med Sci 2020 03 30;359(3):168-176. Epub 2019 Nov 30.

Department of Traditional Chinese Medicine, Beijing Children's Hospital, Capital Medical University, Beijing, China; National Center for Children's Health (Beijing), Beijing, China. Electronic address:

Background: Intestinal-barrier damage plays an important pathogenic role in immunoglobulin A nephropathy (IgAN). In this study, we explored the characteristics of the intestinal barrier in rats with IgAN.

Materials And Methods: We randomly divided 17 Sprague Dawley (SD) male rats into a normal control group (NC; n = 9) and an IgAN model group (n = 8). Feces in the distal ileum were taken for intestinal-microbiota 16sDNA sequencing. We also took a segment of terminal ileum to analyze intestinal morphology and to detect mRNA and protein expression of the tight-junction proteins zonula occludens-1 (ZO-1) and occludin (OCLN), as well as of mucin 2 (MUC2). We then measured levels of serum diamine oxidase (DAO) and D-lactic acid (D-LA), the biomarkers of intestinal permeability.

Results: Compared with the NC group, mRNA expression levels of ZO-1 (t = 4.216, P = 0.0007), OCLN (t = 2.413, P = 0.029) and MUC2 (t = 0.859, P < 0.0001) were significantly decreased in the IgAN model group. Protein expression of ZO-1 (t = 7.349, P < 0.0001) and OCLN (t = 6.367, P < 0.0001) was also decreased in the IgAN model group. Conversely, serum DAO (t = 3.758, P = 0.0024) and D-LA (t = 2.246, P = 0.0427) levels increased in this group. At the genus level, the relative abundance of Ruminococcus2 (P = 0.0086) was increased in the IgAN model group.

Conclusions: Decreased expression of ZO-1, OCLN and MUC2, plus intestinal-microbiota dysbiosis, are associated with intestinal-barrier damage in IgAN rats.
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http://dx.doi.org/10.1016/j.amjms.2019.11.011DOI Listing
March 2020

Safety and Efficacy Evaluation of Traditional Chinese Medicine (Qingre-Lishi-Yishen Formula) Based on Treatment of Regular Glucocorticoid Combined with Cyclophosphamide Pulse in Children Suffered from Moderately Severe Henoch-Schonlein Purpura Nephritis with Nephrotic Proteinuria.

Evid Based Complement Alternat Med 2020 27;2020:3920735. Epub 2020 Jan 27.

Department of Traditional Chinese Medicine, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Beijing 100045, China.

Objective: At present, the most appropriate management of Henoch-Schonlein purpura nephritis (HSPN) with nephrotic-range proteinuria still remains controversial; thus, the purpose of this study is to evaluate safety and efficacy of traditional Chinese medicine (TCM), Qingre-Lishi-Yishen Formula (QLYF), integrated with regular oral glucocorticoid and cyclophosphamide intravenous pulse therapeutic regimen in children suffered from moderately severe HSPN with nephrotic proteinuria.

Methods: From 1 January 2012, to 1 January 2016, totally 150 hospitalized children suffered from HSPN with nephrotic proteinuria were included. All were treated with glucocorticoid and cyclophosphamide, and 100 of them were treated with integrative traditional Chinese decoction QLYF. Patients were followed up for 2 years. Rate of adverse event occurrence, short-term clinical effects, long-term clinical effects, and TCM therapeutic evaluation were all compared.

Results: Total adverse event rate was lower in the QLYF group ( = 5.357, = 0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF ( = 0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF ( = 0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF ( = 0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF ( = 0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF ( = 0.022); rates of respiratory infection, urinary infection, poor appetite, hepatotoxity, cardiotoxicity, and neutropenia were all decreased in patients who received QLYF (.

Conclusion: Compared with merely using regular oral glucocorticoid plus cyclophosphamide pulse therapeutic regimen, the therapeutic regimen that integrates QLYF with the abovementioned western medicine might be a safe means to decrease the occurrence rate of adverse events and improve short-term and long-term clinical effects in children who suffered from moderately severe HSPN with nephrotic proteinuria.
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http://dx.doi.org/10.1155/2020/3920735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007748PMC
January 2020

Induction of WNT16 via Peptide-mRNA Nanoparticle-Based Delivery Maintains Cartilage Homeostasis.

Pharmaceutics 2020 Jan 17;12(1). Epub 2020 Jan 17.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Osteoarthritis (OA) is a progressive joint disease that causes significant disability and pain and for which there are limited treatment options. We posit that delivery of anabolic factors that protect and maintain cartilage homeostasis will halt or retard OA progression. We employ a peptide-based nanoplatform to deliver Wingless and the name Int-1 (WNT) 16 messenger RNA (mRNA) to human cartilage explants. The peptide forms a self-assembled nanocomplex of approximately 65 nm in size when incubated with WNT16 mRNA. The complex is further stabilized with hyaluronic acid (HA) for enhanced cellular uptake. Delivery of peptide-WNT16 mRNA nanocomplex to human cartilage explants antagonizes canonical β-catenin/WNT3a signaling, leading to increased lubricin production and decreased chondrocyte apoptosis. This is a proof-of-concept study showing that mRNA can be efficiently delivered to articular cartilage, an avascular tissue that is poorly accessible even when drugs are intra-articularly (IA) administered. The ability to accommodate a wide range of oligonucleotides suggests that this platform may find use in a broad range of clinical applications.
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http://dx.doi.org/10.3390/pharmaceutics12010073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022671PMC
January 2020

The prognostic value of myeloid derived suppressor cell level in hepatocellular carcinoma: A systematic review and meta-analysis.

PLoS One 2019 2;14(12):e0225327. Epub 2019 Dec 2.

Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China.

Background And Aims: Many studies have investigated the association between the level of myeloid derived suppressor cells (MDSCs) and clinical features and prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. This systematic review and meta-analysis was conducted to summarize all available data and estimate the relationship.

Methods: A comprehensive literature review was carried out using Medline, Embase and Web of Science database through December 2018 to identify relevant studies. The standardized mean difference (SMD) and the hazard ratio (HR) with 95% confidence interval (CI) were utilized for evaluating continuous outcomes and survival analysis, respectively. All statistical analyses were performed by STATA 14.0 software.

Results: A total of 13 studies with 1002 HCC patients were included in the meta-analysis. Overall, the proportion of MDSCs in HCC patients was higher than that in healthy controls (SMD = 4.49, 95% CI = 2.53-6.46, P<0.001), and patients with chronic liver disease (SMD = 3.41, 95% CI = 1.58-5.24, P<0.001). Subgroup analysis based on the phenotypes of MDSCs and geographical areas showed similar results. However, the frequency of MDSCs was not affected by the treatment with conventional approaches for HCC (SMD = -0.25, 95% CI = -0.57-0.06, P = 0.119). Moreover, increased MDSCs level was significantly associated with poorer overall survival (HR = 2.36, 95% CI = 1.70-3.29, P<0.001) and recurrence-free survival (HR = 2.72, 95% CI = 1.70-4.35, P<0.001), but not significantly correlated with any clinicopathological parameters.

Conclusion: The results of this systematic review suggest that elevated MDSCs level appears to be associated with an increased risk for disease progression and poor prognosis for HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886785PMC
April 2020

Nanotherapy Targeting NF-κB Attenuates Acute Pain After Joint Injury.

Precis Nanomed 2019 12;2(1):245-248. Epub 2019 Jan 12.

Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Inflammation after joint injury leads to joint responses that result in eventual osteoarthritis development. Blockade of inflammation, by suppressing NF-κB expression, has been shown to reduce joint injury-induced chondrocyte apoptosis and reactive synovitis . Herein, we demonstrate that the suppression of NF-κB p65 expression also significantly mitigates the acute pain sensitivity induced by mechanical injury to the joint. These results suggest that early intervention with anti-NF-κB nanotherapy mitigates both structural and pain-related outcomes, which in turn may impact the progression of post-traumatic osteoarthritis.
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http://dx.doi.org/10.33218/prnano2(1).181129.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824724PMC
January 2019

TLR2 Stimulation Increases Cellular Metabolism in CD8 T Cells and Thereby Enhances CD8 T Cell Activation, Function, and Antiviral Activity.

J Immunol 2019 12 21;203(11):2872-2886. Epub 2019 Oct 21.

Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, 45122 Essen, Germany;

TLR2 serves as a costimulatory molecule on activated T cells. However, it is unknown how the functionality and antiviral activity of CD8 T cells are modulated by direct TLR2 signaling. In this study, we looked at the TLR2-mediated enhancement of TCR-driven CD8 T cell activation in vitro and in woodchuck hepatitis virus transgenic mice. In vitro stimulation of CD8 T cells purified from C57BL/6 mice showed that TLR2 agonist Pam3CSK4 directly enhanced the TCR-dependent CD8 T cell activation. Transcriptome analysis revealed that TLR2 signaling increased expression of bioenergy metabolism-related genes in CD8 T cells, such as IRF4, leading to improved glycolysis and glutaminolysis. This was associated with the upregulation of genes related to immune regulation and functions such as T-bet and IFN-γ. Glycolysis and glutaminolysis were in turn essential for the TLR2-mediated enhancement of T cell activation. Administration of TLR2 agonist Pam3CSK4 promoted the expansion and functionality of vaccine-primed, Ag-specific CD8 T cells in both wild type and transgenic mice and improved viral suppression. Thus, TLR2 could promote CD8 T cell immunity through regulating the energy metabolism.
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http://dx.doi.org/10.4049/jimmunol.1900065DOI Listing
December 2019

Complement activation on neutrophils initiates endothelial adhesion and extravasation.

Mol Immunol 2019 10 19;114:629-642. Epub 2019 Sep 19.

Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; John Cochran VA Medical Center, Saint Louis, MO, USA. Electronic address:

Neutrophils are essential to the pathogenesis of many inflammatory diseases. In the autoantibody-mediated K/BxN model of inflammatory arthritis, the alternative pathway (AP) of complement and Fc gamma receptors (FcγRs) are required for disease development while the classical pathway is dispensable. The reason for this differential requirement is unknown. We show that within minutes of K/BxN serum injection complement activation (CA) is detected on circulating neutrophils, as evidenced by cell surface C3 fragment deposition. CA requires the AP factor B and FcγRs but not C4, implying that engagement of FcγRs by autoantibody or immune complexes directly triggers AP C3 convertase assembly. The absence of C5 does not prevent CA on neutrophils but diminishes the upregulation of adhesion molecules. In vivo two-photon microscopy reveals that CA on neutrophils is critical for neutrophil extravasation and generation of C5a at the site of inflammation. C5a stimulates the release of neutrophil proteases, which contribute to the degradation of VE-cadherin, an adherens junction protein that regulates endothelial barrier integrity. C5a receptor antagonism blocks the extracellular release of neutrophil proteases, suppressing VE-cadherin degradation and neutrophil transendothelial migration in vivo. These results elucidate the AP-dependent intravascular neutrophil-endothelial interactions that initiate the inflammatory cascade in this disease model but may be generalizable to neutrophil extravasation in other inflammatory processes.
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http://dx.doi.org/10.1016/j.molimm.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815348PMC
October 2019

Yunnan Baiyao reduces hospital-acquired pressure ulcers via suppressing virulence gene expression and biofilm formation of .

Int J Med Sci 2019 21;16(8):1078-1088. Epub 2019 Jul 21.

Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China.

Yunnan Baiyao (YB) as a kind of famous Chinese herbal medicine, possessed hemostatic, invigorating the circulation of blood, and anti-inflammatory effects. Identifying strategies to protect patients at risk for hospital-acquired pressure ulcers (HAPU) is essential. Herein, our results showed that YB treatment can effectively reduce the acne wound area and improve efficacy in a comparative study of 60 cases HAPU patients with positive of acne wound pathogens. Furthermore, YB inhibited HIa expression and suppressed accessory gene regulator () system controlled by regulatory RNA II and RNA III molecule using pALC1740, pALC1742 and pALC1743 . strain linked to gfp reporter gene. Moreover, YB downregulated mRNA expression and inhibited coagulase activity by RT-PCR slide and tube coagulase test. Additionally, YB downregulated , , , and -1 mRNA expression to suppress enterotoxin and tsst-1 secretion and adhesion function related genes , , and mRNA expression. Taken together, the data suggest that YB may reduce HAPU via suppressing virulence gene expression and biofilm formation of
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http://dx.doi.org/10.7150/ijms.33723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743274PMC
February 2020

Applications of RNA interference in the treatment of arthritis.

Transl Res 2019 12 10;214:1-16. Epub 2019 Jul 10.

Department of Cardiovascular Sciences, University of South Florida Health Heart Institute, Morsani School of Medicine, Tampa, Florida.

RNA interference (RNAi) is a cellular mechanism for post-transcriptional gene regulation mediated by small interfering RNA (siRNA) and microRNA. siRNA-based therapy holds significant promise for the treatment of a wide-range of arthritic diseases. siRNA selectively suppresses the expression of a gene product and can thus achieve the specificity that is lacking in small molecule inhibitors. The potential use of siRNA-based therapy in arthritis, however, has not progressed to clinical trials despite ample evidence for efficacy in preclinical studies. One of the main challenges to clinical translation is the lack of a suitable delivery vehicle to efficiently and safely access diverse pathologies. Moreover, the ideal targets in treatment of arthritides remain elusive given the complexity and heterogeneity of these disease pathogeneses. Herein, we review recent preclinical studies that use RNAi-based drug delivery systems to mitigate inflammation in models of rheumatoid arthritis and osteoarthritis. We discuss a self-assembling peptide-based nanostructure that demonstrates the potential of overcoming many of the critical barriers preventing the translation of this technology to the clinic.
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http://dx.doi.org/10.1016/j.trsl.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848781PMC
December 2019

Interleukin-12 and -23 blockade mitigates elastase-induced abdominal aortic aneurysm.

Sci Rep 2019 07 18;9(1):10447. Epub 2019 Jul 18.

John Cochran VA Medical Center, Saint Louis, Missouri, USA.

Macrophages play an important role in the inflammatory process that contributes to the development of abdominal aortic aneurysm (AAA). Studies of human and mouse AAA tissue reveal expanded populations of macrophages producing an abundance of pro-inflammatory cytokines, including TNF-α, IL-12p40 and high level of metalloprotease 9 (MMP-9) at the late stages of disease. Herein, we show that blockade of IL-12p40 in the early phase of aneurysm development suppresses macrophage expansion, inflammatory cytokine and MMP-9 production and mitigates AAA development. Since IL-12 and IL-23 are related cytokines that share the common p40 subunit, we also evaluate the effect of direct IL-23 blockade on the development of AAA. Specific IL-23p19 blockade prevents AAA progression with the same efficiency as IL-12p40 antagonism, suggesting that the efficacy of anti-IL-12p40 treatment may reflect IL-23 blockade. IL-12p40 and IL-23p19 are also abundantly expressed in human AAA tissue. Our findings have potential translational value since IL-12p40 and IL-23p19 antagonists already exist as FDA-approved therapeutics for various chronic inflammatory conditions.
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http://dx.doi.org/10.1038/s41598-019-46909-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639297PMC
July 2019

Assessing capreomycin resistance on tlyA deficient and point mutation (G695A) Mycobacterium tuberculosis strains using multi-omics analysis.

Int J Med Microbiol 2019 Nov 24;309(7):151323. Epub 2019 Jun 24.

Center for Tuberculosis Control of Guangdong Province, Key Laboratory of Translational Medicine of Guangdong, Guangzhou 510630, China; Jinan University, Guangzhou 510632, China. Electronic address:

Capreomycin (CAP), a cyclic peptide antibiotic, is considered to be an ideal second-line drug for tuberculosis (TB). However, in the past few years, the emergence of more CAP-resistant (CAP) TB patients has limited its use. Although it has been reported that CAP resistance to Mycobacterium tuberculosis (Mtb) is associated with rrs or tlyA mutation, the exact mechanism of CAP Mtb strains, especially the mechanism associated with tlyA deficient or mutation, is not fully understood. Herein, we utilized a multi-omics (genome, proteome, and metabolome) approach to assess CAP resistance on tlyA deficient CAP Mtb strains (CAP1) and tlyA point mutation CAP Mtb strains (CAP2) that we established for the first time in vitro to investigate the CAP-resistant mechanism. Our results showed that the CAP1 strains (> 40 μg/ml) was more resistant to CAP than the CAP2 strains (G695A, 10 μg/ml). Furthermore, multi-omics analysis indicated that the CAP1 strains exhibited greater drug tolerance than the CAP2 strains may be associated with the weakening of S-adenosyl-L-methionine-dependent methyltransferase (AdoMet-MT) activity and abnormal membrane lipid metabolism such as suppression of fatty acid metabolism, promotion of glycolipid phospholipid and glycerolipid metabolism. As a result, these studies reveal a new mechanism for CAP resistance to tlyA deficient or mutation Mtb strains, and may be helpful in developing new therapeutic approaches to prevent Mtb resistance to CAP.
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http://dx.doi.org/10.1016/j.ijmm.2019.06.003DOI Listing
November 2019

Activation of the TLR signaling pathway in CD8+ T cells counteracts liver endothelial cell-induced T cell tolerance.

Cell Mol Immunol 2019 09 26;16(9):774-776. Epub 2019 Jun 26.

Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.

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http://dx.doi.org/10.1038/s41423-019-0255-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804679PMC
September 2019

Advantages and Limitations of Integrated Flagellin Adjuvants for HIV-Based Nanoparticle B-Cell Vaccines.

Pharmaceutics 2019 May 1;11(5). Epub 2019 May 1.

Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.

The great advantage of virus-like particle (VLP) nano-vaccines is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter viral proteins in their natural conformation. "Wild-type" viral nanoparticles can be further genetically or biochemically functionalized with biomolecules (antigens and adjuvants). Flagellin is a potent inducer of innate immunity and it has demonstrated adjuvant effectiveness due to its affinity for toll-like receptor 5 (TLR5). In contrast to most TLR ligands, flagellin is a protein and can induce an immune response against itself. To avoid side-effects, we incorporated a less inflammatory and less immunogenic form of flagellin as an adjuvant into HIV-based nanoparticle B-cell-targeting vaccines that display either the HIV-1 envelope protein (Env) or a model antigen, hen egg lysozyme (HEL). While flagellin significantly enhanced HEL-specific IgG responses, anti-Env antibody responses were suppressed. We demonstrated that flagellin did not activate B-cells directly in vitro, but might compete for CD4+ T-cell help in vivo. Therefore, we hypothesize that in the context of VLP-based B-cell nano-vaccines, flagellin serves as an antigen itself and may outcompete a less immunogenic antigen with its antibody response. In contrast, in combination with a strong immunogen, the adjuvant activity of flagellin may dominate over its immunogenicity.
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http://dx.doi.org/10.3390/pharmaceutics11050204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572692PMC
May 2019

New lignans, sesquiterpenes and other constituents from twigs and leaves of Rhododendron micranthum.

Fitoterapia 2019 Jun 25;135:15-21. Epub 2019 Mar 25.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address:

Rhododendron micranthum is used traditionally as a remedy for the treatment of chronic bronchitis in China. To clarify the chemical basis and provide a reference for the rational use of this medicinal plant, a phytochemical study was carried out on the twigs and leaves of R. micranthum, which afforded eight new compounds (1-8) and eight known compounds (9-16). Their structures were rigorously determined by comprehensive HRESIMS, NMR and electronic circular dichroism (ECD) analyses. The anti-inflammatory activities of these compounds were evaluated. Compounds 3, 13, and 14 suppressed the transcription of the NF-κB-dependent reporter gene in LPS-induced 293T/NF-κB-luc cells at 10 μM, while no effect on cell viability was observed.
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http://dx.doi.org/10.1016/j.fitote.2019.03.025DOI Listing
June 2019

Effect of acute maximal exercise on vasodilatory function and arterial stiffness in African-American and white adults.

J Hypertens 2019 06;37(6):1262-1268

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.

Introduction: African-Americans are at increased risk of cardiovascular disease compared with their white counterparts, potentially due to greater arterial stiffness and reduced vasodilatory capacity. Racial differences also exist in arterial stiffness and blood pressure (BP) following maximal aerobic exercise; African-Americans do not exhibit central post exercise BP reductions. Whether impaired vasodilatory function contributes to the lack of BP response is unknown.

Purpose: To evaluate vasodilatory function, arterial stiffness, and hemodynamics following a maximal aerobic exercise test in young, healthy African-American and white adults.

Methods: Twenty-seven African-American and 35 white adults completed measures at baseline, 15 and 30 min after a maximal exercise test. Measures included vasodilatory capacity of forearm resistance arteries, central pulse wave velocity (PWV), and carotid artery stiffness (β).

Results: Forearm reactive hyperemia was greater in white but increased similarly following exercise in both groups (P < 0.05). Carotid β-stiffness increased at 15 and 30 min (P = 0.03) in both groups, but PWV controlled for mean arterial pressure decreased after maximal exercise (P = 0.03). White exhibited reductions in systolic and mean pressure, whereas no changes were seen for African-Americans (interaction effects: P < 0.05).

Conclusion: African-American and white adults had similar decreases in PWV, increases in β-stiffness, and increases in vasodilatory function following maximal exercise. African-American adults, however, did not display reductions in BP and had overall lower vasodilatory function in comparison with white adults. Our results suggest African-Americans exhibit similar vasodilatory function changes following aerobic exercise as their white counterparts, and therefore vasodilatory function likely does not explain the lack of BP response in African-Americans.
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http://dx.doi.org/10.1097/HJH.0000000000002049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524539PMC
June 2019

Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains.

Emerg Microbes Infect 2019 ;8(1):248-261

a Center for Tuberculosis Control of Guangdong Province , Guangzhou , People's Republic of China.

p-Aminosalicylic acid (PAS) is an important second-line antibiotic for treating multidrug-resistant tuberculosis (MDR-TB). Due to gastrointestinal disturbance and intolerance, its potent and efficacy in the treatment of extensively drug-resistant (XDR)-TB commonly are poor. Thus, it is important to reveal the mechanism of susceptibility and resistance of Mycobacterium tuberculosis (Mtb) to this drug. Herein, we screened and established PAS-resistant (PAS) folC mutated and un-mutated Mtb strains, then utilized a multi-omics (genome, proteome, and metabolome) analysis to better characterize the mechanisms of PAS resistance in Mtb. Interestingly, we found that promotion of SAM-dependent methyltransferases and suppression of PAS uptake via inhibiting some drug transport associated membrane proteins were two key pathways for the folC mutated strain evolving into the PAS Mtb strain. However, the folC un-mutated strain was resistant to PAS via uptake of exogenous methionine, mitigating the role of inhibitors, and promoting DfrA, ThyA and FolC expression. Beyond these findings, we also found PAS resistance in Mtb might be associated with the increasing phenylalanine metabolism pathway. Collectively, our findings uncovered the differences of resistant mechanism between folC mutated and un-mutated Mtb strains resistant to PAS using multi-omics analysis and targeting modulators to these pathways may be effective for treatment of PAS Mtb strains.
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http://dx.doi.org/10.1080/22221751.2019.1568179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455211PMC
July 2019

The Effect of Entecavir Therapy on Immune Status in Chronic Hepatitis B Patients.

Iran J Immunol 2019 Mar;16(1):84-91

Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China.

Background: Entecavir (ETV) is an antiviral medication effective in suppressing hepatitis B virus (HBV) replication and improving liver function. However, the relationship between antiviral effect and immune modulation after ETV therapy is not clearly understood.

Objective: The objective of this study is to investigate the immunoregulatory effect of ETV treatment in patients with chronic hepatitis B (CHB).

Methods: The frequencies of immune cells, including IFN-γ-producing CD4+ and CD8+ T cells, Th9 cells, regulatory T (Treg) cells, and myeloid-derived suppressor cells (MDSC) were determined in the peripheral blood from treatment-naïve and ETV-treated CHB patients. The plasma levels of IL-10, TGF-β, IL-9, TNF-α, IFN-γ, and Arg-1 were measured using enzyme-linked immunosorbent assay.

Results: The results showed that ETV treatment significantly reduced the levels of liver function indices as well as HBV DNA loads in CHB patients. However, no significant difference in the immune cells percentage was found between the treatment-naïve and ETV-treated patients. Additionally, ETV treatment did not influence the production of TGF-β, IL-9, Arg-1, IFN-γ, and TNF-α. In contrast, the level of IL-10 was remarkably reduced after ETV therapy.

Conclusion: IL-10 was a more sensitive effector to ETV-induced inhibition of HBV replication in chronic HBV patients.
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http://dx.doi.org/10.22034/IJI.2019.39409DOI Listing
March 2019