Publications by authors named "Lili Huang"

388 Publications

Platelet Function Tests Predicting the Efficacy and Safety of Aspirin Secondary Prevention.

Neurol Res 2021 Sep 28:1-8. Epub 2021 Sep 28.

Department of Neurology, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China.

Objective: To precisely prevent stroke, we evaluated three platelet function tests and their associations with clinical outcomes in ischemic stroke patients.

Methods: On-treatment platelet reactivity of acute minor stroke patients taking aspirin plus clopidogrel was tested by light transmittance aggregometry (LTA), thromboelastography (TEG) and platelet function analyzer (PFA). Mann-Whitney U tests and receiver operating characteristic (ROC) curve analysis were used to assess their associations with recurrent events and clinical outcome prediction.

Results: 127 acute minor stroke patients were stringently selected and followed for 13 months. Eight patients (6.3%) self-reported the recurrence and 13 (10.2%) patients self-reported bleeding. Recurrent patients displayed significantly higher on-treatment platelet reactivity when measured with LTA ( = 0.030) and PFA ( < 0.001). Further ROC analysis demonstrated that LTA and PFA had modest-to-fair ability to predict stroke recurrence (LTA: area under the curve [AUC], 0.765; 95% CI, 0.584-0.945, PFA: AUC, 0.832; 95% CI, 0.658-1.000). However, TEG (measured by the platelet inhibition rate) could not detect the difference between recurrent patients and non-recurrent patients ( = 0.515) and predict recurrent events (AUC, 0.569; 95% CI, 0.368-0.770). None of the tests were associated with bleeding except for PFA ( < 0.001), with AUC of PFA reaching 0.772 (0.726-0.818).

Conclusions: Of the three tests assessed, the predictive accuracies of PFA and LTA were satisfying for aspirin secondary prevention, while TEG's performance was poor. Only PFA could provide accurate prognostic information for bleeding.
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http://dx.doi.org/10.1080/01616412.2021.1981103DOI Listing
September 2021

Measurement of the Total Lung Volume Using an Adjusted Single-Breath Helium Dilution Method in Patients With Obstructive Lung Disease.

Front Med (Lausanne) 2021 8;8:737360. Epub 2021 Sep 8.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Whole-body plethysmography (WBP) is the gold standard for measuring lung volume, but its clinical application is limited as it requires expensive equipment and is not simple to use. Studies have shown that the single-breath helium dilution (SBHD) method, which is commonly used in clinical practice, significantly underestimates lung volume in patients with obstructive lung disease (OLD). By comparing the differences in lung volume measured using SBHD and WBP, we aimed to establish a correction equation for the SBHD method to determine the total lung volume in patients with OLD of different severities. From 628 patients with OLD simultaneously subjected to SBHD and WBP, 407 patients enrolled between January 2018 and November 2019 were in the training group and 221 enrolled between December 2019 and December 2020 were in the prospective verification cohort. The multiple linear regression equation was used for data in the training group to establish a correction equation for SBHD to determine the total lung volume, and this was validated in the prospective validation cohort. There was a moderate positive correlation between total lung capacity (TLC) determined using the SBHD [TLC (SBHD)] and WBP methods [TLC (WBP)] (r = 0.701; < 0.05), and the differences between TLC (SBHD) and TLC (WBP) (ΔTLC) were related to the severity of obstruction. As the severity of obstruction increased, the TLC was underestimated by the SBHD method. We established the following correction equation: () () = -0.669 + 0.756*()() - 0.047* +0.039* ()-0.009*()(r2 = 0.753 and adjusted r2 = 0.751). Next, we validated this equation in the validation cohort. With the correction equation, no statistical difference was observed between TLC (adjusted SBHD) and TLC (WBP) among the obstruction degree groups ( > 0.05). The SBHD method is correlated with WBP to measure the total lung volume, but the SBHD method presents limitations in determining the total lung volume in patients with obstructive lung disease. Here, we established an effective and reliable correction equation in order to accurately assess the total lung volume of patients with OLD using the SBHD method.
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http://dx.doi.org/10.3389/fmed.2021.737360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455942PMC
September 2021

Predictive Value of Eosinophil Count on COVID-19 Disease Progression and Outcomes, a Retrospective Study of Leishenshan Hospital in Wuhan, China.

J Intensive Care Med 2021 Sep 22:8850666211037326. Epub 2021 Sep 22.

Renji Hospital, 71140Shanghai Jiaotong University, Shanghai, China.

Background: The potential protective role of eosinophils in the COVID-19 pandemic has aroused great interest, given their potential virus clearance function and the infection resistance of asthma patients to this coronavirus. However, it is unknown whether eosinophil counts could serve as a predictor of the severity of COVID-19.

Methods: A total of 1004 patients with confirmed COVID-19 who were admitted to Leishenshan Hospital in Wuhan, China, were enrolled in this study, including 905 patients in the general ward and 99 patients in the intensive care unit (ICU). We reviewed their medical data to analyze the association between eosinophils and ICU admission and death.

Results: Of our 1004 patients with COVID-19, low eosinophil counts/ratios were observed in severe cases. After adjusting for confounders that could have affected the outcome, we found that eosinophil counts might not be a predictor of ICU admission. In 99 ICU patients, 58 of whom survived and 41 of whom died, low eosinophil level was an indicator of death in severe COVID-19 patients with a cutoff value of 0.04 × 10/L, which had an area under the curve of 0.665 (95% CI = 1.089-17.839;  = .045) with sensitivity and specificity of 0.569 and 0.7317, respectively.

Conclusion: Our research revealed that a low eosinophil level is a predictor of death in ICU patients rather than a cause of ICU admission.
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http://dx.doi.org/10.1177/08850666211037326DOI Listing
September 2021

Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy.

Oxid Med Cell Longev 2021 7;2021:8532940. Epub 2021 Sep 7.

Municipal Hospital Affiliated to Taizhou University, Taizhou 318000, China.

Accumulating evidence shows that elevated levels of reactive oxygen species (ROS) are associated with cancer initiation, growth, and response to therapies. As concentrations increase, ROS influence cancer development in a paradoxical way, either triggering tumorigenesis and supporting the proliferation of cancer cells at moderate levels of ROS or causing cancer cell death at high levels of ROS. Thus, ROS can be considered an attractive target for therapy of cancer and two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to treat cancer. Despite tremendous resources being invested in prevention and treatment for cancer, cancer remains a leading cause of human deaths and brings a heavy burden to humans worldwide. Chemotherapy remains the key treatment for cancer therapy, but it produces harmful side effects. Meanwhile, the process of de novo development of new anticancer drugs generally needs increasing cost, long development cycle, and high risk of failure. The use of ROS-based repurposed drugs may be one of the promising ways to overcome current cancer treatment challenges. In this review, we briefly introduce the source and regulation of ROS and then focus on the status of repurposed drugs based on ROS regulation for cancer therapy and propose the challenges and direction of ROS-mediated cancer treatment.
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http://dx.doi.org/10.1155/2021/8532940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443364PMC
September 2021

Safety and immunogenicity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger than 18 years: a randomised, double-blind, controlled, phase 1/2 trial.

Lancet Infect Dis 2021 Sep 15. Epub 2021 Sep 15.

Beijing Institute of Biological Products, Beijing, China.

Background: Although SARS-CoV-2 infection often causes milder symptoms in children and adolescents, young people might still play a key part in SARS-CoV-2 transmission. An efficacious vaccine for children and adolescents could therefore assist pandemic control. For further evaluation of the inactivated COVID-19 vaccine candidate BBIBP-CorV, we assessed the safety and immunogenicity of BBIBP-CorV in participants aged 3-17 years.

Methods: A randomised, double-blind, controlled, phase 1/2 trial was done at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan, China. In phases 1 and 2, healthy participants were stratified according to age (3-5 years, 6-12 years, or 13-17 years) and dose group. Individuals with a history of SARS-CoV-2 or SARS-CoV infection were excluded. All participants were randomly assigned, using stratified block randomisation (block size eight), to receive three doses of 2 μg, 4 μg, or 8 μg of vaccine or control (1:1:1:1) 28 days apart. The primary outcome, safety, was analysed in the safety set, which consisted of participants who had received at least one vaccination after being randomly assigned, and had any safety evaluation information. The secondary outcomes were geometric meant titre (GMT) of the neutralising antibody against infectious SARS-CoV-2 and were analysed based on the full analysis set. This study is registered with www.chictr.org.cn, ChiCTR2000032459, and is ongoing.

Findings: Between Aug 14, 2020, and Sept 24, 2020, 445 participants were screened, and 288 eligible participants were randomly assigned to vaccine (n=216, 24 for each dose level [2/4/8 μg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=72, 24 for each age cohort [3-5, 6-12, and 13-17 years]) in phase 1. In phase 2, 810 participants were screened and 720 eligible participants were randomly assigned and allocated to vaccine (n=540, 60 for each dose level [2/4/8 μg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=180, 60 for each age cohort [3-5, 6-12, and 13-17 years]). The most common injection site adverse reaction was pain (ten [4%] 251 participants in all vaccination groups of the 3-5 years cohort; 23 [9·1%] of 252 participants in all vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 20 [7·9%] of 252 participants in all vaccination groups of the 13-17 years cohort). The most common systematic adverse reaction was fever (32 [12·7%] of 251 participants in all vaccination groups and six [7·1%] of 84 participants in the control group of the 3-5 years cohort; 13 [5·2%] of 252 participants in the vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 26 [10·3%] of 252 participants in all vaccination groups and eight [9·5%] of 84 in the control group of the 13-17 years cohort). Adverse reactions were mostly mild to moderate in severity. The neutralising antibody GMT against the SARS-CoV-2 virus ranged from 105·3 to 180·2 in the 3-5 years cohort, 84·1 to 168·6 in the 6-12 years cohort, and 88·0 to 155·7 in the 13-17 years cohort on day 28 after the second vaccination; and ranged from 143·5 to 224·4 in the 3-5 years cohort, 127 to 184·8 in the 6-12 years cohort, and 150·7 to 199 in the 13-17 years cohort on day 28 after the third vaccination.

Interpretation: The inactivated COVID-19 vaccine BBIBP-CorV is safe and well tolerated at all tested dose levels in participants aged 3-17 years. BBIBP-CorV also elicited robust humoral responses against SARS-CoV-2 infection after two doses. Our findings support the use of a 4 μg dose and two-shot regimen BBIBP-CorV in phase 3 trials in the population younger than 18 years to further ascertain its safety and protection efficacy against COVID-19.

Funding: National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1473-3099(21)00462-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443232PMC
September 2021

Smart Tumor-Cell-Derived Microparticles Provide On-Demand Photosensitizer Synthesis and Hypoxia Relief for Photodynamic Therapy.

Angew Chem Int Ed Engl 2021 Sep 16. Epub 2021 Sep 16.

Beijing Institute of Technology, School of Life science, south 5 zhongguancun street, 100081, Beijing, CHINA.

Positioning essential elements of photodynamic therapy (PDT) to mitochondria can conquer the rigorously spatiotemporal limitation of reactive oxygen species (ROS) transfer and make considerable differences in PDT. However, precise accumulation of  photosensitizer (PS) and oxygen within mitochondria is still challenging. Here, Hexyl 5-aminolevulinate hydrochloride (HAL) and 3-bromopyruvic acid (3BP) are simultaneously encapsulated into microparticles collected from X-ray irradiated tumor cells (X-MP). After systemic administration, the developed HAL/[email protected] can specifically target and recognize tumor cells, where HAL induces the efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway; meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co-localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.
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http://dx.doi.org/10.1002/anie.202109258DOI Listing
September 2021

LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity.

Front Endocrinol (Lausanne) 2021 24;12:717544. Epub 2021 Aug 24.

School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin's effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin's activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2's anti-obesity potential. In this review, we will analyze LEAP-2's effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2's potential as a promising therapeutic target for obesity.
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http://dx.doi.org/10.3389/fendo.2021.717544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428150PMC
August 2021

Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models.

Neurobiol Dis 2021 Nov 31;159:105492. Epub 2021 Aug 31.

AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen 67061, Germany. Electronic address:

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.nbd.2021.105492DOI Listing
November 2021

Maternal and fetal metabolomic alterations in maternal lipopolysaccharide exposure-induced male offspring glucose metabolism disorders.

Biomed Chromatogr 2021 Sep 3:e5234. Epub 2021 Sep 3.

School of Nursing, Anhui Medical University, Hefei, China.

Maternal lipopolysaccharide (LPS) exposure during pregnancy induces metabolic abnormalities in male offspring, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of maternal LPS exposure during pregnancy on metabolic profiling of maternal serum and male fetal liver using Liquid Chromatograph Mass Spectrometer techniques. From day 15 to day 17 of gestation, pregnant mice were administered intraperitoneal LPS (experimental group) (50 μg/kg/d) or saline (control group). On day 18 of gestation, maternal serum and male fetal liver were collected. After LPS exposure, levels of 38 and 75 metabolites, mainly glycerophospholipid and fatty acid metabolites, were altered in maternal serum and male fetal liver, respectively. It was found that in maternal serum and male fetal livers, the glycerophospholipids containing saturated fatty acids (SFAs) and the SFAs were upregulated, while the glycerophospholipids containing polyunsaturated fatty acids (PUFAs) and the PUFAs were downregulated. This concordance between maternal and fetal alterations in glycerophospholipid and fatty acid metabolites may be a metabolomic signature of the early intrauterine period and may provide insight into the mechanisms by which maternal LPS exposure induces disorders of glucose metabolism in male offspring.
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http://dx.doi.org/10.1002/bmc.5234DOI Listing
September 2021

The molecular and cellular insight into the toxicology of bortezomib-induced peripheral neuropathy.

Biomed Pharmacother 2021 Oct 24;142:112068. Epub 2021 Aug 24.

Department of Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

The proteasome inhibitor bortezomib (BTZ) is a first-line antitumor drug, mainly used for multiple myeloma treatment. However, BTZ shows prominent toxicity in the peripheral nervous system, termed BTZ-induced peripheral neuropathy (BIPN). BIPN is characterized by neuropathic pain, resulting in a dose reduction or even treatment withdrawal. To date, the pathological mechanism of BIPN has not been elucidated. There is still no effective strategy to prevent or treat BIPN. This review summarizes the pathological mechanisms of BIPN, which involves the pathological changes of Schwann cells, neurons, astrocytes and macrophages. A better knowledge of the pathological mechanisms of BIPN would provide new ideas for therapeutic interventions of BIPN patients.
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http://dx.doi.org/10.1016/j.biopha.2021.112068DOI Listing
October 2021

Evaluation of the role of soluble B7-H3 in association with membrane B7-H3 expression in gastric adenocarcinoma.

Cancer Biomark 2021 Aug 20. Epub 2021 Aug 20.

Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

Background And Objective: Gastric adenocarcinoma (GAC) is one of the most common malignancies. Increasing data have indicated a correlation between soluble B7-H3 (sB7-H3) levels and tumor malignancies. In this study, we aim to investigate the level of soluble B7-H3 in serum of GAC patients. Further, we analyze the correlation between sB7-H3 level and tissue B7-H3 expression and explore the clinical evaluation value of sB7-H3 associated with pathological characteristics and prognosis of GAC patients.

Methods: One hundred and twenty-eight serum and tissue samples of GAC 20 serum and tissue samples of gastritis patients and 77 serum, 5 tissue samples of healthy controls were collected. The serum levels of sB7-H3 were detected by Enzyme-linked immunosorbent assay (ELISA), while the expression of membrane B7-H3 (mB7-H3) and Ki67 were evaluated by immunohistochemistry. The correlation between sB7-H3 and mB7-H3, sB7-H3 and Ki67, sB7-H3 or mB7-H3 and clinical features were analyzed by Pearson's Chi-square test.

Results: Both serum level of sB7-H3 and tissue B7-H3 of GAC patients were significantly higher than those of gastritis patients and healthy controls. sB7-H3 level was correlated with total B7-H3 expression in tissues (r= 0.2801, P= 0.0014). Notably, the concentration of sB7-H3 was correlated with its expression of membrane form in tumor cells (r= 0.3251, P= 0.002) while not in stromal cells (r= 0.07676, P= 0.3891). Moreover, the levels of sB7-H3 in patients with TNM stage III/IV or with Infiltration depth T3/T4 or with lymph node metastasis were significantly higher than those of patients with TNM stage I/II (P= 0.0020) or with Infiltration depth T1/T2 (P= 0.0169) or with no lymph node metastasis (P= 0.0086). Tumor B7-H3 score, but not stromal B7-H3 score, in patients with TNM stage III/IV or with lymph node metastasis was significantly higher than those with TNM stage I/II (P= 0.0150) or with no lymph node metastasis (P= 0.182).

Conclusions: Soluble B7-H3 level may reflect the tissue B7-H3 expression on tumor cells of GAC tissues. Elevated level of sB7-H3 in serum suggests poor clinical pathological characteristics of GAC patients.
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http://dx.doi.org/10.3233/CBM-210178DOI Listing
August 2021

Prognostic and pathogenic role of CXC Motif Ligand 16 in sepsis.

Microbes Infect 2021 Aug 25:104882. Epub 2021 Aug 25.

The Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address:

Chemokine CXC motif ligand 16 (CXCL16) is an important mediator that has been shown to participate in various human diseases. The role of CXCL16 in the immunopathology of sepsis remains unidentified. In this study, we found that human patients with sepsis had significantly higher soluble levels of serum CXCL16 than healthy volunteers on day of intensive care unit (ICU) admission. Soluble CXCL16 remained significantly up-regulated in the patients with sepsis, which correlated with disease severity. Furthermore, nonsurvivors displayed significantly higher admission levels of soluble CXCL16 compared with survivors of septic patients. Soluble CXCL16 levels revealed significant prognostic value for 28-day mortality, and CXCL16 was shown to be an independent predictor of 28-day mortality in the patients with sepsis. In a murine model of cecal ligation and puncture (CLP)-induced nonsevere sepsis, supplementation of recombinant CXCL16 protein could increase sepsis-induced mortality and tissue injury. Conversely, neutralizing CXCL16 by anti-CXCL16 monoclonal antibody could decrease mortality and tissue injury in CLP-induced severe sepsis. However, CXCL16 did not affect the ability of these mice to clear bacteria in CLP. Taken together, CXCL16 could be related to sepsis not only as a novel biomarker of prognosis, but also as a potential target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.micinf.2021.104882DOI Listing
August 2021

Diagnosis Accuracy of Lung Ultrasound for ARF in Critically Ill Patients: A Systematic Review and Meta-Analysis.

Front Med (Lausanne) 2021 10;8:705960. Epub 2021 Aug 10.

Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China.

Acute respiratory failure (ARF) is a commonly distressing condition in critically ill patients. Its early recognition and treatment may improve clinical outcomes. Mounting evidence suggests that lung ultrasound (LUS) could be an alternative to chest X-ray (CXR) or computed tomography (CT) for the diagnosis of ARF in critically ill patients. This meta-analysis aimed to determine whether LUS can be an alternative tool used to investigate the cause of ARF or thoracic pathologies associated with the diagnosis of ARF in critically ill patients. A systematic literature search of the PubMed, Web of Science, Embase, and Cochrane Library databases was conducted from inception to March 2020. Two researchers independently screened studies investigating the accuracy of LUS with CXR or CT for adult critically ill patients with ARF. Data with baseline, true positives, false positives, false negatives, and true negatives were extracted. The study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The pooled sensitivity and specificity were obtained using a bivariate model. Eleven studies, including 1,232 patients, were included in the meta-analysis. Most studies were of low quality. LUS had a pooled sensitivity of 92% (95% confidence interval [CI]: 85-96) and a pooled specificity of 98% (95% CI: 94-99). The area under the summary receiver operating characteristic curve was 98% (95% CI: 97-99). The sensitivity and specificity of LUS to identify different pathological types of ARF were investigated. For consolidation (1,040 patients), LUS had a sensitivity of 89% and a specificity of 97%. For pleural effusion (279 patients), LUS had a pooled sensitivity of 95% and a specificity of 99%. For acute interstitial syndrome (174 patients), LUS had a pooled sensitivity of 95% and a specificity of 91%. LUS is an adjuvant tool that has a moderate sensitivity and high specificity for the diagnosis of ARF in critically ill patients. The study protocol was registered with PROSPERO (CRD42020211493).
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http://dx.doi.org/10.3389/fmed.2021.705960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383297PMC
August 2021

Changes of dendritic cell and natural killer cell on the cord blood with idiopathic fetal growth restriction.

J Matern Fetal Neonatal Med 2021 Aug 11:1-6. Epub 2021 Aug 11.

Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, PR China.

Objective: To investigate the characteristics of dendritic cells (DC) and natural killer cells (NK) in umbilical cord blood of pregnant patients diagnosed with idiopathic fetal growth restriction (IFGR).

Methods: A prospective study cohort of IFGR patients was established who were in the third trimester (28-36 weeks), with a healthy, pregnant woman cohort selected as controls. Umbilical cord blood was collected.

Results: The study included 50 pregnant women in the IFGR group and 50 pregnant women in the healthy, control group. The incidence of SGA in the IFGR group was 52.0%, and the incidence of preterm birth was 18.0%. The incidence of neonatal complications in neonates with live birth in the IFGR group was 12.0%. The birth weight, body length and placental weight of the newborns in the IFGR group were significantly lower than those in the control group ( < .05). Flow cytometry revealed no significant difference in the proportion or maturity of DC in umbilical cord blood between IFGR group and control group ( > .05). The proportion of NK cells in umbilical cord blood of IFGR group was significantly higher than that of normal control group. The proportion of CD56dimCD16+ NK cells was also significantly higher than that of the normal control group ( < .05), but the expression of NK cell surface killing activator receptor NKG2D and inhibitory receptor NKG2A was not statistically significant ( > .05).

Conclusion: The number and proportion of DC cells in cord blood may not be the key factors affecting the outcomes observed during FGR pregnancies. However, we found the proportion of NK cells in cord blood to be significantly increased, as well as the ratio of CD56dimCD16 + NK to CD56highCD16-NK to be imbalanced, which may be one of the pathogenesis of the pathological pregnancy leading to IFGR.
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http://dx.doi.org/10.1080/14767058.2021.1951214DOI Listing
August 2021

Mifepristone regulates macrophage-mediated natural killer cells function in decidua.

Reprod Biol 2021 Sep 5;21(3):100541. Epub 2021 Aug 5.

Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address:

Mifepristone has been used for first-trimester abortion and contraception. Nevertheless, its functional mechanism still needs to be elucidated. Decidua tissues were collected from 40 pregnant women who received (20 patients) or did not receive (20 patients) mifepristone. Immunofluorescence was used to analyze the effect of mifepristone on the quantity of CD56 and CD206 in decidua. in vitro assay, NK cells were isolated from decidua tissue and macrophages were induced from THP-1 cells. NK cells were co-cultured with macrophages pre-treated different concentrations of mifepristone (0 nmol/L, 200 nmol/L, 1800 nmol/L, and 25000 nmol/L); the cells' cytotoxicity and migration ability were analyzed using MTT assay and transwell assay, respectively. Si-TGF-β1, which was utilized to knock down the TGF-β1 expression in macrophages and human recombinant TGF-β1 were used to verify whether TGF-β1 was involved in the mifepristone regulation of NK cells function. The quantity of CD56 and CD206 decreased after mifepristone treatment. Moreover, the NK cells' cytotoxicity and migration ability were significantly increased by macrophages pre-treated with mifepristone in a dose-dependent manner. Moreover, compared with the si-NC group, the MTT absorbance rate of NK cells was significantly increased in the si-TGF-β1 group and was decreased in the human recombinant TGF-β1 group. Our data suggest that mifepristone, which regulates NK cells function through macrophages, was associated with the changes in TGF-β1 secreted by macrophages. This may be one of the mechanisms of mifepristone acting as contraceptive and abortion drugs at the maternal-fetal interface.
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http://dx.doi.org/10.1016/j.repbio.2021.100541DOI Listing
September 2021

The upregulation of PYCR2 is associated with aggressive colon cancer progression and a poor prognosis.

Biochem Biophys Res Commun 2021 Oct 28;572:20-26. Epub 2021 Jul 28.

Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Tongji University Cancer Center, Shanghai, China. Electronic address:

PYCR2 has previously been shown to be related to a range of malignancies including hepatocellular carcinoma and melanoma, but its mechanistic functions and prognostic relevance in colon cancer patients remain to be defined. Herein, we used the Oncomine, Human Protein Atlas, The Cancer Genome Atlas (TCGA), and UALCAN databases to explore the expression of this gene in different human cancer, after which the relationship between PYCR2 expression and patient clinicopathologic characteristics was evaluated. We utilized an in vitro approach to evaluate the association between PYCR2 expression and colon cancer cell proliferation, migration, invasion, and tumor microsphere formation. The cell apoptosis was analyzed by flow cytometry. Gene set enrichment analysis (GSEA) approaches were additionally used to probe signaling pathways related to PYCR2. These analyses confirmed that PYCR2 was upregulated in several cancer types including colon cancer, with such upregulation correlating with a poor patient prognosis and with malignant clinicopathological characteristics. PYCR2 expression was identified as an independent predictor of colon cancer patients' survival, and in vitro analyses suggested that knocking down this gene was sufficient to disrupt the proliferative, migratory, invasive, and microsphere formation activities of colon cancer cells. Moreover, shPYCR2 transfection induced colon cancer cell apoptosis. GSEA suggested that high PYCR2 expression correlates with the differential enrichment of the Wnt β-catenin signaling, MYC targets, RNA polymerase, and Notch signaling pathways. Overall, these data indicate that PYCR2 is an important mediator of tumor progression and metastasis, and suggest that it may be a valuable prognostic indicator for colon cancer patient evaluation.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.084DOI Listing
October 2021

Downregulation of TMEM220 promotes tumor progression in Hepatocellular Carcinoma.

Cancer Gene Ther 2021 Jul 28. Epub 2021 Jul 28.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, PR China.

During the process of long-term carcinogenesis, cells accumulate many mutations. Deregulated genes expression causes profound changes in cell proliferation, which is one of the hallmarks of HCC. A comprehensive understanding of these changes will contribute to the molecular mechanism of HCC progression. Through clinical sample analysis, we found that TMEM220 is downregulated in tumor and lower levels of TMEM220 is associated with poor prognosis in HCC patients. Through overexpressing TMEM220 in HCC cell lines, we found that the proliferation of cancer cells was significantly slowed down and metastasis was significantly reduced. For further study of its molecular mechanism, we performed a reverse-phase protein array (RPPA). The results suggest that phenotypic changes caused by TMEM220 in HCC cells might be associated with FOXO and PI3K-Akt pathways. Mechanism studies showed that overexpression of TMEM220 could regulate β-catenin and FOXO3 transcriptional activity by altering their subcellular localization, affecting the expression of downstream gene p21 and SNAIL, and ultimately reducing the progression of HCC. Altogether, our study proposes a working model in which upregulation of TMEM220 expression alters the genes expression involved in cell proliferation, thereby inhibiting HCC progression, which suggests that TMEM220 might serve as a clinical biomarker.
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http://dx.doi.org/10.1038/s41417-021-00370-0DOI Listing
July 2021

Changes in prevalence of nosocomial infection pre- and post-COVID-19 pandemic from a tertiary Hospital in China.

BMC Infect Dis 2021 Jul 20;21(1):693. Epub 2021 Jul 20.

Intensive Care Unit, Children Hospital of Soochow University, Suzhou, Jiangsu, China.

Background: Nosocomial infections (NIs) are an important cause of mortality, and increasing evidence reveals that the prevalence of NIs can be reduced through effective prevention and control measures. The aim of this study was to investigate the impact of the prevention and control measures for the COVID-19 pandemic on NIs.

Methods: A retrospective study was conducted to analyze the prevalence of NIs before and after COVID-19 pandemic for 6 months in the Children's Hospital of Soochow University.

Results: A total of 39,914 patients in 2019 and 34,645 patients in 2020 were admitted to the hospital during the study. There were 1.39% (481/34645) of patients with NIs in 2020, which was significantly lower than the 2.56% (1021/39914) of patients in 2019. The rate of critical and fatal cases was also decreased. In addition, the rate of appropriate handwashing, the number of protective gloves and aprons used per person and the number of healthcare staff per patients were significantly increased. Except for the ICU, the prevalence of nosocomial infection in most departments decreased from 2019 to 2020. Regarding the source of infections, a significant reduction was mainly observed in respiratory (0.99% vs 0.42%, p = 0.000) and digestive tract (0.63% vs 0.14%, p = 0.000). The microorganism analysis of respiratory infections indicated an obvious decline in acinetobacters and fungi. The most significant decline of pathogens in gastrointestinal infections was observed for rotavirus. The comparison of catheter-related nosocomial infections between 2019 and 2020 did not show significant differences.

Conclusions: The prevention and control measures for the COVID-19 pandemic have reduced the nosocomial infection in almost all departments, except the ICU, mainly regarding respiratory, gastrointestinal, and oral infections, while catheter-related infections did not show any differences.
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http://dx.doi.org/10.1186/s12879-021-06396-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289622PMC
July 2021

Control of stripe rust of wheat using indigenous endophytic bacteria at seedling and adult plant stage.

Sci Rep 2021 07 14;11(1):14473. Epub 2021 Jul 14.

Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan.

Stripe rust (caused by Puccinia striiformis tritici) is one of the most devastating diseases of wheat. The most effective ways to control stripe rust are the use of resistant cultivars and the timely use of an appropriate dose of fungicide. However, the changing nature of rust pathogen outwits the use of resistant cultivars, and the use of a fungicide is associated with environmental problems. To control the disease without sacrificing the environment, we screened 16 endophytic bacteria, which were isolated from stripe rust-resistant wheat cultivars in our previous study, for their biocontrol potential. A total of 5 bacterial strains Serratia marcescens 3A, Bacillus megaterium 6A, Paneibacillus xylanexedens 7A, Bacillus subtilis 11A, and Staphyloccus agentis 15A showed significant inhibition of Puccinia striiformis f. sp. tritici (Pst) urediniospores germination. Two formulations i.e., fermented liquid with bacterial cell (FLBC) and fermented liquid without bacterial cells (FL) of each bacterial strain, were evaluated against the urediniospores germination. Formulations of five selected endophytic bacteria strains significantly inhibited the uredinioospores germination in the lab experiments. It was further confirmed on seedlings of Pakistani susceptible wheat cultivar Inqilab-91 in the greenhouse, as well as in semi-field conditions. FLBC and FL formulations applied 24 h before Pst inoculation (hbi) displayed a protective mode. The efficacy of FLBC was between 34.45 and 87.77%, while the efficacy of FL was between 39.27 and 85.16% when applied 24 hbi. The inoculated wheat cultivar Inqilab-91 was also tested under semi-field conditions during the 2017-2018 cropping season at the adult plant stage. The strains Bacillus megaterium 6A and Paneibacillus xylanexedens 7A alone significantly reduced the disease severity of stripe rust with the efficacy of 65.16% and 61.11% for the FLBC in protective effect, while 46.07% and 44.47% in curative effect, respectively. Inoculated seedlings of Inqilab-91 showed higher activities of antioxidant enzymes, superoxide dismutase (SOD), peroxidase (POD), polyphenol oxidase (PPO), and phenylalanine ammonia-lyase (PAL). The treated seedlings also showed higher expressions of pathogenesis-related (PR) protein genes, antifungal protein (PR-1), β-1,3-endoglucanases (PR-2), endochitinases (PR-4), peroxidase (PR-9), and ribonuclease-like proteins (PR-10). These results indicated that endophytic bacteria have the biocontrol potential, which can be used to manage stripe rust disease. High production antioxidant enzymes, as well as high expression of PR protein genes, might be crucial in triggering the host defense mechanism against Pst.
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http://dx.doi.org/10.1038/s41598-021-93939-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280153PMC
July 2021

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18 years or older: A randomized, double-blind, placebo-controlled, phase 1/2 trial.

EClinicalMedicine 2021 Aug 7;38:101010. Epub 2021 Jul 7.

National Engineering Technology Research Centre for Combined Vaccines, Wuhan Institute of Biological Products Co. Ltd., Wuhan, Hubei, China.

Background: We aimed to assess the safety and immunogenicity of an inactivated vaccine against COVID-19 in Chinese adults aged ≥18 years.

Methods: This is an ongoing randomized, double-blind, placebo-controlled, phase 1/2 clinical trial among healthy adults aged ≥18 years in Henan Province, China. Participants ( = 336 in 18-59 age group and  = 336 in ≥60 age group) were enrolled between April 12 and May 17 2020, and were equally randomized to receive vaccine or placebo (aluminum hydroxide adjuvant) in a three-dose schedule of 2·5, 5, or 10 µg on days 0, 28, and 56. Another 448 adults aged 18-59 years were equally allocated to four groups (a one-dose schedule of 10 µg, and two-dose schedules of 5 µg on days 0 and 14/21/28) and received vaccine or placebo (ratio 3:1 within each group). The primary outcomes were 7-day post-injection adverse reactions and neutralizing antibody titres on days 28 and 90 after the whole-course vaccination. Trial registration: www.chictr.org.cn #ChiCTR2000031809.

Findings: The 7-day adverse reactions occurred in 4·8% to 32·1% of the participants in various groups, and most adverse reactions were mild, transient, and self-limiting. Twenty participants reported 68 serious adverse events which were judged to be unrelated to the vaccine. The 90-day post-injection geometric mean titres of neutralizing antibody ranged between 87 (95% CI: 61-125) and 129 (99-169) for three-dose schedule among younger and older adults; 20 (14-27), 53 (38-75), and 44 (32-61) in 5 µg days 0 and 14/21/28 groups, respectively, and 7 (6-9) in one-dose 10 µg group. There were no detectable antibody responses in all placebo groups.

Interpretation: The inactivated vaccine against COVID-19 was well tolerated and immunogenic in both younger and older adults. The two-dose schedule of 5 µg on days 0 and 21/28 and three-dose schedules on days 0, 28, and 56 could be further evaluated for long-term safety and efficacy in the phase 3 trials.
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http://dx.doi.org/10.1016/j.eclinm.2021.101010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260504PMC
August 2021

The feasibility of laparoscopically assisted, hysteroscopic removal of interstitial pregnancies: A case series.

J Obstet Gynaecol Res 2021 Oct 5;47(10):3447-3455. Epub 2021 Jul 5.

Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, P.R. China.

Objective: The study objective was to assess the feasibility of the management of interstitial pregnancy by laparoscopically assisted hysteroscopic removal.

Methods: This retrospective study included a case series of 17 patients who were diagnosed interstitial pregnancy with dilated proximal tubal ostium by transvaginal ultrasonography at the Women's hospital, School of Medicine, Zhejiang University between August 2017 and October 2020. Laparoscopically assisted hysteroscopic removals of the products of conception were performed. Various data were collected including age, surgical and obstetric history, gestational age, preoperative symptoms, human chorionic gonadotropin level and ultrasonography results. The outcomes measured were intraoperative bleeding, pathologic findings, conversions.

Results: Eleven cases were successfully resected the interstitial gestational products with laparoscopically assisted hysteroscopy. There were four cases failed of hysteroscopic removal, for the proximal tubal ostia were too small for the surgical instruments to enter. Then cornual wedge resections were performed. Two cases were identified as intramural pregnancy by hysteroscopic and laparoscopic view. Most of the intramural pregnancy tissue of one patient was removed by hysteroscopy. The other one converted to laparoscopy.

Conclusion: Laparoscopically assisted hysteroscopic management could be a feasible surgical option to interstitial pregnancies. Further clinical studies are needed to establish detailed criteria to select the appropriate cases for hysteroscopic management.
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http://dx.doi.org/10.1111/jog.14924DOI Listing
October 2021

Design, green synthesis, antioxidant activity screening, and evaluation of protective effect on cerebral ischemia reperfusion injury of novel monoenone monocarbonyl curcumin analogs.

Bioorg Chem 2021 Sep 16;114:105080. Epub 2021 Jun 16.

Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address:

Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an HO-induced oxidative stress damage model, and quantitative evaluation of structure-activity relationship (QSAR) model with regression coefficient of R = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.
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http://dx.doi.org/10.1016/j.bioorg.2021.105080DOI Listing
September 2021

TSPAN1 silencing protects against cerulein-induced pancreatic acinar cell injury via targeting AGR2.

Drug Dev Res 2021 Jul 1. Epub 2021 Jul 1.

Department of Clinical Laboratory, Lishui People's Hospital, Lishui City, Zhejiang Province, China.

Acute pancreatitis (AP) is an inflammatory gastrointestinal disorder affecting the pancreas. Previous study reported that tetraspanin 1 (TSPAN1) expression was significantly upregulated in the pancreas of AP patients. However, the underlying molecular mechanism of TSPAN1 in the pathogenesis of AP remains unclear. Thus, the aim of the present study was to investigate the potential role of TSPAN1 in development of AP. RT-qPCR was carried out to quantify the relative mRNA levels of TSPAN1 and anterior gradient-2 (AGR2). The CCK-8 assay was used to detect the cell viability. The TUNEL assay was performed to visualize the apoptotic cells. Western blot was performed to determine the expressions of proteins related to endoplasmic reticulum (ER) stress and apoptosis. ELISA kits were adopted to detect the concentration of inflammatory cytokines including TNF-α and IL-6. Finally, immunoprecipitation (IP) was used to verify the interaction between TSPAN1 and AGR2. TSPAN1 was upregulated in serum of AP patients and AP cell models. TSPAN1 silencing promoted the cell proliferation and inhibited inflammatory response in cerulein-induced AR42J cells. Moreover, TSPAN1 induced endoplasmic reticulum stress by binding AGR2. Interestingly, the overexpression of AGR2 abolished the effects of TSPAN1 silencing on cell proliferation and inflammatory response in cerulein-induced AR42J cells. In summary, TSPAN1 silencing protects against cerulein-induced pancreatic acinar cell injury through inhibiting ER stress-mediated by AGR2. Hence, TSPAN1 may serve as a promising therapeutic target for AP treatment.
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http://dx.doi.org/10.1002/ddr.21855DOI Listing
July 2021

attenuates neuroinflammation in cerebral ischaemia-reperfusion injury in rats through the TLR4/NF-κB/MAPK pathway.

Pharm Biol 2021 Dec;59(1):828-839

College of Pharmacy, Fujian Key laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Context: (PTH) is traditionally applied to treat various inflammation-related diseases including stroke. However, literature regarding the anti-inflammatory effects and possible mechanisms of PTH in ischaemic stroke is unavailable.

Objective: This study investigates the anti-inflammatory effects and its underlying mechanism of PTH on ischaemic stroke.

Materials And Methods: Cerebral ischaemia-reperfusion injury was induced through 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion in male Sprague-Dawley (SD) rats receiving oral pre-treatment with PTH (180 mg/kg) for 4 days. TLR4 antagonist TAK-242 (3 mg/kg) was injected intraperitoneally at 1.5 h after MCAO. MRI, HE staining, qRT-PCR, western blot, and immunofluorescence methods were employed.

Results: PTH treatment markedly reduced cerebral infarct volume (by 51%), improved neurological function (by 33%), and ameliorated brain histopathological damage in MCAO rats. It also reduced the levels of four inflammatory mediators including IL-1β (by 70%), IL-6 (by 78%), TNF-α (by 60%) and MCP-1 (by 58%); inhibited microglia and astrocyte activation; and decreased protein expression of iNOS and COX-2 in injured brains. Moreover, PTH down-regulated the protein expressions of TLR4, MyD88, and TRAF6; reduced the expression and nuclear translocation of NF-κB; and lowered the protein expressions of p-ERK1/2, p-JNK, and p-p38. Similar effects were observed in MCAO rats with TAK-242 treatment. However, combined administration of PTH and TAK-242 did not significantly reinforce the anti-inflammatory effects of PTH.

Discussion And Conclusion: PTH improved cerebral ischaemia-reperfusion injury by inhibiting neuroinflammation partly via the TLR4/NF-κB/MAPK signalling pathway, which will help guide its clinical application.
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http://dx.doi.org/10.1080/13880209.2021.1942926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253189PMC
December 2021

Suppression of hyperinsulinemia restores growth hormone secretion and metabolism in obese mice.

J Endocrinol 2021 Jul 12;250(3):105-116. Epub 2021 Jul 12.

School of Biomedical Sciences, University of Queensland, Queensland, Australia.

The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment for 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any significant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits occurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic changes following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improves substrate and energy metabolism in DIO mice.
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http://dx.doi.org/10.1530/JOE-20-0616DOI Listing
July 2021

Pien-Tze-Huang, a Chinese patent formula, attenuates NLRP3 inflammasome-related neuroinflammation by enhancing autophagy via the AMPK/mTOR/ULK1 signaling pathway.

Biomed Pharmacother 2021 Sep 17;141:111814. Epub 2021 Jun 17.

College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address:

NLRP3 inflammasome is a key mediator in ischemic stroke-induced neuroinflammation and subsequent brain injury. Our previous study demonstrated the potent activity of Pien-Tze-Huang (PTH), a well-known Chinese patent formula, in reducing mitochondria-mediated neuronal apoptosis in cerebral ischemia/reperfusion impaired rats. This study aims to elucidate the mechanistic action of PTH related to neuroinflammation in LPS-induced BV2 microglial cells and cerebral ischemia/reperfusion impaired rats. BV2 cells were stimulated with LPS for 12 h and treated with PTH with various concentrations. Modulation by PTH of relevant genes (IL-6, IL-1β, IL-18, TNF-α, COX-2 and iNOS mRNA) and proteins (NLRP3 inflammasome, autophagy and AMPK/mTOR/ULK signaling) was analyzed by real-time PCR and western blot, respectively. Similar analyses were conducted in middle cerebral artery occlusion rat model including neurological deficit, infarct volume, microglial activation, and key genes and proteins in modulating autophagy and NLRP3. Our results showed that PTH significantly inhibited the production of key proinflammatory mediators and protein expressions of NLRP3 and caspase-1 p20 in LPS induced BV2 cells. It also enhanced the autophagy response by modulating the key autophagy proteins via AMPK/mTOR/ULK related pathway. The reduced inflammatory responses and NLRP3 expressions by PTH were partially blocked by the autophagy inhibitor (3-MA) and AMPK blocker (compound C). In rats, PTH significantly reduced infarct size, suppressed microglial activation, and improved neuron deficit. It also promoted autophagy and reduced NLRP3 activity. Our study demonstrated that PTH inhibited NLRP3 inflammasome-mediated neuroinflammation, which was associated with enhanced autophagy via AMPK/mTOR/ULK1 pathway in vitro and in vivo.
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http://dx.doi.org/10.1016/j.biopha.2021.111814DOI Listing
September 2021

Discovery and Functional Characterization of a Diverse Diterpene Synthase Family in the Medicinal Herb Isodon lophanthoides var. Gerardiana.

Plant Cell Physiol 2021 Jun 16. Epub 2021 Jun 16.

Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.

Isodon lophanthoides var. gerardiana (Lamiaceae), also named xihuangcao, is a traditional Chinese medicinal herb that exhibits a broad range of pharmacological activities. Abietane-type diterpenoids are the characteristic constituents of I. lophanthoides, yet their biosynthesis has not been elucidated. Although the aerial parts are the most commonly used organs of I. lophanthoides, metabolite profiling by GC-MS showed the underground parts also contain large amounts of labdane diterpenoids including abietatriene, miltiradiene and ferruginol, which is distinct from the 13-hydroxy-8(14)-abietene detected in the aerial parts. Comparative transcriptome analysis of root and leaf samples identified a diverse diterpene synthase (diTPS) family including 6 copalyl diphosphate synthase (IlCPS1-6) and 5 kaurene synthase-like (IlKSL1-5). Here we report the functional characterization of six of these enzymes using yeast heterologous expression system. Both IlCPS1 and IlCPS3 yielded (+)-CPP, in combination with IlKSL1 resulted in miltiradiene, precursor of abietane-type diterpenoids, while coupling with IlKSL5 led to the formation of hydroxylated diterpene scaffold nezukol. Expression profiling and phylogenetic analysis further support the distinct evolutionary relationship and spatial distribution of IlCPS1 and IlCPS3. IlCPS2 converted geranylgeranyl diphosphate (GGPP) into labda-7, 13E-dien-15-ol diphosphate (7,13-CPP). IlCPS6 was identified as ent-CPS, indicating a role in gibberellin metabolism. We further identified a single residue determined the water addition of nezukol synthase IlKSL5. Substitution of alanine 513 with isoleucine completely altered the product outcome from hydroxylated nezukol to isopimara-7,15-diene. Together, these findings elucidated the early steps of bioactive abietane-type diterpenoid biosynthesis in I. lophanthoides and the catalytic mechanism of nezukol synthase.
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http://dx.doi.org/10.1093/pcp/pcab089DOI Listing
June 2021

Infection of Two Heterologous Mycoviruses Reduces the Virulence of , a Fungal Agent of Apple Valsa Canker Disease.

Front Microbiol 2021 25;12:659210. Epub 2021 May 25.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Xianyang, China.

Mycovirus infection has been widely shown to attenuate the virulence of phytopathogenic fungi. is an agriculturally important fungus that causes Valsa canker disease in apple trees. In this study, two unrelated mycoviruses [ 1 (CHV1, genus , and single-stranded RNA) and Mycoreovirus 1 (MyRV1, genus , double-stranded RNA)] that originated from (chestnut blight fungus) were singly or doubly introduced into via protoplast fusion. CHV1 and MyRV1 stably infected and caused a reduction in fungal vegetative growth and virulence. Co-infection of both viruses further reduced the virulence of but compromised the stability of CHV1 infection and horizontal transmission through hyphal anastomosis. Infections of MyRV1 and, to a lesser extent, CHV1 up-regulated the transcript expression of RNA silencing-related genes in . The accumulation of CHV1 (but not MyRV1) was elevated by the knockdown of , a key gene of the RNA silencing pathway. Similarly, the accumulation of CHV1 and the efficiency of the horizontal transmission of CHV1 during co-infection was restored by the knockdown of . Thus, CHV1 and MyRV1 are potential biological control agents for apple Valsa canker disease, but co-infection of both viruses has a negative effect on CHV1 infection in due to the activation of antiviral RNA silencing by MyRV1 infection.
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http://dx.doi.org/10.3389/fmicb.2021.659210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186502PMC
May 2021

Safety and immunogenicity of a quadrivalent inactivated subunit non-adjuvanted influenza vaccine: A randomized, double-blind, active-controlled phase 1 clinical trial.

Vaccine 2021 06 1;39(29):3871-3878. Epub 2021 Jun 1.

Department of Research and Development, Ab&B Biotech Co., Ltd, Taizhou, Jiangsu, China; Department of Research and Development, Yither Biotech Co., Ltd, Shanghai, China. Electronic address:

Quadrivalent influenza inactivated vaccine (IIV4) is more likely to provide wider protection against yearly circulating influenza viruses than trivalent inactivated influenza vaccine (IIV3). In this study, a total of 320 participants were allocated to four age cohorts (6-35 months, 3-8 years, 9-17 years, and ≥ 18 years; 80 participants/cohort) according to their actual date of birth. Participants in each cohort were randomly assigned to two groups to receive intramuscular injection of the trial vaccine or the comparative vaccine in a one-dose (3-8 years, 9-17 years,and ≥ 18 years) schedule on day 0 or two-dose (6-35 months cohort) schedule on day 0 and 28. The first objective is to evaluate the safety and immunogenicity of the full-dose subunit non-adjuvanted IIV4 (FD-subunit NAIIV4) we developed versus an active-control, China-licensed split-virion NAIIV4, in people ≥ 3 years. The second objective is to evaluate the safety and immunogenicity of FD-subunit NAIIV4 versus the half-dose (HD-subunit NAIIV4) in toddlers aged 6-35 months. Results showed that all adverse reactions noted were rare, mild, and self-limited. In ≥ 3 years cohorts, systemic adverse reactions in FD-subunit NAIIV4 groups were less than the active control split-virion NAIIV4 groups ([Systemic adverse reaction rates (95%CI)], 15.0 (8.6-21.4) versus 19.2(12.1-26.2), p = 0.391). The overall seroprotection efficacy after vaccination were comparable between FD-subunit NAIIV4 and the active control split-virion NAIIV4([Seroprotection rates (95%CI)], H1N1, 99.2(81.3-100.0) versus 94.9(90.9-98.9), p = 0.117; H3N2, 81.7(74.7-88.6) versus 82.1(75.1-89.0), p = 0.939; BV, 75.8(68.2-83.5) versus 74.4(66.4-82.3), p = 0.793; BY, 94.2(90.0-98.4) versus 92.3(87.5-97.1), p = 0.568). Additionally, FD-subunit NAIIV4 has comparable safety and better seroprotection versus that of the half-dose in 6-35 months toddlers groups ([Total adverse reaction rates (95%CI)], 37.5(18.5-56.5) versus 47.5(26.1-68.9), p = 0.366) ([Seroprotection rates (95%CI)], H1N1, 85(56.4-100.0) versus 75.7(47.6-100.0), p = 0.117; H3N2, 50(28.1-71.9) versus 29.7(12.2-47.3), p = 0.070; BV, 75(48.2-100.0) versus 29.7(12.2-47.3), p < 0.001; BY, 75(48.2-100.0) versus 56.8(32.5-81.0), p = 0.091). As a result, the FD-subunit NAIIV4 we developed is safe and effective to provide broader and adequate protection against the circulating influenza viruses during 2018-2019, which could be an essential component of the global preventive strategy for influenza pandemic.
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http://dx.doi.org/10.1016/j.vaccine.2021.05.070DOI Listing
June 2021
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