Publications by authors named "Jun Peng"

737 Publications

Circ_0114428 Regulates Sepsis-Induced Kidney Injury by Targeting the miR-495-3p/CRBN Axis.

Inflammation 2021 Apr 8. Epub 2021 Apr 8.

Department of Nephrology, People's Hospital of Rizhao, No. 126, Tai'an Road, Donggang District, Rizhao City, 276826, Shandong Province, China.

Septic acute kidney injury (AKI) is considered as a severe and common complication of sepsis, with complex pathogenesis. Recently, Circular RNA (circRNA) is considered to be implicated in this disease. This study was intended to elucidate the role of circ_0114428 and the potential mechanism of action in sepsis-induced kidney injury. Sepsis-induced kidney injury cell model was established in human kidney 2 (HK2) cells by the treatment of lipopolysaccharide (LPS). The expression of circ_0114428, CRBN mRNA, and miR-495-3p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was assessed by cell counting kit-8 (CCK-8) assay. The inflammatory response was monitored according to the release of proinflammatory factors by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was evaluated by flow cytometry assay. The activities of oxidative indicators were examined using the corresponding kits. Endoplasmic reticulum (ER) stress-related proteins and CRBN protein were quantified by western blot. RNA immunoprecipitation (RIP) assay was performed to ensure whether circ_0114428 could interact with Argonaute 2 (Ago2) protein. The potential miRNAs targeted by circ_0114428 were predicted by the bioinformatics tool and screened by RNA pull-down assay. The interaction between miR-495-3p and circ_0114428 or CRBN was validated by dual-luciferase reporter assay. The results showed that circ_0114428 and CRBN were upregulated in septic AKI serum specimens and LPS-induced HK2 cells. Circ_0114428 knockdown attenuated LPS-induced apoptosis, inflammation, oxidative stress, and ER stress, which were rescued by CRBN overexpression. Further analysis revealed that miR-495-3p was targeted by circ_0114428 and directly bound to CRBN, and circ_0114428 regulated CRBN expression by sponging miR-495-3p. Besides, miR-495-3p inhibition also reversed the effects of circ_0114428 knockdown. In conclusion, circ_00114428 knockdown attenuated LPS-induced HK2 cell injury by regulating CRBN expression via targeting miR-495-3p.
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http://dx.doi.org/10.1007/s10753-021-01432-zDOI Listing
April 2021

MiR-93/HMGB3 regulatory axis exerts tumor suppressive effects in colorectal carcinoma cells.

Exp Mol Pathol 2021 Mar 24:104635. Epub 2021 Mar 24.

Center for Laboratory Medicine, the Affiliated Zhuzhou Hospital Xiangya Medical College CSU, Zhuzhou 412000, China. Electronic address:

Objective: MicroRNA (miR)-93 has been proven to mediate the initiation and progression of colorectal carcinoma (CRC); however, the mechanisms by which miR-93 mediates CRC development need deeper elucidation. The present study is designed to investigate the association between miR-93 and high mobility group box 3 (HMGB3), as well as the functions of miR-93, in CRC.

Methods: miR-93 expression was quantified by RT-qPCR. CRC cells were transfected or cotransfected with miR-93 mimic, miR-93 inhibitor, pcDNA3.1-HMGB3 and sh-HMGB3, and then the proliferative, migratory and invasive capacities were detected in addition to the apoptotic rate. Western blotting assessed the expression levels of HMGB3, PI3K, p-PI3K, AKT and p-AKT. The interaction between miR-93 and HMGB3 was identified.

Results: In CRC tissues, miR-93 was downregulated and HMGB3 was upregulated. LOVO and SW480 cells transfected with miR-93 mimic exhibited reduced proliferation, invasion and migration as well as increased apoptosis. The ratios of p-PI3K/PI3K and p-AKT/AKT were declined after miR-93 mimic was introduced into the CRC cell lines. miR-93 negatively downregulated HMGB3, and introduction of pcDNA3,1-HMGB3 could counteract, in part, the inhibitory effects of miR-93 on the malignant properties of CRC cells as well as the ratios of p-PI3K/PI3K and p-AKT/AKT.

Conclusion: miR-93 targeted HMGB3 to block the activation of the PI3K/AKT pathway and thus enhance CRC cell apoptosis.
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http://dx.doi.org/10.1016/j.yexmp.2021.104635DOI Listing
March 2021

Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.

Lancet Haematol 2021 Apr;8(4):e289-e298

Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Background: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia.

Methods: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 10 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 10 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 10 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 10 cells per L but less than 100 × 10 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626.

Findings: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths.

Interpretation: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response.

Funding: National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S2352-3026(21)00030-2DOI Listing
April 2021

Effect of total glucosides of paeony and Tripterygium wilfordii polyglycosides on erythrocyte methotrexate polyglutamates in rats, analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry.

J Pharm Pharmacol 2021 Mar 22. Epub 2021 Mar 22.

Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.

Objectives: The aim of the study was to explore the effect of total glucosides of paeony (TGP) and Tripterygium wilfordii polyglycosides (TWP) on erythrocyte methotrexate polyglutamates (MTXPGs), the metabolites of methotrexate (MTX).

Methods: An ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) method was developed to determine MTXPGs. The effects of MTXPGs were analysed using 24 male Sprague-Dawley rats that were randomly divided into the MTX alone, MTX-TGP combined, and MTX-TWP combined groups. Rats were administered MTX at a dose of 0.9 mg/kg once a week, TGP at 0.054 g/kg and TWP at 1.8 mg/kg three times a day. Venous blood (1.0 ml) was collected at weeks 2, 4, 6, 9, 12 and 15 and then analysed using the developed UPLC-MS/MS method.

Key Findings: Specificity, linear range, inter-and intra-day precision, recovery, matrix effect and stability of MTXPGs met the standard regulations. This method was successfully used for the detection of MTXPGs. After administration of MTX alone, erythrocyte MTXPGs increased and accumulated in a time- and dose-dependent manner. Compared to MTX alone, the combination with TGP significantly decreased the content of total MTXPGs and short-chain MTXPGs (Methotrexate [MTX/MTXPG1] and 4-amino-10-methylpteroyldiglutamic acid [MTXPG2], P < 0.05), but had no significant effect on long-chain MTXPGs (4-amino-10-methylpteroyltriglutamic acid [MTXPG3], P > 0.05) and very long-chain MTXPGs (4-amino-10-methylpteroyltetraglutamic acid [MTXPG4] and 4-amino-10-methylpteroylpentaglutamic acid [MTXPG5], P > 0.05) at week 15. The combination of MTX with TWP had no significant effect on the content of total MTXPGs, short-chain MTXPGs and long-chain MTXPGs (P > 0.05), but it significantly decreased the content of very long-chain MTXPGs (P < 0.05) at week 15.

Conclusions: The UPLC-MS/MS method was successfully used to determine MTXPGs in rat erythrocytes. TGP and TWP in combination with MTX affected the production of MTXPGs of different chain lengths in erythrocytes.
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http://dx.doi.org/10.1093/jpp/rgab025DOI Listing
March 2021

Qingda granule exerts neuroprotective effects against ischemia/reperfusion-induced cerebral injury via lncRNA GAS5/miR-137 signaling pathway.

Int J Med Sci 2021 6;18(7):1687-1698. Epub 2021 Feb 6.

Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Minhou Shangjie, Fuzhou 350122, China.

Ischemic stroke is the second leading cause of death and disability worldwide, which needs to develop new pharmaceuticals for its prevention and treatment. Qingda granule (QDG), a traditional Chinese medicine formulation, could improve angiotensin II-induced brain injury and decrease systemic inflammation. In this study, we aimed to evaluate the neuroprotective effect of QDG against ischemia/reperfusion-induced cerebral injury and illustrate the potential mechanisms. The middle cerebral artery occlusion/reperfusion (MCAO/R) surgery and oxygen-glucose deprivation/reoxygenation (OGD/R) models were established. Ischemic infarct volume was quantified using magnetic resonance imaging (MRI). Neurobehavioral deficits were assessed using a five-point scale. Cerebral histopathology was determined by hematoxylin-eosin (HE) staining. Neuronal apoptosis was evaluated by TUNEL and immunostaining with NeuN antibodies. The protective effect of QDG on OGD/R-injured HT22 cells was determined by MTT assay and Hoechst 33258 staining. The expression of lncRNA GAS5, miR-137 and apoptosis-related proteins were investigated in MCAO/R-injured rats and in OGD/R-injured HT22 cells using RT-qPCR and western blot analysis. QDG significantly reduced the ischemic infarct volume, which was accompanied with improvements in neurobehavioral deficits. Additionally, QDG significantly ameliorated cerebral histopathological changes and reduced neuron loss in MCAO/R-injured rats. Moreover, QDG improved growth and inhibited apoptosis of HT22 cells injured by OGD/R . Finally, QDG significantly decreased the expression of lncRNA GAS5, Bax and cleaved caspase3, whereas it increased miR-137 and Bcl-2 expression in MCAO/R-injured rats and in OGD/R-injured HT22 cells. QDG plays a neuroprotective role in ischemic stroke via regulation of the lncRNA GAS5/miR-137 signaling pathway.
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http://dx.doi.org/10.7150/ijms.53603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976574PMC
February 2021

Pretreatment of Huoxue Jiedu Formula Ameliorates Myocardial Ischaemia/Reperfusion Injury by Decreasing Autophagy via Activation of the PI3K/AKT/mTOR Pathway.

Front Pharmacol 2021 26;12:608790. Epub 2021 Feb 26.

Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

Myocardial ischaemia/reperfusion (I/R) results in myocardial injury via excessive autophagy. Huoxue Jiedu Formula (HJF) has been widely applied in China for the treatment of ischaemic heart disease. However, the mechanisms of HJF are still poorly understood. Thus, the present experiment was designed to observe the effects of HJF on myocardial I/R injury and explore the possible mechanism. Myocardial injury in rats subjected to myocardial I/R was reflected by nitrotetrazolium blue chloride staining, thioflavin S staining, serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT). Autophagy was determined by electron microscopy, laser confocal microscopy, Q-PCR and western blot. The possible pathway was predicted by network pharmacology and validated and . Pretreatment of HJF decreased the no-reflow area, infarcted area, serum CK-MB levels and serum cTnT levels in I/R rat model. In addition, pretreatment of HJF decreased autophagy in heart tissues (decrease in Beclin-1 and LC3-II, and increase in Bcl-2, p62 and ratio of LC3-I/LC3-II). In the vivo study, pretreatment of HJF significantly decreased hypoxia/reoxygenation (H/R)-induced autophagy in H9C2 cells. Network pharmacology was applied to predict the possible mechanism by which HJF affects cardiac autophagy, and the PI3K/AKT/mTOR signalling pathway was the most significantly enriched pathway. And experimental studies demonstrated that pretreatment of HJF increased the phosphorylation of AKT and mTOR, and the effects of HJF on autophagy would be offset by PI3K inhibitor LY294002. Pretreatment of HJF ameliorates myocardial I/R injury by decreasing autophagy through activating PI3K/AKT/mTOR pathway.
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http://dx.doi.org/10.3389/fphar.2021.608790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952439PMC
February 2021

Antihuman CD44 antibody BJ18 inhibits platelet phagocytosis by correcting aberrant FcɣR expression and M1 polarization in immune thrombocytopenia.

Int Immunopharmacol 2021 Mar 6;95:107502. Epub 2021 Mar 6.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, China. Electronic address:

Background: Immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease with a low platelet count. CD44 is a pivotal component involved in phagocytosis and inflammation, and monoclonal antibodies (mAbs) against CD44 have been shown to be beneficial in several autoimmune diseases. In the present study, we investigated the correlation between CD44 levels and disease severity in patients with ITP and explored the immunomodulatory mechanisms of the antihuman CD44 mAb BJ18 on platelet phagocytosis mediated by monocytes/macrophages.

Methods: Plasma was collected from 45 participants to measure the circulating concentration of CD44 using ELISA. Peripheral blood mononuclear cells from patients and controls were isolated and induced to differentiate into monocytes/macrophages utilizing cytokines and drugs. CD44 expression on circulating cells and the effects of BJ18 on platelet phagocytosis, Fcɣ receptor (FcɣR) expression and M1/M2 polarization of macrophages were evaluated using flow cytometry and qPCR.

Results: CD44 levels of both the soluble form found in plasma and the form expressed on the surface of circulating monocytes/macrophages were significantly elevated in ITP patients. Linear correlations were verified between the CD44 levels and major clinical characteristics. In an in vitro study, BJ18 successfully inhibited platelet phagocytosis by monocytes/macrophages obtained from ITP patients. Further studies indicated that BJ18 corrected abnormal FcγR expression on monocytes/macrophages. Moreover, the polarization of proinflammatory M1 macrophages could also be regulated by BJ18.

Conclusions: Our data indicated that the CD44 level has potential predictive value for disease severity and that the antihuman CD44 mAb BJ18 may be a promising therapy for ITP patients.
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http://dx.doi.org/10.1016/j.intimp.2021.107502DOI Listing
March 2021

Fructus Lycii and Salvia miltiorrhiza Bunge extract alleviate retinitis pigmentosa through Nrf2/HO-1 signaling pathway.

J Ethnopharmacol 2021 Jun 5;273:113993. Epub 2021 Mar 5.

Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Ophthalmology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, China; Hunan Provincial Key Laboratory of Diagnostic Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China. Electronic address:

Ethnopharmacological Relevance: Fructus Lycii and Salvia miltiorrhiza Bunge (FS) are popular Chinese herbs for the treatment of retinitis pigmentosa (RP).

Aim Of The Study: This study was to evaluate protective effects of FS extract on RP and to explore whether FS extract exerts its protective effects via oxidative stress by regulating Nrf2/HO-1 signaling pathway.

Material And Methods: FS extract were identified by UPLC chromatographic analysis. Rd10 mice as the model of RP, followed by a 4-week FS extract treatment by intragastric administration. After the animal sacrifice, histopathological examination and Scotopic electroretinography (ERG) analysis were assessed. The oxidative stress markers were determined and the expression levels of Nrf2 and HO-1 mRNA were evaluated by qRT-PCR. The expression and distribution of Nrf2 and HO-1 protein were determined by Western blot and immunohistochemistry.

Results: The morphological changes of Outer nuclear layer (ONL) thickness and number of the ONL were observed with a significant increased, and the functional changes of a-amplitude and b-wave amplitude were measured with a markedly increased. Treatment with FS extract remarkably increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased level of malondialdehyde (MDA). Moreover, FS extract up-regulated mRNA and protein expression of Nrf2 and HO-1.

Conclusions: This study indicated that FS extract can improve retinal morphology and function, which may have occurred through the regulation of the Nrf2/HO-1 pathway to inhibit the oxidative reaction.
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http://dx.doi.org/10.1016/j.jep.2021.113993DOI Listing
June 2021

Low-Dose Decitabine Inhibits Cytotoxic T Lymphocytes-Mediated Platelet Destruction Modulating PD-1 Methylation in Immune Thrombocytopenia.

Front Immunol 2021 17;12:630693. Epub 2021 Feb 17.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Cytotoxic T lymphocytes (CTLs)-mediated platelet destruction plays an important role in the pathogenesis of primary immune thrombocytopenia (ITP). The programmed cell death protein 1 (PD-1) signaling can turn off autoreactive T cells and induce peripheral tolerance. Herein, we found that the expression of PD-1 and its ligand PD-L1 on CD8 T cells from ITP patients was decreased. Activating PD-1 pathway by PD-L1-Fc fusion protein inhibited CTLs-mediated platelet destruction in ITP . PD-1 promoter hypermethylation in CD8 T cells was found in ITP patients, resulting in decreased PD-1 expression. The demethylating agent decitabine at a low dose was proved to restore the methylation level and expression of PD-1 on CD8 T cells and reduce the cytotoxicity of CTLs of ITP patients. The phosphorylation levels of phosphatidylinositol 3-kinase (PI3K) and AKT in CD8 T cells were significantly downregulated by low-dose decitabine. Furthermore, blocking PD-1 could counteract the effect of low-dose decitabine on CTLs from ITP patients. Therefore, our data suggest that the aberrant PD-1/PD-L1 pathway is involved in the pathophysiology of ITP and enhancing PD-1/PD-L1 signaling is a promising therapeutic approach for ITP management. Our results reveal the immunomodulatory mechanism of low-dose decitabine in ITP by inhibiting CTLs cytotoxicity to autologous platelets through PD-1 pathway.
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http://dx.doi.org/10.3389/fimmu.2021.630693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925841PMC
February 2021

Combination of ponatinib with deferoxamine synergistically mitigates ischemic heart injury via simultaneous prevention of necroptosis and ferroptosis.

Eur J Pharmacol 2021 May 3;898:173999. Epub 2021 Mar 3.

Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. Electronic address:

Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.
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http://dx.doi.org/10.1016/j.ejphar.2021.173999DOI Listing
May 2021

Design and Fabrication of a MEMS Electromagnetic Swing-Type Actuator for Optical Switch.

Micromachines (Basel) 2021 Feb 22;12(2). Epub 2021 Feb 22.

School of Mechanical and Electrical Engineering, Xinyu University, Xinyu 338004, China.

A microelectromechanical systems system (MEMS) electromagnetic swing-type actuator is proposed for an optical fiber switch in this paper. The actuator has a compact size of 5.1 × 5.1 × 5.3 mm, consisting of two stators, a swing disc (rotator), a rotating shaft, and protective covers. Multi-winding stators and a multipole rotator were adopted to increase the output torque of the actuator. The actuator's working principle and magnetic circuit were analyzed. The calculation results show that the actuator's output torque is decisive to the air gap's magnetic flux density between the stators and the swing disc. NiFe alloy magnetic cores were embedded into each winding center to increase the magnetic flux density. A special manufacturing process was developed for fabricating the stator windings on the ferrite substrate. Six copper windings and NiFe magnetic cores were electroplated onto the ferrite substrates. The corresponding six magnetic poles were configured to the SmCo permanent magnet on the swing disc. A magnetizing device with a particular size was designed and fabricated to magnetize the permanent magnet of the swing disc. The actuator prototype was fabricated, and the performance was tested. The results show that the actuator has a large output torque (40 μNm), fast response (5 ms), and a large swing angle (22°).
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http://dx.doi.org/10.3390/mi12020221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927025PMC
February 2021

Therapeutic Effects of Different Animal Bile Powders on Lipid Metabolism Disorders and Their Composition Analysis.

Chin J Integr Med 2021 Feb 20. Epub 2021 Feb 20.

Academy of Integrative Medicine Cardiovascular Research Institute, Fuzhou, 350122, China.

Objective: To compare the therapeutic effect of different animal bile powders on lipid metabolism disorders induced by high-fat diet in rats, and analyze the bioactive components of each animal bile powder.

Methods: Sixty Sprague-Dawley rats were randomly divided into 6 groups (n=10): normal diet control group, high-fat diet model group, high-fat diet groups orally treated with bear, pig, cow and chicken bile powders, respectively. Serum biochemical markers from the abdominal aorta in each group were analyzed. Changes in the body weight and liver weight were recorded. Pathohistological changes in the livers were examined. High performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was used to determine the composition of bioactive components in each animal bile powder.

Results: Treatment with different types of animal bile powders had different inhibitory effects on high-fat diet-induced increase of body weight and/or liver weight in rats, most notably in bear and pig bile powders (P<0.05). High-fat diet induced lipid metabolism disorder in rats, which could be reversed by treatment with all kinds of bile powders. Bear bile and chicken bile showed the most potent therapeutic effect against lipid metabolism disorder. Cow and bear bile effectively alleviated high-fat diet induced liver enlargement and discoloration, hepatocyte swelling, infiltration of inflammatory cells and formation of lipid vacuoles. Bioactive component analysis revealed that there were significant differences in the relative content of taurocholic acid, taurodeoxycholic acid and ursodeoxycholic acid among different types of animal bile. Interestingly, a unique component with molecular weight of 496.2738 Da, whose function has not yet been reported, was identified only in bear bile powder.

Conclusions: Different animal bile powders had varying therapeutic effect against lipid metabolism disorders induced by high-fat diet, and bear bile powder demonstrated the most effective benefits. Bioactive compositions were different in different types of animal bile with a novel compound identified only in bear bile powder.
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http://dx.doi.org/10.1007/s11655-021-3441-3DOI Listing
February 2021

Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia.

Front Immunol 2020 5;11:615941. Epub 2021 Jan 5.

Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Cancer immunotherapy by immune checkpoint blockade has been effective in the treatment of certain tumors. However, the association between immune checkpoints and autoimmune diseases remains elusive and requires urgent investigation. Primary immune thrombocytopenia (ITP), characterized by reduced platelet count and a consequent increased risk of bleeding, is an autoimmune disorder with a hyper-activated T cell response. Here, we investigated the contribution of immune checkpoint-related single-nucleotide polymorphisms (SNPs), including CD28, ICOS, PD1, TNFSF4, DNAM1, TIM3, CTLA4, and LAG3 to the susceptibility and therapeutic effects of ITP. In this case-control study, 307 ITP patients and 295 age-matched healthy participants were recruited. We used the MassARRAY system for genotyping immune checkpoint-related SNPs. Our results revealed that rs1980422 in CD28 was associated with an increased risk of ITP after false discovery rate correction (codominant, CT TT, OR = 1.788, 95% CI = 1.178-2.713, p = 0.006). In addition, CD28 expression at both the mRNA and protein levels was significantly higher in patients with CT than in those with the TT genotype (p = 0.028 and p = 0.001, respectively). Furthermore, the T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. In contrast, the T allele of LAG3 rs870849 was a protective factor for ITP severity, and the T allele of ICOS rs6726035 was protective against corticosteroid-resistance. The TT/CT genotypes of PD1 rs36084323 also showed an 8.889-fold increase in the risk of developing refractory ITP. This study indicates that immune checkpoint-related SNPs, especially CD28 rs1980422, may be genetic factors associated with the development and treatment of ITP patients. Our results shed new light on prognosis prediction, disease severity, and discovering new therapeutic targets.
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http://dx.doi.org/10.3389/fimmu.2020.615941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874092PMC
January 2021

Enhancing CO Catalytic Adsorption on an Fe Nanoparticle-Decorated LaSrFeO Cathode for CO Electrolysis.

ACS Appl Mater Interfaces 2021 Feb 9;13(7):8229-8238. Epub 2021 Feb 9.

Inner Mongolia Key Laboratory of Advanced Materials and Devices, Inner Mongolia University of Science and Technology, Baotou014010, P. R. China.

The development of cathode materials with high catalytic activity and low cost is a challenge for CO electrolysis based on solid oxide electrolysis cells. Herein, we report a low-cost and highly active metallic Fe nanoparticle-decorated Ruddlesden-Popper (La, Sr)FeO cathode catalyst (Fe-RPLSF), which shows a high oxygen vacancy concentration and robust CO reduction rate. At 850 °C, the current density of the electrolysis cell with the Fe-RPLSF cathode reaches -1920 mA cm at a voltage of 1.5 V, and the Faraday efficiency is as high as 100%. The polarization resistance at low frequency (0.1-10 Hz), which is the rate-limit step for CO electrolysis, significantly decreases with the exsolved Fe nanoparticles because of improved CO dissociative adsorption. Moreover, our electrolysis cell demonstrates acceptable short-term stability for direct CO electrolysis.
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http://dx.doi.org/10.1021/acsami.0c18997DOI Listing
February 2021

Qingda granule attenuates cardiac fibrosis via suppression of the TGF-β1/Smad2/3 signaling pathway in vitro and in vivo.

Biomed Pharmacother 2021 May 5;137:111318. Epub 2021 Feb 5.

Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address:

Cardiac fibrosis plays an important role in hypertension-related contractile dysfunction and heart failure. Qingda granule (QDG), derived from the Qingxuan Jiangya decoction, has been used clinically for more than 60 years to treat hypertension. However, the effect of QDG on hypertensive cardiac fibrosis remains largely unknown. The objective of this study was to investigate the effect of QDG on cardiac fibrosis and explore the underlying mechanism in vivo and in vitro. For in vivo experiments, 30 male spontaneously hypertensive rats were randomly divided into groups that received no QDG or one of three doses (0.45, 0.9 or 1.8 g/kg/day). Positive-control animals received valsartan (VAL, 7.2 mg/kg/day). Treatments were administered by gavage for 10 weeks. All three doses of QDG and VAL led to significantly lower blood pressure than in SHR animals. Besides, all three doses of QDG and VAL attenuated pathological changes in SHR animals. However, only intermediate, high concentrations of QDG and VAL led to significantly lower left ventricle ejection fraction and left ventricle fractional shortening than in SHR animals. Therefore, the minimum and effective QDG dose (intermediate concentration of QDG) was selected for subsequent animal experiments in this study. Our results showed that intermediate concentration of QDG also significantly mitigated the increases in levels of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), collagen III, transforming growth factor-β1 (TGF-β1) and in the ratio of phospho-Smad2/3 to total Smad2/3 protein in cardiac tissue, based on immunohistochemistry, Western blotting, and Masson staining. For in vitro experiments, primary cardiac fibroblasts were stimulated with 100 nM angiotensin II in the presence or absence of QDG. And we tested different concentrations of QDG (3.125, 6.25, 12.5, 25, 50 μg/mL) in the cell viability experiment. Our results showed that 3.125, 6.25 and 12.5 μg/mL of QDG treatment for 24 h didn't affect the cell viability of cardiac fibroblasts. Consistently, QDG at 6.25 or 12.5 μg/mL significantly reduced cell viability and down-regulated α-SMA in primary cardiac fibroblasts were stimulated with 100 nM angiotensin II. Therefore, QDG at 12.5 μg/mL was chosen for the following cell experiment. Our results showed that QDG at 12.5 μg/mL alleviated the increase of PCNA, collagen Ⅲ, TGF-β1 expression, and the ratio of phospho-Smad2/3 to total Smad2/3 protein. Our studies in vitro and in vivo suggest that QDG reduces blood pressure and cardiac fibrosis as well as protecting cardiac function, and that it exerts these effects in part by suppressing TGF-β1/Smad2/3 signaling.
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http://dx.doi.org/10.1016/j.biopha.2021.111318DOI Listing
May 2021

Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia.

Front Immunol 2020 20;11:603278. Epub 2021 Jan 20.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. We found that the expression of the immunoproteasome catalytic subunit, large multifunctional protease 2 (LMP2), was significantly upregulated in peripheral blood mononuclear cells of active ITP patients compared to those of healthy controls. No significant differences in LMP7 expression were observed between patients and controls. ML604440, an specific LMP2 inhibitor, had no significant impact on the platelet count of ITP mice, while ONX-0914 (an inhibitor of both LMP2 and LMP7) increased the number of platelets. assays revealed that ONX-0914 decreased the expression of FcγRI in ITP mice and decreased that of FcγRIII in ITP patients, inhibited the activation of CD4 T cells, and affected the differentiation of Th1 cells in patients with ITP. These results suggest that the inhibition of immunoproteasome is a potential therapeutic approach for ITP patients.
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http://dx.doi.org/10.3389/fimmu.2020.603278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855704PMC
January 2021

Eltrombopag inhibits Type I interferon-mediated antiviral signaling by decreasing cellular iron.

Biochem Pharmacol 2021 Feb 1;186:114436. Epub 2021 Feb 1.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address:

Thrombocytopenia is common among patients with viral hepatitis, limiting the use of antiviral therapy. Eltrombopag (EP) is a thrombopoietin receptor (TPO-R) agonist that has been approved for treatment of immune thrombocytopenia patients with hepatitis virus infection. Interferon-α (IFN-α) plays a crucial role in the antiviral response, and is recommended as the first-line agent for chronic hepatitis B patients. Here, we investigated whether EP inhibits the production of IFN-stimulated genes (ISGs) induced by IFN-α through the TPO-R-independent pathway by mediating reactive oxygen species production by iron chelation. Our results assessed the inhibitory effect of EP on IFN-α signaling, which contributes to the downregulation of ISGs produced by monocytes and sheds light on the underlying mechanisms using iron chelation to treat patients with hepatitis-related immunological thrombocytopenia.
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http://dx.doi.org/10.1016/j.bcp.2021.114436DOI Listing
February 2021

IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model.

Oxid Med Cell Longev 2021 19;2021:5913424. Epub 2021 Jan 19.

Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California, USA.

Aims: Blood clots play the primary role in neurological deficits after germinal matrix hemorrhage (GMH). Previous studies have shown a beneficial effect in blood clot clearance after hemorrhagic stroke. The purpose of this study is to investigate interleukin-19's role in hematoma clearance after GMH and its underlying mechanism of IL-20R1/ERK/Nrf2 signaling pathway.

Methods: A total of 240 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. rIL-19 was administered intranasally 1 hour post-GMH. IL-20R1 CRISPR was administered intracerebroventricularly, or Nrf2 antagonist ML385 was administered intraperitoneally 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, immunohistochemistry, histology, and hemoglobin assay were used to evaluate treatment regiments in the short- and long-term.

Results: Endogenous IL-19, IL-20R1, IL-20R2, and scavenger receptor CD163 were increased after GMH. rIL-19 treatment improved neurological deficits, reduced hematoma volume and hemoglobin content, reduced ventriculomegaly, and attenuated cortical thickness loss. Additionally, treatment increased ERK, Nrf2, and CD163 expression, whereas IL-20R1 CRISPR-knockdown plasmid and ML385 inhibited the effects of rIL-19 on CD163 expression.

Conclusion: rIL-19 treatment improved hematoma clearance and attenuated neurological deficits induced by GMH, which was mediated through the upregulation of the IL-20R1/ERK/Nrf2 pathways. rIL-19 treatment may provide a promising therapeutic strategy for the GMH patient population.
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http://dx.doi.org/10.1155/2021/5913424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837781PMC
January 2021

Epigallocatechin-3-gallate prevents inflammation and diabetes -Induced glucose tolerance through inhibition of NLRP3 inflammasome activation.

Int Immunopharmacol 2021 Apr 30;93:107412. Epub 2021 Jan 30.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address:

Epigallocatechin-3-gallate (EGCG), the primary polyphenol component of green tea, has been shown to inhibit both oxidation and inflammation. However, the exact mechanism through which EGCG exhibits anti-inflammatory effects remains unclear. In this study, we assessed the potential pathways by which EGCG regulates NLRP3 inflammasome activity in vitro. We found that EGCG inhibits caspase-1 activation and IL-1β secretion by suppressing NLRP3 inflammasome activation in mouse bone marrow-derived macrophages (BMDMs). EGCG was also observed to block NLRP3-mediated ASC speckle formation and to alleviate pyroptosis in BMDMs. In addition, EGCG treatment could improve high-fat diet (HFD)-induced glucose tolerance and prevent NLRP3 inflammasome-dependent inflammation in a mouse model of HFD-induced type 2 diabetes (T2D). Taken together, our results show that EGCG is a general inhibitor of NLRP3 inflammasome activation and administration of EGCG in T2D mice could improve glucose tolerance in vivo.
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http://dx.doi.org/10.1016/j.intimp.2021.107412DOI Listing
April 2021

Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer's Disease or Mild Cognitive Impairment.

J Alzheimers Dis 2021 ;80(1):299-310

Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.

Background: Patients with Alzheimer's disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare.

Objective: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI.

Methods: Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected.

Results: Although there was no difference in the microbial α-diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI.

Conclusion: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.
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http://dx.doi.org/10.3233/JAD-201040DOI Listing
January 2021

Effects of Qing Hua Chang Yin on lipopolysaccharide‑induced intestinal epithelial tight junction injury in Caco‑2 cells.

Mol Med Rep 2021 Mar 26;23(3). Epub 2021 Jan 26.

Spleen and Stomach Research Room, Second People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350003, P.R. China.

Disruption of the intestinal mucosal barrier integrity is a pathogenic process in inflammatory bowel disease (IBD) development, and is therefore considered a drug discovery target for IBD. The well‑known traditional Chinese formulation Qing Hua Chang Yin (QHCY) has been suggested as a potential therapeutic agent for the treatment of ulcerative colitis. However, the possible underlying molecular mechanisms regarding its therapeutic effect remain unclear. Consequently, the present study investigated the effects of QHCY on lipopolysaccharide (LPS)‑induced loss of intestinal epithelial barrier integrity using the Caco‑2 cell model of intestinal epithelium. QHCY reversed the LPS‑induced decrease in transepithelial electrical resistance and significantly alleviated the increased fluorescently‑labeled dextran 4 flux caused by LPS. Moreover, QHCY upregulated the mRNA and protein expression levels of occludin, zona occludens‑1 and claudin‑1 in LPS‑exposed Caco‑2 cells. In conclusion, QHCY was able to protect intestinal epithelial barrier integrity following an inflammatory insult; the protective effects of QHCY may be mediated by modulation of the expression of tight junction proteins.
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http://dx.doi.org/10.3892/mmr.2021.11844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821280PMC
March 2021

Donor KIR3DL1/receptor HLA-Bw4-80I Combination Reduces Acute Leukemia Relapse after Umbilical Cord Blood Transplantation without in Vitro T-cell Depletion.

Mediterr J Hematol Infect Dis 2021 1;13(1):e2021005. Epub 2021 Jan 1.

Department of Hematology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, 230001, China.

Background: Donor natural killer (NK) cell alloreactivity in umbilical cord bone marrow transplantation (UCBT) can lead to leukemic relapse. However, NK cell function is calibrated by interaction with human leukocyte antigens (HLAs). This study aimed to investigate graft-resistant leukemia after transplantation and compared specific genotypes of killer immunoglobulin-like receptors (KIRs) in donors and human leukocyte antigen ligands in patients.

Methods: We retrospectively analyzed 232 patients with acute leukemia from a single center. Patients had undergone UCBT with myeloablative conditioning and without anti-thymocyte globulin. We identified the KIR genotypes of cord blood donors using polymerase chain reaction with sequence-specific primers. All of the donors contained KIR3DL1.

Results: The patients were divided into three groups according to the HLA-B locus. The donor KIR3DL1 and recipient HLA-Bw4-80I combination was predictive of being highly educated and was associated with a lower relapse (=0.006) and better overall survival (probability of relapse=0.13, < 0.001) than the uneducated group. We found no significant increase in the incidence of acute or chronic graft-versus-host disease.

Conclusions: Our data suggest that the donor KIR3DL1/receptor and HLA-Bw4-80I combination in UCBT results in stronger graft-versus-leukemia effects and improved outcomes in patients with acute leukemia.
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http://dx.doi.org/10.4084/MJHID.2021.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813285PMC
January 2021

Nanoscale localized contacts for high fill factors in polymer-passivated perovskite solar cells.

Science 2021 01;371(6527):390-395

Research School of Electrical, Energy and Materials Engineering, The Australian National University, Canberra Australian Capital Territory 2600, Australia.

Polymer passivation layers can improve the open-circuit voltage of perovskite solar cells when inserted at the perovskite-charge transport layer interfaces. Unfortunately, many such layers are poor conductors, leading to a trade-off between passivation quality (voltage) and series resistance (fill factor, FF). Here, we introduce a nanopatterned electron transport layer that overcomes this trade-off by modifying the spatial distribution of the passivation layer to form nanoscale localized charge transport pathways through an otherwise passivated interface, thereby providing both effective passivation and excellent charge extraction. By combining the nanopatterned electron transport layer with a dopant-free hole transport layer, we achieved a certified power conversion efficiency of 21.6% for a 1-square-centimeter cell with FF of 0.839, and demonstrate an encapsulated cell that retains ~91.7% of its initial efficiency after 1000 hours of damp heat exposure.
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http://dx.doi.org/10.1126/science.abb8687DOI Listing
January 2021

Tumor Necrosis Factor-α Blockade Corrects Monocyte/Macrophage Imbalance in Primary Immune Thrombocytopenia.

Thromb Haemost 2021 Jan 14. Epub 2021 Jan 14.

Department of Haematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. Monocytes and macrophages are the major cells involved in autoantibody-mediated platelet clearance in ITP. In the present study, we found increased percentages of peripheral blood proinflammatory CD16 monocytes and elevated frequencies of splenic tumor necrosis factor-α (TNF-α)-expressing macrophages in ITP patients compared with healthy controls. Concurrently, we observed elevated TNF-α secretion in plasma as well as higher TNF-α mRNA expression in total peripheral blood mononuclear cells and CD14 monocytes of ITP patients. Of note, in vitro TNF-α blockade with neutralizing antibody remarkably reduced polarization to M1 macrophages by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, TNF-α blockade dampened macrophage phagocytosis and T cell stimulatory capacity. Finally, in passive and active murine models of ITP, anti-TNF-α therapy reduced the number of nonclassical monocytes and M1 macrophages, ameliorated the retention of platelets in spleen and liver, and increased the platelet count of ITP mice. Taken together, TNF-α blockade decreased the number and function of proinflammatory subsets of monocytes and macrophages by inhibiting the NF-κB signaling pathway, leading to remarkable attenuation of antibody-mediated platelet destruction. Thus, TNF-α blockade may be a promising therapeutic strategy for the management of ITP.
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http://dx.doi.org/10.1055/s-0040-1722186DOI Listing
January 2021

Qingjie Fuzheng Granules regulates cancer cell proliferation, apoptosis and tumor angiogenesis in colorectal cancer xenograft mice via Sonic Hedgehog pathway.

J Gastrointest Oncol 2020 Dec;11(6):1123-1134

Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Background: Sonic Hedgehog (SHh) signaling pathway plays a critical role in cell proliferation, apoptosis, and tumor angiogenesis in various types of malignancies including colorectal cancer (CRC). Qingjie Fuzheng Granules (QFG) is a traditional Chinese medicinal formula, which has been clinically used in various cancer treatments, including CRC. In this study, we explored the potential molecular mechanisms of QFG treatment effects on CRC via the SHh pathway.

Methods: A CRC HCT-116 xenograft mouse model was utilized for all experiments. Mice were treated with intra-gastric administration of 1 g/kg of QFG or saline 6 days a week for 28 days (4 weeks). Body weight, length and shortest diameter of the tumor were measured every 3 days. At the end of the treatment, the tumor weight was measured. TUNEL staining assays were used to detect tumor apoptosis. Western blot and immunohistochemistry (IHC) assays were used to detect the expression of relative proteins.

Results: In our results, QFG inhibited the increase of tumor volume and weight, and exhibited no impact on mouse body weight. Furthermore, QFG significantly decreased the expression of SHh, Smo and Gli proteins, indicating the action of SHh signaling. Consequently, the expression of pro-proliferative survivin, Ki-67, Cyclin-D1 and CDK4 were decreased and expression of anti-proliferative p21 was increased. The pro-apoptotic Bax/Bcl-2 ratio, cle-caspase-3 and TUNEL-positive cell percentage in tumor tissues were increased. Meanwhile, the pro-angiogenic VEGF-A and VEGFR-2 expression was down-regulated.

Conclusions: QFG inhibited CRC cell proliferation and promoted CRC cell apoptosis and tumor angiogenesis through the suppression of SHh pathway, suggesting that QFG could be a potential therapeutic drug for CRC.
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http://dx.doi.org/10.21037/jgo-20-213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807284PMC
December 2020

Signaling pathways of genetic variants and miRNAs in the pathogenesis of myasthenia gravis.

Gland Surg 2020 Dec;9(6):1933-1944

School of Electronic Information in the Yunnan Normal University, Kunming, China.

Background: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder causing muscle weakness and characterized by a defect in synaptic transmission at the neuromuscular junction. The pathogenesis of this disease remains unclear. We aimed to predict the key signaling pathways of genetic variants and miRNAs in the pathogenesis of MG, and identify the key genes among them.

Methods: We searched published information regarding associated single nucleotide polymorphisms (SNPs) and differentially-expressed miRNAs in MG cases. We search of SNPs and miRNAs in literature databases about MG, then we used bioinformatic tools to predict target genes of miRNAs. Moreover, functional enrichment analysis for key genes was carried out utilizing the Cytoscape-plugin, known as ClueGO. These key genes were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then a miRNA-target gene regulatory network was established to screen key genes.

Results: Five genes containing SNPs associated with MG risk were involved in the inflammatory bowel disease (IBD) signaling pathway, and was the key gene. and were predicted to be targeted by the 18 miRNAs and to act as the key genes in adherens, junctions, apoptosis, or cancer-related pathways respectively. These five key genes containing SNPs or targeted by miRNAs were found to be involved in negative regulation of T cell differentiation.

Conclusions: We speculate that SNPs cause the genes to be defective or the miRNAs to downregulate the factors that subsequently negatively regulate regulatory T cells and trigger the onset of MG.
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http://dx.doi.org/10.21037/gs-20-39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804555PMC
December 2020

Intravenous versus Volatile Anesthetic Effects on Postoperative Cognition in Elderly Patients Undergoing Laparoscopic Abdominal Surgery.

Anesthesiology 2021 03;134(3):381-394

Background: Delayed neurocognitive recovery after surgery is associated with poor outcome. Most surgeries require general anesthesia, of which sevoflurane and propofol are the most commonly used inhalational and intravenous anesthetics. The authors tested the primary hypothesis that patients with laparoscopic abdominal surgery under propofol-based anesthesia have a lower incidence of delayed neurocognitive recovery than patients under sevoflurane-based anesthesia. A second hypothesis is that there were blood biomarkers for predicting delayed neurocognitive recovery to occur.

Methods: A randomized, double-blind, parallel, controlled study was performed at four hospitals in China. Elderly patients (60 yr and older) undergoing laparoscopic abdominal surgery that was likely longer than 2 h were randomized to a propofol- or sevoflurane-based regimen to maintain general anesthesia. A minimum of 221 patients was planned for each group to detect a one-third decrease in delayed neurocognitive recovery incidence in propofol group compared with sevoflurane group. The primary outcome was delayed neurocognitive recovery incidence 5 to 7 days after surgery.

Results: A total of 544 patients were enrolled, with 272 patients in each group. Of these patients, 226 in the propofol group and 221 in the sevoflurane group completed the needed neuropsychological tests for diagnosing delayed neurocognitive recovery, and 46 (20.8%) in the sevoflurane group and 38 (16.8%) in the propofol group met the criteria for delayed neurocognitive recovery (odds ratio, 0.77; 95% CI, 0.48 to 1.24; P = 0.279). A high blood interleukin-6 concentration at 1 h after skin incision was associated with an increased likelihood of delayed neurocognitive recovery (odds ratio, 1.04; 95% CI, 1.01 to 1.07; P = 0.007). Adverse event incidences were similar in both groups.

Conclusions: Anesthetic choice between propofol and sevoflurane did not appear to affect the incidence of delayed neurocognitive recovery 5 to 7 days after laparoscopic abdominal surgery. A high blood interleukin-6 concentration after surgical incision may be an independent risk factor for delayed neurocognitive recovery.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000003680DOI Listing
March 2021

Anlotinib Overcomes Multiple Drug Resistant Colorectal Cancer Cells via Inactivating PI3K/AKT Pathway.

Anticancer Agents Med Chem 2021 Jan 11. Epub 2021 Jan 11.

Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122. China.

Background: Anlotinib is a multi-target tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the mechanisms of how anlotinib mediates drug-resistance of colorectal cancer have not been fully described. Particularly the potential mechanisms regarding to the inhibition of proliferation and induction of apoptosis remain unknown.

Objective: In this study, we intended to study the effect and related-mechanism of the proliferation, migration, invasion and induced apoptosis of anlotinib overcoming multidrug resistant colorectal cancer cells through in vitro experiments.

Methods: Cell viability was determined by MTT assays and the resistant index was calculated. Colony formation and PI/RNase Staining were used for testing the proliferation of resistant cells. DAPI staining and Annexin V-FITC/PI staining were used to detect cell apoptosis. Migration and invasion were examined by transwell. Protein expression and activation of PI3K/AKT pathway were detected by western blot. LY294002 was used to verify whether anlotinib overcomes the drug-resistance of CRC cells by inactivating the PI3K/AKT pathway.

Results: The results showed that the HCT-8/5-FU cells were resistant to multiple chemotherapy drugs (5-FU, ADM and DDP). Anlotinib significantly inhibited the cell viability, proliferation, migration, invasion and induced the cell apoptosis. Moreover, anlotinib downregulated the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, MMP-9, vimentin and N-cadherin, but up-regulated cleaved-caspase-3, Bax and E-cadherin and blocked the activity of the PI3K/AKT in HCT-8/5-FU cells. We found anlotinib and LY294002 overcame the drug resistance of HCT-8/5-FU cells by reducing the expression of PI3K/p-AKT.

Conclusions: Anlotinib inhibited the proliferation, migration, invasion and induced apoptosis of HCT-8/5-FU cells, and the mechanisms may be that anlotinib conquered multidrug resistance of colorectal cancer cells via inactivating of PI3K/AKT pathway.
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http://dx.doi.org/10.2174/1871520621666210112113852DOI Listing
January 2021

Babao Dan () Alleviates 5-Fluorouracil-Induced Intestinal Damage via Wnt/β-Catenin Pathway.

Chin J Integr Med 2021 Jan 9. Epub 2021 Jan 9.

Academy of Integrative Medicine, Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.

Objective: To evaluate the protective function of Babao Dan (, BBD) on 5-flurouracil (5-FU)-induced intestinal mucositis (IM) and uncover the underlying mechanism.

Methods: A total of 18 male mice were randomly divided into 3 groups by a random number table, including control, 5-FU and 5-FU combined BBD groups, 6 mice in each group. A single intraperitoneal injection of 5-FU (150 mg/kg) was performed in 5-FU and 5-FU combined BBD groups on day 0. Mice in 5-FU combined BBD group were gavaged with BBD (250 mg/kg) daily from day 1 to 6. Mice in the control group were gavaged with saline solution for 6 days. The body weight and diarrhea index of mice were recorded daily. On the 7th day, the blood from the heart of mice was collected to analyze the proportional changes of immunological cells, and the mice were subsequently euthanized by mild anesthesia with 2% pentobarbital sodium. Colorectal lengths and villus heights were measured. Intestinal-cellular apoptosis and proliferation were evaluated by Tunel assay and immunohistochemical staining of proliferating cell nuclear antigen, respectively. Immunohistochemistry and Western blot were performed to investigate the expressions of components in Wnt/β-catenin pathway (Wnt3, LRP5, β-catenin, c-Myc, LRG5 and CD44).

Results: BBD obviously alleviated 5-FU-induced body weight loss and diarrhea, and reversed the decrease in the number of white blood cells, including monocyte, granulocyte and lymphocyte, and platelet (P<0.01). The shortening of colon caused by 5-FU was also reversed by BBD (P<0.01). Moreover, BBD inhibited apoptosis and promoted proliferation in jejunum tissues so as to reduce the intestinal mucosal damage and improve the integrity of villus and crypts. Mechanically, the expression levels of Wnt/β -catenin mediators such as Wnt3, LRP5, β-catenin were upregulated by BBD, activating the transcription of c-Myc, LRG5 and CD44 (P<0.01).

Conclusions: BBD attenuates the adverse effects induced by 5-FU via Wnt/β-catenin pathway, suggesting it may act as a potential agent against chemotherapy-induced intestinal mucositis.
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http://dx.doi.org/10.1007/s11655-021-3282-0DOI Listing
January 2021

ZnO nanorods/FeO-graphene oxide/metal-organic framework nanocomposite: recyclable and robust photocatalyst for degradation of pharmaceutical pollutants.

Environ Sci Pollut Res Int 2021 Jan 7. Epub 2021 Jan 7.

Department of Analytical Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, Jiangsu Province, China.

Nanosized semiconductors are widely utilized as solar energy based photocatalyst. However, the deficiencies such as poor adsorption toward contaminants and recyclability issues, rapid recombination of photo-introduced radicals, and deactivation by scavengers are still be the obstacle. To addressing those obstacles, zeolitic imidazolate framework-8 (ZIF-8), photosensitive ZnO, and paramagnetic FeO were anchored on conductive graphene oxide (GO) to prepare a nanocomposite photocatalyst ZnO/FeO-GO/ZIF. The photocatalyst showed good robustness to scavengers of hydroxyl radicals (OH), superoxide radicals (O), and hole (h) with hydrophobic ZIF-8 modified surface. Finally, four pharmaceuticals (sulfamethazine, metronidazole, norfloxacin, and 4-acetaminophen) were degraded rapidly under simulated solar irradiation for 1 h, and the photocatalyst could be recycled at least ten times without obvious deactivation. The final results show that combination of semiconductor, graphene oxide and ZIF-8 is a good idea for construction of efficient photocatalyst. It offers new views in interface modification of nanomaterials, photocatalysis, and adsorption.
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http://dx.doi.org/10.1007/s11356-020-12253-2DOI Listing
January 2021