Publications by authors named "Aijun Liu"

137 Publications

Rhein promotes the proliferation of keratinocytes by targeting oestrogen receptors for skin ulcer treatment.

BMC Complement Med Ther 2022 Aug 5;22(1):209. Epub 2022 Aug 5.

Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.

Background: The Sheng-ji Hua-yu (SJHY) formula is a quite effective Traditional Chinese Medicines (TCM) in the treatment of delayed diabetic wounds. Previous research has shown that the SJHY formula has significant anti-inflammatory and wound-healing effects, but the precise mechanism remains unknown. The purpose of this study was to evaluate the effects of rhein, a compound extracted from SJHY formula, in keratinocytes and to investigate the underlying mechanisms.

Methods: Microscale thermophoresis (MST) technology was used to confirm that rhein binds directly to oestrogen receptors (ERs). Rhein was then used to treat keratinocytes in vitro. Cell cycle and proliferation analysis, Real-time polymerase chain reaction (RT-PCR) and Western-blot were conducted.

Results: Rhein increased the proportion of cells in the S phase of the cell cycle and promoted keratinocyte proliferation. ICI 182,780, an ER inhibitor, was also used to treat keratinocytes. The expression of c-myc mRNA and protein induced by rhein was antagonized by ICI 182,780, indicating that this induction is ER dependent. Intervention with ICI 182,780 had no effect on the upregulation of FosB and JunD, indicating that activator protein 1 (AP-1) members (FosB and JunD) are involved in rhein-induced c-myc mRNA and protein expression but does not require the ER.

Conclusion: The present study found that rhein stimulates keratinocyte proliferation by activating the oestrogen signalling pathway via the oestrogen receptor, which induces the expression of c-myc in collaboration with FosB and JunD, thereby accelerating the process of re-epithelialization.
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http://dx.doi.org/10.1186/s12906-022-03691-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354312PMC
August 2022

Bone-Related Extramedullary Disease in Newly Diagnosed Myeloma Patients is an Independent Poor Prognostic Predictor.

Clin Med Insights Oncol 2022 18;16:11795549221109500. Epub 2022 Jul 18.

Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China.

Background: Bone-related extramedullary disease (EMD-B) is mass of clonal plasma cells derived from adjacent bone lesions and has obvious heterogeneities in clinical outcomes. This retrospective study aims to evaluate the treatment outcomes and long-term prognosis of newly diagnosed myeloma patients with EMD-B.

Methods: This was a retrospective study conducted in Beijing Chaoyang Hospital from January 1, 2010 to December 31, 2019. Seventy-seven newly diagnosed multiple myeloma patients with EMD-B were selected. Propensity score matching (1:2) was used to match patients with and without EMD-B. After matching, 132 patients without extramedullary disease (non-EMD) were included in the study. All patients received bortezomib-based regimens as induction therapy.

Results: After matching, baseline data of the 2 groups were comparable. The Cox regression analysis of patients with EMD-B showed that age, paravertebral lesions, and immunoglobulin D (IgD) type may have adverse effects on survival. Bone-related extramedullary disease at new diagnosis was a risk predictor of survival (hazard ration [HR] = 1.80, 95% confidence interval [CI]: 1.09-2.98,  = .022). The median survival time of the EMD-B group was significantly shorter than that of the non-EMD group (52 months vs 96 months,  = .043). Induction therapy did not show any significant differences in effectiveness between the 2 groups. Autologous stem cell transplantation (ASCT) significantly increased complete remission rate of patients with EMD-B (EMD-B vs non-EMD: no ASCT 15.7% vs 31.9%,  = .035; ASCT 42.3% vs 48.8%,  = .626) and improved their median overall survival rate (EMD-B vs non-EMD: no ASCT 49 months vs 75 months,  = .003; ASCT not reached vs 96 months,  = .505).

Conclusions: This study demonstrated that newly diagnosed myeloma patients with EMD-B had poor outcomes, which could be improved by ASCT.
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http://dx.doi.org/10.1177/11795549221109500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301125PMC
July 2022

A multiomics and network pharmacological study reveals the neuroprotective efficacy of Fu-Fang-Dan-Zhi tablets against glutamate-induced oxidative cell death.

Comput Biol Med 2022 Jul 16;148:105873. Epub 2022 Jul 16.

School of Pharmacy, Second Military Medical University, Shanghai, China. Electronic address:

Neuroprotective therapy after ischemic stroke remains a significant need, but current measures are still insufficient. The Fu-Fang-Dan-Zhi tablet (FFDZT) is a proprietary Chinese medicine clinically employed to treat ischemic stroke in the recovery period. This work aims to systematically investigate the neuroprotective mechanism of FFDZT. A systems strategy that integrated metabolomics, transcriptomics, network pharmacology, and in vivo and in vitro experiments was used. First, middle cerebral artery occlusion (MCAO) model rats were treated with FFDZT. FFDZT treatment significantly reduced the infarct volume in the brains of middle cerebral artery occlusion (MCAO) model rats. Then, samples of serum and brain tissue were taken for metabolomics and transcriptomics studies, respectively; gene expression profiles of MCF7 cells treated with FFDZT and its 4 active compounds (senkyunolide I, formononetin, drilodefensin, and tanshinone IIA) were produced for CMAP analysis. Computational analysis of metabolomics and transcriptomics results suggested that FFDZT regulated glutamate and oxidative stress-related metabolites (2-hydroxybutanoic acid and 2-hydroxyglutaric acid), glutamate receptors (NMDAR, KA, and AMPA), glutamate involved pathways (glutamatergic synapse pathway; d-glutamine and d-glutamate metabolism; alanine, aspartate and glutamate metabolism), as well as the reactive oxygen species metabolic process. CMAP analysis indicated that two active ingredients of FFDZT (tanshinone ⅡA and senkyunolide I) could act as glutamate receptor antagonists. Next, putative therapeutic targets of FFDZT's active ingredients identified in the brain were collected from multiple resources and filtered by statistical criteria and tissue expression information. Network pharmacological analysis revealed extensive interactions between FFDZT's putative targets, anti-IS drug targets, and glutamate-related enzymes, while the resulting PPI network exhibited modular topology. The targets in two of the modules were significantly enriched in the glutamatergic synapse pathway. The interactions between FFDZT's ingredients and important targets were verified by molecular docking. Finally, in vitro experiments validated the effects of FFDZT and its ingredients in suppressing glutamate-induced PC12 cell injury and reducing the generation of reactive oxygen species. All of our findings indicated that FFDZT's efficacy for treating ischemic stroke could be due to its neuroprotection against glutamate-induced oxidative cell death.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105873DOI Listing
July 2022

Toward Therapeutic Drug Monitoring of Lenalidomide in Hematological Malignancy? Results of an Observational Study of the Exposure-Safety Relationship.

Front Pharmacol 2022 23;13:931495. Epub 2022 Jun 23.

Department of Hematology, Peking University Third Hospital, Beijing, China.

Continuous lenalidomide (LEN) therapy is important to achieve a therapeutic effect in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). However, despite dose adjustment according to kidney function, many patients discontinue LEN therapy because of hematological toxicity. To date, therapeutic drug monitoring (TDM) of LEN has not been performed in oncology, and no target concentration level has been yet defined. The aim of this study was to evaluate the exposure-safety relationship of LEN and determine the target concentration for toxicity. A prospective observational study was designed and implemented. Blood samples were collected at 0.5 h (trough concentration, C) before oral administration and 1 h (C) thereafter on the day. Clinical data were gathered from patients' medical records and laboratory reports. Outcome measures of hematological toxicity were defined by the Common Terminology Criteria for Adverse Events. The concentration values were dichotomized by receiver operating characteristic (ROC) curve analysis, and the association between exposure and outcome was determined using the logistic regression model. Out of the 61 patients enrolled in this study, 40 (65.57%) had MM, and 21 (34.43%) had NHL. Hematological toxicity was reported in 15 (24.59%) patients. The LEN C showed remarkable differences ( 0.031) among patients with or without hematological toxicity, while no association between C values and toxicity was noted (>0.05). By ROC analysis, a C threshold of 10.95 ng/mL was associated with the best sensitivity/specificity for toxicity events (AUC = 0.687; sensitivity = 0.40; specificity = 0.935). By multivariate logistic regression, an LEN C below 10.95 ng/mL was associated with a markedly decreased risk of hematological toxicity (<10.95 ng/mL vs. >10.95 ng/mL: OR = 0.023, 95% CI = 0.002-0.269; = 0.003). We demonstrate that the LEN trough concentration correlates with hematological toxicity, and the C threshold for hematological toxicity (10.95 ng/mL) is proposed. Altogether, LEN TDM appears to be a new approach to improve medication safety and achieve continuous treatment for patients with NHL or MM in routine clinical care.
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http://dx.doi.org/10.3389/fphar.2022.931495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259783PMC
June 2022

H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity.

Nat Chem Biol 2022 Jun 23. Epub 2022 Jun 23.

Department of Chemistry, Tsinghua-Peking Joint Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China.

Ubiquitination-dependent histone crosstalk plays critical roles in chromatin-associated processes and is highly associated with human diseases. Mechanism studies of the crosstalk have been of the central focus. Here our study on the crosstalk between H2BK34ub and Dot1L-catalyzed H3K79me suggests a novel mechanism of ubiquitination-induced nucleosome distortion to stimulate the activity of an enzyme. We determined the cryo-electron microscopy structures of Dot1L-H2BK34ub nucleosome complex and the H2BK34ub nucleosome alone. The structures reveal that H2BK34ub induces an almost identical orientation and binding pattern of Dot1L on nucleosome as H2BK120ub, which positions Dot1L for the productive conformation through direct ubiquitin-enzyme contacts. However, H2BK34-anchored ubiquitin does not directly interact with Dot1L as occurs in the case of H2BK120ub, but rather induces DNA and histone distortion around the modified site. Our findings establish the structural framework for understanding the H2BK34ub-H3K79me trans-crosstalk and highlight the diversity of mechanisms for histone ubiquitination to activate chromatin-modifying enzymes.
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http://dx.doi.org/10.1038/s41589-022-01067-7DOI Listing
June 2022

Electroacupuncture of the Baihui and Shenting acupoints for vascular dementia in rats through the miR-81/IL-16/PSD-95 pathway.

Ann Transl Med 2022 May;10(10):540

Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.

Background: There is currently no effective treatment for vascular dementia (VaD). Scalp electroacupuncture (EA) has served clinically as an alternative treatment for VaD, but its mechanism is still unclear. In this study, we investigated the effect of EA at the Baihui (GV 20) and Shenting (GV 24) acupoints on spatial learning and memory ability, and the expression level of (), (), and postsynaptic density protein-95 (PSD-95) in the frontal cortex of VaD rats.

Methods: Male Sprague-Dawley rats were randomly divided into four groups, sham, VaD, non-acupuncture (non-AP) and EA group. The VaD model was established by permanent bilateral occlusion of the common carotid arteries. Morris Water Maze was used to assess the rats' spatial learning and memory. Immunochemistry (IHC), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blot analysis were performed to detect the expression level of , , and PSD-95. Finally, luciferase assay was used to determine the effect of on expression in PC12 cells.

Results: The space exploration experiment of MWM showed the time and distance of the rat's activities around the platform were decreased in the EA group. Compared to the VaD and non-AP group, the number of terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling (TUNEL)-positive frontal cortical neurons was significantly decreased in EA group. The number of the PSD-95-positive cells and the expression level in the frontal cortical in the EA group was dramatically increased in comparison with the other groups. In the PC12 cell validation experiment, expression level was reduced under the condition of the mimic treatment, while increased in the inhibitor group. The PSD-95 protein level was up-regulated in the small interfering () group compared to the groups with or without oxygen/glucose deprivation/reperfusion (OGD/R) conditions (P<0.05). However, this was abolished by mimic.

Conclusions: In VaD rats, EA may improve spatial learning and memory through miR-81/IL-16/PSD-95 pathway.
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http://dx.doi.org/10.21037/atm-22-2068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201176PMC
May 2022

Improved depressive symptoms in patients with refractory Gilles de la Tourette syndrome after deep brain stimulation of posteroventral globus pallidus interna.

Brain Behav 2022 07 27;12(7):e2635. Epub 2022 May 27.

Department of Neurosurgery, the Chinese PLA General Hospital, Haidian, Beijing, China.

Objective: Deep brain stimulation (DBS) has been used on drug-resistant Gilles de la Tourette syndrome (GTS) for more than two decades until now, but the stimulating targets are still under exploration until now. In this study, the authors reported the efficacy of the bilateral posteroventral globus pallidus interna (GPi) DBS on tic severity and neuropsychiatry symptoms of seven individuals with GTS.

Method: Seven patients with drug-resistant GTS were enrolled in this study. The severity of these patients was evaluated with Yale Global Tics Severity Scale (YGTSS), Yale Brown Obsessive Compulsive Scale (YBOCS), Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and Global Assessment of Functioning Scale (GAF). Bilateral posteroventral GPi were selected as the permanent stimulating targets. Follow-up period was at least 5 years after surgery in the enrolled patients.

Results: After surgery, one patient reported no improvement during the follow-up period, and a device removal surgery was performed. The other six patients reported minor to significant improvement. The overall YGTSS, YBOCS, HAMA HAMD, and GAF scores of these patients were changed positively after surgery, but only the improvement of the motor tic and HAMD scores had a statistical difference. No surgical complication was reported.

Conclusions: Bilateral posteroventral GPi DBS could relieve the motor tics and depressive symptoms of the enrolled patients significantly, but the vocal tics and other psychiatric symptoms presented a progression without statistical difference during the follow-up period. The results of this study suggested that bilateral posteroventral GPi are effective targets for the motor tics in GTS patients, especially with prominent depressive symptoms.
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http://dx.doi.org/10.1002/brb3.2635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304849PMC
July 2022

Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation.

Commun Biol 2022 05 25;5(1):495. Epub 2022 May 25.

Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.

The chondrogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) has been used in the treatment and repair of cartilage defects; however, the in-depth regulatory mechanisms by which RNA modifications are involved in this process are still poorly understood. Here, we found that Sox9, a critical transcription factor that mediates chondrogenic differentiation, exhibited enhanced translation by ribosome sequencing in chondrogenic pellets, which was accompanied by increased 5-methylcytosine (mC) and N6-methyladenosine (mA) levels. Nsun4-mediated mC and Mettl3-mediated mA modifications were required for Sox9-regulated chondrogenic differentiation. Interestingly, we showed that in the 3'UTR of Sox9 mRNA, Nsun4 catalyzed the mC modification and Mettl3 catalyzed the mA modification. Furthermore, we found that Nsun4 and Mettl3 co-regulated the translational reprogramming of Sox9 via the formation of a complex. Surface plasmon resonance (SPR) assays showed that this complex was assembled along with the recruitment of Ythdf2 and eEF1α-1. Moreover, BMSCs overexpressing Mettl3 and Nsun4 can promote the repair of cartilage defects in vivo. Taken together, our study demonstrates that mC and mA co-regulate the translation of Sox9 during the chondrogenic differentiation of BMSCs, which provides a therapeutic target for clinical implications.
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http://dx.doi.org/10.1038/s42003-022-03420-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133052PMC
May 2022

Association between LDL/HDL ratio and in-stent restenosis in patients with acute coronary syndrome after stent implantation.

Biomark Med 2022 06 16;16(9):673-680. Epub 2022 May 16.

Department of Cardiology, Benxi Central Hospital, Benxi, Liaoning Province, 117000, China.

The relationship between LDL/HDL ratio and in-stent restenosis in acute coronary syndrome is unknown. This observational study recruited 256 patients with acute coronary syndrome who were being followed up by angiography after stenting. The patients were divided into in-stent restenosis (59%) and non-in-stent restenosis (41%) groups. Three stepwise multivariate logistic regression models and area under the curve were conducted to determine the role of LDL/HDL ratio in predicting in-stent restenosis. LDL/HDL ratio was significantly associated with risk of in-stent restenosis (odds ratio ≈ 2.00; p < 0.05 for all) in three models. A good predictive performance of LDL/HDL ratio on in-stent restenosis was found with an area under the curve of 0.74. LDL/HDL ratio was independently associated with the risk of in-stent restenosis in acute coronary syndrome.
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http://dx.doi.org/10.2217/bmm-2021-1089DOI Listing
June 2022

Mid-Term Results and Risk Factors For 10 Years of Functional Single Ventricle Associated With Total Anomalous Pulmonary Venous Connection.

Heart Surg Forum 2022 Mar 8;25(2):E181-E186. Epub 2022 Mar 8.

Pediatric Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

Background: There are few surgical treatment results in elderly patients with functional single ventricle (FSV) and total anomalous pulmonary venous connection (TAPVC). We retrospectively analyzed 10 years of mid-term surgical treatment results and risk factors of these age-specific people.

Methods: Between March 2008 and December 2018, 43 consecutive patients with FSV and TAPVC received initial surgical palliation in our center. There were 20 cases of supracardiac TAPVC, 21 of cardiac type, and two cases of mixed type. Initial surgical palliation procedures involved pulmonary artery banding (PAB) for patients, modified Blalock-Taussing shunt (mBTs) for five patients, and bidirectional Glenn (BDG) for 34 patients. TAPVC repair was performed in 12 patients during BDG.

Results: The 1-year and 5-year overall survival rates were 69.7% and 62.8%, respectively. In TAPVC repair group and non-TAPVC repair group, the 1-year overall survival rates after initial surgical palliation were 41.7 and 80.5%, respectively, and the 3-year ones were 25% and 77%, respectively. There were significant differences in the type of TAPVC (P < 0.001), preoperative pulmonary venous obstruction (P = 0.001), and overall mortality (P = 0.001) between these two groups. Cox univariate and multivariable analysis indicated concomitant TAPVC repair was the only risk factor for mortality.

Conclusions: The mid-term results of surgical treatment of FSV and TAPVC, especially for patients who underwent concomitant TAPVC repair, remain poor. TAPVC repair may be a priority over single-ventricular palliative surgery for patients with FSV and TAPVC.
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http://dx.doi.org/10.1532/hsf.4343DOI Listing
March 2022

Comprehensive Landscape of Prognostic Significance and Immune Characteristics of Myosins in Squamous Cell Carcinoma of the Head and Neck.

J Immunol Res 2022 18;2022:5501476. Epub 2022 Apr 18.

School of Clinical Medicine, Weifang Medical University, Weifang, China.

Myosin superfamily, a large and diverse family of molecular motors important for cell motility and migration, has been illustrated to play contradictory roles during the development of several kinds of tumors. However, the function and prognostic values of MYOs in head and neck squamous cell carcinoma (HNSCC) still remain largely unknown. In the current manuscript, the expression levels and clinical data of MYOs in HNSCC were investigated by online databases, including Oncomine, GEPIA, GEO, TCGA, HPA, UALCAN, Kaplan-Meier plotter, and CancerSEA; we found that the expression levels of MYO1B, MYO5A, and MYO10 were significantly elevated in HNSCC tissues, which were also correlated with the unfavorable overall survival (OS) of the patients. Furthermore, MYO1B/MYO5A/MYO10 interacting genes were identified, and the protein-protein interaction (PPI) networks were constructed by STRING and GeneMANIA. The enrichment analysis revealed that MYO1B/MYO5A/MYO10 associated genes mainly participated in cell metastasis and EMT processes, which were also confirmed by cell functional experiments. At last, the ssGSEA method was conducted to investigate the extent of immune cell infiltration, and we found that both the expression of MYO1B/MYO5A/MYO10 were closely correlated with the infiltration of immune cells in HNSCC. These findings implied that MYO1B, MYO5A, and MYO10 as novel prognostic factors for HNSCC and provided new strategy for HNSCC treatment.
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http://dx.doi.org/10.1155/2022/5501476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038433PMC
April 2022

The Association Between Low T3 Syndrome and Survival in Patients With Newly Diagnosed Multiple Myeloma: A Retrospective Study.

Technol Cancer Res Treat 2022 Jan-Dec;21:15330338221094422

Department of Endocrinology, 74639Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.

The correlation between low triiodothyronine (T3) syndrome and shorter survival in malignant tumor patients has been increasingly reported. The objective of the present study was to investigate the association between low T3 syndrome and survival in multiple myeloma (MM) patients. A total of 201 newly diagnosed MM patients were included in this retrospective study. All participants were divided into 2 groups based on serum free T3 (FT3) level: low T3 syndrome group (FT3 < 2.3 pg/mL) and non-low T3 syndrome group (FT3 ≥ 2.3 pg/mL). Baseline clinical characteristics, overall survival (OS) and progression free survival (PFS) were analyzed. 80 (39.8%) patients had low T3 syndrome. Patients with low T3 syndrome had significantly lower blood hemoglobin and albumin, higher creatinine and β2-microglobulin (β2-MG), higher neutrophil/lymphocyte and (neutrophil + monocyte)/lymphocyte ratio, and more advanced ISS and R-ISS stages (all  < .05). Serum FT3 level was positively associated with blood hemoglobin and albumin, and negatively correlated with β2-MG, creatinine, neutrophil/lymphocyte ratio, and (neutrophil + monocyte)/lymphocyte ratio (all  < .05). Patients with low T3 syndrome had significantly inferior OS time and PFS time (both  < .001). In multivariate Cox analysis, low T3 syndrome was found to be an independent factor associated with OS ( < .001) and PFS ( = .002). Receiver operator characteristic curve analyses showed that FT3 was a predictive marker for death during the entire follow-up period (the area under the curve [AUC] = 0.720, < .001) and during 1 year (AUC = 0.747, < .001). Low T3 syndrome might be useful for predicting survival in patients with newly diagnosed MM.
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http://dx.doi.org/10.1177/15330338221094422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047795PMC
April 2022

Serum proteomic analysis reveals the cardioprotective effects of Shexiang Baoxin Pill and Suxiao Jiuxin Pill in a rat model of acute myocardial infarction.

J Ethnopharmacol 2022 Jul 8;293:115279. Epub 2022 Apr 8.

CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Ethnopharmacological Relevance: Shexiang Baoxin Pill (SBP) and Suxiao Jiuxin Pill (SJP) are traditional Chinese medicines used to treat cardiovascular disease (CVD) in China. However, the mechanism of their therapeutic effect on CVD has not been clearly elucidated yet.

Aims: The aim of this study is to investigate the cardioprotective effect of SBP and SJP in the treatment of acute myocardial infarction (AMI) model rats by applying serum proteomic approach.

Materials And Methods: The rat model of AMI was generated by ligating the left anterior descending coronary artery. 42 rats were randomly divided into four groups: sham-operating (Sham, n = 10) group, model (Mod, n = 8) group, Shexiang Baoxin pills pretreatment (SBP, n = 12) group and Suxiao Jiuxin pills pretreatment (SJP, n = 12) group. Data Independent Acquisition (DIA) proteomic approach was utilized to investigate the serum proteome from the rat individuals. The differentially expressed proteins were subsequently obtained with bioinformatic analysis.

Results: DIA-MS identified 415 proteins within 42 samples, and 84 differentially expressed proteins may contribute to the therapeutic effects of SBP and SJP. GOBP and KEGG pathway analysis of 84 differentially expressed proteins revealed that the proteins were mainly involved in platelet activation and adhesion processes. All 84 differentially expressed proteins presented the same changing tendency in the SBP and SJP groups when compared with the Mod group. Among these 84 proteins, 25 proteins were found to be related to CVD. Among these 25 proteins, ACTB, ACTG1, FGA, FGB, FGG, PF4 and VWF were found to be involved in platelet aggregation and activation. FN1, HSPA5 and YWHAZ were associated with adhesion.

Conclusions: The results of our study suggest that the cardioprotective effects of SBP and SJP are achieved through the modulation of focal adhesion, platelet activation pathways.
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http://dx.doi.org/10.1016/j.jep.2022.115279DOI Listing
July 2022

Clinical Observation and Pharmacoeconomic Evaluations of Original Research Drug and Generic Drug Bortezomib in the Treatment of Multiple Myeloma.

J Healthc Eng 2022 29;2022:5201354. Epub 2022 Mar 29.

Department of Pharmacy, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China.

Background: Multiple myeloma (MM) is one of the hitherto incurable malignant blood tumors. Bortezomib plays an important role in the treatment of MM.

Objective: We aimed to compare effectiveness, safety, and pharmacoeconomic evaluations of the original research drug and the generic drug Bortezomib in the treatment of MM, so as to provide a reasonable basis for the selection of drugs in clinical diagnosis and treatment.

Methods: A collection of 374 patients with MM were diagnosed and treated with combined Bortezomib in our hospital from July 2019 to January 2020.Two hundred and sixty nine cases met the criteria for inclusion and discharge. According to the different drug manufacturers, divided into the original research drug group ( = 149) and the generic drug group ( = 120). The effectiveness and safety were separately counted, and use the cost-minimization analysis to make the pharmacoeconomic evaluations.

Results: Compared with the results of the two groups, there was no statistical difference between the two groups of treatment efficacy or adverse reaction rates ( > 0.05). The average daily cost of the original research drug group was 2954.38 Chinese yuan (CNY), the average treatment cost per cycle was 32967.69 CNY, the average daily cost of the generic drug group was 2697.29 CNY, and the average treatment cost per cycle was 29129.57 CNY. The price of the generic drug group is lower than the original drug group, and there was a statistical difference between the two groups ( < 0.05).

Conclusion: There was no difference between the two groups of effectiveness or safety, and the generic drug is more economical in the treatment.
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http://dx.doi.org/10.1155/2022/5201354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983228PMC
April 2022

Myocardial fibroblast activation imaging in light chain cardiac amyloidosis.

J Nucl Cardiol 2022 Apr 7. Epub 2022 Apr 7.

Department of Nuclear Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.

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http://dx.doi.org/10.1007/s12350-022-02963-0DOI Listing
April 2022

Fibroblast growth factor 12 attenuated cardiac remodeling via suppressing oxidative stress.

Peptides 2022 07 16;153:170786. Epub 2022 Mar 16.

Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Fibroblast growth factors (FGFs) mediate key cardiac functions from development to homeostasis and disease. The current research was to explore the effects of FGF12 in the fibrosis of cardiac function and heart failure, and whether FGF12 alleviated cardiac fibrosis via inhibition of oxidative stress. Ligation of left coronary artery in mice induced heart failure and myocardial infarction (MI). Angiotensin II (Ang II) was administered to cardiac fibroblasts (CFs). FGF12 upregulation or FGF12 transgenic (Tg) mice could improve cardiac dysfunction of MI mice, and attenuated cardiac fibrosis of heart failure induced by MI in mice. FGF12 overexpression suppressed the increases of collagen I, collagen III and fibronectin which was induced by Ang II in CFs. The oxidative stress was enhanced in the heart of MI mice and CFs treated with Ang II, and these enhances were attenuated via FGF12 overexpression. Superoxide dismutase (SOD) overexpression inhibited the enhancements of collagen I, collagen III and fibronectin in the heart of MI mice, and in the CFs treated with Ang II. Overexpression of nicotinamide adenine dinucleotide phosphate oxidases (Nox1) reversed the attenuating influences of FGF12 on the enhancements of collagen I, collagen III and fibronectin in the CFs induced by Ang II. These outcomes showed that FGF12 upregulation can improve cardiac dysfunction and heart fibrosis of heart failure. FGF12 attenuates oxidative stress to suppress the cardiac fibrosis.
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http://dx.doi.org/10.1016/j.peptides.2022.170786DOI Listing
July 2022

Maclurin Promotes the Chondrogenic Differentiation of Bone Marrow Mesenchymal Stem Cells by Regulating miR-203a-3p/Smad1.

Cell Reprogram 2022 02;24(1):9-20

Center for Experimental Teaching, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.

Bone marrow mesenchymal stem cells (BMSCs) differentiate into chondrocytes under appropriate conditions, providing a method for the treatment of bone- and joint-related diseases. Previously, we found that mulberry () promoted the chondrogenic differentiation of BMSCs. Although the mechanism of action and active ingredients remain unknown, several studies describe the involvement of micro-RNAs. We obtained BMSCs from the bone marrow of Sprague Dawley rats. Cell Counting Kit-8 assays showed that maclurin (25 μg/mL) treatment was not toxic to BMSCs, and compared with untreated controls, maclurin upregulated Sox9 and Col2a expression. Quantitative-PCR revealed that miR-203a-3p levels decreased significantly during chondrogenic differentiation of BMSCs promoted by maclurin. Compared with treatment with an miR-203a-3p inhibitor, miR-203a-3p mimic inhibited expression of Sox9 and Col2a as evidenced by immunofluorescence staining and Western blotting. was identified as a key target gene of miR-203a-3p according to biological-prediction software, and miR-203a-3p negatively regulated its transcription and translation in the dual-luciferase reporter gene assay and Western blotting. Sox9 and Col2a expression was downregulated following transfection of short interfering Smad1 (siSmad1) plasmids into BMSCs. We elucidated how maclurin promotes the chondrogenic differentiation of BMSCs by regulating miR-203a-3p/Smad1, which provides a strategy for future exploration of osteoarthritis therapy through cell transplantation.
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http://dx.doi.org/10.1089/cell.2021.0122DOI Listing
February 2022

Targeted treprostinil delivery inhibits pulmonary arterial remodeling.

Eur J Pharmacol 2022 May 5;923:174700. Epub 2022 Feb 5.

Department of Pediatric Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. Electronic address:

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease caused by the progressive remodeling of pulmonary arteries (PAs). Treprostinil (TPS) is a tricyclic benzidine prostacyclin clinically used for PAH treatment. However, due to low bioavailability, short half-times, and severe systemic side effects, TPS efficacy remains limited.

Methods: In this study, glucuronic acid (GlcA)-modified liposomes were developed to improve the site-specific delivery of TPS to pulmonary arterial smooth muscle cells (PASMCs) by targeting the glucose transporter-1 (GLUT-1) in vitro and in vivo.

Results: Non-GlcA-modified and GlcA-modified liposomes encapsulating TPS were 106 ± 1.12 nm in diameter. The drug encapsulation efficiency (EE) was 92%. Data from rat PASMCs showed that GlcA-liposomes enhanced the inhibitory effects of TPS on PASMC proliferation and migration by suppressing growth factor expression, including transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and cAMP, which was possibly mediated by the cAMP-C/EBP-α p42-p21 signaling pathway. In PAH model rats, GlcA-modified liposomes significantly improved TPS bioavailability and sustained its release over time. Most importantly, the selective inhibition of pulmonary arterial pressure, rather than systemic arterial pressure, indicated the increased pulmonary-specific accumulation of TPS. Of the three TPS formulations, TPS-loaded GlcA-modified liposomes exhibited the most potent activity by inhibiting PA remodeling and muscularization, decreasing PA medial thickening, suppressing collagen deposition in PAs, and attenuating right ventricle hypertrophy (RVH) in sugen-5416-induced PAH rats.

Conclusions: The GLUT-1-targeted delivery of TPS increased pulmonary specificity and enhanced TPS anti-PAH activities in vivo and in vitro.
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http://dx.doi.org/10.1016/j.ejphar.2021.174700DOI Listing
May 2022

International Students' Mental Health Care in China: A Systematic Review.

Healthcare (Basel) 2021 Nov 25;9(12). Epub 2021 Nov 25.

School of Overseas Education, Nanjing Xiaozhuang University, 41 Beiwei Road, Nanjing 210017, China.

International students in China are facing difficulties while adapting their Chinese culture, and their life is influenced by the widespread of the Coronavirus Disease 2019 (COVID-19), and caring for their mental health is currently challenging. As a result, our aim is to explore the current mental health care of this minority in China and to provide useful suggestions for future research and institutes. We used the systematic review method, and it was conducted on 11 existing pieces of literature. Our results confirm the unsatisfying psychological situation of international students and the lack of research in this area. We focus on the causes and symptoms of mental problems and explore the effectiveness of methods.
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http://dx.doi.org/10.3390/healthcare9121634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700832PMC
November 2021

Trimethylamine N-oxide promotes atherosclerosis via regulating the enriched abundant transcript 1/miR-370-3p/signal transducer and activator of transcription 3/flavin-containing monooxygenase-3 axis.

Bioengineered 2022 01;13(1):1541-1553

Department of Cardiology, Binhai People's Hospital, Jiangsu China.

Atherosclerosis (AS) is one of the main causes of cardiovascular diseases (CVDs). Trimethylamine N-oxide (TMAO) exacerbates the development of AS. This study aimed to investigate the roles of TMAO in AS. In this study, mice were fed with high fat food (HF) and/or injected with TMAO. Oil red O staining was applied for histological analysis. ELISA, qRT-PCR, and Western blot were conducted to determine the TMAO, serum, mRNA, and protein levels. CCK-8, colony formation assay, and flow cytometry assays were performed to detect the functions of human aortic endothelial cells (HUVECs). The results showed that TMAO induced thick internal and external walls and intimal plaques , and HUVEC dysfunction . TMAO and lncRNA enriched abundant transcript 1 (NEAT1) were increased in AS clinical samples and TMAO-HUVECs. Downregulated NEAT1 inhibited proliferation and promoted the apoptosis of HUVECs. NEAT1 regulated the expression of signal transducer and activator of transcription 3 (STAT3) via sponging miR-370-3p. Overexpression of miR-370-3p facilitated the effects of NEAT1 on the cellular functions of HUVECs, while STAT3 exerted opposing effects. The activation of STAT3 promoted the expression of flavin-containing monooxygenase-3 (FMO3). Taken together, our results show that TMAO-NEAT1/miR-370-3p/STAT3/FMO3 forms a positive feedback loop to exacerbate the development of AS. This novel feedback loop may be a promising therapeutic target for AS.
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http://dx.doi.org/10.1080/21655979.2021.2010312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805905PMC
January 2022

Structural and Functional Analysis of SsaV Cytoplasmic Domain and Variable Linker States in the Context of the InvA-SsaV Chimeric Protein.

Microbiol Spectr 2021 12 1;9(3):e0125121. Epub 2021 Dec 1.

State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.

The type III secretion (T3S) injectisome is a syringe-like protein-delivery nanomachine widely utilized by Gram-negative bacteria. It can deliver effector proteins directly from bacteria into eukaryotic host cells, which is crucial for the bacterial-host interaction. Intracellular pathogen Salmonella enterica serovar Typhimurium encodes two sets of T3S injectisomes from Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2), which are critical for its host invasion and intracellular survival, respectively. The inner membrane export gate protein, SctV (InvA in SPI-1 and SsaV in SPI-2), is the largest component of the injectisome and is essential for assembly and function of T3SS. Here, we report the 2.11 Å cryo-EM structure of the SsaV cytoplasmic domain (SsaV) in the context of a full-length SctV chimera consisting of the transmembrane region of InvA, the linker of SsaV (SsaV) and SsaV. The structural analysis shows that SsaV exists in a semi-open state and SsaV exhibits two major orientations, implying a highly dynamic process of SsaV for the substrate selection and secretion in a full-length context. A biochemical assay indicates that SsaV plays an essential role in maintaining the nonameric state of SsaV. This study offers near atomic-level insights into how SsaV and SsaV facilitate the assembly and function of SsaV and may lead to the development of potential anti-virulence therapeutics against T3SS-mediated bacterial infection. Type III secretion system (T3SS) is a multicomponent nanomachine and a critical virulence factor for a wide range of Gram-negative bacterial pathogens. It can deliver numbers of effectors into the host cell to facilitate the bacterial host infection. Export gate protein SctV, as one of the engines of T3SS, is at the center of T3SS assembly and function. In this study, we show the high-resolution atomic structure of the cytosolic domain of SctV in the nonameric state with variable linker conformations. Our first observation of conformational changes of the linker region of SctV and the semi-open state of the cytosolic domain of SctV in the full-length context further support that the substrate selection and secretion process of SctV is highly dynamic. These findings have important implications for the development of therapeutic strategies targeting SctV to combat T3SS-mediated bacterial infection.
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http://dx.doi.org/10.1128/Spectrum.01251-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635156PMC
December 2021

Tumoral Morphologic Features From Cervical Biopsies That Are Predictive of a Negligible Risk for Nodal Metastasis and Tumor Recurrence in Usual-type Cervical Adenocarcinomas: A Multi-institutional Study.

Am J Surg Pathol 2022 05;46(5):713-724

Obstetrics and Gynecology.

The metastatic or recurrent potential of localized human papillomavirus-associated endocervical adenocarcinoma (HPVA EAC) is difficult to predict, especially based upon biopsy alone. Recent analyses of small cohorts indicate that high tumor nuclear grade (TNG) and the presence of necrotic tumor debris (NTD) from HPVA EACs in cervical biopsy specimens are highly predictive of nodal metastasis (NM). In the present study, we aimed to investigate how reliably tumoral morphologic features from cervical biopsy specimens predict NM or tumor recurrence (TR) and patient outcomes in a large cohort of endocervical adenocarcinoma patients. A cohort comprised of 397 patients with HPVA EAC treated at 18 institutions was identified, and cervical biopsies were paired with their associated complete tumor resections for a total of 794 specimens. A variety of tumoral histologic features were examined for each paired specimen, including TNG (assessed on a 3-tiered scale of increasing abnormalities-TNG1, TNG2, TNG3) and NTD (defined by the presence of necrotic and apoptotic tumor cells within tumor glandular lumens admixed with granular and eosinophilic amorphous material and inflammatory cells), which were correlated with outcomes. The distribution of TNG in biopsies was as follows: 86 (21.7%) TNG1, 223 (56.2%) TNG2, and 88 (22.2%) TNG3. NTD was identified in 176 (44%) of the biopsy specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of a TNG1 assignment in the biopsy being predictive of the same assignment in the full resection were 0.82 (95% confidence interval [CI]: 0.7-0.9), 0.895 (0.86-0.93), 0.593 (0.48-0.696), and 0.96 (0.94-0.98), respectively. Respective values for an NTD-negative status were 0.89 (95% CI: 0.83-0.92), 0.715 (0.64-0.77), 0.72 (0.65-0.77), and 0.89 (0.83-0.93), respectively. Compared with the other cases in each category, both TNG1 and an NTD-negative status were each significantly associated with lower rates of NM (odds ratio for TNG1=0.245, 95% CI: 0.070-0.857, P=0.0277; for NTD=0.199, 95% CI: 0.094-0.421, P<0.0001) and TR (odds ratio for TNG1=0.225, 95% CI: 0.051-0.987, P=0.0479; for NTD=0.367, 95% CI: 0.171-0.786, P=0.0099) independent of depth of stromal invasion, lymphovascular invasion, tumor size, FIGO stage, and Silva pattern. Overall, 73/379 (19%) cases were both TNG1 and NTD-negative on the biopsy, and none of these 73 cases showed NM (0%), but a single case (1.4%) showed TR. In contrast, among the 324 biopsies with TNG2/3 and/or presence of NTD, 62 (19.1%) had NM, and 41 (12.9%) had TR. In summary, 2 variables in combination (ie, TNG1 and NTD-negative) identified a subset of HPVA EAC patients-∼19%-with a 0% frequency of nodal metastases and only 1.4% frequency of recurrence. Biopsies highly but imperfectly predicted these features. Nonetheless, these findings may potentially be of clinical utility in the risk stratification of patients with HPVA EACs. This may allow some patients with a minimal risk of nodal metastases and TR to be identified at the biopsy phase, thereby facilitating more personalized, possibly less aggressive treatment.
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http://dx.doi.org/10.1097/PAS.0000000000001833DOI Listing
May 2022

Structural insights into RNA polymerase III-mediated transcription termination through trapping poly-deoxythymidine.

Nat Commun 2021 10 21;12(1):6135. Epub 2021 Oct 21.

Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Radiation Oncology, and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai, 200032, China.

Termination of the RNA polymerase III (Pol III)-mediated transcription requires the conversion of an elongation complex (EC) to a pre-termination complex (PTC) on poly-deoxythymidine (dT)-containing non-template strand, a mechanism distinct from Pol I and Pol II. Here, our in vitro transcription elongation assay showed that 5-7 dT-containing DNA template led to transcription termination of Pol III, but not Pol I or Pol II. We assembled human Pol III PTC on a 7 dT-containing DNA template and determined the structure at 3.6 Å resolution. The structure reveals that poly-dT are trapped in a narrow exit tunnel formed by RPC2. A hydrophobic gate of the exit tunnel separates the bases of two connected deoxythymidines and may prevent translocation of the non-template strand. The fork loop 2 stabilizes both template and non-template strands around the transcription fork, and may further prevent strand translocation. Our study shows that the Pol III-specific exit tunnel and FL2 allow for efficient translocation of non-poly-dT sequence during transcription elongation but trap poly-dT to promote DNA retention of Pol III, revealing molecular mechanism of poly-dT-dependent transcription termination of Pol III.
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http://dx.doi.org/10.1038/s41467-021-26402-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531034PMC
October 2021

Angiotensin-(3-7) alleviates isoprenaline-induced cardiac remodeling via attenuating cAMP-PKA and PI3K/Akt signaling pathways.

Amino Acids 2021 Oct 7;53(10):1533-1543. Epub 2021 Sep 7.

Department of Cardiology, Binhai County People's Hospital, 188 Fudong Middle Road, Yancheng, 224500, Jiangsu, China.

The renin-angiotensin system is involved in the regulation of various heart diseases. The present study aimed to determine the effects of angiotensin (Ang)-(3-7) on cardiac remodeling and its downstream signaling pathways in neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs). The administration of Ang-(3-7) alleviated isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis of mice. ISO treatment increased the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) in NRCMs, and reduced the levels of collagen I, collagen III, fibronectin, and alpha-smooth muscle actin (α-SMA) in NRCFs. These changes were inhibited by Ang-(3-7) administration. The levels of protein kinase A (PKA), phosphorylated phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-Akt) were increased in NRCMs and NRCFs treated with ISO. The increase of PKA, but not p-PI3K or p-Akt was attenuated by Ang-(3-7) treatment in NRCMs. The increases of p-PI3K and p-Akt, but not PKA were reversed by Ang-(3-7) treatment in NRCFs. Treatment with cAMP or PKA overexpression reversed the attenuating effects of Ang-(3-7) on ISO-induced hypertrophy of NRCMs. The administration of PI3K inhibitor or Akt inhibitor alleviated ISO-induced fibrosis of NRCFs. These results indicated that Ang-(3-7) could alleviate cardiac remodeling. The administration of Ang-(3-7) attenuated hypertrophy of NRCMs via inhibiting the cAMP/PKA signaling pathway, and alleviated fibrosis of NRCFs via inhibiting PI3K/Akt signaling pathway.
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http://dx.doi.org/10.1007/s00726-021-03074-9DOI Listing
October 2021

RNA sequencing analyses in infants patients with coarctation of the aorta.

Hereditas 2021 Aug 23;158(1):32. Epub 2021 Aug 23.

Department of Pediatric Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, An Zhen Rd, Beijing, 100029, China.

Background: Coarctation of the aorta (CoA) is a serious innate heart disease. Although surgery results are generally good, some complications such as recoarctation and aortic aneurysm or persistent hypertension were serious threats to patient's health. To better understand the pathology of CoA and its underlying molecular mechanism is particularly important for early diagnosis and preventing the occurrence of its complications. However, the mechanisms of CoA remain unclear, especially for infants.

Methods: RNA sequencing (RNA-seq) was used to identify the differentially expressed genes (DEGs) in vascular tissues of 12 patients with CoA and 10 normal participants form 3- to 34-month-old infants. The characteristic of DEGs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunochemical staining (IHC) in vessels of patients with CoA and normal infants.

Results: A total of 2491 DEGs with the false discovery rate less than 0.05(> 1.5-fold, P < 0.05 change) were identified, including 443 upregulated genes and 2048 downregulated genes. The Gene Ontology enrichment analysis showed that 26 out of the 2491 DEGs identified were associated with cardiovascular diseases. These 26 genes were mainly associated with extracellular matrix (ECM) and smooth muscle cells (SMCs) differentiation. Three DEGs, that is, CNN1 (calponin), α-actinin1 and myosin heavy chain 11 MYH11, were validated using qRT-PCR and Western blot analysis. In addition, immunochemical staining showed that calponin and MYH11 were highly expressed on the surface and in the deep layers of the thickened intima respectively.

Conclusion: This study comprehensively characterized the CoA transcriptome. Migration of extracellular matrix (ECM) and smooth muscle cells (SMCs) to the subendothelial space may be the major characteristic of CoA in infants.
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http://dx.doi.org/10.1186/s41065-021-00194-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381523PMC
August 2021

High glucose exacerbates neuroinflammation and apoptosis at the intermediate stage after post-traumatic brain injury.

Aging (Albany NY) 2021 06 27;13(12):16088-16104. Epub 2021 Jun 27.

Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, China.

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.
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http://dx.doi.org/10.18632/aging.203136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266309PMC
June 2021

SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma.

Biomark Res 2021 Jun 16;9(1):48. Epub 2021 Jun 16.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Background: SMAD1, a central mediator in TGF-β signaling, is involved in a broad range of biological activities including cell growth, apoptosis, development and immune response, and is implicated in diverse type of malignancies. Whether SMAD1 plays an important role in multiple myeloma (MM) pathogenesis and can serve as a therapeutic target are largely unknown.

Methods: Myeloma cell lines and primary MM samples were used. Cell culture, cytotoxicity and apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, and migration assay, Chromatin immunoprecipitation (Chip), animal xenograft model studies and statistical analysis were applied in this study.

Results: We demonstrate that SMAD1 is highly expressed in myeloma cells of MM patients with advanced stages or relapsed disease, and is associated with significantly shorter progression-free and overall survivals. Mechanistically, we show that SMAD1 is required for TGFβ-mediated proliferation in MM via an ID1/p21/p27 pathway. TGF-β also enhanced TNFα-Induced protein 8 (TNFAIP8) expression and inhibited apoptosis through SMAD1-mediated induction of NF-κB1. Accordingly, depletion of SMAD1 led to downregulation of NF-κB1 and TNFAIP8, resulting in caspase-8-induced apoptosis. In turn, inhibition of NF-κB1 suppressed SMAD1 and ID1 expression uncovering an autoregulatory loop. Dorsomorphin (DM), a SMAD1 inhibitor, exerted a dose-dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells, and further synergized with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells in vitro and in a myeloma xenograft model.

Conclusions: This study identifies SMAD1 regulation of NF-κB1/TNFAIP8 and ID1-p21/p27 as critical axes of MM drug resistance and provides a potentially new therapeutic strategy to treat drug resistance MM through targeted inhibition of SMAD1.
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http://dx.doi.org/10.1186/s40364-021-00296-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207655PMC
June 2021

A re-testing range is recommended for C- and C-urea breath tests for Helicobacter pylori infection in China.

Gut Pathog 2021 Jun 12;13(1):38. Epub 2021 Jun 12.

The Marshall Centre for Infectious Diseases Research and Training, University of Western Australia, Perth, 6009, Australia.

Background: The urea breath test (UBT) is widely used for diagnosing Helicobacter pylori infection. In the Shenzhen Kuichong People's Hospital, some UBT findings were contradictory to the histology outcomes, therefore this study aimed to assess and compare the diagnostic performance of both C- and C-UBT assays.

Methods: We recruited 484 H. pylori-treatment naïve patients, among which 217 and 267 were tested by the C-UBT or C-UBT, respectively. The cutoff value for H. pylori positivity based on manufacturer's instruction was 4% delta over baseline (DOB) for the C-UBT, and 100 disintegrations per minute (DPM) for the C-UBT. Gastric biopsies of the antrum and corpus were obtained during endoscopy for histopathology.

Results: In patients who were tested using the C-UBT kit, histopathology was positive in 136 out of 164 UBT-positive patients (82.9% concordance), and negative in 46 out of 53 UBT-negative cases (86.8% concordance). For the C-UBT-tested patients, histopathology was positive for H. pylori in 186 out of 220 UBT-positive patients (84.5% concordance), and negative in 41 out of 47 UBT-negative cases (87.2% concordance). While the C-UBT and C-UBT each had a high sensitivity level of 95.1% and 96.9%, respectively, their specificity was low, at 62.2% and 54.7%, respectively. By using new optimal cutoff values and including an indeterminate range (3-10.3% DOB for C-UBT and 87-237 DPM for C-UBT), the specificity values can be improved to 76.7% and 76.9% for the C- and C-UBT, respectively.

Conclusions: The establishment of an indeterminate range is recommended to allow for repeated testing to confirm H. pylori infection, and thereby avoiding unnecessary antibiotic treatment.

Trial Registration: Chinese Clinical Trial Registry, ChiCTR2000041570. Registered 29 December 2020- Retrospectively registered, http://www.chictr.org.cn/edit.aspx?pid=66416&htm=4.
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http://dx.doi.org/10.1186/s13099-021-00435-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199820PMC
June 2021

Novel Non-coding RNA Analysis in Multiple Myeloma Identified Through High-Throughput Sequencing.

Front Genet 2021 24;12:625019. Epub 2021 May 24.

Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

This study aimed to explore the potential effects of novel non-coding ribose nucleic acids (ncRNAs) in patients with multiple myeloma (MM). The gene expression profile of plasma cells was used for sequence analysis to explore the expression pattern of ncRNAs in MM. The expression patterns of non-coding RNAs in MM were analyzed by RNA sequencing (whole-transcriptome-specific RNA sequencing). Next, the expression of the selected ncRNAs was verified by quantitative real-time polymerase chain reaction. Further, the lncRNA-associated competitive endogenous RNA network in MM was elucidated using deep RNA-seq. Differentially expressed (DE) ncRNAs were significantly regulated in patients with MM. DE target lncRNAs were analyzed by and targeting prediction. Two new lncRNAs were shown to be related to MM oncogenes. MSTRG.155519 played a carcinogenic role in myeloma by targeting CEACAM1; MSTRG.13132 was related to FAM46C. Finally, the network of lncRNA-mRNA-miRNA in MM was constructed in this study. The expression of non-coding RNAs through sequence and functional analyses might be helpful for further studies on the pathogenesis of MM and the development of new MM-targeted therapy for non-coding RNAs.
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http://dx.doi.org/10.3389/fgene.2021.625019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181418PMC
May 2021

Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies.

Biomark Res 2021 May 6;9(1):34. Epub 2021 May 6.

Laboratory medicine program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada.

The myristoylated alanine-rich C-kinase substrate (MARCKS) protein has been at the crossroads of multiple signaling pathways that govern several critical operations in normal and malignant cellular physiology. Functioning as a target of protein kinase C, MARCKS shuttles between the phosphorylated cytosolic form and the unphosphorylated plasma membrane-bound states whilst regulating several molecular partners including, but not limited to calmodulin, actin, phosphatidylinositol-4,5-bisphosphate, and phosphoinositide-3-kinase. As a result of these interactions, MARCKS directly or indirectly modulates a host of cellular functions, primarily including cytoskeletal reorganization, membrane trafficking, cell secretion, inflammatory response, cell migration, and mitosis. Recent evidence indicates that dysregulated expression of MARCKS is associated with the development and progression of hematological cancers. While it is understood that MARCKS impacts the overall carcinogenesis as well as plays a part in determining the disease outcome in blood cancers, we are still at an early stage of interpreting the pathophysiological roles of MARCKS in neoplastic disease. The situation is further complicated by contradictory reports regarding the role of phosphorylated versus an unphosphorylated form of MARCKS as an oncogene versus tumor suppressor in blood cancers. In this review, we will investigate the current body of knowledge and evolving concepts of the physical properties, molecular network, functional attributes, and the likely pathogenic roles of MARCKS in hematological malignancies. Key emphasis will also be laid upon understanding the novel mechanisms by which MARCKS determines the overall disease prognosis by playing a vital role in the induction of therapeutic resistance. Additionally, we will highlight the importance of MARCKS as a valuable therapeutic target in blood cancers and will discuss the potential of existing strategies available to tackle MARCKS-driven blood cancers.
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http://dx.doi.org/10.1186/s40364-021-00286-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101130PMC
May 2021
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