Publications by authors named "Lan Zhao"

263 Publications

Neural stem cell therapy for brain disease.

World J Stem Cells 2021 Sep;13(9):1278-1292

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China.

Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovascular diseases, and traumatic brain injuries, are among the major disorders influencing human health, currently with no effective therapy. Due to the low regeneration capacity of neurons, insufficient secretion of neurotrophic factors, and the aggravation of ischemia and hypoxia after nerve injury, irreversible loss of functional neurons and nerve tissue damage occurs. This damage is difficult to repair and regenerate the central nervous system after injury. Neural stem cells (NSCs) are pluripotent stem cells that only exist in the central nervous system. They have good self-renewal potential and ability to differentiate into neurons, astrocytes, and oligodendrocytes and improve the cellular microenvironment. NSC transplantation approaches have been made for various neurodegenerative disorders based on their regenerative potential. This review summarizes and discusses the characteristics of NSCs, and the advantages and effects of NSCs in the treatment of brain diseases and limitations of NSC transplantation that need to be addressed for the treatment of brain diseases in the future.
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http://dx.doi.org/10.4252/wjsc.v13.i9.1278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474718PMC
September 2021

Inhibition of Vascular Growth by Modulation of the Anandamide/Fatty Acid Amide Hydrolase Axis.

Arterioscler Thromb Vasc Biol 2021 Dec 7;41(12):2974-2989. Epub 2021 Oct 7.

Institute of Physiology I, Life&Brain Center, Medical Faculty (S.R., S.K., B.K.F., D.W.), University of Bonn, Germany.

Objective: Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority. Approach and Results: Here, we show that inactivation of FAAH (fatty acid amide hydrolase), the enzyme responsible for degradation of the endocannabinoid anandamide, strongly impairs angiogenesis in vitro and in vivo. Both, the pharmacological FAAH inhibitor URB597 and anandamide induce downregulation of gene sets for cell cycle progression and DNA replication in endothelial cells. This is underscored by cell biological experiments, in which both compounds inhibit proliferation and migration and evoke cell cycle exit of endothelial cells. This prominent antiangiogenic effect is also of pathophysiological relevance in vivo, as laser-induced choroidal neovascularization in the eye of mice is strongly reduced.

Conclusions: Thus, elevation of endogenous anandamide levels by FAAH inhibition represents a novel antiangiogenic mechanism.
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http://dx.doi.org/10.1161/ATVBAHA.121.316973DOI Listing
December 2021

A Retrospective Study of Perioperative Nursing Care of Patients After Percutaneous Left Atrial Appendage Occlusion.

J Perianesth Nurs 2021 Sep 24. Epub 2021 Sep 24.

Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), PR China; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia. Electronic address:

Purpose: To describe the retrospective audit examining nursing care of nonvalvular atrial fibrillation treated by percutaneous left atrial appendage closure (PLAAC).

Design: PLAAC is a new technique for patients with atrial fibrillation unsuited for long-term oral anticoagulation treatment. The nursing care for patients treated by PLAAC has not yet been standardized.

Methods: We performed a retrospective analysis of 259 patients with nonvalvular atrial fibrillation who underwent PLAAC in our department between August 2014 and June 2018. The data included preoperative evaluations, discussions, and preparations, including psychological care and atrial thrombosis screening; postoperative observations, including electrocardiograph monitoring; prevention and care of complications; administration of postoperative anticoagulation therapy; and postoperative education, including detailed discharge guidance and regular follow-up.

Findings: All patients were discharged after 5-10 days of hospitalization. In the perioperative period, 4 cases (1.5%) developed serious complications, including 3 cases (1.2%) of delayed cardiac tamponade, cured by pericardial drainage, and 1 case of a suspected air embolism, which spontaneously recovered. During a mean follow-up period of 25.9 ± 7.9 months, all patients had good adherence to medical instructions and there were no cases of occluder displacement or shedding, thromboembolism, or severe bleeding complications.

Conclusions: The best therapeutic effect of PLAAC is strongly associated with the preoperative and postoperative training of nursing staff and the development of standard nursing procedures, including the establishment of observation and nursing manuals for complications. This study provides nursing practice information to aid in the standardization of nursing procedures for this new type of interventional therapy.
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http://dx.doi.org/10.1016/j.jopan.2020.12.013DOI Listing
September 2021

Malware detection based on semi-supervised learning with malware visualization.

Math Biosci Eng 2021 07;18(5):5995-6011

School of Cyber Science and Engineering, Sichuan University, China.

The traditional signature-based detection method requires detailed manual analysis to extract the signatures of malicious samples, and requires a large number of manual markers to maintain the signature library, which brings a great time and resource costs, and makes it difficult to adapt to the rapid generation and mutation of malware. Methods based on traditional machine learning often require a lot of time and resources in sample labeling, which results in a sufficient inventory of unlabeled samples but not directly usable. In view of these issues, this paper proposes an effective malware classification framework based on malware visualization and semi-supervised learning. This framework includes mainly three parts: malware visualization, feature extraction, and classification algorithm. Firstly, binary files are processed directly through visual methods, without assembly, decompression, and decryption; Then the global and local features of the gray image are extracted, and the visual image features extracted are fused on the whole by a special feature fusion method to eliminate the exclusion between different feature variables. Finally, an improved collaborative learning algorithm is proposed to continuously train and optimize the classifier by introducing features of inexpensive unlabeled samples. The proposed framework was evaluated over two extensively researched benchmark datasets, i.e., Malimg and Microsoft. The results show that compared with traditional machine learning algorithms, the improved collaborative learning algorithm can not only reduce the cost of sample labeling but also can continuously improve the model performance through the input of unlabeled samples, thereby achieving higher classification accuracy.
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http://dx.doi.org/10.3934/mbe.2021300DOI Listing
July 2021

Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8.

Genome Med 2021 09 6;13(1):145. Epub 2021 Sep 6.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305-5151, USA.

We developed a sensitive sequencing approach that simultaneously profiles microsatellite instability, chromosomal instability, and subclonal structure in cancer. We assessed diverse repeat motifs across 225 microsatellites on colorectal carcinomas. Our study identified elevated alterations at both selected tetranucleotide and conventional mononucleotide repeats. Many colorectal carcinomas had a mix of genomic instability states that are normally considered exclusive. An MSH3 mutation may have contributed to the mixed states. Increased copy number of chromosome arm 8q was most prevalent among tumors with microsatellite instability, including a case of translocation involving 8q. Subclonal analysis identified co-occurring driver mutations previously known to be exclusive.
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http://dx.doi.org/10.1186/s13073-021-00958-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420050PMC
September 2021

[RhoA/ROCK pathway involved in effects of Sanjiao acupuncture on learning and memory and synaptic plasticity in Alzheimer's disease mice].

Zhen Ci Yan Jiu 2021 Aug;46(8):635-41

Research Institute of Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193.

Objective: To observe the effect of Sanjiao acupuncture(triple energizer acupuncture)on the small G protein guanosine triphosphate enzyme subfamily protein RhoA/Rho kinase (ROCK) pathway in Alzheimer's disease mice, and explore its effect on learning and memory function and neurosynaptic plasticity.

Methods: Forty SAMP8 senile dementia mice were randomly divided into model, Sanjiao acupuncture (acupuncture), non acupoint acupuncture (non-acupoint) and fasudil groups, with 10 mice in each group, another 10 SAMR normal aging mice were selected as normal aging group. Mice in the acupuncture group were treated with acupuncture intervention on "Danzhong"(CV18), "Zhongwan"(CV13), "Qihai"(BL24) and bilateral "Xuehai"(SP10) and "Zusanli" (ST36). Mice in the non-acupoint group were treated with acupuncture at each of the left and right non-acupoints under the ribs and mice in the fasudil group were intraperitoneally injected with fasudil (25 mg/kg). The mice in each group were given medicine or acupuncture on the second day after grouping for 28 continuously days, once a day. Morris water maze test was used to test the learning and memory ability of mice. HE staining was used to observe the pathological changes of neurons in hippocampus. The number of hippocampal neuron dendritic spine was detected by FD fast Golgi staining kit. The contents of β-amyloid 42 (Aβ42) and phosphorylated tau protein (p-tau) in hippocampus were detected by ELISA. Western blot was used to detect the protein relative expression levels of RhoA, ROCK, F-actin and p-cofilin in hippocampus.

Results: Compared with those in the normal aging group, the hippocampal neurons of the model group were disorderly arranged, the number of neuron was reduced, the escape latency, hippocampal Aβ42 and p-tau contents, RhoA and ROCK protein expressions increased (<0.05), the number of crossing the original platform, the number of neuronal dendritic spines, expressions of F-actin and p-cofilin decreased (<0.05). After the interventions, there was no statistically significant difference in the above indicators in the non-acupoint group relevant to the model group (>0.05). The acupuncture group and fasudil group improved the hippocampal pathological damage. The escape latency, hippocampal Aβ42 and p-tau contents, the expressions of RhoA and ROCK protein decreased (<0.05), and the number of crossing the original platform, the number of hippocampal neuron dendritic spines, expressions of F-actin and p-cofilin increased (<0.05) in both of the acupuncture and fasudil groups in contrast to the model and non-acupoint groups. Compared with the acupuncture group, there was no significant difference in the above indicators in the fasudil group (>0.05).

Conclusion: Sanjiao acupuncture may inhibit the activation of the RhoA/ROCK pathway, so as to improve the learning and memory function of AD mice, increase the number of hippocampal neuron dendritic spines, and promote synaptic plasticity.
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http://dx.doi.org/10.13702/j.1000-0607.200985DOI Listing
August 2021

Tailored nanodisc immobilization for one-step purification and reconstitution of cytochrome P450: A tool for membrane proteins' hard cases.

J Sep Sci 2021 Sep 6;44(18):3429-3440. Epub 2021 Aug 6.

State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, P. R. China.

A novel nanodisc-based immobilization method was developed for high-efficient purification and reconstitution of cytochrome P450 in one step. Using membrane scaffold protein containing a histidine tag, charged-nanodiscs were prepared in the form of self-assembly of lipid-protein nanoparticles. Their properties including the particle diameter and its distribution and Zeta potential were controlled well by adjusting molar ratios of phospholipids to membrane scaffold protein. At an optimum lipid-to-membrane scaffold protein molar ratio of 60:1, uniformly regular-shaped and discoidal nanodiscs with an average particle diameter of 10 nm and Zeta potential of -19 mV were obtained. They can be well fractionated by size exclusion chromatography. Charged-nanodiscs were successfully immobilized onto Ni-chelating microspheres via histidine tags with a density of 6.6 mg membrane scaffold protein/mL gel. After being packed in a column, chromatography studies demonstrated that this nanodisc-immobilized chromatographic medium had a specific binding to cytochrome P450 in rat liver microsome. Nanodiscs containing cytochrome P450 can be furthermore eluted from the column with a diameter of about 87.0 nm and height of about 8.0 nm, respectively. The purity of cytochrome P450 after purification increased 25 folds strikingly. This nanodisc-immobilized chromatography method is promising for the one-step purification and reconstitution of membrane protein.
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http://dx.doi.org/10.1002/jssc.202100284DOI Listing
September 2021

Application of [18F]FLT-PET in pulmonary arterial hypertension: a clinical study in pulmonary arterial hypertension patients and unaffected bone morphogenetic protein receptor type 2 mutation carriers.

Pulm Circ 2021 Jul-Sep;11(3):20458940211028017. Epub 2021 Jun 30.

Department of Pulmonology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Pulmonary arterial hypertension is a heterogeneous group of diseases characterized by vascular cell proliferation leading to pulmonary vascular remodelling and ultimately right heart failure. Previous data indicated that 3'-deoxy-3'-[18F]-fluorothymidine (FLT) positron emission tomography (PET) scanning was increased in pulmonary arterial hypertension patients, hence providing a possible biomarker for pulmonary arterial hypertension as it reflects vascular cell hyperproliferation in the lung. This study sought to validate FLT-PET in an expanded cohort of pulmonary arterial hypertension patients in comparison to matched healthy controls and unaffected bone morphogenetic protein receptor type 2 mutation carriers. FLT-PET scanning was performed in 21 pulmonary arterial hypertension patients (15 hereditary pulmonary arterial hypertension and 6 idiopathic pulmonary arterial hypertension), 11 unaffected mutation carriers and 9 healthy control subjects. In-depth kinetic analysis indicated that there were no differences in lung FLT k3 phosphorylation among pulmonary arterial hypertension patients, unaffected bone morphogenetic protein receptor type 2 mutation carriers and healthy controls. Lung FLT uptake did not correlate with haemodynamic or clinical parameters in pulmonary arterial hypertension patients. Sequential FLT-PET scanning in three patients demonstrated uneven regional distribution in FLT uptake by 3D parametric mapping of the lung, although this did not follow the clinical course of the patient. We did not detect significantly increased lung FLT uptake in pulmonary arterial hypertension patients, nor in the unaffected bone morphogenetic protein receptor type 2 mutation carriers, as compared to healthy subjects. The conflicting results with our preliminary human FLT report may be explained by a small sample size previously and we observed large variation of lung FLT signals between patients, challenging the application of FLT-PET as a biomarker in the pulmonary arterial hypertension clinic.
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http://dx.doi.org/10.1177/20458940211028017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256252PMC
June 2021

Identification of DNA-Repair-Related Five-Gene Signature to Predict Prognosis in Patients with Esophageal Cancer.

Pathol Oncol Res 2021 30;27:596899. Epub 2021 Mar 30.

Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.

Esophageal cancer (ESCA) is a leading cause of cancer-related mortality, with poor prognosis worldwide. DNA damage repair is one of the hallmarks of cancer. Loss of genomic integrity owing to inactivation of DNA repair genes can increase the risk of cancer progression and lead to poor prognosis. We aimed to identify a novel gene signature related to DNA repair to predict the prognosis of ESCA patients. Based on gene expression profiles of ESCA patients from The Cancer Genome Atlas and gene set enrichment analysis, 102 genes related to DNA repair were identified as candidates. After stepwise Cox regression analysis, we established a five-gene prognostic model comprising DGCR8, POM121, TAF9, UPF3B, and BCAP31. Kaplan-Meier survival analysis confirmed a strong correlation between the prognostic model and survival. Moreover, we verified the clinical value of the prognostic signature under the influence of different clinical parameters. We found that small-molecule drugs (trametinib, selumetinib, and refametinib) could help to improve patient survival. In summary, our study provides a novel and promising prognostic signature based on DNA-repair-related genes to predict survival of patients with ESCA. Systematic data mining provides a theoretical basis for further exploring the molecular pathogenesis of ESCA and identifying therapeutic targets.
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http://dx.doi.org/10.3389/pore.2021.596899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262199PMC
March 2021

Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L.

Adv Healthc Mater 2021 08 26;10(16):e2100821. Epub 2021 Jun 26.

Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, China.

Extracellular matrix (ECM) stiffness has profound effects on the regulation of cell functions. DNA methylation is an important epigenetic modification governing gene expression. However, the effects of ECM stiffness on DNA methylation remain elusive. Here, it is reported that DNA methylation is sensitive to ECM stiffness, with a global hypermethylation under stiff ECM condition in mouse embryonic stem cells (mESCs) and embryonic fibroblasts compared with soft ECM. Stiff ECM enhances DNA methylation of both promoters and gene bodies, especially the 5' promoter regions of pluripotent genes. The enhanced DNA methylation is functionally required for the loss of pluripotent gene expression in mESCs grown on stiff ECM. Further experiments reveal that the nuclear transport of DNA methyltransferase 3-like (DNMT3L) is promoted by stiff ECM in a protein kinase C α (PKCα)-dependent manner and DNMT3L can be binding to Nanog promoter regions during cell-ECM interactions. These findings unveil DNA methylation as a novel target for the mechanical sensing mechanism of ECM stiffness, which provides a conserved mechanism for gene expression regulation during cell-ECM interactions.
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http://dx.doi.org/10.1002/adhm.202100821DOI Listing
August 2021

Base-promoted, CBr-mediated tandem bromination/intramolecular Friedel-Crafts alkylation of N-aryl enamines: a facile access to 1H- and 3H-indoles.

Org Biomol Chem 2021 Jun 28;19(24):5377-5382. Epub 2021 May 28.

College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P. R. China. and State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P. R. China.

Described here is a general and highly efficient method for the synthesis of 1H- and 3H-indoles. In the presence of CBr and a suitable base, the cyclization of N-aryl enamines proceeds with high efficiency. Unlike previous intramolecular cross dehydrogenative coupling (CDC) of the same substrates, this process does not require the use of either a transition metal or a stoichiometric amount of oxidant. This method also features operational simplicity, easy scalability and good substrate tolerability. Control experiments indicate the reactions may proceed in a tandem sequence of bromination and intramolecular Friedel-Crafts alkylation in a simple one-pot procedure.
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http://dx.doi.org/10.1039/d1ob00731aDOI Listing
June 2021

Peach allergen Pru p 1 content is generally low in fruit but with large variation in different varieties.

Clin Transl Allergy 2021 May 14;11(3):e12034. Epub 2021 May 14.

Departments of Experimental Immunology and Otorhinolaryngology Amsterdam UMC University of Amsterdam Amsterdam The Netherlands.

Background: Pru p 1 is a major allergen in peach and nectarine, and the different content in varieties may affect the degree of allergic reactions. This study aimed to quantify Pru p 1 levels in representative peach varieties and select hypoallergenic Pru p 1 varieties.

Methods: To obtain monoclonal and polyclonal antibodies, mice and rabbits, respectively, were immunized with recombinant Pru p 1.01 and Pru p 1.02. The Pru p 1 levels in fruits from 83 representative peach varieties was quantified by sandwich enzyme-linked immunosorbent assay (sELISA). nPru p 1 was obtained through specific monoclonal antibody affinity purification and confirmed by Western blot and mass spectrometry. The variable Pru p 1 content of selected varieties was evaluated by Western blot and the expression level of encoding genes by quantitative polymerase chain reaction.

Results: A sELISA method with monoclonal and polyclonal antibodies was built for quantifying Pru p 1 levels in peach. Pru p 1 was mainly concentrated in the peel (0.20-73.44 μg/g, fresh weight), being very low in the pulp (0.05-9.62 μg/g) and not detected in wild peach. For the 78 peach and nectarine varieties, Pru p 1 content varied widely from 0.12 to 6.45 μg/g in whole fruit. We verified that natural Pru p 1 is composed of 1.01 and 1.02 isoallergens, and the expression level and Pru p 1 band intensity in the immunoblots were in agreement with protein quantity determined by ELISA for some tested varieties. In some cases, the reduced levels of Pru p 1 did not coincide with low Pru p 3 in the same variety in whole fruit, while some ancient wild peach and nectarines contained low levels of both allergens, and late-ripening yellow flesh varieties were usually highly allergenic.

Conclusion: Pru p 1 content is generally low in peach compared to Pru p 3. Several hypoallergenic Pru p 1 and Pru p 3 varieties, "Zi Xue Tao," "Wu Yue Xian," and "May Fire," were identified, which could be useful in trials for peach allergy patients.
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http://dx.doi.org/10.1002/clt2.12034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120414PMC
May 2021

ATF3 Promotes Arsenic-Induced Apoptosis and Oppositely Regulates DR5 and Bcl-xL Expression in Human Bronchial Epithelial Cells.

Int J Mol Sci 2021 Apr 19;22(8). Epub 2021 Apr 19.

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Institute of Engineering Biology and Health, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.

Arsenic is one of the most common environmental pollutants eliciting serious public health issues; however, it is also a well-recognized chemotherapeutic agent for acute promyelocytic leukemia. The association between arsenic exposure and lung diseases has been established, but underlying molecular mechanisms are poorly defined. Here we investigated the toxicology of arsenic in airway epithelium. Arsenic rapidly induced the activating transcription factor ATF3 expression through the JNK and p38 pathways. The ATF3-deficient BEAS-2B cells were relatively resistant to apoptosis upon arsenic exposure, indicating a facilitatory role of ATF3 in arsenic-induced apoptosis. We further showed that ATF3 oppositely regulated the transcription of death receptor (DR5) and Bcl2-like 1 (Bcl-xL) by directly binding to the promoter DR5 and Bcl-xL. Altogether, our findings establish ATF3 as a pro-apoptotic protein in arsenic-induced airway epithelial apoptosis through transcriptionally regulating DR5 and Bcl-xL, highlighting the potential of ATF3 as an early and sensitive biomarker for arsenic-caused lung injury.
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http://dx.doi.org/10.3390/ijms22084223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072958PMC
April 2021

SOX17 loss-of-function variation underlying familial congenital heart disease.

Eur J Med Genet 2021 May 29;64(5):104211. Epub 2021 Mar 29.

Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China; Cardiovascular Research Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China; Central Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China. Electronic address:

As the most prevalent form of human birth defect, congenital heart disease (CHD) contributes to substantial morbidity, mortality and socioeconomic burden worldwide. Aggregating evidence has convincingly demonstrated that genetic defects exert a pivotal role in the pathogenesis of CHD, and causative mutations in multiple genes have been causally linked to CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic components underpinning CHD in the overwhelming majority of patients remain obscure. In this research, a four-generation consanguineous family suffering from CHD transmitted in an autosomal dominant mode was recruited. By whole-exome sequencing and bioinformatics analyses as well as Sanger sequencing analyses of the family members, a new heterozygous SOX17 variation, NM_022454.4: c.553G > T; p.(Glu185*), was identified to co-segregate with CHD in the family, with complete penetrance. The nonsense variation was neither detected in 310 unrelated healthy volunteers used as controls nor retrieved in such population genetics databases as the Exome Aggregation Consortium database, Genome Aggregation Database, and the Single Nucleotide Polymorphism database. Functional assays by utilizing a dual-luciferase reporter assay system unveiled that the Glu185*-mutant SOX17 protein had no transcriptional activity on its two target genes NOTCH1 and GATA4, which have been reported to cause CHD. Furthermore, the mutation abrogated the synergistic transactivation between SOX17 and NKX2.5, another established CHD-causing transcription factor. These findings firstly indicate SOX17 loss-of-function mutation predisposes to familial CHD, which adds novel insight to the molecular mechanism of CHD, implying potential implications for genetic risk appraisal and individualized prophylaxis of the family members affected with CHD.
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http://dx.doi.org/10.1016/j.ejmg.2021.104211DOI Listing
May 2021

Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Ann Am Thorac Soc 2021 06;18(6):981-988

National Heart and Lung Institute and.

Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. To evaluate the safety and efficacy of parenteral iron replacement in PAH. In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 μg/L or iron <10.3 μmol/L or transferrin saturations <16.4%. Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).
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http://dx.doi.org/10.1513/AnnalsATS.202009-1131OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456720PMC
June 2021

A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe.

Sci Adv 2021 Mar 17;7(12). Epub 2021 Mar 17.

School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China.

The suite of adaptations associated with the extreme stature of the giraffe has long interested biologists and physiologists. By generating a high-quality chromosome-level giraffe genome and a comprehensive comparison with other ruminant genomes, we identified a robust catalog of giraffe-specific mutations. These are primarily related to cardiovascular, bone growth, vision, hearing, and circadian functions. Among them, the giraffe gene is an outlier with seven unique amino acid substitutions not found in any other ruminant. Gene-edited mice with the giraffe-type show exceptional hypertension resistance and higher bone mineral density, both of which are tightly connected with giraffe adaptations to high stature. Our results facilitate a deeper understanding of the molecular mechanism underpinning distinct giraffe traits, and may provide insights into the study of hypertension in humans.
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http://dx.doi.org/10.1126/sciadv.abe9459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968835PMC
March 2021

The pathophysiological role of novel pulmonary arterial hypertension gene .

Eur Respir J 2021 09 23;58(3). Epub 2021 Sep 23.

National Heart and Lung Institute, Imperial College London, London, UK

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural remodelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole-genome and whole-exome sequencing studies have identified as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance. Rare deleterious variants in the gene and more common variants in upstream enhancer sites have both been associated with the disease, and a deficiency of expression may predispose to PAH. This review aims to consolidate the evidence linking genetic variants in to PAH, and explores the numerous targets and effects of the transcription factor, focusing on the pulmonary vasculature and the pathobiology of PAH.
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http://dx.doi.org/10.1183/13993003.04172-2020DOI Listing
September 2021

The Inflammatory Factors Associated with Disease Severity to Predict COVID-19 Progression.

J Immunol 2021 04 12;206(7):1597-1608. Epub 2021 Feb 12.

Department of Clinical Laboratory, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China

Coronavirus disease 2019 (COVID-19) is associated with immune dysregulation and cytokine storm. Exploring the immune-inflammatory characteristics of COVID-19 patients is essential to reveal pathogenesis and predict progression. In this study, COVID-19 patients showed decreased CD3, CD4, and CD8 T cells but increased neutrophils in circulation, exhibiting upregulated neutrophil-to-lymphocyte and neutrophil-to-CD8 T cell ratio. IL-6, TNF-α, IL-1β, IL-18, IL-12/IL-23p40, IL-10, Tim-3, IL-8, neutrophil extracellular trap-related proteinase 3, and S100A8/A9 were elevated, whereas IFN-γ and C-type lectin domain family 9 member A (clec9A) were decreased in COVID-19 patients compared with healthy controls. When compared with influenza patients, the expressions of TNF-α, IL-18, IL-12/IL-23p40, IL-8, S100A8/A9 and Tim-3 were significantly increased in critical COVID-19 patients, and carcinoembryonic Ag, IL-8, and S100A8/A9 could serve as clinically available hematologic indexes for identifying COVID-19 from influenza. Moreover, IL-6, IL-8, IL-1β, TNF-α, proteinase 3, and S100A8/A9 were increased in bronchoalveolar lavage fluid of severe/critical patients compared with moderate patients, despite decreased CD4 T cells, CD8 T cells, B cells, and NK cells. Interestingly, bronchoalveolar IL-6, carcinoembryonic Ag, IL-8, S100A8/A9, and proteinase 3 were found to be predictive of COVID-19 severity and may serve as potential biomarkers for predicting COVID-19 progression and potential targets in therapeutic intervention of COVID-19.
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http://dx.doi.org/10.4049/jimmunol.2001327DOI Listing
April 2021

Rapid and high-capacity loading of IgG monoclonal antibodies by polymer brush and peptides functionalized microspheres.

J Chromatogr A 2021 Mar 30;1640:461948. Epub 2021 Jan 30.

State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China. Electronic address:

Fast-throughput and cost reduction of current purification platforms are becoming increasing requests during antibody manufacture. The macroporous-matrix absorbents have presented extensive potentiality in improving operational throughput during purification of macromolecule. And meanwhile the peptide ligand has become a promising alternative to recombinant protein ligands for cost reduction of chromatographic purification. Therefore, here we designed a functionalized microspheres resin with both macroporous matrix of polymerized glycidyl methacrylate and ethylene glycol dimethacrylate (PGMA-EDMA) and peptide ligand of hexapeptide (FYEILH). In order to circumvent the steric effect of peptides and amplify the binding sites on macroporous matrix, the peptide ligand was coupled on a liner PGMA polymer brushes grafted on microspheres. Comparing to the conventional agarose-matrix resin and the general peptide-grafted microspheres, the functionalized microspheres presented excellent permeability and high capacity to rapid loading hIgG by maintaining a stable level of dynamic binding capacity at fast flow rate above 110 column volume per hour (cv/h) and very short residence time below 0.5 min. Such functionalized microspheres provide a facile and broadly applicable strategy to develop the attractive candidate for rapid and cost-reduced purification of antibody.
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http://dx.doi.org/10.1016/j.chroma.2021.461948DOI Listing
March 2021

Screening and identifying hepatobiliary diseases through deep learning using ocular images: a prospective, multicentre study.

Lancet Digit Health 2021 02;3(2):e88-e97

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China; Centre for Precision Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address:

Background: Ocular changes are traditionally associated with only a few hepatobiliary diseases. These changes are non-specific and have a low detection rate, limiting their potential use as clinically independent diagnostic features. Therefore, we aimed to engineer deep learning models to establish associations between ocular features and major hepatobiliary diseases and to advance automated screening and identification of hepatobiliary diseases from ocular images.

Methods: We did a multicentre, prospective study to develop models using slit-lamp or retinal fundus images from participants in three hepatobiliary departments and two medical examination centres. Included participants were older than 18 years and had complete clinical information; participants diagnosed with acute hepatobiliary diseases were excluded. We trained seven slit-lamp models and seven fundus models (with or without hepatobiliary disease [screening model] or one specific disease type within six categories [identifying model]) using a development dataset, and we tested the models with an external test dataset. Additionally, we did a visual explanation and occlusion test. Model performances were evaluated using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and F1* score.

Findings: Between Dec 16, 2018, and July 31, 2019, we collected data from 1252 participants (from the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Sun Yat-sen University, the Department of Infectious Diseases of the Affiliated Huadu Hospital of Southern Medical University, and the Nantian Medical Centre of Aikang Health Care [Guangzhou, China]) for the development dataset; between Aug 14, 2019, and Jan 31, 2020, we collected data from 537 participants (from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University and the Huanshidong Medical Centre of Aikang Health Care [Guangzhou, China]) for the test dataset. The AUROC for screening for hepatobiliary diseases of the slit-lamp model was 0·74 (95% CI 0·71-0·76), whereas that of the fundus model was 0·68 (0·65-0·71). For the identification of hepatobiliary diseases, the AUROCs were 0·93 (0·91-0·94; slit-lamp) and 0·84 (0·81-0·86; fundus) for liver cancer, 0·90 (0·88-0·91; slit-lamp) and 0·83 (0·81-0·86; fundus) for liver cirrhosis, and ranged 0·58-0·69 (0·55-0·71; slit-lamp) and 0·62-0·70 (0·58-0·73; fundus) for other hepatobiliary diseases, including chronic viral hepatitis, non-alcoholic fatty liver disease, cholelithiasis, and hepatic cyst. In addition to the conjunctiva and sclera, our deep learning model revealed that the structures of the iris and fundus also contributed to the classification.

Interpretation: Our study established qualitative associations between ocular features and major hepatobiliary diseases, providing a non-invasive, convenient, and complementary method for hepatobiliary disease screening and identification, which could be applied as an opportunistic screening tool.

Funding: Science and Technology Planning Projects of Guangdong Province; National Key R&D Program of China; Guangzhou Key Laboratory Project; National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S2589-7500(20)30288-0DOI Listing
February 2021

Acupuncture accelerates neural regeneration and synaptophysin production after neural stem cells transplantation in mice.

World J Stem Cells 2020 Dec;12(12):1576-1590

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China.

Background: Synaptophysin plays a key role in synaptic development and plasticity of neurons and is closely related to the cognitive process of Alzheimer's disease (AD) patients. Exogenous neural stem cells (NSCs) improve the damaged nerve function. The effects of Sanjiao acupuncture on cognitive impairment may be related to the regulation of the NSC microenvironment.

Aim: To explore the anti-dementia mechanism of acupuncture by regulating the NSC microenvironment.

Methods: NSCs were isolated from pregnant senescence-accelerated mouse resistant 1 (SAMR1) mice, labeled with BrdU, and injected into the hippocampus of senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old senescence-accelerated mice (SAM) were randomly divided into six groups: SAMR1 (RC), SAMP8 (PC), sham transplantation (PS), NSC transplantation (PT), NSC transplantation with acupuncture (PTA), and NSC transplantation with non-acupoint acupuncture (PTN). Morris water maze test was used to study the learning and memory ability of mice after NSC transplantation. Hematoxylin-eosin staining and immunofluorescence were used to observe the his-topathological changes and NSC proliferation in mice. A co-culture model of hippocampal slices and NSCs was established , and the synaptophysin expression in the hippocampal microenvironment of mice was observed by flow cytometry after acupuncture treatment.

Results: Morris water maze test showed significant cognitive impairment of learning and memory in 8-mo-old SAMP8, which improved in all the NSC transplantation groups. The behavioral change in the PTA group was stronger than those in the other two groups ( < 0.05). Histopathologically, the hippocampal structure was clear, the cell arrangement was dense and orderly, and the necrosis of cells in CA1 and CA3 areas was significantly reduced in the PTA group when compared with the PC group. The BrdU-positive proliferating cells were found in NSC hippocampal transplantation groups, and the number increased significantly in the PTA group than in the PT and PTN groups ( < 0.05). Flow cytometry showed that after co-culture of NSCs with hippocampal slices , the synaptophysin expression in the PC group decreased in comparison to the RC group, that in PT, PTA, and PTN groups increased as compared to the PC group, and that in the PTA group increased significantly as compared to the PTN group with acupoint-related specificity ( < 0.05).

Conclusion: Acupuncture may promote nerve regeneration and synaptogenesis in SAMP8 mice by regulating the microenvironment of NSC transplantation to improve the nerve activity and promote the recovery of AD-damaged cells.
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http://dx.doi.org/10.4252/wjsc.v12.i12.1576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789117PMC
December 2020

Additive-Free Copper(I)-Mediated Synthesis of 5- or 6-Brominated 2-Aryl-1-Indole-3-Carboxylates from α,α-Dibromo β-Iminoesters.

J Org Chem 2021 01 4;86(2):1964-1971. Epub 2021 Jan 4.

College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P. R. China.

Additive-free copper(I)-bromide-mediated radical cyclization reactions of α,α-dibromo β-iminoesters were investigated, enabling the synthesis of a series of 5- or 6-brominated 2-aryl-1-indole-3-carboxylates in moderate to good yields. The mechanistic study showed that (i) the bromine atom originated from the substrates and (ii) the bromination might be related to a 3-bromo-3 indole intermediate via an electrophilic bromine atom transfer. Furthermore, the practicality of this method was demonstrated by gram-scale synthesis and the potential for product derivatization toward other valuable multisubstituted indoles.
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http://dx.doi.org/10.1021/acs.joc.0c02497DOI Listing
January 2021

Variation in IgE binding potencies of seven Artemisia species depending on content of major allergens.

Clin Transl Allergy 2020 Nov 18;10(1):50. Epub 2020 Nov 18.

Departments of Experimental Immunology and of Otorhinolaryngology, UMC, University Of Amsterdam, Meibergdreef 9, 1105 AZ , Amsterdam, The Netherlands.

Background: Artemisia weed pollen allergy is important in the northern hemisphere. While over 350 species of this genus have been recorded, there has been no full investigation into whether different species may affect the allergen diagnosis and treatment. This study aimed to evaluate the variations in amino acid sequences and the content of major allergens, and how these affect specific IgE binding capacity in representative Artemisia species.

Methods: Six representative Artemisia species from China and Artemisia vulgaris from Europe were used to determine allergen amino acid sequences by transcriptome, gene sequencing and mass spectrometry of the purified allergen component proteins. Sandwich ELISAs were developed and applied for Art v 1, Art v 2 and Art v 3 allergen quantification in different species. Aqueous pollen extracts and purified allergen components were used to assess IgE binding by ELISA and ImmunoCAP with mugwort allergic patient serum pools and individual sera from five areas in China.

Results: The Art v 1 and Art v 2 homologous allergen sequences in the seven Artemisia species were highly conserved. Art v 3 type allergens in A. annua and A. sieversiana were more divergent compared to A. argyi and A. vulgaris. The allergen content of Art v 1 group in the seven extracts ranged from 3.4% to 7.1%, that of Art v 2 from 1.0% to 3.6%, and Art v 3 from 0.3% to 10.5%. The highest IgE binding potency for most Chinese Artemisia allergy patients was with A. annua pollen extract, followed by A. vulgaris and A. argyi, with A. sieversiana significantly lower. Natural Art v 1-3 isoallergens from different species have almost equivalent IgE binding capacity in Artemisia allergic patients from China.

Conclusion And Clinical Relevance: There was high sequence similarity but different content of the three group allergens from different Artemisia species. Choice of Artemisia annua and A. argyi pollen source for diagnosis and immunotherapy is recommended in China.
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http://dx.doi.org/10.1186/s13601-020-00354-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677751PMC
November 2020

Manipulation of pore structure during manufacture of agarose microspheres for bioseparation.

Eng Life Sci 2020 Nov 23;20(11):504-513. Epub 2020 Sep 23.

State Key Laboratory of Biochemical Engineering Institute of Process Engineering Chinese Academy of Sciences Beijing P. R. China.

Agarose microspheres with a controllable pore structure were manufactured by varying agarose types and crosslinking degrees. Various agarose could tailor the gel formation of microspheres matrix and thus affect the final pore structures. Small pores in microspheres could be fabricated by agarose with a higher molecular weight, which was demonstrated by the packed column with lower distribution coefficient ( ) values measured by gel filtration chromatography. Further, higher values also demonstrated that more and larger pores were formed with increasing the crosslinking degree of agarose microspheres. Either using agarose with a high molecular weight or increasing the crosslinking degree would finally lead to the enhancement of the flow rate during flow performance of packed column as necessary for improving separation efficiency. This provides a foundation for high-resolution chromatography with a controllable separation range as beneficial for downstream process.
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http://dx.doi.org/10.1002/elsc.202000023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645642PMC
November 2020

FoxC1-Induced Vascular Niche Improves Survival and Myocardial Repair of Mesenchymal Stem Cells in Infarcted Hearts.

Oxid Med Cell Longev 2020 4;2020:7865395. Epub 2020 Jul 4.

Department of Cardiology, GuangZhou Red Cross Hospital Medical College of Ji-Nan University, 396 Tongfuzhong Road, Haizhu District, Guangzhou 510220, China.

Aims: Forkhead box C1 (FoxC1) is essential for maintaining the hair follicle stem cell niche. The role of FoxC1 in maintaining mesenchymal stem cell (MSC) niches after myocardial infarction (MI) has not been directly determined to date. In this study, we determined to explore the possible roles and mechanisms of FoxC1 on MSC survival and function in the ischemic niche.

Methods And Results: MI model was established in this study, and expression level of FoxC1 was overexpressed or knocked down through efficient delivery of FoxC1 transfection or FoxC1. Fifteen days later, the animals were allocated randomly to receive phosphate-buffered saline (PBS) injection or MSC transplantation. We identified FoxC1 as a key regulator of maintaining the vascular niche in the infarcted hearts (IHs) by driving proangiogenic and anti-inflammatory cytokines while repressing inflammatory and fibrotic factor expression. This vascular niche improved MSC survival and capacity in the IHs. Importantly, FoxC1 interacted with MSCs and was required for vessel specification and differentiation of engrafted MSCs in the ischemic niches, promoting myocardial repair. Inhibiting FoxC1 abolished these effects.

Conclusion: These results definitively implicate FoxC1 signaling in maintaining ischemic vascular niche, which may be helpful in myocardial repair induced by MSC therapy.
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http://dx.doi.org/10.1155/2020/7865395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490631PMC
May 2021

Stem cell therapy for Alzheimer's disease.

World J Stem Cells 2020 Aug;12(8):787-802

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell-derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.
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http://dx.doi.org/10.4252/wjsc.v12.i8.787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477654PMC
August 2020

Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension.

Sci Rep 2020 07 30;10(1):12864. Epub 2020 Jul 30.

Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circumvent off-target effects.
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http://dx.doi.org/10.1038/s41598-020-69737-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393135PMC
July 2020

A high-throughput strategy for COVID-19 testing based on next-generation sequencing.

Authors:
Jian Huang Lan Zhao

medRxiv 2020 Jun 19. Epub 2020 Jun 19.

COVID-19 testing as sufficient as needed is essential for healthcare workers, patients, and authorities to make informed decisions to confront and eventually defeat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, diagnosis of COVID-19 relies on quantitative reverse-transcription PCR, which is low-throughput, laborious, and often false-negative, making it overwhelmingly challenging to meet testing needs even in industrialized countries. Here we propose a new strategy, which employs a modified loop-mediated isothermal amplification (LAMP) assay, a simple procedure requiring no sophisticated instruments, to index and amplify viral genes from individual specimens, of which the products are readily available for construction of multiplexed libraries for next-generation sequencing. Our strategy would allow precise diagnosis of thousands of specimens in 1-2 days with significantly lower operating expenses. Furthermore, this strategy will make it possible for patients to collect, process, and mail their own samples to facilities for a quick, reliable diagnosis at a population scale.
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http://dx.doi.org/10.1101/2020.06.12.20129718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310665PMC
June 2020

Involvement of MEK5/ERK5 signaling pathway in manganese-induced cell injury in dopaminergic MN9D cells.

J Trace Elem Med Biol 2020 May 11;61:126546. Epub 2020 May 11.

School of Public Health, Zunyi Medical University, Zunyi, Guizhou, PR China. Electronic address:

Background: Over-exposure to manganese (Mn) causes irreversible movement disorders with signs and symptoms similar, but not identical, to idiopathic Parkinson's disease (IPD). Recent data suggest that Mn toxicity occurs in dopaminergic (DA) neurons, although the mechanism remains elusive. This study was designed to investigate whether Mn interfered the apoptotic signaling transduction cascade in DA neurons.

Methods: Mouse midbrain dopaminergic MN9D cells were exposed to Mn in a concentration range of 0, 400, 800, or 1200 μM as designated as control, low, medium, and high exposure groups, respectively. The flow cytometry with Annexin V/PI double staining and immunohistochemistry were used to assess the apoptosis.

Results: Data indicated that Mn exposure caused morphological alterations typical of apoptosis, increased apoptotic cells by 2-8 fold, and produced reactive oxidative species (ROS) by 1.5-2.2 fold as compared to controls (p < 0.05). Studies by qPCR and Western blot revealed that Mn exposure significantly increased the protein expression of extracellular signal-regulated kinase-5 (ERK5) and mitogen-activated ERK kinase-5 (MEK5) (p < 0.05). The presence of BIX02189, a specific inhibitor of MER/ERK, caused a much greater cytotoxicity, i.e., higher cell death, more ROS production, and worsened apoptosis, than did the treatment with Mn alone. Following Mn exposure, the expression of a downstream effector Bcl- 2 was reduced by 48 % while those of Bax and Caspase-3 were increased by 266.7 % and 90.1 %, respectively, as compared to controls (p < 0.05).

Conclusion: Taken together, these data provide the initial evidence that the signaling transduction cascade mediated by MEK5/ERK5 is responsible to Mn-induced cytotoxicity; Mn exposure, by suppressing anti-apoptotic function while facilitating pro-apoptotic activities, alters neuronal cell's survival and functionally inhibits DA production by MN9D cells.
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http://dx.doi.org/10.1016/j.jtemb.2020.126546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655554PMC
May 2020

Hypoxia-induced pulmonary hypertension-Utilizing experiments of nature.

Br J Pharmacol 2021 01 28;178(1):121-131. Epub 2020 Aug 28.

National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK.

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest in understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature, specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather than cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
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http://dx.doi.org/10.1111/bph.15144DOI Listing
January 2021
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