Publications by authors named "Haiyan Li"

833 Publications

A membrane arm of mitochondrial complex I sufficient to promote respirasome formation.

Cell Rep 2021 Apr;35(2):108963

Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325000, China; Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310000, China. Electronic address:

The assembly pathways of mitochondrial respirasome (supercomplex I+III+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (P-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of P-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.
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http://dx.doi.org/10.1016/j.celrep.2021.108963DOI Listing
April 2021

Case Report: Coinheritance of Germline Mutations in and in Colorectal Cancer.

Front Oncol 2021 25;11:658389. Epub 2021 Mar 25.

Department of Oncology, Nanjing Tongren Hospital, Nanjing, China.

Deleterious mutations in gene cause the autosomal dominant familial adenomatous polyposis (FAP) which is typically characterized by the occurrence of hundreds to thousands of colorectal adenomas that eventually lead to colorectal cancers (CRCs). are the two major susceptibility genes for breast and ovarian cancers. Here, we reported a coinheritance of mutations in and genes in a 20-year-old CRC patient with typical clinical features for FAP. Multiple relatives in the family of the patient were affected by colorectal and other cancers. Next-generation sequencing analysis using a panel consisting of 53 hereditary cancer related genes revealed a maternally inherited (exon15cn_del) mutation and a paternally inherited (p.lle1824AspfsX3) mutation. This is the first coexistence of and mutations in a CRC patient with the mutation inheritance pattern comprehensively characterized in the family. The patient underwent a colonoscopy and a subtotal colectomy and was subsequently diagnosed with colonic adenocarcinomas accompanied with hundreds of tubulovillous adenomas. The case reveals the scenario where two disease-causing mutations of different hereditary tumor syndromes coexist, and illustrates the importance of evaluating detailed family history and performing a multiple-gene panel test in patients with hereditary cancer.
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http://dx.doi.org/10.3389/fonc.2021.658389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030582PMC
March 2021

Sodium alginate-bioglass-encapsulated hAECs restore ovarian function in premature ovarian failure by stimulating angiogenic factor secretion.

Stem Cell Res Ther 2021 Apr 1;12(1):223. Epub 2021 Apr 1.

The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 1961 Hua-Shan Road, Shanghai, 200030, People's Republic of China.

Background: Human amniotic epithelial cells (hAECs) exhibit a strong capability to restore ovarian function in chemotherapy-induced premature ovarian failure (POF). However, the therapeutic efficacy of hAECs is usually affected by the limited number and proliferative ability of grafted hAECs in target organs. The transplantation of stem cells encapsulated in sodium alginate-bioglass (SA-BG) composite hydrogel has recently been shown to be an effective strategy for tissue regeneration. The current study aims to investigate the therapeutic potential of hAECs or hAEC-derived conditioned medium (CM) encapsulated in SA-BG in mice with chemotherapy-induced POF.

Methods: C57BL/6 mice were intraperitoneally injected with chemotherapy drugs to induce POF. hAECs or CM were harvested and encapsulated in SA-BG composite hydrogel, which were transplanted onto the injured ovaries of mice with POF. Follicle development, granulosa cell function, and ovarian angiogenesis were evaluated by morphological methods. To further elucidate the effect of SA-BG-encapsulated hAECs/CM on vascularization, the tube formation of human umbilical vein epithelial cells (hUVECs) was conducted in vitro. Cytokine array and ELISA were used to analyze and quantify the effects of bioactive components released by SA-BG on the secretion of angiogenic factors by hAECs.

Results: The transplantation of SA-BG-encapsulated hAECs/CM restored follicle development, repaired granulosa cell function, and enhanced ovarian angiogenesis in POF mice. The further study showed that SA-BG significantly promoted the tube formation of hUVECs in vitro. Moreover, encapsulating hAECs could facilitate the effect of SA-BG on inducing the formation of the capillary tube in a paracrine manner. In addition, we found that SA-BG extracts significantly enhanced the viability of hAECs and stimulated the secretion of pro-angiogenic factors of hAECs. Notably, compared with SA-BG/CM, SA-BG/hAECs achieve better therapeutic effects, possibly because stimulation of BG enhanced the viability and paracrine capacity of hAECs.

Conclusions: The present study initially demonstrates that SA-BG-encapsulated hAECs or CM can exert a therapeutic effect on chemotherapy-induced POF mainly by protecting granulosa cell function and enhancing ovarian vascularization, which might provide a novel strategy for the delivery of hAECs for treating POF.
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http://dx.doi.org/10.1186/s13287-021-02280-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015041PMC
April 2021

Bone marrow stem cells secretome accelerates simulated birth trauma-induced stress urinary incontinence recovery in rats.

Aging (Albany NY) 2021 Mar 31;13. Epub 2021 Mar 31.

Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Stress urinary incontinence (SUI) is defined as involuntary urine leakage during physical activities that increase the intra-abdominal pressure on the bladder. We studied bone marrow stem cell (BMSC) secretome-induced activation of anterior vaginal wall (AVW) fibroblasts and its ability to accelerate SUI recovery following vaginal distention (VD) in a rat model of birth trauma using BMSC-conditioned medium (BMSC-CM) and concentrated conditioned medium (CCM). BMSC-CM enhanced the proliferation, migration, and collagen synthesizing abilities of fibroblasts. Differentially expressed genes in BMSC-CM-induced fibroblasts were mainly enriched for cell adhesion, extracellular fibril organization and angiogenesis. Treatment with the JAK2 inhibitor AG490 reversed BMSC-CM-induced activation of the JAK2/STAT4 pathway. Periurethral injection with BMSC-CCM markedly enhanced the abdominal leak point pressure (LPP) in rats after VD. Histological analysis revealed increased numbers of fibroblasts, improved collagen fibers arrangement and elevated collagens content in the AVW of rats receiving BMSC-CCM. These findings suggest the BMSC secretome activates AVW fibroblasts and contributes to the functional and anatomic recovery of simulated birth trauma-induced SUI in rats.
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http://dx.doi.org/10.18632/aging.202812DOI Listing
March 2021

PCAF attenuated M1 macrophage inflammatory responses possibly through KLF2 and KLF4.

Immunol Cell Biol 2021 Mar 26. Epub 2021 Mar 26.

Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Macrophages exhibit distinct phenotypes in response to environmental signals. The polarization of M1 macrophages plays an essential role in the inflammatory response. However, the specific molecular mechanisms regulating the inflammatory response during M1 macrophage polarization remain to be further understood. Here, we found that the histone acetyltransferase PCAF was a potential negative regulator of the M1 macrophage inflammatory response. During M1 macrophage polarization, the inflammatory response gradually reduced, but PCAF expression increased. Furthermore, the overexpression of PCAF significantly inhibited the expression of the M1 macrophage-related pro-inflammatory genes TNF-α, IL-6 and CXCL10, while PCAF deficiency enhanced the expression of these genes. Furthermore, we found that PCAF overexpression suppressed the NF-κB signaling pathway and promoted the expression of the Krüppel-like factors KLF2 and KLF4 through regulating their transcriptional levels. In addition, KLF2 and KLF4 deficiency reversed the PCAF-induced inhibition of the expression of pro-inflammatory genes in M1 macrophages. Collectively, the present results demonstrate a potential negative regulatory mechanism of the inflammatory response during M1 macrophage polarization and propose a novel mechanism of inflammation resolution for maintaining homeostasis.
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http://dx.doi.org/10.1111/imcb.12455DOI Listing
March 2021

Regulatory effect of mitoQ on the mtROS-NLRP3 inflammasome pathway in leptin-pretreated BEAS-2 cells.

Exp Ther Med 2021 May 8;21(5):466. Epub 2021 Mar 8.

Discipline of Pediatric Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Obese asthma is a phenotype of asthma whose occurrence is gradually increasing in both adults and children. The majority of studies have demonstrated that obesity is a major risk factor for asthma and the effect of obesity on the lungs is considerable. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been previously demonstrated to serve a role in obese asthma mediated by mitochondrial reactive oxygen species (mtROS). The aim of the present study was to investigate the effect of leptin on airway epithelial cells and the protective effect of the mitochondrial-targeted antioxidant mitoquinone (mitoQ). Human normal bronchial epithelial cell lines BEAS-2 cells were used and divided into 6 groups: Control group (negative control), DMSO group (solvent control), lipopolysaccharide (LPS) group (positive control), LPS + mitoQ group, Leptin group and Leptin + mitoQ group. CCK8 assay was used to establish the optimal concentration and incubation time of the drugs. mitoTracker probe and mitoSOX reagent were used to detect the integrity of mitochondrial membranes and the content of mtROS. mRNA expression levels were detected by reverse transcription-quantitative PCR analysis. It was revealed that the mitochondrial membrane was disrupted in the Leptin group, which recovered after treatment with mitoQ. As a result, the production of mitochondrial reactive oxygen species (mtROS) in the Leptin group was significantly increased (P<0.01), but following treatment with mitoQ, this overproduction of mtROS was significantly decreased to normal levels (P<0.01). Furthermore, the expression levels of NOD-, LRR- and pyrin domain-containing protein 3 NLRP3 and caspase-1 mRNA in the leptin-pretreated BEAS-2 cells were significantly increased compared with those in the control group (P<0.01), while they were decreased following mitoQ treatment (P<0.01). Taken together, these data suggested that leptin may promote airway inflammation partially through upregulating the mtROS-NLRP3 inflammasome signaling pathway in airway epithelial cells and mitoQ may be a potential treatment for obese asthma.
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http://dx.doi.org/10.3892/etm.2021.9897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983181PMC
May 2021

Reconstruction and optimization of the 3D geometric anatomy structure model for subject-specific human knee joint based on CT and MRI images.

Technol Health Care 2021 ;29(S1):221-238

Department of Magnetic Resonance Imaging, Xi'an Honghui Hospital Affiliated to Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China.

Background: Nowadays, the total knee arthroplasty (TKA) technique plays an important role in surgical treatment for patients with severe knee osteoarthritis (OA). However, there are still several key issues such as promotion of osteotomy accuracy and prosthesis matching degree that need to be addressed.

Objective: It is significant to construct an accurate three-dimensional (3D) geometric anatomy structure model of subject-specific human knee joint with major bone and soft tissue structures, which greatly contributes to obtaining personalized osteotomy guide plate and suitable size of prosthesis.

Methods: Considering different soft tissue structures, magnetic resonance imaging (MRI) scanning sequences involving two-dimensional (2D) spin echo (SE) sequence T1 weighted image (T1WI) and 3D SE sequence T2 weighted image (T2WI) fat suppression (FS) are selected. A 3D modeling methodology based on computed tomography (CT) and two sets of MRI images is proposed.

Results: According to the proposed methods of image segmentation and 3D model registration, a novel 3D knee joint model with high accuracy is finally constructed. Furthermore, remeshing is used to optimize the established model by adjusting the relevant parameters.

Conclusions: The modeling results demonstrate that reconstruction and optimization model of 3D knee joint can clearly and accurately reflect the key characteristics, including anatomical structure and geometric morphology for each component.
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http://dx.doi.org/10.3233/THC-218022DOI Listing
January 2021

Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations.

Technol Health Care 2021 ;29(S1):103-114

Shandong Provincial Key Laboratory of Biophysics (Dezhou University), Dezhou, Shandong 253023, China.

Background: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations.

Objective: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models.

Methods: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations.

Results: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation.

Conclusions: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.
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http://dx.doi.org/10.3233/THC-218011DOI Listing
January 2021

Acupuncture for Chronic Pain-Related Depression: A Systematic Review and Meta-Analysis.

Pain Res Manag 2021 22;2021:6617075. Epub 2021 Feb 22.

Jiangxi University of Traditional Chinese Medicine, Nanchang, China.

Objective: The aim of this systematic review was to summarize and evaluate the existing evidence on the effectiveness and safety of acupuncture in relieving chronic pain-related depression (CPRD).

Methods: We searched seven online databases to identify eligible randomized controlled trials (RCTs) of acupuncture for CPRD published before September 2020. We included studies that used acupuncture as the intervention group, with or without a control group, and the control group was treated with conventional drugs. Meta-analysis was performed using RevMan 5.3 software. For outcomes, assessments were performed using the Hamilton Depression Scale (HAMD), Visual Analogue Scale (VAS), and adverse events.

Results: Eight studies involving 636 participants were identified and included in the meta-analysis. The results showed that single acupuncture treatment and drug treatment have the same effect in improving the HAMD score (MD = -0.14, 95% CI = [-0.88, 0.59],  = 0.71) and alleviating the VAS score (MD = -0.42, 95% CI = [-1.10, -0.27],  = 0.23), but acupuncture treatment is safer (OR = 0.03, 95% CI = [0.01, 0.21],  = 0.0003). In addition, acupuncture combined with drugs (control group) is more beneficial than single-drug treatment in improving the HAMD score (MD = -2.95, 95% CI = [-3.55, -2.36],  < 0.00001) and alleviating the VAS score (MD = -1.06, 95% CI = [-1.65, -0.47],  = 0.0004).

Conclusion: Acupuncture is an effective and safe treatment for CPRD, and acupuncture combined with drug therapy is more effective than single-drug therapy. Nevertheless, the conclusions were limited due to the low quality and a small number of included studies.
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http://dx.doi.org/10.1155/2021/6617075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925064PMC
February 2021

Author Response to Comment on: Dynamic Adsorption of Sulfamethoxazole from Aqueous Solution by Lignite Activated Coke.

Materials (Basel) 2021 Feb 11;14(4). Epub 2021 Feb 11.

Beijing Engineering Research Center of Sustainable Urban Sewage System Construction and Risk Control, Beijing University of Civil Engineering and Architecture,100044 Beijing, China.

The authors would like to thank the comment by Diego M. Juela for contributing to helpful scientific discussions and correction suggestions, and to also express thanks to the editors.
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http://dx.doi.org/10.3390/ma14040868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918909PMC
February 2021

The Epidemiology, Molecular, and Clinical of Human Adenoviruses in Children Hospitalized With Acute Respiratory Infections.

Front Microbiol 2021 16;12:629971. Epub 2021 Feb 16.

Department of Children's Respiration Disease, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.

Introduction: Human adenovirus (HAdV) is a common pathogen in children with acute respiratory infections (ARIs). The aim was to describe the epidemiology, molecular, and clinical characteristics of HAdV among children hospitalized with ARIs in Wenzhou in southeastern China.

Methodology: From January 2018 to December 2019, nasopharyngeal swab or sputum specimens were prospectively collected from hospitalized children with ARIs. HAdV was detected using direct immunofluorescence. We used a multiplex PCR assay combined with capillary electrophoresis targeting the hexon gene's hypervariable region to identify HAdV types 1, 2, 3, 4, 5, 7, 14, 21, 37, 40, 41, and 55. We analyzed the epidemiological, molecular, and clinical data according to the HAdV type.

Results: HAdVs were detected in 1,059 (3.5%) of the total of 30,543 children tested. A total of 947 cases with monotype HAdV identified by the PCR assay were included in the analysis. HAdV-3 (415/947, 43.8%), HAdV-7 (318/947, 33.6%), HAdV-2 (108/947, 11.4%), and HAdV-1 (70/947, 7.4%) were the predominant types. Of the 550 (58.1%) cases detected from December 2018 to August 2019, HAdV-3, and HAdV-7 were the main types. The main diagnoses included 358 cases of pneumonia, 232 cases of tonsillitis, 198 cases of bronchitis, and 159 cases of upper respiratory tract infection (URTI). Among children with pneumonia the main types were HAdV-7 (51.1%), HAdV-3 (36.9%), and HAdV-1 (2.2%). Among children with bronchitis, the main types were HAdV-3 (48.0%), HAdV-7 (28.3%), and HAdV-2 (10.6%). Among children with URTIs, the main types were HAdV-3 (49.7%), HAdV-7 (22.6%), and HAdV-2 (13.2%). Among children with tonsillitis, the main types were HAdV-3 (47.4%), HAdV-2 (22.4%), and HAdV-7 (18.5%). In total, 101 (55.2%) patients required supplemental oxygen, 15 (8.2%) required critical care, and 1 child (0.5%) with HAdV-7 pneumonia died.

Conclusion: HAdV-3 -7, -2, and -1 were the predominant types identified in hospitalized children with ARIs in Wenzhou. From December 2018 to August 2019, there were outbreaks of HAdV-3 and -7. There were significant differences in HAdV types among children with pneumonia, tonsillitis, bronchitis, and URTI. HAdV-7 can cause more severe pneumonia in children than HAdV-3.
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http://dx.doi.org/10.3389/fmicb.2021.629971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921318PMC
February 2021

Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.

Front Pharmacol 2020 20;11:574720. Epub 2020 Nov 20.

Center of Basic Medicine Research (CBMR), Peking University Third Hospital, Beijing, China.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0-72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (R) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, R was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.
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http://dx.doi.org/10.3389/fphar.2020.574720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919379PMC
November 2020

"Hand as foot" teaching method in the education of diet and exercise for diabetic patients.

Asian J Surg 2021 Mar 27;44(3):574-576. Epub 2021 Feb 27.

Inner Mongolia Medical University, Department of Orthopedics, Affiliated Hospital of Inner Mongolia Medical University, Huhhot North Street, Inner Mongolia, 010050, China.

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http://dx.doi.org/10.1016/j.asjsur.2020.12.038DOI Listing
March 2021

Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients.

Front Pharmacol 2020 12;11:585021. Epub 2021 Feb 12.

Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant and experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.
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http://dx.doi.org/10.3389/fphar.2020.585021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907647PMC
February 2021

Pore texture analysis in automated 3D breast ultrasound images for implanted lightweight hernia mesh identification: a preliminary study.

Biomed Eng Online 2021 Feb 25;20(1):23. Epub 2021 Feb 25.

Department of Ultrasound, Huadong Hospital, Fudan University, Shanghai, China.

Background: Precise visualization of meshes and their position would greatly aid in mesh shrinkage evaluation, hernia recurrence risk assessment, and the preoperative planning of salvage repair. Lightweight (LW) meshes are able to preserve abdominal wall compliance by generating less post-implantation fibrosis and rigidity. However, conventional 3D imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) cannot visualize the LW meshes. Patients sometimes have to undergo a second-look operation for visualizing the mesh implants. The goal of this work is to investigate the potential advantages of Automated 3D breast ultrasound (ABUS) pore texture analysis for implanted LW hernia mesh identification.

Methods: In vitro, the appearances of four different flat meshes in both ABUS and 2D hand-held ultrasound (HHUS) images were evaluated and compared. In vivo, pore texture patterns of 87 hernia regions were analyzed both in ABUS images and their corresponding HHUS images.

Results: In vitro studies, the imaging results of ABUS for implanted LW meshes are much more visualized and effective in comparison to HHUS. In vivo, the inter-class distance of 40 texture features was calculated. The texture features of 2D sectional plans (axial and sagittal plane) have no significant contribution to implanted LW mesh identification. Significant contribution was observed in coronal plane. However, since the mesh may have spatial variation such as shrinkage after implantation surgery, the inter-class distance of 3D coronal plane pore texture features are bigger than 2D coronal plane, so the contribution of 3D coronal plane pore texture features are more valuable than 2D coronal plane for implanted LW mesh identification. The use of 3D pore texture features significantly improved the robustness of the identification method in distinguishing between LW mesh and fascia.

Conclusions: An innovative new ABUS provides additional pore texture visualization, by separating the LW mesh from the fascia tissues. Therefore, ABUS has the potential to provides more accurate features to characterize pore texture patterns, and ultimately provide more accurate measures for implanted LW mesh identification.
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http://dx.doi.org/10.1186/s12938-021-00859-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908764PMC
February 2021

Naringenin promotes cell autophagy to improve high-fat-diet-induced atherosclerosis in ApoE-/- mice.

Braz J Med Biol Res 2021 12;54(4):e9764. Epub 2021 Feb 12.

Department of Neurology, Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang, China.

Naringenin (NAR) is a major flavanone in citrus fruits that has multiple pharmacological attributes such as anticancer and antiatherogenic. This study aims to investigate the mechanism of NAR in high-fat-diet (HFD)-induced atherosclerosis (AS) in apolipoprotein E-knockout (ApoE-/-) mice. A HFD-induced AS ApoE-/- mouse model was established. The mice were treated with HFD, different doses of NAR and simvastatin (Simv). After drug treatment, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and alanine aminotransferase (ALT) were determined. The expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected using qRT-PCR and enzyme-linked immunosorbent assay. The plaque area of the aorta of AS mice was determined using oil red O staining. Western blot analysis was applied to measure the levels of autophagy-related proteins [protein 1 light chain 3B (LC3B), beclin 1, and p62]. The TC, TG, LDL-C, TNF-α, ALT, and MDA levels were significantly increased while the HDL-C, SOD, and GSH-Px levels were decreased in the HFD-induced AS ApoE-/- mice. NAR treatment reversed the expression of the above indicators in mice. After they were treated with different doses of NAR, the LC3B and beclin 1 levels were improved while the p62 protein level was decreased. This study suggested that NAR could promote cell autophagy to improve HFD-induced AS in ApoE-/- mice.
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http://dx.doi.org/10.1590/1414-431X20209764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894389PMC
February 2021

Macrophages activated by akermanite/alginate composite hydrogel stimulate migration of bone marrow-derived mesenchymal stem cells.

Biomed Mater 2021 Feb 19. Epub 2021 Feb 19.

The Chinese University of Hong Kong, Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China, Hong Kong, 000000, HONG KONG.

Akermanite (Aker) has been widely used for bone regeneration through regulating osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). Previously, we developed an injectable Aker/sodium alginate (Aker/SA) hydrogel to facilitate bone regeneration. However, the effect of this injectable hydrogel on the in vivo response, particularly the inflammatory response, has not been fully understood. Here, to elucidate the response following the implantable of Aker/SA hydrogel, we investigated the interaction among Aker/SA hydrogel, inflammatory cells and cells involved in bone regeneration (BMSCs). Specifically, we cultured macrophages (RAW 264.7 cell line) with the extract liquid of Aker/SA and assessed their phenotypic changes. Subsequently, BMSCs (2*10^5 cells per 24 well) were cultured with different conditioned media including that of Aker/SA hydrogel-activated macrophages to investigate their effect on cell migration. Finally, Aker/SA hydrogel was injected subcutaneously (1*10^6 cells per ml) in rat to verify its effect in vivo. The in vitro results indicated that Aker/SA hydrogel activated macrophages towards M2 phenotype and stimulated macrophages to express anti-inflammatory factors. In addition, the conditioned medium collected from Aker-activated macrophages could accelerate the migration of BMSCs in 24h. Consistent with the in vitro results, when the Aker/SA hydrogel was injected subcutaneously, more M2 macrophages could be observed than when the SA solution was injected after 7 days. Besides, when BMSCs were delivered via subcutaneous injection, more BMSCs were recruited by the Aker/SA hydrogel than the SA solution. All these results suggest that the Aker/SA hydrogel can modulate the immune environment at the implantation site and subsequently recruit BMSCs, which can be one of the mechanisms through which the Aker/SA hydrogel accelerates new bone formation.
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http://dx.doi.org/10.1088/1748-605X/abe80aDOI Listing
February 2021

Calcium Dobesilate (CaD) Attenuates High Glucose and High Lipid-Induced Impairment of Sarcoplasmic Reticulum Calcium Handling in Cardiomyocytes.

Front Cardiovasc Med 2021 2;8:637021. Epub 2021 Feb 2.

Department of Endocrinology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China.

Calcium dobesilate (CaD) is used effectively in patients with diabetic microvascular disorder, retinopathy, and nephropathy. Here we sought to determine whether it has an effect on cardiomyocytes calcium mishandling that is characteristic of diabetic cardiomyopathy. Cardiomyocytes were sterile isolated and cultured from 1 to 3 days neonatal rats and treated with vehicle (Control), 25 mM glucose+300 μM Palmitic acid (HG+PA), 100 μM CaD (CaD), or HG+PA+CaD to test the effects on calcium signaling (Ca sparks, transients, and SR loads) and reactive oxygen species (ROS) production by confocal imaging. Compared to Control, HG+PA treatment significantly reduced field stimulation-induced calcium transient amplitudes (2.22 ± 0.19 vs. 3.56 ± 0.21, < 0.01) and the levels of caffeine-induced calcium transients (3.19 ± 0.14 vs. 3.72 ± 0.15, < 0.01), however significantly increased spontaneous Ca sparks firing levels in single cardiomyocytes (spontaneous frequency 2.65 ± 0.23 vs. 1.72 ± 0.12, < 0.01) and ROS production (67.12 ± 4.4 vs. 47.65 ± 2.12, < 0.05), which suggest that HG+PA treatment increases the Spontaneity Ca spark frequency, and then induced partial reduction of SR Ca content and subsequently weaken systolic Ca transient in cardiomyocyte. Remarkably, these impairments in calcium signaling and ROS production were largely prevented by pre-treatment of the cells with CaD. Therefore, CaD may contribute to a good protective effect on patients with calcium mishandling and contractile dysfunction in cardiomyocytes associated with diabetic cardiomyopathy.
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http://dx.doi.org/10.3389/fcvm.2021.637021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884338PMC
February 2021

A magnetic bead-mediated selective adsorption strategy for extracellular vesicle separation and purification.

Acta Biomater 2021 04 10;124:336-347. Epub 2021 Feb 10.

School of Biomedical Engineering /Med-X Research Institute, Shanghai Jiaotong University, Shanghai, PR China. Electronic address:

Extracellular vesicles (EVs) are membrane-encapsulated particles with critical biomedical functions, including mediating intercellular communication, assisting tumor metastasis, and carrying protein and microRNA biomarkers. The downstream applications of EVs are greatly influenced by the quality of the isolated EVs. However, almost none of the separation methods can simultaneously achieve both high yield and high purity of the isolated EVs, thus making the isolation of EVs an essential challenge in EV research. Here, we developed a magnetic bead-mediated selective adsorption strategy (MagExo) for easy-to-operate EV isolation. Benefited from the presence of an adsorption window between EVs and proteins under the effect of a hydrophilic polymer, EVs tend to adsorb on the surface of magnetic beads selectively and can be separated from biological fluids with high purity by simple magnetic separation. The proposed method was used for EV isolation from plasma and cell culture media (CCM), with two times higher yield and comparable purity of the harvested EVs to that obtained by ultracentrifugation (UC). Downstream applications in proteomics analysis showed 86.6% (plasma) and 86.5% (CCM) of the analyzed proteins were matched with the ExoCarta database, which indicates MagExo indeed enriches EVs efficiently. Furthermore, we found the target RNA amount of the isolated EVs by MagExo were almost dozens and hundred times higher than the gold standard DG-UC and ultracentrifugation (UC) methods, respectively. All the results show that MagExo is a reliable, easy, and efficient approach to harvest EVs for a wide variety of downstream applications with minimized sample usage. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) are presently attracting increasing interest among clinical and scientific researchers. Although the downstream applications of EVs are recognized to be greatly affected by the quality of the isolated EVs, almost none of the separation methods can simultaneously achieve high yield and high purity of the isolated EVs; this makes the isolation of EVs an essential challenge in EV research. In the present work, we proposed a simple and easy-to-operate method (MagExo) for the separation and purification of EVs based on the phenomenon that EVs can be selectively adsorbed on the surface of magnetic microspheres in the presence of a hydrophilic polymer. The performance of MagExo was comparable to or even better than that of gold standard methods and commercial kits, with two times higher yield and comparable purity of the harvested EVs to that achieved with ultracentrifugation (UC); this could meet the requirements of various EV-associated downstream applications. In addition, MagExo can be easily automated by commercial liquid workstations, thus significantly improving the isolation throughput and paving a new way in clinical diagnosis and treatment.
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http://dx.doi.org/10.1016/j.actbio.2021.02.004DOI Listing
April 2021

The prognostic value of longitudinal circulating tumor DNA profiling during osimertinib treatment.

Transl Lung Cancer Res 2021 Jan;10(1):326-339

Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Background: Serial profiling of circulating tumor DNA (ctDNA) could reflect dynamic molecular changes in response to treatment and potentially predict impending disease progression (PD). Herein, we investigated the molecular factors and dynamic changes in ctDNA that can serve as predictors of survival outcomes of patients with epidermal growth factor receptor ()-mutated advanced non-small cell lung cancer (NSCLC) who received osimertinib therapy after progression from prior EGFR inhibitor regimen.

Methods: Capture-based targeted sequencing was performed on the baseline and longitudinal plasma samples collected from 72 and 57 patients, respectively, using a 168-gene panel.

Results: Analysis revealed that inferior overall survival (OS) was correlated with various baseline molecular features including high allelic fraction (AF) of sensitizing mutations (P=0.045), high maximum AF (maxAF, P=0.060), or harboring concurrent genomic alterations such as copy number amplification (CNA) in (P=0.026) or in other genes (P=0.026), and genes involved in the cell cycle (P=0.004) or TP53 signaling pathway (P=0.032). Moreover, ctDNA clearance at first follow-up after 6 weeks of osimertinib therapy was correlated with significantly longer progression-free survival (PFS) (P=0.022) and OS (P=0.009). Molecular PD, reflected by the emergence of new mutation or increased AF of existing mutations, was detected at an average lead time of 2.5 months prior to radiological PD. Patients with molecular PD were more likely to harbor CNA (P=0.035) and mutations (P=0.023).

Conclusions: Molecular factors derived from serial ctDNA profiling can serve as predictive and prognostic markers, which could allow early detection of PD, preceding imaging modalities by 2.5 months.
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http://dx.doi.org/10.21037/tlcr-20-371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867761PMC
January 2021

The Impact of the Economic Corridor on Economic Stability: A Double Mediating Role of Environmental Sustainability and Sustainable Development Under the Exceptional Circumstances of COVID-19.

Front Psychol 2020 25;11:634375. Epub 2021 Jan 25.

School of Business, Nanjing University, Nanjing, China.

This study discusses the impact of different economic indicators on economic stability, including honest leadership, improved infrastructure, revenue generation, and CPEC taking into account the double mediating role of environmental sustainability and sustainable development, while considering the latest COVID-19 situation. This study adopted primary data collection methods and obtained data from the employees of CPEC by using questionnaires and smart-PLS for analysis purposes. The results revealed that honest leadership, improved infrastructure, revenue generation, and CPEC have a positive nexus with economic stability. Despite the severe impact of COVID-19 on the country's economy, the economic corridor plays a vital role in stabilizing the state's economy and supports all those related to this phenomenal project either directly or indirectly.
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http://dx.doi.org/10.3389/fpsyg.2020.634375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869893PMC
January 2021

Etiological diagnosis of linear-array endoscopic ultrasonography in distal common bile duct dilatation.

Ultrasound Q 2021 Feb 5. Epub 2021 Feb 5.

Department of Gastroenterology, The Third People's Hospital of Kunshan Department of General Practice, The First People's Hospital of Kunshan, Kunshan Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Jiangsu, China.

Abstract: The etiology of distal common bile duct (CBD) dilatation is complex. Linear-array endoscopic ultrasonography (EUS) can not only visualize the distal and surrounding structures of the bile duct closely but also obtain pathological specimens by fine-needle aspiration, which provides an important basis for the diagnosis and differential diagnosis. The purpose of this study was to evaluate the diagnostic value of linear-array EUS in the etiology of distal CBD dilatation. Patients with distal CBD dilatation underwent linear-array EUS in the endoscopic center of The Second Affiliated Hospital of Soochow University and Traditional Chinese Medicine Hospital of Kunshan were collected from January 2015 to June 2019. The pathology results after surgery, endoscopic pathology, computed tomography (CT), and magnetic resonance imaging (MRI) results were retrospectively analyzed. The diagnostic accuracy of linear-array EUS and CT or MRI was compared. For the diagnosis of choledocholithiasis, the diagnostic accuracy of linear-array EUS was 97.5%, which was significantly higher than that of MRI (86.36%) and CT (89.74) (P < 0.001 and 0.006, respectively). The diagnostic accuracy of linear-array EUS for periampullary tumors was 93.75%, which was higher than MRI and CT with an accuracy of 82.73% and 80.34% (P = 0.004 and 0.001, respectively). Linear EUS was effective for the etiological diagnosis of distal CBD dilatation.
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http://dx.doi.org/10.1097/RUQ.0000000000000553DOI Listing
February 2021

HER2 copy number as predictor of disease-free survival in HER2-positive resectable gastric adenocarcinoma.

J Cancer Res Clin Oncol 2021 May 4;147(5):1315-1324. Epub 2021 Feb 4.

Burning Rock Biotech, Guangzhou, China.

Purpose: The identification of HER2 overexpression in a subset of gastric adenocarcinoma (GA) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GA patients has been investigated. However, its predictive value in resectable patients remains elusive.

Methods: We enrolled 98 treatment-naïve resectable Chinese GA patients with HER2 overexpression assessed using IHC. Capture-based targeted sequencing using a panel consisting of 41 gastrointestinal cancer-related genes was performed on tumor tissues. Furthermore, we also investigated the correlation between HER2 copy number (CN) and survival outcomes.

Results: Of the 98 HER2-overexpressed patients, 90 had HER2 CN amplification assessed using next-generation sequencing, achieving 92% concordance. The most commonly seen concurrent mutations were occurring in TP53, EGFR and PIK3CA. We found HER2 CN as a continuous variable was an independent predictor associated with DFS (p = 0.029). Our study revealed HER2 CN-high patients showed a trend of intestinal-type GA predominant (p = 0.075) and older age (p = 0.07). The median HER2 CN was 15.34, which was used to divide the cohort into CN-high and CN-low groups. Patients with high HER2 CN had a significantly shorter DFS than patients with low HER2 CN (p = 0.002). Furthermore, HER2 CN as a categorical variable was also an independent predictor associated with DFS in patients.

Conclusion: We elucidated the mutation spectrum of HER2-positive resectable Chinese GA patients and the association between HER2 CN and DFS. Our work revealed HER2 CN as an independent risk factor predicted unfavorable prognosis in HER2-positive GA patients and allowed us to further stratify HER2-positive resectable GA patients for disease management.
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http://dx.doi.org/10.1007/s00432-021-03522-9DOI Listing
May 2021

Silencing of KIF3B Suppresses Breast Cancer Progression by Regulating EMT and Wnt/-Catenin Signaling.

Front Oncol 2020 19;10:597464. Epub 2021 Jan 19.

Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Breast cancer is the most common malignant tumors in women. Kinesin family member 3B (KIF3B) is a critical regulator in mitotic progression. The objective of this study was to explore the expression, regulation, and mechanism of KIF3B in 103 cases of breast cancer tissues, 35 metastatic lymph nodes and breast cancer cell lines, including MDA-MB-231, MDA-MB-453, T47D, and MCF-7. The results showed that KIF3B expression was up-regulated in breast cancer tissues and cell lines, and the expression level was correlated with tumor recurrence and lymph node metastasis, while knockdown of KIF3B suppressed cell proliferation, migration, and invasion both and . In addition, UALCAN analysis showed that KIF3B expression in breast cancer is increased, and the high expression of KIF3B in breast cancer is associated with poor prognosis. Furthermore, we found that silencing of KIF3B decreased the expression of Dvl2, phospho-GSK-3, total and nucleus -catenin, then subsequent down-regulation of Wnt/-catenin signaling target genes such as CyclinD1, C-myc, MMP-2, MMP-7 and MMP-9 in breast cancer cells. In addition, KIF3B depletion inhibited epithelial mesenchymal transition (EMT) in breast cancer cells. Taken together, our results revealed that KIF3B is up-regulated in breast cancer which is potentially involved in breast cancer progression and metastasis. Silencing KIF3B might suppress the Wnt/-catenin signaling pathway and EMT in breast cancer cells.
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http://dx.doi.org/10.3389/fonc.2020.597464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851081PMC
January 2021

Camelina lipid droplets as skin delivery system promotes wound repair by enhancing the absorption of hFGF2.

Int J Pharm 2021 Apr 2;598:120327. Epub 2021 Feb 2.

College of Life Science, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun 130118, China; College of Tropical Crops, Hainan University, Haikou, China. Electronic address:

Human basic fibroblast growth factor (hFGF2) is widely recognized for accelerating skin wound healing in both animal models and randomized clinical trials. However, the low skin permeation and bioavailability of hFGF2 remain the most limiting factors in the pharmacological application. For the first time, Camelina Lipid Droplets (CLD) delivery system was displayed important virtue, by promoting the skin absorption of hFGF2, which is a key factor that accelerates the skin wound repair, and provide a new alternative for skin therapy. In this study, we used the CLD as a safer material to prepare the nanoparticles, which were characterized by size and morphology. Our data revealed that particle sizes of Camelina Lipid Droplets linked to hFGF2 (CLD-hFGF2) were around 133.5 nm; it also displayed that the complex of CLD-hFGF2 penetrates the skin barrier in deeper than an individual hFGF2. This suggests that once the hFGF2 is fixed onto the surface of CLD, it can cross the stratum corneum and play a therapeutic role into the dermis. Furthermore, we demonstrated that CLD-hFGF2 enhances fibroblast migration, and significantly improves skin regeneration for accelerating wound healing without any significant toxicity. This paper highlights the importance of CLD as an emerging delivery system; it is also providing a new and applicable therapeutic research direction through enhancing the skin permeation of hFGF2 to accelerate wound healing.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120327DOI Listing
April 2021

Ischemic Conditioning Ameliorated Hypertension and Vascular Remodeling of Spontaneously Hypertensive Rat via Inflammatory Regulation.

Aging Dis 2021 Feb 1;12(1):116-131. Epub 2021 Feb 1.

1Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 10053, China.

Vascular remodeling is an initial step in the development of hypertension. Limb remote ischemic conditioning (LRIC) is a physiological treatment that induces endogenous protective effect during acute ischemic injury. However, the impact of long-term LRIC on hypertension, a chronic disease, is unknown. In this study, we aimed to investigate the LRIC effect on blood pressure and vascular remodeling in spontaneously hypertensive rat (SHR) model and patients with prehypertension and early-stage hypertension. LRIC of rats was performed once a day for 6-weeks. Blood pressure, vascular remodeling (cross-sectional area, extracellular deposition, and smooth muscle cell area), inflammation (inflammatory factors, and inflammatory cells) were compared among normotensive Wistar-Kyoto rats (WKY), WKY RIC group, SHR control group, and SHR RIC. Long-term LRCI treatment (twice a day for 4-weeks) was performed on patients with prehypertension or early-stage hypertension. Blood pressure and pulse wave velocity (PWV) were analyzed before and after LRIC treatment. LRIC treatment decreased blood pressure in SHR (n = 9-10). LRIC ameliorated vascular remodeling by decreasing cross-sectional area, suppressing deposition of the extracellular matrix, and hypertrophy of smooth muscle cell in conduit artery and small resistance artery (n = 7). LRIC decreased proinflammatory factors while increasing the anti-inflammatory factors in the circulation (n = 5). LRIC decreased circulating monocyte and natural killer T-cell levels (n = 5). Furthermore, LRIC treatment decreased blood pressure and improved vascular stiffness in patients (n = 20). In conclusion, long term LRIC could decrease blood pressure and ameliorate vascular remodeling via inflammation regulation. LRIC could be a preventive treatment for people with blood pressure elevation or prehypertension.
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http://dx.doi.org/10.14336/AD.2020.0320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801289PMC
February 2021

Efficacy and Safety of Antiplatelet Agents for Adult Patients With Ischemic Moyamoya Disease.

Front Neurol 2020 15;11:608000. Epub 2021 Jan 15.

Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

The use of antiplatelet agents in ischemic moyamoya disease (MMD) is controversial. This study aimed to investigate the effectiveness and safety of antiplatelet therapy compared with conservative treatment and surgical revascularization in ischemic MMD patients. Ischemic MMD patients were retrospectively enrolled from eight clinical sites from January 2013 to December 2018. Follow-up was performed through clinical visits and/or telephone interviews from first discharge to December 2019. The primary outcome was the episodes of further ischemic attacks, and the secondary outcome was the individual functional status. Risk factors for future stroke were identified by the LASSO-Cox regression model. Propensity score matching was applied to assemble a cohort of patients with similar baseline characteristics using the package. Among 217 eligible patients, 159 patients were included in the analyses after a 1:1:1 propensity score matching. At a mean follow-up of 33 months, 12 patients (7.5%) developed further incident cerebral ischemic events (surgical:antiplatelet:conservative = 1:3:8; = 0.030), 26 patients (16.4%) developed a poor functional status (surgical:antiplatelet:conservative = 7:12:7; = 0.317), and 3 patients (1.8%) died of cerebral hemorrhage (surgical:antiplatelet:conservative = 1:2:0; = 0.361). The survival curve showed that the risk of further cerebral ischemic attacks was lowest with surgical revascularization, while antiplatelet therapy was statistically significant for preventing recurrent risks compared with conservative treatment (χ = 8.987; = 0.011). No significant difference was found in the functional status and bleeding events. The LASSO-Cox regression model revealed that a family history of MMD (HR = 6.93; 95% CI: 1.28-37.52; = 0.025), a past history of stroke or transient ischemic attack (HR = 4.35; 95% CI: 1.09-17.33; = 0.037), and treatment (HR = 0.05; 95% CI: 0.01-0.32; = 0.001) were significantly related to the risk of recurrent strokes. Antiplatelet agents were effective and safe in preventing further cerebral ischemic attacks in adult patients with ischemic MMD. They may be a replacement therapy for patients with surgical contraindications and for patients prior to revascularization.
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http://dx.doi.org/10.3389/fneur.2020.608000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844095PMC
January 2021

Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method.

Front Pharmacol 2020 14;11:602880. Epub 2021 Jan 14.

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

To evaluate the biodistribution of hydroxychloroquine (HCQ) in cynomolgus macaques and receive dynamic quantitative relationship between plasma, blood, and lung tissue concentration using the population pharmacokinetic modeling method, seventeen cynomolgus macaques were divided into six groups according to different HCQ dosing regimens over 5 days. The monkeys were euthanized, and blood, plasma, urine, feces and ten tissues were collected. All the samples were prepared by protein precipitation and analyzed by HPLC-MS/MS detection. The population pharmacokinetics of HCQ in the plasma, red blood cells, and lung tissue was conducted and simulated via ADAPT program. Results demonstrated that the maximum concentration () of HCQ was 292.33 ng/mL in blood and 36.90 ng/mL in plasma after single dose of 3 mg/kg. The value of area under curve (AUC) was determined as 5,978.94 and 363.31 h* ng/mL for the blood and plasma, respectively. The descending order of the tissue-to-plasma concentration ratio was liver > spleen > kidney > lung > heart > subcutaneous fat > brain. The tissue-to-plasma concentration ratio and the tissue-to-blood concentration ratio for lung were found to be time-dependent with 267.38 and 5.55 at 120 h postdose, respectively. A five-compartment model with first-order oral absorption and elimination best described the plasma, blood, and lung tissue pharmacokinetics. The estimated elimination rate constant (ke) for a typical monkey was 0.236 h. The volume of distribution in central (Vc/F) and other two peripheral compartments (Vb/F and Vl/F) were 114, 2.68, and 5.55 L, respectively. Model-based simulation with PK parameters from cynomolgus macaques showed that the ratio of the blood or plasma to lung tissue was a dynamic change course, which suggested that the rate of HCQ concentration decrease in the blood or plasma was faster than that in the lung tissue. HCQ was found to be accumulated in tissues, especially in the liver, kidney, lung, and spleen. Also, the tissue-to-plasma concentration ratio increased over time. The population pharmacokinetic model developed could allow for the assessment of pharmacokinetics-pharmacodynamics relationships, especially relevant tissue concentration-response for HCQ. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
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http://dx.doi.org/10.3389/fphar.2020.602880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841297PMC
January 2021

A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling.

Exp Eye Res 2021 Apr 29;205:108472. Epub 2021 Jan 29.

Department of Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; BioInspired Institute, Syracuse University, Syracuse, NY, 13244, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, NY, 13244, USA. Electronic address:

Abnormal human trabecular meshwork (HTM) cell function and extracellular matrix (ECM) remodeling contribute to HTM stiffening in primary open-angle glaucoma (POAG). Most current cellular HTM model systems do not sufficiently replicate the complex native three dimensional (3D) cell-ECM interface, limiting their use for investigating POAG pathology. Tissue-engineered hydrogels are ideally positioned to overcome shortcomings of current models. Here, we report a novel biomimetic HTM hydrogel and test its utility as a POAG disease model. HTM hydrogels were engineered by mixing normal donor-derived HTM cells with collagen type I, elastin-like polypeptide and hyaluronic acid, each containing photoactive functional groups, followed by UV crosslinking. Glaucomatous conditions were induced with dexamethasone (DEX), and effects of the Rho-associated kinase (ROCK) inhibitor Y27632 on cytoskeletal organization and tissue-level function, contingent on HTM cell-ECM interactions, were assessed. DEX exposure increased HTM hydrogel contractility, f-actin and alpha smooth muscle actin abundance and rearrangement, ECM remodeling, and fibronectin deposition - all contributing to HTM hydrogel condensation and stiffening consistent with glaucomatous HTM tissue behavior. Y27632 treatment produced precisely the opposite effects and attenuated the DEX-induced pathologic changes, resulting in HTM hydrogel relaxation and softening. For model validation, confirmed glaucomatous HTM (GTM) cells were encapsulated; GTM hydrogels showed increased contractility, fibronectin deposition, and stiffening vs. normal HTM hydrogels despite reduced GTM cell proliferation. We have developed a biomimetic HTM hydrogel model for detailed investigation of 3D cell-ECM interactions under normal and simulated glaucomatous conditions. Its bidirectional responsiveness to pharmacological challenge and rescue suggests promising potential to serve as screening platform for new POAG treatments with focus on HTM biomechanics.
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http://dx.doi.org/10.1016/j.exer.2021.108472DOI Listing
April 2021

Evaluation of modified permeable pavement systems with coal gangue to remove typical runoff pollutants under simulated rainfall.

Water Sci Technol 2021 Jan;83(2):381-395

Key Laboratory of Urban Stormwater System and Water Environment, Ministry of Education, Beijing University of Civil Engineering and Architecture, Beijing 102616, China E-mail: Beijing Engineering Research Center of Sustainable Urban Sewage System Construction and Risk Control, Beijing University of Civil Engineering and Architecture, Beijing 100044, China.

Coal gangue (CG) as mineral waste was properly treated and applied as the filter media in permeable pavement systems due to its good sorption ability and mechanical strength. Batch experiments show the maximum adsorption capacity of calcined CG to phosphorus could reach 2.63 mg/g. To evaluate the removal effect of typical runoff pollutants including chemical oxygen demand (COD), total nitrogen (TN), total phosphorus (TP) and ammonia (NH-N), the gravel and sand in a traditional pavement system were replaced by CG respectively. The leaching behavior of the four pollutants in CG modified systems is limited and comparable with traditional system, indicating pretreated CG as filler would not cause environmental risk. CG-based pavement systems improved the removal efficiency of the four pollutants especially for TP. The removal mechanisms including interception, adsorption and microorganism degradation. The removal rates of COD, NH-N and TN by CG modified and traditional systems decreased with rainfall duration, while it is not obviously changed with rainfall recurrence period and drying period. Overall, the permeable pavement with CG layers that replaced both sand and gravel layers show best removal efficiency of all pollutants investigated especially for TP (>95%). This study provides a new way for CG utilization and gives the reference for the process design of permeable pavement.
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http://dx.doi.org/10.2166/wst.2020.574DOI Listing
January 2021