Publications by authors named "Guorong Li"

138 Publications

Tumor suppressor gene DLC1: Its modification, interactive molecules, and potential prospects for clinical cancer application.

Int J Biol Macromol 2021 Apr 6. Epub 2021 Apr 6.

Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China. Electronic address:

Deleted in liver cancer 1 (DLC1) is a recognized tumor suppressor gene that negatively regulates Rho family proteins by hydrolyzing the active GTP-bound state to its inactive GDP-bound state. Active Rho proteins play a positive role in tumorigenesis. Numerous in vitro and in vivo experiments have shown that DLC1 is downregulated or inactivated in various solid tumors, which may be due to the following five reasons: genomic deletion, epigenetic modification, and ubiquitin-dependent proteasomal degradation may cause DLC1 underexpression; phosphorylation at the post-translation level may cause DLC1 inactivation; and failure to localize at focal adhesions (FAs) may prevent DLC1 from exerting full activity. All of the causes could be attributed to molecular binding. Experimental evidence suggests that direct or indirect targeting of DLC1 is feasible for cancer treatment. Therefore, elucidating the interaction of DLC1 with its binding partners might provide novel targeted therapies for cancer. In this review, we summarized the binding partners of DLC1 at both the gene and protein levels and expounded a variety of anticancer drugs targeting DLC1 to provide information about DLC1 as a cancer diagnostic indicator or therapeutic target.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.04.022DOI Listing
April 2021

Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis.

Elife 2021 Mar 30;10. Epub 2021 Mar 30.

Department of Ophthalmology, Duke University, Durham, United States.

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.
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http://dx.doi.org/10.7554/eLife.60831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009676PMC
March 2021

WeChat-based education and rehabilitation program in unprotected left main coronary artery disease patients after coronary artery bypass grafting: an effective approach in reducing anxiety, depression, loss to follow-up, and improving quality of life.

Braz J Med Biol Res 2021 12;54(4):e10370. Epub 2021 Feb 12.

Ministry of Nursing, 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.

This study aimed to investigate the effect of WeChat-based education and rehabilitation program (WERP) on anxiety, depression, health-related quality of life (HRQoL), major adverse cardiac/cerebrovascular events (MACCE)-free survival, and loss to follow-up rate in unprotected left main coronary artery disease (ULMCAD) patients after coronary artery bypass grafting (CABG). In this randomized controlled study, 140 ULMCAD patients who underwent CABG were randomly assigned to WERP group (n=70) or control care (CC) group (n=70). During the 12-month intervention period, anxiety and depression (using hospital anxiety and depression scale (HADS)) and HRQoL (using 12-Item Short-Form Health Survey (SF-12)) were assessed longitudinally. During the total 36-month follow-up period (12-month intervention and 24-month non-intervention periods), MACCE and loss to follow-up were recorded. During the intervention period, HADS-anxiety score at month 9 (M9) (P=0.047) and month 12 (M12) (P=0.034), anxiety rate at M12 (P=0.028), and HADS-D score at M12 (P=0.048) were all reduced in WERP group compared with CC group. As for HRQoL, SF-12 physical component summary score at M9 (P=0.020) and M12 (P=0.010) and SF-12 mental component summary score at M9 (P=0.040) and M12 (P=0.028) were all increased in WERP group compared with CC group. During the total follow-up period, WERP group displayed a trend of longer MACCE-free survival than that in CC group but without statistical significance (P=0.195). Additionally, loss to follow-up rate was attenuated in WERP group compared with CC group (P=0.033). WERP serves as an effective approach in optimizing mental health care and promoting life quality in ULMCAD patients after CABG.
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http://dx.doi.org/10.1590/1414-431X202010370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894386PMC
February 2021

The Economic Burden of Alzheimer's Disease in Zhejiang Province.

J Alzheimers Dis 2021 ;80(2):539-553

Department of Geriatric, The Second People's Hospital of Lishui, Lishui, Zhejiang, China.

Background: The World Alzheimer Report has described and predicted the economic burden of Alzheimer's disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province.

Objective: To investigate the economic burden and main factors influencing Alzheimer's disease (AD) in Zhejiang Province.

Methods: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity.

Results: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province's GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity.

Conclusion: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it.
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http://dx.doi.org/10.3233/JAD-201285DOI Listing
January 2021

Coumarin Sulfonamides and Amides Derivatives: Design, Synthesis, and Antitumor Activity In Vitro.

Molecules 2021 Feb 3;26(4). Epub 2021 Feb 3.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.

Coumarins possesses immeasurable antitumor potential with minimum side effects depending on the substitutions on the basic nucleus, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, a series of coumarin sulfonamides and amides derivatives were designed and synthetized. The majority of these derivatives showed good cytotoxic activity against MDA-MB-231 and KB cell lines, among which compound was the most potent against MDA-MB-231 cells, with IC value of 9.33 μM, comparable to 5-fluorouracil. Further investigation revealed that compound had versatile properties against tumors, including inhibition of cell migration and invasion as well as inducing apoptosis. Reactive oxygen species (ROS) assay and western blotting analysis suggested that compound promoted cancer cell apoptosis by increasing ROS levels and upregulating the expression of caspase-3 in MDA-MB-231 cells. These results indicated that compound could be promising lead compound for further antitumor drug research.
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http://dx.doi.org/10.3390/molecules26040786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913302PMC
February 2021

Learning Self-Supervised Space-Time CNN for Fast Video Style Transfer.

IEEE Trans Image Process 2021 1;30:2501-2512. Epub 2021 Feb 1.

Style transfer on images has achieved significant advances in recent years, with the deep convolutional neural network (CNN). Directly applying image style transfer algorithms to each frame of a video independently often leads to flickering and unstable results. In this work, we present a self-supervised space-time convolutional neural network (CNN) based method for online video style transfer, named as VTNet, which is end-to-end trained from nearly unlimited unlabeled video data to produce temporally coherent stylized videos in real-time. Specifically, our VTNet transfer the style of a reference image to the source video frames, which is formed by the temporal prediction branch and the stylizing branch. The temporal prediction branch is used to capture discriminative spatiotemporal features for temporal consistency, pretrained in an adversarial manner from unlabeled video data. The stylizing branch is used to transfer the style image to a video frame with the guidance from the temporal prediction branch to ensure temporal consistency. To guide the training of VTNet, we introduce the style-coherence loss net (SCNet), which assembles the content loss, the style loss, and the new designed coherence loss. These losses are computed based on high-level features extracted from a pretrained VGG-16 network. The content loss is used to preserve high-level abstract contents of the input frames, and the style loss introduces new colors and patterns from the style image. Instead of using optical flow to explicitly redress the stylized video frames, we design the coherence loss to make the stylized video inherit the dynamics and motion patterns from the source video to remove temporal flickering. Extensive subjective and objective evaluations on various styles demonstrate that the proposed method achieves favorable results against the state-of-the-arts with high efficiency.
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http://dx.doi.org/10.1109/TIP.2021.3052709DOI Listing
February 2021

Embedding Perspective Analysis Into Multi-Column Convolutional Neural Network for Crowd Counting.

IEEE Trans Image Process 2021 29;30:1395-1407. Epub 2020 Dec 29.

The crowd counting is challenging for deep networks due to several factors. For instance, the networks can not efficiently analyze the perspective information of arbitrary scenes, and they are naturally inefficient to handle the scale variations. In this work, we deliver a simple yet efficient multi-column network, which integrates the perspective analysis method with the counting network. The proposed method explicitly excavates the perspective information and drives the counting network to analyze the scenes. More concretely, we explore the perspective information from the estimated density maps and quantify the perspective space into several separate scenes. We then embed the perspective analysis into the multi-column framework with a recurrent connection. Therefore, the proposed network matches various scales with the different receptive fields efficiently. Secondly, we share the parameters of the branches with various receptive fields. This strategy drives the convolutional kernels to be sensitive to the instances with various scales. Furthermore, to improve the evaluation accuracy of the column with a large receptive field, we propose a transform dilated convolution. The transform dilated convolution breaks the fixed sampling structure of the deep network. Moreover, it needs no extra parameters and training, and the offsets are constrained in a local region, which is designed for the congested scenes. The proposed method achieves state-of-the-art performance on five datasets (ShanghaiTech, UCF CC 50, WorldEXPO'10, UCSD, and TRANCOS).
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http://dx.doi.org/10.1109/TIP.2020.3043122DOI Listing
December 2020

A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure.

Invest Ophthalmol Vis Sci 2020 Dec;61(14):12

Department of Ophthalmology, Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States.

Purpose: Tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) activation in Schlemm's canal (SC) endothelium is required for the maintenance of IOP, making the angiopoietin/Tie2 pathway a target for new and potentially disease modifying glaucoma therapies. The goal of the present study was to examine the effects of a Tie2 activator, AKB-9778, on IOP and outflow function.

Methods: AKB-9778 effects on IOP was evaluated in humans, rabbits, and mice. Localization studies of vascular endothelial protein tyrosine phosphatase (VE-PTP), the target of AKB-9778 and a negative regulator of Tie2, were performed in human and mouse eyes. Mechanistic studies were carried out in mice, monitoring AKB-9778 effects on outflow facility, Tie2 phosphorylation, and filtration area of SC.

Results: AKB-9778 lowered IOP in patients treated subcutaneously for diabetic eye disease. In addition to efficacious, dose-dependent IOP lowering in rabbit eyes, topical ocular AKB-9778 increased Tie2 activation in SC endothelium, reduced IOP, and increased outflow facility in mouse eyes. VE-PTP was localized to SC endothelial cells in human and mouse eyes. Mechanistically, AKB-9778 increased the filtration area of SC for aqueous humor efflux in both wild type and in Tie2+/- mice.

Conclusions: This is the first report of IOP lowering in humans with a Tie2 activator and functional demonstration of its action in remodeling SC to increase outflow facility and lower IOP in fully developed mice. Based on these studies, a phase II clinical trial is in progress to advance topical ocular AKB-9778 as a first in class, Tie2 activator for treatment for ocular hypertension and glaucoma.
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http://dx.doi.org/10.1167/iovs.61.14.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735951PMC
December 2020

In vivo estimation of murine iris stiffness using finite element modeling.

Exp Eye Res 2021 01 28;202:108374. Epub 2020 Nov 28.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. Electronic address:

The iris plays an important role in certain types of glaucoma, including primary angle-closure glaucoma and pigmentary glaucoma. Iris mechanics are also important in influencing trabecular meshwork deformation in response to intraocular pressure changes in some animal species. Although mice are widely used to study ocular disease, including glaucoma, the in vivo biomechanical properties of the murine iris are unknown. Thus, the primary objective of this study was to estimate murine iris biomechanical stiffness. We used optical coherence tomography (OCT) images of the anterior segment of living mice (n = 13, age = 7.3 ± 3.2 [mean ± SD] months) at sequentially increasing IOP levels, observing IOP-dependent iris deformations. We then used an inverse finite element model to predict iris deformations under the same conditions, estimating iris stiffness by maximizing agreement between OCT data and numerical simulations. Our results show an in vivo murine iris stiffness of 96.1 ± 54.7 kPa (mean ± SD), which did not correlate with age but was dependent on gender. Our results further showed strong evidence of reverse pupillary block, with mean posterior chamber pressure remaining at approximately 12 mmHg even as anterior chamber pressure was set to much higher levels. Our approach to monitoring iris stiffness in vivo is applicable to study potential changes of iris stiffness in various pathophysiological conditions and thus has significant potential for clinical care of ocular disease involving iris biomechanics.
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http://dx.doi.org/10.1016/j.exer.2020.108374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855533PMC
January 2021

Combination of dihydroartemisinin and resveratrol effectively inhibits cancer cell migration regulation of the DLC1/TCTP/Cdc42 pathway.

Food Funct 2020 Nov;11(11):9573-9584

Shandong Provincial Key Laboratory of Animal Resistant Biology, School of Life Sciences, Shandong Normal University, Jinan, China.

Resveratrol (RES) is a polyphenolic plant antitoxin that increases the level of the tumor suppressor gene deleted in liver cancer 1 (DLC1) to suppress cancer progression. Dihydroartemisinin (DHA), a main active metabolite of anti-malarial drug artemisinin (ART), inhibits cancer cell invasion and migration by decreasing the translationally controlled tumor protein (TCTP), as reported in a few literature studies. Compelling evidence has shown that combination therapy with two or more compounds is more effective than treatment with a compound alone. However, the mechanism of combination of DHA and RES on inhibition of cancer cell migration has not been reported. In this study, our results showed that combination of DHA and RES, compared to each compound alone, synergistically inhibited migration along with the decrease of wound closures and F-actin formation in HepG2 and MDA-MB-231 cancer cells. This combination treatment up-regulated DLC1 and down-regulated TCTP expressions significantly. The two proteins were identified to colocalize in focal adhesions and form a complex. Depletion of DLC1 increased TCTP expression, and transfection with either GFP-DLC1-WT or GFP-DLC1-R718A (GAP-dead mutant) decreased the TCTP level markedly, indicating that DLC1 negatively regulated TCTP in a RhoGAP-independent manner. Furthermore, this combination treatment impeded the migration of HepG2 and MDA-MB-231 cancer cells via Cdc42 regulating JNK/NF-κB and N-WASP signaling pathways, and knockdown of DLC1 obviously increased the levels of Cdc42 and the molecules related to both signaling pathways in MDA-MB-231 cells. The combination also effectively inhibited the growth of xenograft tumors in an avian embryo model. In sum, we reveal a novel combination of DHA and RES that inhibits cancer cell migration by modulating the DLC1/TCTP axis to hinder the Cdc42 related signaling pathway. This combination treatment may be a promising therapeutic strategy to inhibit cancer cell migration by targeting DLC1 and TCTP.
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http://dx.doi.org/10.1039/d0fo00996bDOI Listing
November 2020

Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma.

Small 2020 10 4;16(43):e2004205. Epub 2020 Oct 4.

Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208, USA.

Increased stiffness of the Schlemm's canal (SC) endothelium in the aqueous humor outflow pathways has been associated with elevated intraocular pressure (IOP) in glaucoma. Novel treatments that relax this endothelium, such as actin depolymerizers and rho kinase inhibitors, are in development. Unfortunately, these treatments have undesirable off-target effects and a lower than desired potency. To address these issues, a targeted PEG-b-PPS micelle loaded with actin depolymerizer latrunculin A (tLatA-MC) is developed. Targeting of SC cells is achieved by modifying the micelle surface with a high affinity peptide that binds the VEGFR3/FLT4 receptor, a lymphatic lineage marker found to be highly expressed by SC cells relative to other ocular cells. During in vitro optimization, increasing the peptide surface density increased micellar uptake in SC cells while unexpectedly decreasing uptake by human umbilical vein endothelial cells (HUVEC). The functional efficacy of tLatA-MC, as measured by decreased SC cell stiffness compared to non-targeted micelles (ntLatA-MC) or targeted blank micelles (tBL-MC), is verified using atomic force microscopy. tLatA-MC reduced IOP in an in vivo mouse model by 30-50%. The results validate the use of a cell-softening nanotherapy to selectively modulate stiffness of SC cells for therapeutic reduction of IOP and treatment of glaucoma.
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http://dx.doi.org/10.1002/smll.202004205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647937PMC
October 2020

Physiologic Consequences of Caveolin-1 Ablation in Conventional Outflow Endothelia.

Invest Ophthalmol Vis Sci 2020 09;61(11):32

Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.

Purpose: Polymorphisms at the caveolin-1/2 locus are associated with glaucoma and IOP risk and deletion of caveolin-1 (Cav1) in mice elevates IOP and reduces outflow facility. However, the specific location/cell type responsible for Cav1-dependent regulation of IOP is unclear. We hypothesized that endothelial Cav1 in the conventional outflow (CO) pathway regulate IOP via endothelial nitric oxide synthase (eNOS) signaling.

Methods: We created a mouse with targeted deletion of Cav1 in endothelial cells (Cav1ΔEC) and evaluated IOP, outflow facility, outflow pathway distal vascular morphology, eNOS phosphorylation, and tyrosine nitration of iridocorneal angle tissues by Western blotting.

Results: Endothelial deletion of Cav1 resulted in significantly elevated IOP versus wild-type mice but not a concomitant decrease in outflow facility. Endothelial Cav1 deficiency did not alter the trabecular meshwork or Schlemm's canal morphology, suggesting that the effects observed were not due to developmental deformities. Endothelial Cav1 deletion resulted in eNOS hyperactivity, modestly increased protein nitration, and significant enlargement of the drainage vessels distal to Schlemm's canal. L-Nitro-arginine methyl ester treatment reduced outflow in Cav1ΔEC but not wild-type mice and had no effect on the size of drainage vessels. Endothelin-1 treatment decrease the outflow and drainage vessel size in both wild-type and Cav1ΔEC mice.

Conclusions: Our results suggest that hyperactive eNOS signaling in the CO pathway of both Cav1ΔEC and global Cav1 knockout mice results in chronic dilation of distal CO vessels and protein nitration, but that Cav1 expression in the trabecular meshwork is sufficient to rescue CO defects reported in global Cav1 knockout mice.
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http://dx.doi.org/10.1167/iovs.61.11.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500130PMC
September 2020

Functional characterization of the chlorzoxazone 6-hydroxylation activity of human cytochrome P450 2E1 allelic variants in Han Chinese.

PeerJ 2020 31;8:e9628. Epub 2020 Jul 31.

Bio-X Institutes, Shanghai Jiaotong University, Shanghai, China.

Backgrounds: Cytochrome P450 (P450) 2E1 is one of the primary enzymes responsible for the metabolism of xenobiotics, such as drugs and environmental carcinogens. The genetic polymorphisms of the gene in promoter and coding regions have been identified previously in the Han Chinese population from four different geographic areas of Mainland China.

Methods: To investigate whether genetic variants identified in the coding region affect enzyme function, the enzymes of four single nucleotide polymorphism (SNP) variants in the coding region (novel c.1009C>T, causing p.Arg337X, where X represents the translational stop codon; c.227G>A, causing p.Arg76His; c.517G>A, yielding p.Gly173Ser; and c.1263C>T, presenting the highest allele frequency), two novel alleles (c.[227G>A;1263C>T] and c.[517G>A;1263C>T]), and the wild-type were heterologously expressed in COS-7 cells and functionally characterized in terms of expression level and chlorzoxazone 6-hydroxylation activity. The impact of the CYP2E1 variant sequence on enzyme activity was predicted with three programs: Polyphen 2, PROVEAN and SIFT.

Results: The prematurely terminated p.Arg337X variant enzyme was undetectable by western blotting and inactive toward chlorzoxazone 6-hydroxylation. The c.1263C>T and c.[517G>A;1263C>T] variant enzymes exhibited properties similar to those of the wild-type CYP2E1. The variants c.227G>A and c.[227G>A;1263C>T] displayed significantly reduced enzyme activity relative to that of the wild-type enzyme (decreased by 42.8% and 32.8%, respectively;  < 0.01). The chlorzoxazone 6-hydroxylation activity of the c.517G>A transfectant was increased by 31% compared with the wild-type CYP2E1 enzyme ( < 0.01). Positive correlations were observed between the protein content and enzyme activity for CYP2E1 ( = 0.0005,  = 0.8833). The characterization of enzyme function allelic variants in vitro was consistent with the potentially deleterious effect of the amino acid changes as determined by prediction tools.

Conclusions: These findings indicate that the genetic polymorphisms of i.e., c.1009C>T (p.Arg337X), c.227G>A (p.Arg76His), and c.517G>A (p.Gly173Ser), could influence the metabolism of CYP2E1 substrates, such as chlorzoxazone.
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http://dx.doi.org/10.7717/peerj.9628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397980PMC
July 2020

Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.

FASEB J 2020 08 5;34(8):10762-10777. Epub 2020 Jul 5.

Department of Ophthalmology, Duke University, Durham, NC, USA.

Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in elastin fiber maintenance, is essential for the stability and strength of elastic vessels and tissues. Variants in the LOXL1 locus associate with a dramatic increase in risk of exfoliation syndrome (XFS), a systemic fibrillopathy, which often presents with ocular hypertension and exfoliation glaucoma (XFG). We examined the role of LOXL1 in conventional outflow function, the prime regulator of intraocular pressure (IOP). Using Loxl1 , Loxl1 , and Loxl1 mice, we observed an inverse relationship between LOXL1 expression and IOP, which worsened with age. Elevated IOP in Loxl1 mice was associated with a larger globe, decreased ocular compliance, increased outflow facility, extracellular matrix (ECM) abnormalities, and dilated intrascleral veins, yet, no dilation of arteries or capillaries. Interestingly, in living Loxl1 mouse eyes, Schlemm's canal (SC) was less susceptible to collapse when challenged with acute elevations in IOP, suggesting elevated episcleral venous pressure (EVP). Thus, LOXL1 expression is required for normal IOP control, while ablation results in altered ECM repair/homeostasis and conventional outflow physiology. Dilation of SC and distal veins, but not arteries, is consistent with key structural and functional roles for elastin in low-pressure vessels subjected to cyclical mechanical stress.
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http://dx.doi.org/10.1096/fj.202000702RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688556PMC
August 2020

Sex-specific association of serum uric acid dynamics with the incidence of metabolic syndrome in a health check-up Chinese population: a prospective cohort study.

BMJ Open 2020 07 2;10(7):e035289. Epub 2020 Jul 2.

Department of Health Statistics, School of Public Health, Dalian Medical University, Dalian, Liaoning, China

Objective: Many studies have demonstrated that elevated serum uric acid (SUA) level is linked with metabolic syndrome (MetS). However, whether there is a sex difference in the association between SUA and MetS has not been determined. This study aimed to accurately explore the impact of SUA longitudinal changes on MetS by sex.

Design: A prospective cohort study.

Setting: The Health Check-up Centre of the Second Hospital affiliated with Dalian Medical University from 2010 to 2016.

Participants: A health check-up cohort of 577 men and 1698 women aged 20-60 years who did not exhibit MetS or hyperuricaemia at baseline and underwent at least two physical examinations from 2010 to 2016.

Primary And Secondary Outcome Measures: Weight, height, blood pressure and blood biochemistry parameters, including SUA, were measured. MetS was defined according to the Joint Interim Statement criteria.

Methods: Based on longitudinal data, a linear mixed-effects model was constructed to explore the characteristics of SUA dynamic changes in males and females, and joint modelling of longitudinal and survival data was done to analyse the association between SUA dynamic changes and MetS occurrence.

Results: The natural logarithm of SUA (LNSUA) in females exhibited a gradually increasing trend, and its annual growth rate in females who developed MetS was greater than that of the non-MetS females. The longitudinal growth of SUA in females was a risk factor for the onset of MetS, and the estimated HR was 13.2580 (95% CI 1.9106 to 91.9957) for each 1-unit rise in LNSUA longitudinally. An association between the longitudinal growth of LNSUA and MetS was not found in males.

Conclusions: The longitudinal increase in SUA in females could increase the risk of MetS, even if the SUA changes within the normal range. The longitudinal increase in SUA in males was not a predictor for MetS.
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http://dx.doi.org/10.1136/bmjopen-2019-035289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333806PMC
July 2020

Effects of Metformin on Life Span, Cognitive Ability, and Inflammatory Response in a Short-Lived Fish.

J Gerontol A Biol Sci Med Sci 2020 10;75(11):2042-2050

Shandong Provincial Key Laboratory of Animal Resistant Biology, School of Life Sciences, Shandong Normal University, Jinan, China.

Metformin, an oral antidiabetic drug, prolongs the life span in nematode, silkworm, and other transgenic rodents, but its effects on longevity and aging-related cognitive ability using natural aging vertebrate models remain poorly understood. The genus of annual fish Nothobranchius show accelerated growth and expression of aging biomarkers. Here, using the short-lived fish Nothobranchius guentheri, we investigated effects of metformin on life span and aging-related cognitive ability and inflammation. Total of 145 fish, 72 fish were fed with metformin in the concentration of 2 mg/g food and 73 fish without metformin from 16 weeks of age until the end of their lives. The chronic feeding with metformin prolonged the life span of the fish and delayed aging with retarded accumulation of lipofuscin in liver, senescence-associated beta-galactosidase (SA-β-gal) activity in skin and serum levels of cholesterol and triglyceride significantly in the 10-month-old fish. Furthermore, metformin improved motor, learning, and memory skills by behavior tests accompanying with reduction of SA-β-gal activity and neurofibrillary degeneration and inhibition of inflammatory response including downregulated NF-κB and proinflammatory cytokines IL-8, TNF-α, and IL-1β expression and enhanced anti-inflammatory cytokine IL-10 level in brain. These findings demonstrate that metformin prolongs the life span and exerts neuroprotective and anti-inflammation function to improve cognitive ability in annual fish. It might be an effective strategy by using metformin to raise the possibility of promoting healthy aging of old population in aging process.
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http://dx.doi.org/10.1093/gerona/glaa109DOI Listing
October 2020

Exploring the effectiveness of ECA policies in reducing pollutant emissions from merchant ships in Shanghai port waters.

Mar Pollut Bull 2020 Jun 15;155:111164. Epub 2020 Apr 15.

College of Transport and Communications, Shanghai Maritime University, Shanghai 201306, China.

Using the AIS data in 2017, this study aims to investigate the effectiveness of five ECA policies on pollutant emissions from merchant ships in Shanghai Port waters. Results show that the estimated annual emissions from merchant ships including cargo ships, container ships and tankers are 3.4029 × 10 tons for NO, 2.1037 × 10 tons for SO, 2.291 × 10 tons for PM, and 2.921 × 10 tons for PM in 2017, respectively. Impact analysis results highlight the fact that effects of each ECA policy vary significantly among different merchant ship types and different water areas. The amount of pollutant emissions from cargo ships (e.g., SO and PM) is most affected by the ECA policy. However, the NO emissions are not significantly changed under different ECA policies. Results also show that future ECA policies could cause a much greater decrease of pollutant emissions in water areas of Yangshan and Wusong.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111164DOI Listing
June 2020

Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis.

Cell Cycle 2020 05 14;19(10):1089-1104. Epub 2020 Apr 14.

Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China.

Pyroptosis is a form of programmed cell death initiated by inflammasomes and is critical for immunity. SIRT1, a NAD+-dependent deacetylase, plays multiple roles in inflammatory response and immunity. Metformin can activate SIRT1 to participate in different biological processes and exert its anticancer effects. However, the mechanism by which metformin activates SIRT1 to drive cancer cell pyroptosis has not been reported. In this study, we treated cancer cells with metformin for diverse periods of time (0-24 h) and found that cell viability was decreased obviously. Interestingly, pyroptosis occurred when cancer cells were treated with metformin for the indicated time (4, 8 and 12 h), which was elucidated by the cell swelling and bubbles blowing in the membrane. Metformin also increased the release of lactate dehydrogenase (LDH, an indication of pyroptotic cell cytotoxicity) remarkably. The underlying mechanisms were that metformin enhanced AMPK/SIRT1 pathway and further increased NF-κB p65 expression to stimulate Bax activation and cytochrome c release, triggering caspase3 cleavage of GSDME, which is a characteristic pyroptotic marker. Depletion of SIRT1 inhibited metformin-induced these protein expression, revealing that metformin promotes AMPK/SIRT1/NF-κB signaling to drive cancer cell pyroptosis. Meantime, metformin induced mitochondrial dysfunction to trigger activation of caspase3 and generation of GSDME-N. Moreover, mitochondrial dysfunction activated AMPK/SIRT1 pathway to cause pyroptotic death upon metformin treatment. This research firstly reveals that metformin as a sensitizer amplifies AMPK/SIRT1/NF-κB signaling to induce caspase3/GSDME-mediated cancer cell pyroptosis. Induction of cellular pyroptosis by metformin is considered as a novel therapeutic option against various cancers.
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http://dx.doi.org/10.1080/15384101.2020.1743911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217368PMC
May 2020

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer.

Int J Mol Sci 2020 Feb 20;21(4). Epub 2020 Feb 20.

Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan 250014, China.

Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.
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http://dx.doi.org/10.3390/ijms21041456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073143PMC
February 2020

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer.

Int J Mol Sci 2020 Jan 20;21(2). Epub 2020 Jan 20.

Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan 250014, Shandong, China.

Cancer is one of the most serious diseases endangering human health. In view of the side effects caused by chemotherapy and radiotherapy, it is necessary to develop low-toxic anti-cancer compounds. Polyphenols are natural compounds with anti-cancer properties and their application is a considerable choice. Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. It is of great significance to clarify the mechanisms of polyphenols on tumor suppression by inducing senescence. In this review, we delineated the characteristics of senescent cells, and summarized the mechanisms of polyphenols targeting tumor microenvironment and inducing cancer cell senescence for cancer prevention and therapy. Although many studies have shown that polyphenols effectively inhibit cancer by targeting senescence, it warrants further investigation in preclinical and clinical studies.
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http://dx.doi.org/10.3390/ijms21020684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013714PMC
January 2020

Genetic associations of docetaxel-based chemotherapy-induced myelosuppression in Chinese Han population.

J Clin Pharm Ther 2020 Apr 28;45(2):354-364. Epub 2019 Nov 28.

The Fourth People's Hospital of Jinan City, Taishan Medical College, Jinan, China.

What Is Known And Objective: Myelosuppression, an adverse drug reaction (ADR), often causes medical treatment termination in cancer patients. It has been known that genetic components, such as single-nucleotide polymorphisms (SNPs), influence the risk of myelosuppression at the individual-patient level. However, due to ethnic variation in frequency of genetic polymorphisms, results reported in Caucasian patients may not be generalizable to the Chinese Han population. Until now, few researches on myelosuppression included Chinese Han patients. In this study, we conducted a systematic study of potential biomarkers for docetaxel-induced myelosuppression in Han Chinese patients.

Methods: We examined 61 SNPs in 36 genes that code for drug transporters, metabolism enzymes, nuclear receptors and DNA repair pathway in 110 Chinese Han patients receiving docetaxel-based chemotherapy. Genotyping was conducted using the Sequenom MassARRAY system. Significant SNPs were identified by logistic regression, and gene-gene interactions were investigated by generalized multifactor dimensionality reduction (GMDR) analysis.

Results And Discussion: Our results revealed that 11 SNPs in nine genes (SLC15A1, SLCO1A2, CYP2D6, FMO3, UGT1A1, NAT2, SULT2A1, PXR and HNF4α) were associated with docetaxel-induced myelosuppression. GMDR analyses suggested that a 3-locus model: SLC15A1 rs2297322-PXR rs3732359-FMO3 rs2266782 was an appropriate predictive model of docetaxel-induced myelosuppression (P = .017, Testing Bal.Acc = 0.653, CV Consistency = 10/10).

What Is New And Conclusion: Our findings suggest multiple novel predictive biomarkers of docetaxel-induced myelosuppression: SLC15A1 rs2297322, PXR rs3732359 and FMO3 rs2266782. These discoveries should help in advancing future personalized therapy of docetaxel-based chemotherapy specific to Chinese Han patients.
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http://dx.doi.org/10.1111/jcpt.13084DOI Listing
April 2020

A tumor suppressor DLC1: The functions and signal pathways.

J Cell Physiol 2020 06 26;235(6):4999-5007. Epub 2019 Nov 26.

Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China.

Deleted in liver cancer-1 (DLC1), a potential tumor suppressor, acts as a GTPase-activating protein for Rho family members. In many human cancers, the DLC1 expression is frequently downregulated or inactivated, which allows cancer cells to proliferate and disseminate. In this review, we describe the characteristics and other members of the DLC1 family and delineate the signal pathways DLC1 involved in regulating cancer cell growth, colony formation, apoptosis, senescence, autophagy, migration and invasion. In addition, we explore the clinical data of DLC1 and the mechanisms that natural products upregulate the DLC1 expression to inhibit cancer. Despite these insights, many important unanswered questions remain about the exact mechanisms of DLC1-mediated cancer suppression.
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http://dx.doi.org/10.1002/jcp.29402DOI Listing
June 2020

Size-Controllable Synthesis of Uniform Spherical Covalent Organic Frameworks at Room Temperature for Highly Efficient and Selective Enrichment of Hydrophobic Peptides.

J Am Chem Soc 2019 11 4;141(45):18271-18277. Epub 2019 Nov 4.

Ministry of Education Key Laboratory of Analytical Science for Food Safety and Biology, College of Chemistry , Fuzhou University , Fuzhou , Fujian 350116 , China.

Covalent organic frameworks (COFs) represent a new class of porous crystalline polymers with a diversity of applications. However, synthesis of uniform spherical COFs poses a great challenge. Here, we present size-controllable synthesis of uniform spherical COFs from nanometer to micrometer scale by a facile approach at room temperature. The as-prepared spherical COFs with different sizes exhibited ultrahigh surface area, good crystallinity, and chemical/thermal stability. Multifarious microscopic and spectroscopic techniques were performed to understand the formation mechanism and influencing factors of the spherical COFs. Moreover, the general applicability for room-temperature synthesis of the spherical COFs was demonstrated by varying different building blocks. Spherical COFs, because of the advantageous nature of their surface area, hydrophobicity, and mesoporous microenvironment, serve as an attractive restricted-access adsorption material for highly selective and efficient enrichment of hydrophobic peptides and size exclusion of macromolecular proteins simultaneously. On this basis, the spherical COFs were successfully applied to the specific capture of ultratrace C-peptide from human serum and urine samples. This research provides a new strategy for room-temperature controllable synthesis of uniform spherical COFs with different sizes and extends the application of COFs as an attractive sample-enrichment probe for clinical analysis.
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http://dx.doi.org/10.1021/jacs.9b09189DOI Listing
November 2019

Monitoring of biological response to clopidogrel after treatment for non-cardioembolic ischemic stroke or transient ischemic attack.

Am J Transl Res 2019 15;11(9):5332-5337. Epub 2019 Sep 15.

University of Lyon, UJM - Saint-Etienne, Inserm Sainbiose U1089, Saint-Etienne F-42023, France.

Background And Purpose: Biological response to clopidogrel prescribed after a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) has been little studied. The aim of our study (AAPIX) was to assess this response and investigate the agreement between different biological assays in revealing poor responders.

Methods: Patients hospitalized following a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) and prescribed clopidogrel were consecutively included from September 2013 to November 2015 in the Stroke Center of Saint-Etienne Hospital. Blood was drawn after 5 to 8 days of standard-dose clopidogrel. Light transmission aggregometry (LTA) and flow cytometric assays, using vasodilator-stimulated phosphoprotein [VASP] and CD62P, were accomplished for all patients. Transmission electron microscopy (TEM) was performed for a poor clopidogrel-responder and for a patient with discordant platelet assay results (platelet reactivity index (PRI) >50% and maximum platelet aggregation <70%), after activation with adenosine diphosphate (ADP) 10 µM.

Results: 72 patients were included. According to LTA, VASP assay and CD62P test results, 65%, 71% and 0% of patients, respectively, had a low response to clopidogrel, indicating poor agreement between these assays. Images of ADP-activated platelet samples from a patient manifesting a low response to clopidogrel and from a patient with discordant platelet assay results showed an ultrastructural pattern typical of activation and a state of slight activation, respectively.

Conclusions: Platelet function results obtained using different assays for patients having experienced a non-cardioembolic ischemic stroke or TIA were discordant. Transmission electron microscopy could be useful in certain clinical contexts when platelet function assay results disagree.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789282PMC
September 2019

Discovery of Novel Biomarkers of Therapeutic Responses in Han Chinese Pemetrexed-Based Treated Advanced NSCLC Patients.

Front Pharmacol 2019 23;10:944. Epub 2019 Aug 23.

Life Science College, Anhui Medical University, Hefei, China.

Pemetrexed, one of the most commonly used drugs in advanced non-small cell lung cancer (NSCLC) therapies, often leads to various therapeutic responses in patients. These therapeutic responses to pemetrexed, including adverse drug reactions (ADRs) and its intended therapeutic effects, have been demonstrated to be highly individual-specific. Such difference in therapeutic responses across individuals may be caused by the unique genetic variations in each patient. However, only a few pemetrexed-based studies have been performed using Han Chinese patients. In this study, we aimed to identify genetic signatures of therapeutic responses of pemetrexed-based treatment using 203 Han Chinese patients with advanced NSCLC. All the participants received two different types of therapies: 1) treatment with only pemetrexed and 2) treatment with both pemetrexed and platinum (mainly cisplatin and carboplatin). We then performed a genetic association analysis on 16 selected single-nucleotide polymorphisms (SNPs) in 7 genes using these 2 groups. The analysis of patients receiving only pemetrexed suggests that the SNP rs1051298 on the gene (c.*746C > T) increased the risk of all ADRs (collected all types of ADRs) in different cycles of pemetrexed therapy [1-2 cycles: = 0.0059, odds ratio (OR) = 3.143; 1-4 cycles: = 0.0072, OR = 2.340; 1-6 cycles: = 0.0071, OR = 2.243]. This influence of rs1051298 is particularly significant in terms of liver injury (1-4 cycles: = 0.0056, OR = 3.863; 1-6 cycles: = 0.0071, OR = 3.466). In all the patients, including patients who received both pemetrexed and platinum, SNP rs1801133 on the gene (665C > T) was found to be significantly associated with hematological ADRs in 1 to 2 cycles ( = 0.0079, OR = 3.566). Additionally, we discovered that SNP rs12995526 (c.815-102T > C) in the gene and SNP rs11545077 (c.91G > T) in the gene were associated with both ADRs and therapeutic effects. In summary, our study identified several potential biomarkers that were significantly associated with ADRs and therapeutic effects of pemetrexed-related treatments using Han Chinese patients. Our discoveries will provide important clues for personalized pemetrexed-based treatment design for Han Chinese NSCLC patients in the future.
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http://dx.doi.org/10.3389/fphar.2019.00944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716463PMC
August 2019

Transition Patterns of Weight Status and Their Associated Factors among Elementary School Children: A Longitudinal Cohort Study Using Multistate Markov Model.

Child Obes 2019 07 6;15(5):306-312. Epub 2019 May 6.

1 School of Public Health, Daltan Medical University, Daltan, China.

Childhood obesity is a recognized public health concern worldwide. It is essential to study the natural progression of obesity in the interest of prevention. This study aimed to describe the dynamic changes in weight status among elementary school children and identify the significant factors influencing the progression or regression of weight status. This study involved 928 elementary school children who were followed up annually during their elementary school years. Heights, weights, and vital capacity (VC) were measured each school year. A multistate Markov model containing three weight states was fit to longitudinal weight status data. Children with healthy weight and obesity tended to stay in their preceding weight state. Children with overweight, in contrast, were more likely to move to the other two states. The mean sojourn time in obesity and in overweight states was 5.15 years (95% confidence interval [CI]: 4.22-6.3) and 2 years (95% CI: 1.76-2.28), respectively. Children in lower grades, those with a lower VC index, those with a higher initial BMI, those with a higher annual weight increment, and boys were at increased risk of progression to overweight or obesity, with a decreased probability of regression. Children with obesity were more resistant to recovery than those with overweight. Prevention and intervention measures should be adopted early when abnormal weight onset occurs. The multistate Markov model was an advanced tool to analyze dynamic changes in status and identify significant factors for progression and regression and helped to develop prevention and intervention targeting strategies.
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http://dx.doi.org/10.1089/chi.2018.0345DOI Listing
July 2019

Photoactivated oxidase mimetics derived from dicyandiamide and barbituric acid for colorimetric detection of glutathione.

Spectrochim Acta A Mol Biomol Spectrosc 2019 May 1;215:307-312. Epub 2019 Mar 1.

Ministry of Education Key Laboratory of Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, College of Chemistry, Fuzhou University, Fuzhou 350116, China. Electronic address:

In this work, photoactivated oxidase mimetics was prepared by copolymerizing dicyandiamide with barbituric acid (BA) and characterized by X-ray diffraction pattern, Fourier transformed infrared spectrum, X-ray photoelectron spectroscopy, transmission electron microscopy, photoluminescence spectrum, diffuse reflectance spectrum. Experimental results and density functional theory calculation indicated that the substitution of nitrogen atoms by carbon atoms in tri-s-triazine structure due to the copolymerization of BA enhanced visible light absorption and weakened the barrier of photocarrier transfer. In the presence of visible light and oxygen, 3, 3', 5, 5'-tetramethylbenzidine was oxidized under the catalysis of photoactivated oxidase mimetics to produce a green colored product, which could be reduced by glutathione (GSH). Therefore, a facile method based on the photoactivated oxidase mimetic has been developed for colorimetric detection of GSH. The linear range for GSH was ranged from 2.0 to 50.0 μmol L (R = 0.998) with the detection limit of 1.4 μmol L. The proposed method was applied to detect the cellular GSH with satisfactory results.
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http://dx.doi.org/10.1016/j.saa.2019.02.109DOI Listing
May 2019

Ultralow doses of dextromethorphan protect mice from endotoxin-induced sepsis-like hepatotoxicity.

Chem Biol Interact 2019 Apr 26;303:50-56. Epub 2019 Feb 26.

Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.

Dextromethorphan, a wildly used over-the-counter antitussive drug, is reported to have anti-inflammatory effects. Previously, we and others have demonstrated that dextromethorphan at micromolar doses displays potent hepatoprotective effects and enhances mice survival in a sepsis model. Moreover, we also observed potent anti-inflammatory and neuroprotective effects of subpicomolar concentrations of dextromethorphan in rodent primary neuron-glial cultures. The purpose of this study was to provide a proof of principle that ultralow dose dextromethorphan displays anti-inflammatory and cytoprotective effects in animal studies. Here, we report that subpico- and micromolar doses of dextromethorphan showed comparable efficacy in protecting mice from lipopolysaccharide/d-galactosamine (LPS/GalN)-induced hepatotoxicity and mortality. Mice were given injections of dextromethorphan from 30 min before and 2, 4 h after an injection of LPS/GalN (20 μg/600 mg/kg). Our results showed that dextromethorphan at subpicomolar doses promoted survival rate in LPS/GalN-injected mice. Ultralow dose dextromethorphan also significantly reduced serum alanine aminotransferase activity, TNF-α level and liver cell damage of endotoxemia mice. Mechanistic studies using primary liver Kupffer cell cultures revealed that subpicomolar concentrations of dextromethorphan reduced the NADPH oxidase-generated superoxide free radicals from Kupffer cells, which in turn reduced the elevation of its downstream reactive oxygen species (iROS) to relieve the oxidative stress and decreased TNF-α production in Kupffer cells. Taken together, these findings suggest a novel therapeutic concept of using ultralow doses of dextromethorphan for the intervention of sepsis or septic shock.
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http://dx.doi.org/10.1016/j.cbi.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492266PMC
April 2019

In vivo measurement of trabecular meshwork stiffness in a corticosteroid-induced ocular hypertensive mouse model.

Proc Natl Acad Sci U S A 2019 01 16;116(5):1714-1722. Epub 2019 Jan 16.

Department of Ophthalmology, Duke University, Durham, NC 27710;

Ocular corticosteroids are commonly used clinically. Unfortunately, their administration frequently leads to ocular hypertension, i.e., elevated intraocular pressure (IOP), which, in turn, can progress to a form of glaucoma known as steroid-induced glaucoma. The pathophysiology of this condition is poorly understood yet shares similarities with the most common form of glaucoma. Using nanotechnology, we created a mouse model of corticosteroid-induced ocular hypertension. This model functionally and morphologically resembles human ocular hypertension, having titratable, robust, and sustained IOPs caused by increased resistance to aqueous humor outflow. Using this model, we then interrogated the biomechanical properties of the trabecular meshwork (TM), including the inner wall of Schlemm's canal (SC), tissues known to strongly influence IOP and to be altered in other forms of glaucoma. Specifically, using spectral domain optical coherence tomography, we observed that SC in corticosteroid-treated mice was more resistant to collapse at elevated IOPs, reflecting increased TM stiffness determined by inverse finite element modeling. Our noninvasive approach to monitoring TM stiffness in vivo is applicable to other forms of glaucoma and has significant potential to monitor TM function and thus positively affect the clinical care of glaucoma, the leading cause of irreversible blindness worldwide.
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http://dx.doi.org/10.1073/pnas.1814889116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358695PMC
January 2019