Publications by authors named "Qihang Li"

37 Publications

Corrigendum: High Circulating Follicle-Stimulating Hormone Level Is a Potential Risk Factor for Renal Dysfunction in Post-Menopausal Women.

Front Endocrinol (Lausanne) 2021 31;12:710836. Epub 2021 Aug 31.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

[This corrects the article DOI: 10.3389/fendo.2021.627903.].
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http://dx.doi.org/10.3389/fendo.2021.710836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439174PMC
August 2021

Computational design of binder as the LC3-p62 protein-protein interaction.

Bioorg Chem 2021 10 13;115:105241. Epub 2021 Aug 13.

School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.

Cellular autophagy is an intracellular degradation pathway, which transports damaged, deformed, senescent or non-functional proteins and organelles to lysosome for digestion and degradation. Cellular autophagy is deeply evolutionarily conservedfromyeasttomammaliancells, and many homologous proteins of the autophahgy regulators are found in several species. This physiological process maintains the steady state of cells. Furtheremore, autophagy dysfunction is closely related to various diseases, such as neurodegenerative diseases, inflammation-related diseases, cardiovascular diseases, metabolic diseases, etc. The LC3 and p62 protein protein interaction (PPI) promotes the formation of autophagosomes and delivers polyubiquitinated "cargoes" to autophagic degradation. Therefore, LC3-p62 PPI plays an integral role in the formation of autophagosomes and effectively inhibits autophagy. However, there are still few studies on the LC3-p62 PPI inhibitors for its unclear molecular mechanism. Furthermore, most of these inhibitors are macromolecules with poorly active, and small molecules are particularly scarce. In this article, the computation method was used to identify the hot spot and design peptides as the binder of LC3-p62 PPI. Findings from this work provide a reference for the follow-up research of discovering small molecule inhibitors targeting LC3-p62 PPI.
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http://dx.doi.org/10.1016/j.bioorg.2021.105241DOI Listing
October 2021

Scanning Electron Microscope Study of Antennae and Mouthparts in the Pollen-Beetle () (Coleoptera: Nitidulidae: Meligethinae).

Insects 2021 Jul 20;12(7). Epub 2021 Jul 20.

Department of Biology and Biotechnology, Sapienza Rome University, Viale dell'Università 32, 00185 Rome, Italy.

() is a common Chinese phytophagous species in the family Nitidulidae. Its main larval host plant is L. (Rosaceae), and adults feed on pollen and other floral parts. In this study, we used scanning electron microscopy (SEM) to observe and study the fine morphology of sensilla on the antennae and mouthparts of . The results show that there are six types and twelve subtypes of sensilla on male antennae; seven types and fourteen subtypes on female antennae; seven types and seventeen subtypes on male mouthparts; seven types and sixteen subtypes on female mouthparts. Sensilla coeloconica (SCo) are found on the female antennae of only, and they are also reported on the antennae of Nitidulidae for the first time. SCo2 on the labrum present sexual dimorphism, and one subtype of sensilla basiconica (SB6) is presented on the tip of maxillary and labial palps of the male only, while other types of sensilla are very similar on the mouthparts of male and female. Finally, by comparing similar sensilla in other insects, we also attempted to discuss the functions of all sensilla on the antennae and mouthparts of .
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http://dx.doi.org/10.3390/insects12070659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304583PMC
July 2021

Design, Bio-evaluation and Molecular Dynamics Simulation of Novel GSK-3β Inhibitors.

Mol Inform 2021 Jul 29. Epub 2021 Jul 29.

School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.

Glycogen synthase kinase 3 beta (GSK-3β) is considered as a promising drug target for the treatment of Alzheimer's disease (AD). In the present study, two compound libraries were selected for virtual screening based on pharmacophore models of GSK-3β to discover new inhibitors. Nine potential hits were retained for biological investigation and four of these compounds showed GSK-3β inhibitory activity (with the IC values in sub-micromolar range on GSK-3β). Compounds 6 and 9 have good safety. They do not have any significant in vitro cytotoxicity against PC12 and SH-SY5Y neuroblastoma cells at concentrations up to 90 μM. Based on the inhibitory activity and druggability properties, compound 8 is the preferred molecule, and it is a promising lead for the development of the GSK-3β inhibitors for reducing the abnormal hyperphosphorylation of tau protein and relieving AD.
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http://dx.doi.org/10.1002/minf.202060031DOI Listing
July 2021

Association Between the Triglyceride-Glucose Index and Outcomes of Nonalcoholic Fatty Liver Disease: A Large-Scale Health Management Cohort Study.

Diabetes Metab Syndr Obes 2021 21;14:2829-2839. Epub 2021 Jun 21.

Department of Endocrinology, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly becoming a major health burden. Due to the difficulty of liver biopsy, there is no reliable indicator to evaluate the outcomes of NAFLD. The triglyceride-glucose (TyG) index is a simple and convenient marker of insulin resistance for use in medical practice. Whether the TyG index is predictive of later risk of NAFLD remains unknown.

Objective: To evaluate the relationship between TyG index with NAFLD progression and improvement during a median follow-up period of 21 months.

Material And Methods: A total of 11,424 subjects (9327 men) diagnosed with NAFLD were included. The TyG index was calculated as follows: ln [fasting triglycerides (mg/dL) * fasting glucose (mg/dL)/2]. Multivariable Cox regression analysis was applied to analyze the data.

Results: In this study, the severity of NAFLD remained the same in 38.8% of subjects, worsened in 17.4% of subjects, and improved in 43.8% of subjects. Compared with the lowest quartile of the TyG index, the adjusted HR of NAFLD progression in the highest quartile (TyG≥9.34) was 1.448 (1.229 to 1.706), and the adjusted HR of NAFLD improvement was 0.817 (0.723 to 0.923). Subgroup analysis found that smoking increased the correlation between the TyG index and the risk of NAFLD progression, while female, vegan diet, and weight control enhanced the correlation between the TyG index and the risk of NAFLD improvement.

Conclusion: The TyG index may be a simple and helpful indicator for further risk appraisal of NAFLD in daily clinical practice.
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http://dx.doi.org/10.2147/DMSO.S316864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232855PMC
June 2021

Associations Between Serum Free Fatty Acid Levels and Incident Diabetes in a 3-Year Cohort Study.

Diabetes Metab Syndr Obes 2021 17;14:2743-2751. Epub 2021 Jun 17.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.

Purpose: High circulating free fatty acid (FFA) is associated with the development of diabetes. This study was designed to evaluate longitudinal associations between FFA levels, changes in FFA levels, and mean FFA levels and incident diabetes.

Participants And Methods: This 3-year cohort study was conducted in Ningyang between 2011 and 2014. Serum FFA, fasting blood glucose (FPG), 2-hour postprandial blood glucose (2hPG), and glycosylated hemoglobin (HbA1c) levels were measured at baseline and at the end of follow-up. A multivariate stepwise logistic regression model was used to evaluate associations between serum FFA levels in various groups and the risk of incident diabetes.

Results: Of the 2905 individuals without baseline diabetes, 290 developed diabetes by the 3-year follow-up. With increasing baseline FFA levels, the mean FPG, 2hPG, and HbA1c levels, and the prevalence of diabetes at the end of follow-up increased. The trend of FPG and HbA1c increase was not statistically significant. Higher baseline FFA levels were not significantly associated with greater risk of incident diabetes. However, longitudinal changes in serum FFA levels showed that individuals with serum FFA levels from normal to high (OR = 2.956, 95% CI: 2.089-4.184) or from high to high (OR = 3.343, 95% CI: 2.300-4.857) had greater risk of incident diabetes compared with those with normal to normal FFA levels. Similarly, individuals with ΔFFA ≥ 0 mmol/L (OR = 1.762, 95% CI: 1.373-2.262) or high mean serum FFA levels (OR = 2.120, 95% CI: 1.620-2.775) were at higher risk of incident diabetes than those with ΔFFA < 0 mmol/L or normal mean serum FFA levels.

Conclusion: The longitudinal status of serum FFA levels, including chronic increases and sustained high levels, was more closely associated with high risk of incident diabetes than was high baseline FFA levels.
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http://dx.doi.org/10.2147/DMSO.S302681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216696PMC
June 2021

Effect of trachea stiffness on tumor distribution in papillary thyroid microcarcinoma.

Oncol Lett 2021 Jul 7;22(1):518. Epub 2021 May 7.

Department of Maxillofacial and Ear Nose and Throat Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300020, P.R. China.

Biomechanical factors play an important role in tumor distribution, epithelial-mesenchymal transition (EMT), invasion and other important processes. Despite fewer reports investigating biomechanical function in papillary thyroid carcinoma (PTC), a large number of PTC cases are located close to the trachea and the majority of advanced cases of PTC have been associated with invasion of the trachea. However, the effect of trachea stiffness on PTC distribution and growth remains unknown. To clarify this issue, two types of PTC cells (TPC-1 and KTC-1) were seeded on a substrate with different stiffness to observe cell proliferation and movement. To identify the effect of trachea stiffness on the thyroid, two thyroid lobes (left and right) were evenly divided into interior (close to the trachea) and lateral (away from the trachea) parts, based on the vertical line between the trachea and thyroid lateral margin with different von Mises stress values. As PTC originates from papillary thyroid microcarcinoma (PTMC) with a maximum diameter of <1 cm, the present study selected PTMC as the study subject to reflect initial PTC distribution in the thyroid. The association between the percentage of PTMC distribution in different parts of the thyroid and von Mises stress values was analyzed. Both PTC cells exhibited stronger proliferation and mobility on the stiff substrate compared with that on the soft substrate. Furthermore, the results of finite element analysis revealed that the von Mises stress values of the interior parts of the trachea were notably higher compared with that in the lateral parts. PTMC distribution in the interior trachea was notably greater compared with that in the lateral section. There was also an observed association between von Mises stress values and PTMC distribution. In addition, the results of RNA-sequencing and reverse transcription-quantitative PCR demonstrated that three biomechanical genes were overexpressed in PTMC located in the interior section compared with that in adjacent normal tissue, and the related signaling pathways were also activated in these tissues. On the whole, these results indicated that trachea stiffness may supply a suitable biomechanical environment for PTMC growth, and the related biomechanical genes may serve as novel targets for PTMC diagnosis and prognostic estimation.
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http://dx.doi.org/10.3892/ol.2021.12779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130054PMC
July 2021

High Circulating Follicle-Stimulating Hormone Level Is a Potential Risk Factor for Renal Dysfunction in Post-Menopausal Women.

Front Endocrinol (Lausanne) 2021 1;12:627903. Epub 2021 Apr 1.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Objective: Menopause contributes to renal dysfunction in women, which is generally attributed to estrogen withdrawal. In addition to decreased estrogen level, serum follicle-stimulating hormone (FSH) level increases after menopause. This study investigated the association between high circulating FSH level and renal function in post-menopausal women.

Methods: This observational cross-sectional study included 624 pre-menopausal, 121 peri-menopausal, and 2540 post-menopausal women. The levels of female sex hormones were examined by chemiluminescence and indices of renal function were measured using a clinical chemistry analyzer. The post-menopausal women were grouped into quartiles according to serum FSH levels.

Results: Renal function progressively declined from pre-menopause to peri-menopause to post-menopause, which was accompanied by increasing serum FSH level. In post-menopausal women, serum creatinine level increased with increasing FSH quartile, which was accompanied by a decrease in estimated glomerular filtration rate (eGFR) (p for trend <0.001); moreover, the prevalence of declined eGFR (<90 ml/min/1.73 m) and chronic kidney disease (CKD; eGFR <60 ml/min/1.73 m) increased (p for trend <0.001). Even after adjusting for confounders, the odds ratios (ORs) of declined eGFR and CKD increased with increasing FSH quartiles in post-menopausal women. The ORs of declined eGFR (OR=2.19, 95% confidence interval [CI]: 1.63-2.92) and CKD (OR=10.09, 95% CI: 2.28-44.65) in the highest FSH quartile were approximately 2- and 10-fold higher, respectively, than in the lowest FSH quartile (p<0.05). After stratifying post-menopausal women by median age (61 years), the OR for declined eGFR for each FSH quartile in the older group was higher than that for the corresponding FSH quartile in the younger group.

Conclusions: A high circulating FSH level is an independent risk factor for renal dysfunction in women after menopause. Additionally, aging may aggravate the association of high FSH levels with reduced renal function in post-menopausal women.
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http://dx.doi.org/10.3389/fendo.2021.627903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047631PMC
April 2021

Tracing the Origins of Blueberries by Their Mineral Element Contents and Sr/Sr Ratios.

Biol Trace Elem Res 2021 Apr 6. Epub 2021 Apr 6.

College of Agriculture, Guizhou University, Guiyang, 550025, Guizhou, China.

This study investigated the feasibility of using the mineral element contents and Sr/Sr ratios of blueberries to trace their origins. The contents of 28 mineral elements, including K, Al, and Mg, were determined in 104 blueberry samples from three blueberry-producing areas in Guizhou Province, China. Also determined were both the Sr/Sr ratios in 48 blueberry samples as well as the type of soil in which the blueberries were grown. Cluster analysis of Sr/Sr ratios, stepwise discriminant analysis of mineral element contents, and combined discriminant analyses of Sr/Sr ratios and mineral element contents were done. The results show that ten elements (Ca, Cr, Cs, Mg, Mn, P, Rb, Sb, Th, and Y) were selected by linear discriminant analysis, which could be used to establish the provenance traceability model of blueberries in Guizhou. The original accuracy of linear discriminant analysis was 89.4%, and the accuracy of cross-validation was 83.6%. When Sr/Sr ratios were used for tracing, the accuracies of both the original discrimination and the cross-validation were 81.3% as determined by linear discriminant analysis, and the accuracy rate of origin discrimination was 81.25% by cluster analysis. The results of combined discrimination were the best: the accuracy of the original discrimination was 95.8%, and the accuracy of cross-validation was 93.8%. Mineral element contents and Sr/Sr ratios can be used to trace the origins of blueberries, and combining them can significantly improve the discrimination accuracy. Fisher linear discriminant analysis had the greatest accuracy followed by cluster analysis, while principal component analysis was relatively poor in the research of Guizhou blueberry origin traceability.
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http://dx.doi.org/10.1007/s12011-021-02701-6DOI Listing
April 2021

Association between different obesity phenotypes and hypothyroidism: a study based on a longitudinal health management cohort.

Endocrine 2021 06 5;72(3):688-698. Epub 2021 Apr 5.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Purpose: Obese individuals have an increased risk of hypothyroidism. This study investigated the sex-specific association between obesity phenotypes and the development of hypothyroidism.

Methods: The study population was derived from a health management cohort in Shandong Provincial Hospital from 2012 to 2016. In total, 9011 baseline euthyroid adults were included and classified into four groups according to obesity phenotype: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). The median follow-up time was 1.92 (1.00-2.17) years. Incidence density was evaluated and a generalized estimation equation method was used to investigate the associations between obesity phenotypes and the development of hypothyroidism.

Results: The incidence densities of hypothyroidism in males with a consistent obesity phenotype were 12.19 (8.62-16.76), 15.87 (11.39-21.56), 14.52 (6.74-27.57), and 19.88 (14.06-27.34) per 1000 person-years in the MHNO, MHO, MUNO, and MUO groups, respectively. After adjusting for confounding factors, compared with the MHNO phenotype, the MHO, MUNO, and MUO phenotypes were independent risk factors for developing hypothyroidism in males. In the subgroup analysis, the MHO and MUO phenotypes were independent risk factors for developing hypothyroidism in males under 55 years, while the MUNO phenotype was an independent risk factor in males over 55 years. The MHO, MUNO, and MUO phenotypes were not independent risk factors for hypothyroidism in females.

Conclusion: Both obesity and metabolic abnormities are associated with a higher risk of hypothyroidism in males. The underlying mechanism of the sex and age differences in this association needs further investigation.
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http://dx.doi.org/10.1007/s12020-021-02677-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159820PMC
June 2021

Statin Use and Benefits of Thyroid Function: A Retrospective Cohort Study.

Front Endocrinol (Lausanne) 2021 2;12:578909. Epub 2021 Mar 2.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Purpose: Previous studies have suggested that cholesterol may influence thyroid function. Since statins are widely used for their cholesterol-lowering effect, we aimed to assess the association between statin use and thyroid function, and also to explore the role of the cholesterol-lowering effect in it.

Methods: We performed a retrospective cohort study derived from REACTION study. Eligible subjects receiving statin therapy were included in the statin group, and sex-, age-, total cholesterol (TC)-, and thyroid function-matched participants without lipid-lowering therapy were included in the control group. The median follow-up time was three years. Outcomes of thyroid function were evaluated at the end of follow-up. We used multivariable regression models to assess the association between statin use and outcomes of thyroid function, and also performed mediation analyses to explore the role of cholesterol in it.

Results: A total of 5,146 participants were screened, and 201 eligible subjects in the statin group and 201 well-matched subjects in the control group were analyzed. At the end of follow-up, TC and thyroid-stimulating hormone (TSH) levels in the statin group were lower than those in the control group (both p < 0.05), and the percentage of euthyroid subjects was higher in the statin group (88.06% vs. 76.12%, p = 0.002). The incidence rate of subclinical hypothyroidism (SCH) in euthyroid subjects was lower in the statin group (6.29% vs. 14.86%, p = 0.009), and the remission rate among subjects with SCH was higher in the statin group (50.00% vs. 15.38%, p = 0.008). In multivariable regression analyses, statin use was independently associated with lower TSH levels and higher odds to be euthyroid (OR 2.335, p = 0.004) at the end of follow-up. Mediation analyses showed the association between statin use and TSH levels were mediated by TC changes during follow-up.

Conclusion: Statin use was associated with benefits of thyroid function, and TC changes serve as a mediator of the association between statin use and TSH levels. Further studies are needed to clarify the possible underlying mechanism.
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http://dx.doi.org/10.3389/fendo.2021.578909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962670PMC
March 2021

Genomics Analyses Reveal Unique Classification, Population Structure and Novel Allele of Neo-Tetraploid Rice.

Rice (N Y) 2021 Feb 6;14(1):16. Epub 2021 Feb 6.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China.

Background: Neo-tetraploid rice (NTR) is a useful new germplasm that developed from the descendants of the autotetraploid rice (ATR) hybrids. NTR showed improved fertility and yield potential, and produced high yield heterosis when crossed with indica ATR for commercial utilization. However, their classification, population structure and genomic feature remain elusive.

Results: Here, high-depth genome resequencing data of 15 NTRs and 18 ATRs, together with 38 publicly available data of diploid rice accessions, were analyzed to conduct classification, population structure and haplotype analyses. Five subpopulations were detected and NTRs were clustered into one independent group that was adjacent to japonica subspecies, which maybe the reason for high heterosis when NTRs crossed with indica ATRs. Haplotype patterns of 717 key genes that associated with yield and other agronomic traits were revealed in these NTRs. Moreover, a novel specific SNP variation was detected in the first exon of HSP101, a known heat-inducible gene, which was conserved in all NTRs but absent in ATRs, 3KRG and RiceVarMap2 databases. The novel allele was named as HSP101-1, which was confirmed to be a heat response factor by qRT-PCR, and knockout of HSP101-1 significantly decreased the thermotolerance capacity of NTR. Interestingly, HSP101-1 was also specifically expressed in the anthers of NTR at pre-meiotic and meiosis stages under optimal environment without heat stress, and its loss-of-function mutant showed significant decrease in fertility of NTR.

Conclusion: The construction of first genomic variation repository and the revelation of population structure provide invaluable information for optimizing the designs of tetraploid rice breeding. The detection of specific genomic variations offered useful genomic markers and new directions to resolve high fertility mechanism of NTR.
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http://dx.doi.org/10.1186/s12284-021-00459-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867503PMC
February 2021

approaches using pharmacophore model combined with molecular docking for discovery of novel ULK1 inhibitors.

Future Med Chem 2021 02 11;13(4):341-361. Epub 2021 Jan 11.

School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.

Discovery of effective autophagy-initiating kinase ULK1 inhibitors has attracted more and more attention in cancer treatment. The present study describes the application of a pharmacophore-based virtual screening and structure-based docking approach guided drug design. Compound U-2 exhibited a nanomolar range of IC against the ULK1 target. Molecular dynamics simulation was used to assess the quality of docking studies. The determinants of binding affinity were investigated, and a different binding pattern was observed. Subsequently, prediction properties of ADMET (absorption, distribution, metabolism, excretion and toxicity) and hepatotoxicity studies indicated that U-2 possessed good drug-like properties. Moreover, western blot analysis indicated that the compound inhibited autophagic flux in cells. The present study provides an appropriate guideline for discovering novel ULK1 inhibitors. The novel compound may serve as a good starting point for further development and optimizations.
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http://dx.doi.org/10.4155/fmc-2020-0253DOI Listing
February 2021

Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer's disease.

Bioorg Med Chem 2021 01 11;30:115940. Epub 2020 Dec 11.

Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

In the present work, a novel series of pyridinethiazole bearing benzylpiperidine hybrids were designed and synthesized as dual-target inhibitors of GSK-3β/AChE. Among them, GD29 was the most promising candidate, with an IC value of 0.3 μM for hAChE and an IC value of 0.003 μM for hGSK-3β, respectively. The compounds exhibited good drug-like properties with optimal inhibitory enzyme activities. Moreover, GD29 showed anti-inflammatory properties at micromolar concentrations and displayed interesting neuroprotective profiles in an in vitro model of oxidative stress-induced neuronal death. Notably, the compounds also exhibited good permeability across the blood-brain-barrier (BBB) both in vitro. Central cholinomimetic activity was confirmed using a scopolamine-induced cognition impairment model in Institute of Cancer Research (ICR) mice upon oral administration. The current work identified optimized compounds and explored the therapeutic potential of glycogen synthase kinase 3/cholinesterase inhibition for the treatment of AD.
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http://dx.doi.org/10.1016/j.bmc.2020.115940DOI Listing
January 2021

Dysfunction of VIPR2 leads to myopia in humans and mice.

J Med Genet 2020 Dec 14. Epub 2020 Dec 14.

School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China

Background: Myopia is the leading cause of refractive errors. As its pathogenesis is poorly understood, we determined if the retinal VIP-VIPR2 signalling pathway axis has a role in controlling signalling output that affects myopia development in mice.

Methods: Association analysis meta-study, single-cell transcriptome, bulk RNA sequencing, pharmacological manipulation and VIPR2 gene knockout studies were used to clarify if changes in the VIP-VIPR2 signalling pathway affect refractive development in mice.

Results: The SNP rs6979985 of the gene was associated with high myopia in a Chinese Han cohort (randomceffect model: p=0.013). After either 1 or 2 days' form deprivation (FD) retinal mRNA expression was downregulated. Retinal single-cell transcriptome sequencing showed that VIPR2 expressed mainly by bipolar cells. Furthermore, the cAMP signalling pathway axis was inhibited in some clusters after 2 days of FD. The selective VIPR2 antagonist PG99-465 induced relative myopia, whereas the selective VIPR2 agonist Ro25-1553 inhibited this response. In knockout (-KO) mice, refraction was significantly shifted towards myopia (p<0.05). The amplitudes of the bipolar cell derived b-waves in 7-week-old -KO mice were significantly larger than those in their WT littermates (p<0.05).

Conclusions: Loss of VIPR2 function likely compromises bipolar cell function based on presumed changes in signal transduction due to altered signature electrical wave activity output in these mice. As these effects correspond with increases in form deprivation myopia (FDM), the VIP-VIPR2 signalling pathway axis is a viable novel target to control the development of this condition.
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http://dx.doi.org/10.1136/jmedgenet-2020-107220DOI Listing
December 2020

Geochemical Characteristics of Heavy Metals in Soil and Blueberries of the Core Majiang Blueberry Production Area.

Bull Environ Contam Toxicol 2021 Jan 3;106(1):57-64. Epub 2020 Oct 3.

College of Agriculture, Guizhou University, Guiyang, 550025, Guizhou, China.

By using field survey, sampling, and indoor analysis, we analyzed the geochemical characteristics of heavy metals in the blueberries and soil of the core blueberry production area of Majiang in Guizhou, China. Analyses were based on national standards for soil pollution risk control on agricultural land (GB15618-2018) and pollution index limits in food (GB2762-2017/2012). The results demonstrated that heavy metal content in the soil profile of this area exceeds standards, but standards were exceeded mainly in the lower layer of the profile, and blueberry growth was not substantially affected. Except for in Lanmenggu, heavy metals in the cultivation soil layer of Majiang Blueberry Farms did not considerably exceed standards. The content of heavy metals in blueberry did not exceed the standard, so it was a safe fruit. These results can provide a reference for the safe cultivation of Majiang blueberries.
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http://dx.doi.org/10.1007/s00128-020-03007-4DOI Listing
January 2021

Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor.

J Med Chem 2020 09 13;63(17):10030-10044. Epub 2020 Aug 13.

School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.

To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound (BChE IC = 0.18 ± 0.03 μM, BChE IC = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with could almost entirely recover the Aβ (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ total amount confirmed its anti-amyloidogenic profile. Moreover, possessed blood-brain barrier (BBB) penetrating ability, a long , and low intrinsic clearance. Hence, the novel potential BChE inhibitor can be considered as a promising lead compound for further investigation of anti-AD agents.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01129DOI Listing
September 2020

Discovery of a Selective 6-Hydroxy-1, 4-Diazepan-2-one Containing Butyrylcholinesterase Inhibitor by Virtual Screening and MM-GBSA Rescoring.

Dose Response 2020 Apr-Jun;18(2):1559325820938526. Epub 2020 Jun 29.

School of Pharmacy, China Pharmaceutical University, Nanjing, China.

Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure-activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.
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http://dx.doi.org/10.1177/1559325820938526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324897PMC
June 2020

Production Assessment and Genome Comparison Revealed High Yield Potential and Novel Specific Alleles Associated with Fertility and Yield in Neo-Tetraploid Rice.

Rice (N Y) 2020 Jun 3;13(1):32. Epub 2020 Jun 3.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China.

Background: Neo-tetraploid rice (NTR) is a new tetraploid rice germplasm that developed from the crossing and directional selection of different autotetraploid rice lines, which showed high fertility and promising yield potential. However, systematic yield assessment, genome composition and functional variations associated with fertility and yield remain elusive.

Results: Two season's field trials of 15 NTRs and 27 autotetraploid rice (ATR) lines revealed that the improvement of YPP (yield per plant, 4.45 g increase) were significantly associated with the increase of SS (seed setting, 29.44% increase), and yield and seed setting of NTRs improved significantly compared to parental lines. Whole genome resequencing of 13 NTR sister lines and their parents at about 48.63 depth were conducted and genome compositions were illustrated using inherited chromosomal blocks. Interestingly, 222 non-parental genes were detected between NTRs and their low fertility parental lines, which were conserved in 13 NTRs. These genes were overlapped with yield and fertility QTLs, and RNA-Seq analysis revealed that 81 of them were enriched in reproductive tissues. CRISPR/Cas9 gene knockout was conducted for 9 non-parental genes to validate their function. Knockout mutants showed on an average 25.63% and 4.88 g decrease in SS and YPP, respectively. Notably, some mutants showed interesting phenotypes, e.g., kin7l (kinesin motor gene) and kin14m (kinesin motor gene), bzr3 (BES1/BZR1 homolog) and nrfg4 (neo-tetraploid rice fertility related gene) exhibited 44.65%, 24.30%, 24.42% and 28.33% decrease in SS and 8.81 g, 4.71 g, 5.90 g, 6.22 g reduction in YPP, respectively.

Conclusion: Comparative genomics provides insights into genome composition of neo-tetraploid rice and the genes associated with fertility and yield will play important role to reveal molecular mechanisms for the improvement of tetraploid rice.
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http://dx.doi.org/10.1186/s12284-020-00387-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271338PMC
June 2020

p62/SQSTM1, a Central but Unexploited Target: Advances in Its Physiological/Pathogenic Functions and Small Molecular Modulators.

J Med Chem 2020 09 5;63(18):10135-10157. Epub 2020 May 5.

School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.

p62/SQSTM1, encoded by gene , is widely known as an adaptor protein of selective autophagy to promote aggregate-prone proteins for degradation. It is also a stress-induced scaffold protein involved in Nrf2 activation to resist oxidative stress. Multiple domains of p62 interact with several essential pathways implicated in cell differentiation and proliferation, placing p62 at a significant position to mediate cell survival and apoptosis. The p62 protein has been suggested as a potential target in recent years, since its abnormal expression or gene mutation is tightly associated with various diseases including cancer such as hepatocellular carcinoma and prostate cancer, neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, atherosclerosis, and Paget's disease of bone. In this review, we will discuss the relationship between p62 and these diseases, and we attempt to put forward novel methods for current diagnosis or therapy by regulating the p62 expression level.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02038DOI Listing
September 2020

Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer's Diseases.

Molecules 2020 Jan 23;25(3). Epub 2020 Jan 23.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.

A series of novel compounds -, -, -, and - were synthesized and evaluated, together with the known analogs -, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound showed the strongest inhibitory effect on both AChE (eeAChE IC = 0.39 μM) and BChE (eqBChE IC = 0.28 μM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer's disease (anti-AD) agents. In summary, these data suggest that compound is a promising multipotent agent for the treatment of AD.
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http://dx.doi.org/10.3390/molecules25030489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038160PMC
January 2020

Reasonably activating Nrf2: A long-term, effective and controllable strategy for neurodegenerative diseases.

Eur J Med Chem 2020 Jan 8;185:111862. Epub 2019 Nov 8.

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Food and Pharmaceutical Science College, No.4 Meicheng Road, Huai'an, 223003, PR China. Electronic address:

Neurodegenerative diseases are a variety of debilitating and fatal disorder in central nervous system (CNS). Besides targeting neuronal activity by influencing neurotransmitters or their corresponding receptors, modulating the underlying processes that lead to cell death, such as oxidative stress and mitochondrial dysfunction, should also be emphasized as an assistant strategy for neurodegeneration therapy. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been closely verified to be related to anti-inflammation and oxidative stress, rationally regulating its belonging pathway and activating Nrf2 is emphasized to be a potential treatment approach. There have existed multiple Nrf2 activators with different mechanisms and diverse structures, but those applied for neuro-disorders are still limited. On the basis of research arrangement and compound summary, we put forward the limitations of existing Nrf2 activators for neurodegenerative diseases and their future developing directions in enhancing the blood-brain barrier permeability to make Nrf2 activators function in CNS and designing Nrf2-based multi-target-directed ligands to affect multiple nodes in pathology of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.ejmech.2019.111862DOI Listing
January 2020

SOX9/miR-203a axis drives PI3K/AKT signaling to promote esophageal cancer progression.

Cancer Lett 2020 01 7;468:14-26. Epub 2019 Oct 7.

Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Department of Pathology, Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China. Electronic address:

Deregulation of SOX9 in esophageal cancer has been reported. However, the regulatory mechanisms underlying SOX9 during esophageal squamous cell carcinoma (ESCC) progression remain poorly understood. Here, we independently confirmed the increased SOX9 expression in two ESCC cohorts and its correlation with poor prognosis. We demonstrated that SOX9 was required for maintaining self-renewal, motility, and chemoresistance in vitro and that ectopic expression of SOX9 promoted tumorigenicity in vivo. Screening for potential SOX9-regulated miRNAs revealed that target genes of differentially expressed miRNAs were enriched in the PI3K/AKT signaling pathway and identified the downregulated miR-203a as a candidate. Mechanistically, SOX9 activation caused repression of miR-203a transcription by binding to miR-203a promoter, thus preventing the miR-203a-mediated inhibition of multiple PI3K/AKT/mTOR components, including PIK3CA, AKT2, and RPS6KB1. The association between SOX9 expression and PI3K/AKT/mTOR signaling was further validated in clinical samples. Moreover, rapamycin treatment attenuated the SOX9-mediated malignant phenotypes and potentiated cisplatin-mediated inhibition of tumor growth. Together, these findings uncover a novel activation of the PI3K/AKT pathway by the SOX9/miR-203a axis and define a subgroup of patients who may benefit from targeted therapy.
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http://dx.doi.org/10.1016/j.canlet.2019.10.004DOI Listing
January 2020

Design, synthesis, biological evaluation, and molecular modeling studies of quinoline-ferulic acid hybrids as cholinesterase inhibitors.

Bioorg Chem 2019 12 23;93:103310. Epub 2019 Sep 23.

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China; Jiangsu Food and Pharmaceuticals Science College, Institute of Food and Pharmaceuticals Research, 223005, People's Republic of China. Electronic address:

A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC = 0.62 ± 0.17 μm), and 14 was the most potent inhibitor against BChE (IC = 0.10 ± 0.01 μm). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against HO-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.
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http://dx.doi.org/10.1016/j.bioorg.2019.103310DOI Listing
December 2019

SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma.

Cancer Med 2019 11 27;8(16):7055-7064. Epub 2019 Sep 27.

Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.

Whether SOX2 and ACTL6A/TP63 interact with the Hippo-YAP1 pathway in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and upregulated in ESCC samples. Multiple SOX2 binding peaks in the locus of WWC1, a Hippo-YAP1 regulator, and an inverse correlation between the expression of SOX2 and WWC1 are identified, suggesting direct repression of WWC1 by SOX2. Expression scores of SOX2 are higher in tumors than normal tissues and positively correlated with nuclear YAP1 staining in primary ESCC. Moreover, SOX2 gain-of-function significantly promotes nuclear YAP1 expression in ESCC cells while silencing of SOX2 expression inhibits YAP1 activation. SOX2 overexpression leads to a significant enhancement of cell migration and invasion as well as chemoresistance to cisplatin, whereas knockdown of SOX2 or ectopic expression of WWC1 suppresses the SOX2-induced migration ability and invasive potential. Disruption of this SOX2-WWC1-YAP1 axis could be a therapeutic strategy for SOX2-dependent tumors.
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http://dx.doi.org/10.1002/cam4.2569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853808PMC
November 2019

Discovery, molecular dynamic simulation and biological evaluation of structurally diverse cholinesterase inhibitors with new scaffold through shape-based pharmacophore virtual screening.

Bioorg Chem 2019 11 19;92:103294. Epub 2019 Sep 19.

Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China; Jiangsu Food and Pharmaceutical Science College, Huaian 223003, People's Republic of China. Electronic address:

Designing small molecule inhibitors targeting cholinesterases (ChEs) is considered as an efficient strategy for the treatment of Alzheimer's disease (AD). In the present study, based on a shaped-based pharmacophore (SBP) model that we reported previously, virtual screening was performed on four commercial compound databases, from which eight small molecules containing new structurally scaffolds were retained and evaluated. In general, six of these potential hits were identified to be selective ChEs inhibitors. Three compounds exhibited IC values and K values in micromolar range on acetylcholinesterase (AChE), the most active compound 4 showed IC value of 6.31 ± 2.68 μM and K value of 4.76 μM. Other three compounds displayed IC values and K values in micromolar range on butyrylcholinesterase (BChE) with high target selectivity, the most active compound 1 showed IC value of 3.87 ± 2.48 μM and K value of 1.52 μM. Multiple biological evaluations were performed to determine their cytotoxicity, cyto-protective effects, antioxidant effect as well as druglike properties. These compounds provide new cores for the further design and optimization, with the aim to discover new ChEs inhibitors for the treatment of AD.
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http://dx.doi.org/10.1016/j.bioorg.2019.103294DOI Listing
November 2019

Elevation of pS262-Tau and Demethylated PP2A in Retina Occurs Earlier than in Hippocampus During Hyperhomocysteinemia.

J Alzheimers Dis 2019 ;68(1):367-381

Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.

Hyperhomocysteinemia is an independent risk factor of Alzheimer's disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage.
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http://dx.doi.org/10.3233/JAD-180978DOI Listing
June 2020

Expansion of the scaffold diversity for the development of highly selective butyrylcholinesterase (BChE) inhibitors: Discovery of new hits through the pharmacophore model generation, virtual screening and molecular dynamics simulation.

Bioorg Chem 2019 04 21;85:117-127. Epub 2018 Dec 21.

Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China. Electronic address:

Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer's disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC values in sub-micromolar range on eqBChE and three displayed IC values < 2 μM on huBChE. The diverse scaffolds of the active compounds provided good starting point further development of selective BChE inhibitors. As far as we concerned, here we disclose the first selective pharmacophore model targeting BChE. The high rate of the model in the identification of active hits indicates it is a valuable tool for the development of selective BChE inhibitors, which may benefit the treatment of AD.
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http://dx.doi.org/10.1016/j.bioorg.2018.12.023DOI Listing
April 2019

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol.

Cell Res 2019 02 17;29(2):151-166. Epub 2018 Dec 17.

Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, 250021, Jinan, Shandong, China.

Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.
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http://dx.doi.org/10.1038/s41422-018-0123-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355920PMC
February 2019

Opposing Effects of PPARα Agonism and Antagonism on Refractive Development and Form Deprivation Myopia in Guinea Pigs.

Invest Ophthalmol Vis Sci 2018 12;59(15):5803-5815

School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Purpose: To determine if drug-induced peroxisome proliferator-activated receptor α (PPARα) signal pathway modulation affects refractive development and myopia in guinea pigs.

Methods: Pigmented guinea pigs were randomly divided into normal vision (unoccluded) and form deprivation myopia (FDM) groups. Each group received daily peribulbar injections of either a vehicle or (1) PPARα agonist, GW7647, clofibrate, or bezafibrate or (2) PPARα antagonist, GW6471, for 4 weeks. Baseline and posttreatment refraction and ocular biometric parameters were measured. Immunofluorescent staining of PPARα and two of its downstream readouts, cytosolic malic enzyme 1 (ME1) and apolipoproteinA II (apoA-II), was undertaken in selected scleral sections. Western blot analysis determined collagen type I expression levels.

Results: GW6471 induced a myopic shift in unoccluded eyes, but had no effect on form-deprived eyes. Conversely, GW7647 inhibited FDM progression without altering unoccluded eyes. Bezafibrate and clofibrate had effects on refraction similar to those of GW7647 in unoccluded and form-deprived eyes. GW6471 downregulated collagen type I expression in unoccluded eyes whereas bezafibrate inhibited collagen type I decreases in form-deprived eyes. GW6471 also reduced the density of ME1- and apoA-II-stained cells in unoccluded eyes whereas bezafibrate increased apoA-II-positive cell numbers in form-deprived eyes.

Conclusions: As GW7647 and GW6471 had opposing effects on myopia development, PPARα signaling modulation may be involved in this condition in guinea pigs. Fibrates are potential candidates for treating myopia since they reduced both FDM and the associated axial elongation. Bezafibrate also inhibited form deprivation-induced decreases in scleral collagen type I expression and the density of apoA-II expressing cells.
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http://dx.doi.org/10.1167/iovs.17-22297DOI Listing
December 2018
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