Publications by authors named "Shijun Wang"

210 Publications

Cryptotanshinone Inhibits ERα-Dependent and -Independent BCRP Oligomer Formation to Reverse Multidrug Resistance in Breast Cancer.

Front Oncol 2021 22;11:624811. Epub 2021 Apr 22.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.

Both long-term anti-estrogen therapy and estrogen receptor-negative breast cancer contribute to drug resistance, causing poor prognosis in breast cancer patients. Breast cancer resistance protein (BCRP) plays an important role in multidrug resistance. Here, we show that cryptotanshinone (CPT), an anti-estrogen compound, inhibited the oligomer formation of BCRP on the cell membrane, thus blocking its efflux function. The inhibitory effect of CPT on BCRP was dependent on the expression level of estrogen receptor α (ERα) in ERα-positive breast cancer cells. Furthermore, ERα-negative breast cancer cells with high expression of BCRP were also sensitive to CPT because CPT was able to bind to BCRP and inhibit its oligomer formation on the cell membrane, suggesting that the high level of BCRP expression is crucial for CPT to reverse drug resistance. The combination of CPT and chemotherapeutic agents displayed enhanced anticancer effects. The results suggest that CPT is a novel BCRP inhibitor blocking the oligomer formation of BCRP on the cell membrane. CPT is able to inhibit the activity of BCRP in an ERα-dependent and -independent manner, sensitizing breast cancer cells to chemotherapy.
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http://dx.doi.org/10.3389/fonc.2021.624811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100513PMC
April 2021

Fluorescence live cell imaging revealed wogonin targets mitochondria.

Talanta 2021 Aug 23;230:122328. Epub 2021 Mar 23.

Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, People's Republic of China; University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China; Basic Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China; National Centre for Mass Spectrometry in Beijing, China. Electronic address:

Scutellaria baicalensis is one of the widely used Chinese traditional medicines, and wogonin is one of major active components in it. However, the mechanism of action of wogonin has largely remained unclear. In this work, we designed a fluorescent probe, namely ATTO565-WGN, by conjugating wogonin with the fluorophore ATTO565 based on Mannich reaction via a flexible chain linker. In vitro assays verified that the ATTO565-WGN conjugate has a similar anti-proliferative activity to wogonin against human A549 and HeLa cancer cell lines. Combining co-localization and competition studies, confocal fluorescence imaging clearly demonstrated that the fluorescent wogonin probe predominantly located in mitochondrial area of living cells, indicating that wogonin acts at mitochondrion to exert its pharmacological functions. Significantly, the conjugated ATTO565 fluorophore conferred the wogonin probe STED (Stimulated Emission Depletion) feature, enabling STED fluorescence living cell imaging with a 55 nm of ultrahigh spatial resolution. This will greatly beneficial for the in situ investigation of interactions between wogonin and biological targets at the finely organized and dynamic mitochondria of living cells. Moreover, this work also provides novel insights into rational design of mitochondrion targeting fluorescence probes for ultrahigh resolution living cell imaging.
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http://dx.doi.org/10.1016/j.talanta.2021.122328DOI Listing
August 2021

Caspase-1 Abrogates the Salutary Effects of Hypertrophic Preconditioning in Pressure Overload Hearts via IL-1β and IL-18.

Front Mol Biosci 2021 24;8:641585. Epub 2021 Mar 24.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Cardiac hypertrophic preconditioning (HP) signifies cardioprotection induced by transient pressure overload to resist hypertrophic effects of subsequently sustained pressure overload. Although it is recently found that inflammation triggers the development of nonischemic cardiomyopathy, whether inflammation plays a role in the antecedent protective effects of HP remains unknown. Caspase-1 is a critical proinflammatory caspase that also induces pyroptosis; thus, we investigated the role of caspase-1 using a unique model of HP in mice subjected longitudinally to 3 days of transverse aortic constriction (TAC 3d), 4 days of de-constriction (De-TAC 4d), and 4 weeks of Re-TAC (Re-TAC 4W). Echocardiography, hemodynamics, histology, PCR, and western blot confirmed preserved cardiac function, alleviated myocardial hypertrophy and fibrosis, and less activated hypertrophic signaling effectors in Re-TAC 4W mice, compared with TAC 4W mice. Mechanistically, caspase-1 and its downstream targets IL-1β and IL-18, but not GSDMD, were less activated in Re-TAC 4W mice. Furthermore, in HP mice with AAV-9-mediated cardiac-specific caspase-1 overexpression, the salutary effects of HP were remarkably abrogated, as evidenced by exacerbated cardiac remodeling, dysfunction, and activation of IL-1β and IL-18. Collectively, this study revealed a previously unrecognized involvement of caspase-1 in cardiac HP by regulation of IL-1β and IL-18 and shed light on caspase-1 as an antecedent indicator and target for cardiac hypertrophy.
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http://dx.doi.org/10.3389/fmolb.2021.641585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024560PMC
March 2021

20()-ginsenoside Rh2 induces caspase-dependent promyelocytic leukemia-retinoic acid receptor A degradation in NB4 cells via Akt/Bax/caspase9 and TNF-α/caspase8 signaling cascades.

J Ginseng Res 2021 Mar 15;45(2):295-304. Epub 2020 May 15.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, PR China.

Background: Acute promyelocytic leukemia (APL) is a hematopoietic malignancy driven by promyelocytic leukemia-retinoic acid receptor A (PML-RARA) fusion gene. The therapeutic drugs currently used to treat APL have adverse effects. 20()-ginsenoside Rh2 (GRh2) is an anticancer medicine with high effectiveness and low toxicity. However, the underlying anticancer mechanisms of GRh2-induced PML-RARA degradation and apoptosis in human APL cell line (NB4 cells) remain unclear.

Methods: Apoptosis-related indicators and PML-RARA expression were determined to investigate the effect of GRh2 on NB4 cells. Z-VAD-FMK, LY294002, and C 87, as inhibitors of caspase, and the phosphatidylinositol 3-kinase (PI3K) and tumor necrosis factor-α (TNF-α ) pathways were used to clarify the relationship between GRh2-induced apoptosis and PML-RARA degradation.

Results: GRh2 dose- and time-dependently decreased NB4 cell viability. GRh2-induced apoptosis, cell cycle arrest, and caspase3, caspase8, and caspase9 activation in NB4 cells after a 12-hour treatment. GRh2-induced apoptosis in NB4 cells was accompanied by massive production of reactive oxygen species, mitochondrial damage and upregulated Bax/Bcl-2 expression. GRh2 also induced PML/PML-RARA degradation, PML nuclear bodies formation, and activation of the downstream p53 pathway in NB4 cells. Z-VAD-FMK inhibited caspase activation and significantly reversed GRh2-induced apoptosis and PML-RARA degradation. GRh2 also upregulated TNF-α expression and inhibited Akt phosphorylation. LY294002, an inhibitor of the PI3K pathway, enhanced the antitumor effects of GRh2, and C 87, an inhibitor of the TNF-α pathway, reversed NB4 cell viability, and GRh2-mediated apoptosis in a caspase-8-dependent manner.

Conclusion: GRh2 induced caspase-dependent PML-RARA degradation and apoptosis in NB4 cells via the Akt/Bax/caspase9 and TNF-α/caspase8 pathways.
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http://dx.doi.org/10.1016/j.jgr.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020289PMC
March 2021

Coix lacryma-jobi Seed Oil Reduces Fat Accumulation in Nonalcoholic Fatty Liver Disease by Inhibiting the Activation of the p-AMPK/SePP1/apoER2 Pathway.

J Oleo Sci 2021 May 12;70(5):685-696. Epub 2021 Apr 12.

Shandong University of Traditional Chinese Medicine.

The lipid metabolism disorder is the key role of Nonalcoholic fatty liver disease (NAFLD). Selenoprotein P plays an important role in the pathological process of lipid accumulation. Coix lacryma-jboi seed oil (CLSO) is an active component extracted from Coix lacryma-jobi seed (CLS) which has been found to be effective of reducing blood fat and antioxidative. But the effect and mechanism of CLSO on NAFLD are not clear. The aim of this study was to explore the therapeutic effect and mechanism of CLSO in the treatment of NAFLD. Our result showed that CLSO decreased the liver/body weight ratio, lowered the total cholesterol (TC) and triacylglycerol (TG), and elevated the high density lipoprotein (HDL) in serum. CLSO reduced the lipid deposition in the liver of NAFLD rats. In addition, CLSO could bring down the abnormal expression of superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, CLSO significantly declined the liver apolipoprotein E (apoE), apolipoprotein E receptor (apoER) and selenoprotein P 1 (SePP1) expression. In vivo, CLSO decreased the lipid droplets and TG level, reduced the protein expression of SePP1, apoER, phosphor-adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK) in the cytoplasm of HepG2 cells induced by oleic acid and palmitic acid (OP). At the same time, lipid accumulation was observed in the Sepp1 high expression cells induced by endoplasmic reticulum (ER) activator tunicamycin (Tm). CLSO could identically reduce the protein expression of SePP1, apoER, p-AMPK in the cytoplasm of HepG2 cells induced by Tm. This result not only proved the CLSO had therapeutic effect on NAFLD, but also confirmed its mechanism associated with degrading the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) which led to the decrease of the expression SePP1/apoER2 in order to reduce lipid accumulation. The study suggests CLSO has great medicinal value in treating NAFLD besides its edibility.
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http://dx.doi.org/10.5650/jos.ess20255DOI Listing
May 2021

Ancient noeggerathialean reveals the seed plant sister group diversified alongside the primary seed plant radiation.

Proc Natl Acad Sci U S A 2021 Mar 8;118(11). Epub 2021 Mar 8.

Indiana Geological and Water Survey, Bloomington, IN 47404;

Noeggerathiales are enigmatic plants that existed during Carboniferous and Permian times, ∼323 to 252 Mya. Although their morphology, diversity, and distribution are well known, their systematic affinity remained enigmatic because their anatomy was unknown. Here, we report from a 298-My-old volcanic ash deposit, an in situ, complete, anatomically preserved noeggerathialean. The plant resolves the group's affinity and places it in a key evolutionary position within the seed plant sister group. sp. nov. is a small tree producing gymnospermous wood with a crown of pinnate, compound megaphyllous leaves and fertile shoots each with Ω-shaped vascular bundles. The heterosporous (containing both microspores and megaspores), bisporangiate fertile shoots appear cylindrical and cone-like, but their bilateral vasculature demonstrates that they are complex, three-dimensional sporophylls, representing leaf homologs that are unique to Noeggerathiales. The combination of heterospory and gymnospermous wood confirms that , and thus the Noeggerathiales, are progymnosperms. Progymnosperms constitute the seed plant stem group, and extends their range 60 My, to the end of the Permian. Cladistic analysis resolves the position of the Noeggerathiales as the most derived members of a heterosporous progymnosperm clade that are the seed plant sister group, altering our understanding of the relationships within the seed plant stem lineage and the transition from pteridophytic spore-based reproduction to the seed. Permian Noeggerathiales show that the heterosporous progymnosperm sister group to seed plants diversified alongside the primary radiation of seed plants for ∼110 My, independently evolving sophisticated cone-like fertile organs from modified leaves.
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http://dx.doi.org/10.1073/pnas.2013442118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980368PMC
March 2021

The Association between Five Genetic Variants in MicroRNAs (rs2910164, rs11614913, rs3746444, rs11134527, and rs531564) and Cervical Cancer Risk: A Meta-Analysis.

Biomed Res Int 2021 15;2021:9180874. Epub 2021 Mar 15.

Department of Obstetrics and Gynecology, Xuanwu Hospital, Capital Medical University, Beijing, China.

The objective of this study was to conduct a meta-analysis to systematically summarize and investigate the association of miRNA-124 rs531564, miRNA-218 rs11134527, miRNA-146a rs2910164, miRNA-196a2 rs11614913, and miRNA-499 rs3746444 polymorphisms with cervical cancer. A systematic review was performed to identify relevant studies using Embase and PubMed databases. A chi-square-based -test combined with the inconsistency index () was used to check the heterogeneity between studies. A total of six case-control studies on rs2910164 and rs11614913, 4 studies on rs3746444 and rs11134527, and three studies on rs531564 were included. No evidence of association was found between miR-146a rs2910164, miR-196a2 rs11614913, miRNA-499 rs3746444, and miR-218 rs11134527 polymorphisms and cervical cancer risk in all the genetic models. The miR-124 rs531564 polymorphism was associated with a statistically increased risk of cervical cancer in a homozygote model (CC vs. GG: OR = 2.87, 95% CI: 1.40-5.91, = 0.887), dominant model (GC/CC vs. GG: OR = 1.38, 95% CI: 1.07-1.80, = 0.409), and recessive model (CC vs. GC/GG: OR = 2.26, 95% CI: 1.58-3.23, = 0.979). However, this finding should be interpreted with caution for limited samples and heterogeneity. Large-scale and well-designed studies are needed to validate our result.
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http://dx.doi.org/10.1155/2021/9180874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987420PMC
March 2021

Research progress on the pharmacological effect and clinical application of Tongqiao Huoxue Decoction in the treatment of ischaemic stroke.

Biomed Pharmacother 2021 Jun 10;138:111460. Epub 2021 Mar 10.

College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China. Electronic address:

Ischaemic stroke (IS) is a common type of stroke characterised by sudden fainting and communication disorders, alongside a number of other symptoms. It is characterised by high morbidity, disability, and mortality rates. Tongqiao Huoxue Decoction (THD) is effective in the treatment of stroke. As a representative prescription for promoting blood circulation and removing blood stasis, THD has been widely used clinically. This paper systematically introduces clinical and experimental studies of THD in the treatment of IS, summarising its clinical application, pharmacological mechanisms, and active components in the treatment of IS. It also explores its key pathways in the treatment of IS through network pharmacology analyses, thereby speculating on its underlying mechanisms. It is of great significance for the secondary development of this classic prescription as well as for the research and development of new drugs.
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http://dx.doi.org/10.1016/j.biopha.2021.111460DOI Listing
June 2021

ShengMai-San Attenuates Cardiac Remodeling in Diabetic Rats by Inhibiting NOX-Mediated Oxidative Stress.

Diabetes Metab Syndr Obes 2021 11;14:647-657. Epub 2021 Feb 11.

College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China.

Background And Purpose: ShengMai-San (SMS) is traditionally used to treat ischemic cardiovascular and cerebrovascular diseases. Recently, several studies have reported the cardioprotective effects of SMS in diabetic animals. However, the potential mechanisms have not yet been fully elucidated. In this study, we investigated whether SMS exerts a beneficial effect in diabetic cardiomyopathy (DCM) by alleviating NADPH oxidase (NOX)-mediated oxidative stress.

Methods: SD rats were randomly divided into a negative control group (NC), diabetes mellitus group (DM) and SMS-treated group (SMS). The myocardial structure alterations, apoptosis and biomarkers of oxidative stress were observed. Moreover, to explore the protective mechanism of SMS, the activation of AMPKα, expression and translocation of NOX-related proteins were assessed.

Results: Diabetes led to excessive collagen content, fibrosis, and apoptosis in the myocardium. Oxidative stress in diabetic hearts was indicated by low levels of T-AOC, high levels of 8-iso-PGF2α and 8-OHdG, inactivation of AMPKα, elevated expression of NOX2 and NOX4 and translocation of NOX isoforms p47phox and p67phox. Treatment with SMS for 10 weeks resulted in the alleviation of diabetes-associated myocardial structure abnormalities and apoptosis. Additionally, SMS attenuated the accumulation of oxidative stress markers in myocardial tissue. Further investigation showed that SMS was able to reverse the levels of oxidative stress-associated proteins NOX2 and NOX4 in the DM rats. Moreover, SMS treatment blunted the translocation of NADPH oxidase isoforms p47phox and p67phox as well. Furthermore, SMS promoted the activation of AMPK in the cardiac tissue of diabetic rats.

Conclusion: These findings indicate that SMS exhibits therapeutic properties against diabetic cardiomyopathy by attenuating myocardial oxidative damage via activation of AMPKα and inhibition of NOX signaling.
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http://dx.doi.org/10.2147/DMSO.S287582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884944PMC
February 2021

Depression with Comorbid Diabetes: What Evidence Exists for Treatments Using Traditional Chinese Medicine and Natural Products?

Front Pharmacol 2020 25;11:596362. Epub 2021 Jan 25.

Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, China.

Comorbidity between diabetes mellitus (DM) and depression, two chronic and devastating diseases spreading worldwide, has been confirmed by a large body of epidemiological and clinical studies. Due to the bidirectional relationship between DM and depression, this comorbidity leads to poorer outcomes in both conditions. Given the adverse effects and limited effectiveness of the existing therapies for depression associated with diabetes, the development of novel therapeutic drugs with more potency and fewer side effects is still the most important goal. Hence, many researchers have made great efforts to investigate the potential usefulness of traditional Chinese medicine (TCM) and natural products, including natural extracts and purified compounds, in the treatment of comorbid depression in diabetes. Here, we reviewed the related literature on TCM and natural products that can remedy the comorbidity of diabetes and depression and presented them on the basis of their mechanism of action, focusing on shared risk factors, including insulin resistance, oxidative stress and inflammation, and nervous disturbances. In short, this review suggests that TCM and natural products could expand the therapeutic alternatives to ameliorate the association between DM and depressive disorders.
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http://dx.doi.org/10.3389/fphar.2020.596362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868339PMC
January 2021

High-strength scalable graphene sheets by freezing stretch-induced alignment.

Nat Mater 2021 May 4;20(5):624-631. Epub 2021 Feb 4.

School of Chemistry, Key Laboratory of Bio-inspired Smart Interfacial Science and Technology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, China.

Abstracct: Efforts to obtain high-strength graphene sheets by near-room-temperature assembly have been frustrated by the misalignment of graphene layers, which degrades mechanical properties. While in-plane stretching can decrease this misalignment, it reappears when releasing the stretch. Here we use covalent and π-π inter-platelet bridging to permanently freeze stretch-induced alignment of graphene sheets, and thereby increase isotropic in-plane sheet strength to 1.55 GPa, in combination with a high Young's modulus, electrical conductivity and weight-normalized shielding efficiency. Moreover, the stretch-bridged graphene sheets are scalable and can be easily bonded together using a commercial resin without appreciably decreasing the performance, which establishes the potential for practical applications.
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http://dx.doi.org/10.1038/s41563-020-00892-2DOI Listing
May 2021

Somatically acquired mutations in primary myelofibrosis: A case report and meta-analysis.

Exp Ther Med 2021 Mar 7;21(3):193. Epub 2021 Jan 7.

Medical Genetics Center, School of Medicine at Ningbo University, Ningbo, Zhejiang 315211, P.R. China.

Familial myeloproliferative disease (MPD) cases account for 7.6% of the global MPD cases. The present study reported 2 cases of primary myelofibrosis (PMF). The patients were two sisters; the older sister succumbed to the disease at the age of 37, whereas the younger sister maintained a stable disease status and gave birth to a son through fertilization. Genetic analysis of bone marrow DNA samples showed that both sisters carried a Janus kinase 2 (JAK2) V617F mutation, and the older sister also had a trisomy 8 chromosomal abnormality (47, XX, +8). A systematic literature search was also performed using PubMed, CNKI and Wanfang databases, to determine the association between JAK2 and PMF. Following comprehensive screening of the published literature, 19 studies were found to be eligible for the current meta-analysis. The results showed that JAK2 V617F was a risk factor of PMF, and no sex dimorphism was observed in JAK2 V617F mutation prevalence amongst all PMF cases. In addition, there was a lack of association between the JAK2 V617F mutation and PMF-related mortality.
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http://dx.doi.org/10.3892/etm.2021.9625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812576PMC
March 2021

Variations in Energy Metabolism Precede Alterations in Cardiac Structure and Function in Hypertrophic Preconditioning.

Front Cardiovasc Med 2020 11;7:602100. Epub 2020 Dec 11.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Recent studies have unveiled that myocardial hypertrophic preconditioning (HP), which is produced by de-banding (De-TAC) of short-term transverse aortic constriction (TAC), protects the heart against hypertrophic responses caused by subsequent re-constriction (Re-TAC) in mice. Although cardiac substrate metabolism is impaired in heart failure, it remains unclear about the role of HP-driven energetics in the development of cardiac hypertrophy. Here, we investigated energy metabolism, cardiac hypertrophy, and function following variational loading conditions, as well as their relationships in HP. Male C57BL/6J mice (10-12 weeks old) were randomly subjected to Sham, HP [TAC for 3days (TAC 3d), de-banding the aorta for 4 days (De-TAC 4d), and then re-banding the aorta for 4 weeks (Re-TAC 4W)], and TAC (TAC for 4 weeks without de-banding). Cardiac echocardiography, hemodynamics, and histology were utilized to evaluate cardiac remodeling and function. The mRNA expression levels of fetal genes ( and ), glucose metabolism-related genes (), and fatty acid oxidation-related genes (α, α) were quantitated by real-time quantitative PCR. Activation of hypertrophy regulators ERK1/2, a metabolic stress kinase AMP-activated protein kinase (AMPK), and its downstream target acetyl-coA carboxylase (ACC) were explored by western blot. Compared with TAC 4W mice, Re-TAC 4W mice showed less impairment in glucose and fatty acid metabolism, as well as less cardiac hypertrophy and dysfunction. Moreover, no significant difference was found in myocardial hypertrophy, fibrosis, and cardiac function in TAC 3d and De-TAC 4d groups compared with Sham group. However, α, , and α were all decreased, while AMPK and ACC were activated in TAC 3d and returned to Sham level in De-TAC 4d, suggesting that the change in myocardial energy metabolism in HP mice was earlier than that in cardiac structure and function. Collectively, HP improves energy metabolism and delays cardiac remodeling, highlighting that early metabolic improvements drive a potential beneficial effect on structural and functional restoration in cardiac hypertrophy.
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http://dx.doi.org/10.3389/fcvm.2020.602100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793816PMC
December 2020

Critical role of mTOR in regulating aerobic glycolysis in carcinogenesis (Review).

Int J Oncol 2021 Jan 25;58(1):9-19. Epub 2020 Nov 25.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.

Mammalian target of rapamycin (mTOR) serves an important role in regulating various biological processes, including cell proliferation, metabolism, apoptosis and autophagy. Among these processes, energy metabolism is the dominant process. The metabolism of not only amino acids, fatty acids and lipids, but also that of nucleotides and glucose has been indicated to be regulated by mTOR. Aerobic glycolysis, which is a specific form of glucose metabolism, is prevalent in carcinomas, and it has been considered to be a potential target for cancer therapy. In reviewing the complexity of the mTOR pathway, it is important to elucidate the central role and detailed pathway via which mTOR regulates glycolysis. In the present study, the complex mechanisms via which mTOR regulates aerobic glycolysis were comprehensively reviewed to highlight the potential of drug development via targeting the molecules associated with mTOR and glycolysis and to further provide strategies for the clinical treatment of cancer.
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http://dx.doi.org/10.3892/ijo.2020.5152DOI Listing
January 2021

Curcumol inhibits KLF5-dependent angiogenesis by blocking the ROS/ERK signaling in liver sinusoidal endothelial cells.

Life Sci 2021 Jan 4;264:118696. Epub 2020 Nov 4.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address:

Aims: Liver fibrosis is a difficult problem in the medical field. We previously reported that curcumol, a bioactive substance, may inhibit the pathological angiogenesis of liver sinusoidal endothelial cells (LSECs) and play a good anti-hepatic fibrosis effect. However, the mechanism of curcumol inhibiting angiogenesis in LSEC needs to be further clarified. Here, we focus on how curcumol inhibits LSEC angiogenesis in liver fibrosis.

Materials And Methods: Primary rat LSECs were cultured in vitro, and various molecular experiments including real-time PCR, western blot, immunofluorescence, tube formation assay and transwell migration assay were used to clarify the potential mechanism of curcumol. Carbon tetrachloride (CCl) was applied to create a mouse liver fibrosis model. Blood and livers were taken to elucidate the efficacy of curcumol in vivo.

Key Findings: We found that curcumol could effectively inhibit LSEC angiogenesis in vitro. Interestingly, this process may depend on curcumol's inhibition of the expression of transcription factor KLF5. Mice experiment also showed that curcumol could alleviate chronic liver injury by reducing KLF5 expression. In addition, we suggested that curcumol could reduce the production of mitochondrial ROS and improve mitochondrial morphology in LSEC. More importantly, we proved that curcumol could suppress KLF5-mediated LSEC angiogenesis by inhibiting ROS/ERK signaling.

Significance: We suggested that transcription factor KLF5 could be considered as a new target molecule of curcumol in improving liver fibrosis, and pointed out that curcumol targeted ROS/ERK-mediated KLF5 expression could inhibit LSEC angiogenesis. This provided a new theoretical basis for curcumol to ameliorate liver fibrosis.
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http://dx.doi.org/10.1016/j.lfs.2020.118696DOI Listing
January 2021

Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/β-catenin signalling via interaction with Gli1.

Br J Pharmacol 2021 Jun 14;178(11):2246-2265. Epub 2021 Apr 14.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.

Background And Purpose: Portal hypertension is a lethal complication of cirrhosis. Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications.

Experimental Approach: Liver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC-LX2 cells using real-time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation and site-directed mutagenesis.

Key Results: Wnt/β-catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo-independent Gli1 nuclear translocation followed by LARG-mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a-induced Gli1 nuclear translocation. Wnt/β-catenin repressed transcription of Sufu dependent on β-catenin/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site-directed mutagenesis identified the β-catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short-term liver-targeting β-catenin deficiency or acute treatment with β-catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long-term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation.

Conclusion And Implications: Interaction between Wnt/β-catenin and Smo-independent Gli1 pathways promoted HSC contraction via TCF4-dependent transrepression of Sufu. HSC-specific inhibition of β-catenin may have therapeutic benefits for cirrhotic portal hypertension.
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http://dx.doi.org/10.1111/bph.15289DOI Listing
June 2021

From the perspective of Traditional Chinese Medicine: Treatment of mental disorders in COVID-19 survivors.

Biomed Pharmacother 2020 Dec 30;132:110810. Epub 2020 Sep 30.

Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China. Electronic address:

Purpose: The aim of this study is to explore the possible benefits of traditional Chinese medicine on the pathogenesis of psychological and mental health of COVID-19 survivors.

Methods: A literature search was conducted to confirm the effects of COVID-19 on psychological and mental health of survivors. In addition to this, on the basis of signs and symptoms, TCM were used on treat mental disorder as per suggested clinical and animal experimental data plus relevant records in classical Chinese medicine books written by Zhang Zhongiing during Han Dynasty. A series of treatment plans were prescribed for COVID-19 survivors with psychological and mental disorders.

Results: According to previous extensive studies focusing on effects on mental health of survivors, high incidence was observed in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) survivors. During investigations of mental health of COVID-19 patients and survivors, it is observed that they also had symptoms of mental disorders and immune dysfunction. Furthermore, it was also proposed that depression, anxiety and post-traumatic stress disorder (PTSD) were most common mental disorders requiring special attention after the recovery from COVID-19. The symptoms of COVID-19 were analyzed, and the TCM syndrome of the depression, anxiety and PTSD after recovered from COVID19 was interpreted as internal heat and Yin deficiency. These three mental disorders pertains the category of "Lily disease", "hysteria" and "deficient dysphoria" in TCM.

Conclusion: Lily Bulb, Rhizoma Anemarrhena Decoction and Ganmai Dazao Decoction were used to treat depression. Suanzaoren Decoction, Huanglian Ejiao Decoction and Zhizi Chi Decoction were suggested for anxiety. Moreover, Lily Bulb, Rehmannia Decoction and Guilu Erxian Decoction were the formula for PTSD.
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http://dx.doi.org/10.1016/j.biopha.2020.110810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524684PMC
December 2020

Novel copper complex CTB regulates methionine cycle induced TERT hypomethylation to promote HCC cells senescence via mitochondrial SLC25A26.

Cell Death Dis 2020 10 11;11(10):844. Epub 2020 Oct 11.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.

Related research has recognized the vital role of methionine cycle metabolism in cancers. However, the role and mechanism of methionine cycle metabolism in hepatocellular carcinoma are still unknown. In this study, we found that [Cu(ttpy-tpp)Br]Br (Referred to as CTB) could induce hepatocellular carcinoma cells senescence, which is a new copper complex synthesized by our research group. Interestingly, CTB induces senescence by inhibiting the methionine cycle metabolism of HCC cells. Furthermore, the inhibitory effect of CTB on the methionine cycle depends on mitochondrial carrier protein SLC25A26, which was also required for CTB-induced HCC cells senescence. Importantly, we found that CTB-induced upregulation of SLC25A26 could cause abnormal methylation of TERT and inhibited TERT expression, which is considered to be an essential cause of cell senescence. The same results were also obtained in vivo, CTB inhibits the growth of subcutaneously implanted tumors in nude mice and promoted the expression of senescence markers in tumor tissues, and interference with SLC25A26 partially offset the antitumor effect of CTB.
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http://dx.doi.org/10.1038/s41419-020-03048-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548283PMC
October 2020

Iron regulatory protein 2 is required for artemether -mediated anti-hepatic fibrosis through ferroptosis pathway.

Free Radic Biol Med 2020 11 15;160:845-859. Epub 2020 Sep 15.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address:

Background: Currently, the existing treatments have not cured the liver fibrosis thoroughly. Ferroptosis is a newly discovered way of cell death, which is closely related to many diseases. Previous studies have shown that ferroptosis plays an important role in the occurrence and development of liver fibrosis, but the further mechanism remains to be discovered.

Methods: LX-2 cells were used as the research object, fibrosis activation index was detected by Western blot, PCR and Immunofluorescence, ferroptosis was detected by kits, the binding and interaction between IRP2 (iron regulatory protein 2) and STUB1 (STIP1 homology and U-box containing protein 1) were detected by Immunoprecipitation and ubiquitin test, and IRP2 knockdown mice were constructed by interfering plasmid to verify the results of in vitro experiment.

Result: Our research showed that ART (artemether) had a good anti-fibrosis effect in vivo and in vitro, and ferroptosis played an important role in this process. Further studies have found that ART could lead to the accumulation of IRP 2 a in hepatic stellate cell by inhibiting the ubiquitination of it, thus inducing the increase of iron in HSC (hepatic stellate cell), which could product a large number of ROS (reactive oxide species), resulting the occurrence of ferroptosis in cells. Our findings provided an experimental basis for ART to become a drug for the treatment of liver fibrosis.

Conclusion: Our results show that IRP2-Iron-ROS axis is necessary for ART to induce ferroptosis in HSC and play an anti-fibrotic effect.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.09.008DOI Listing
November 2020

The expression of intracellular cytokines of decidual natural killer cells in unexplained recurrent pregnancy loss.

J Matern Fetal Neonatal Med 2020 Sep 9:1-7. Epub 2020 Sep 9.

Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Objective: This study aims to investigate the expression levels of TNF-α, IFN-γ, IL-4, and IL-10 in dNK cells and determine whether or not the MAPK signal pathway is involved in the regulation of cytokine secretion by dNK cells at the maternal-fetal interface.

Methods: In this study, we collected decidua specimens from patients with apparently normal pregnant and unexplained recurrent pregnancy loss (URPL) and extracted dNK cells by enzymatic digestion. Then the expression of cytokines were analyzed by flow cytometry and Real-Time PCR respectively.

Results: The secretions of both IFN-γ and TNF-α in dNK cells in URPL were significantly higher than those in normal pregnancy. Furthermore, p38/MAPK inhibitors can inhibit the secretion of four cytokines in normal pregnancy, while in URPL cases, p38/MAPK inhibitors only significantly inhibit the secretion of IL-4 and IFN-γ. ERK inhibitors had no effect on the expression of all four cytokines and JNK/MAPK inhibitors varied on different cytokines.

Conclusion: URPL is associated with a NK1 cytokine profile. MAPK signaling pathway is involved in the regulation of cytokine secretion by decidual NK cells at maternal-fetal interface.
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http://dx.doi.org/10.1080/14767058.2020.1817369DOI Listing
September 2020

The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells.

Redox Biol 2020 09 24;36:101619. Epub 2020 Jun 24.

Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address:

Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis.
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http://dx.doi.org/10.1016/j.redox.2020.101619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330619PMC
September 2020

Super-durable ultralong carbon nanotubes.

Science 2020 08;369(6507):1104-1106

Beijing Key Laboratory of Green Chemical Reaction Engineering and Technology, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China.

Fatigue resistance is a key property of the service lifetime of structural materials. Carbon nanotubes (CNTs) are one of the strongest materials ever discovered, but measuring their fatigue resistance is a challenge because of their size and the lack of effective measurement methods for such small samples. We developed a noncontact acoustic resonance test system for investigating the fatigue behavior of centimeter-long individual CNTs. We found that CNTs have excellent fatigue resistance, which is dependent on temperature, and that the time to fatigue fracture of CNTs is dominated by the time to creation of the first defect.
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http://dx.doi.org/10.1126/science.aay5220DOI Listing
August 2020

Improving diagnostic performance of differentiating ocular adnexal lymphoma and idiopathic orbital inflammation using intravoxel incoherent motion diffusion-weighted MRI.

Eur J Radiol 2020 Sep 25;130:109191. Epub 2020 Jul 25.

Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; Clinical Center for Eye Tumors, Capital Medical University, Beijing 100730, China. Electronic address:

Purpose: To investigate the utility of intravoxel incoherent motion diffusion-weighted MRI (IVIM-DWI) derived diffusion and perfusion parameters in differentiating ocular adnexal lymphoma (OAL) from idiopathic orbital inflammation (IOI), and to assess whether IVIM-DWI provides improved diagnostic performance for the distinction.

Method: Twenty-one patients with OAL and 24 patients with IOI underwent IVIM-DWI. Apparent diffusion coefficient (ADC) and IVIM-DWI parameters including true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) were measured in lesions by two independent radiologists. The MRI parameter differences between OAL and IOI were tested using two-sample t-test. The receiver operating characteristic (ROC) analysis curves were used to determine the diagnostic performance of significant parameters for differentiation between OAL and IOI.

Results: The ADC, D, and f were lower in OAL than those in IOI (ADC = 0.78 ± 0.12 vs. 0.99 ± 0.16 × 10 mm/s, P < 0.001; D = 0.34 ± 0.15 vs. 0.76 ± 0.25 × 10 mm/s, P < 0.001; f = 0.31 ± 0.06 vs. 0.41 ± 0.08 × 100 %, P < 0.001). There was no significant difference in D* between OAL and IOI (P = 0.235). The optimal cut-off values of ADC, D, and f in differentiating OAL from IOI were 0.83 × 10 mm/s, 0.56 × 10 mm/s, and 0.36 × 100 %, respectively. No significant differences were found in areas under the curve (AUCs) among ADC, D and f (all P > 0.05). The combination of D and f provided significantly higher AUC than ADC (AUC = 0.984 vs. 0.838, Z = 2.128, P = 0.033), and had higher sensitivity of 95.24 %, specificity of 95.83 %, and accuracy of 95.56 %.

Conclusions: IVIM-DWI is valuable in differentiating OAL from IOI, and D combined f can improve the performance of differential diagnosis.
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http://dx.doi.org/10.1016/j.ejrad.2020.109191DOI Listing
September 2020

Hierarchical TiCT MXene/Ni Chain/ZnO Array Hybrid Nanostructures on Cotton Fabric for Durable Self-Cleaning and Enhanced Microwave Absorption.

ACS Nano 2020 Jul 9;14(7):8634-8645. Epub 2020 Jul 9.

Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology, Ministry of Education, School of Chemistry, Beihang University, Beijing 100191, China.

The increasing demand for wearable electronics and the intensification of electromagnetic pollution have boosted the exploration of high-performance flexible microwave absorption (MA) materials. Herein, the hierarchical TiCT MXene/Ni chain/ZnO array hybrid nanostructures are rationally constructed on cotton fabric for acquiring enhanced MA performance and durable self-cleaning ability. Based on the high dielectric loss capacity of MXenes and ZnO arrays, by controlling dip-coating numbers of Ni chains, the magnetic loss can be manipulated to modulate the impedance matching, reflection loss (RL), and effective absorption bandwidth (EAB, the bandwidth of RL < -10 dB). The minimum RL value of the designed fabric can reach -35.1 dB at 8.3 GHz with a thickness of 2.8 mm, and its EAB can cover the whole X-band with only a 2.2 mm thickness. In addition, the designed fabric also exhibits superior liquid repellency and durable self-cleaning ability due to the combination of the hybrid nanostructures and a superhydrophobic coating. This work provides an insight for rational design of textile-based MA materials, showing potential applications in flexible and wearable functional electronics.
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http://dx.doi.org/10.1021/acsnano.0c03013DOI Listing
July 2020

Chinese herbal medicine Baoyuan Jiedu decoction inhibits the accumulation of myeloid derived suppressor cells in pre-metastatic niche of lung via TGF-β/CCL9 pathway.

Biomed Pharmacother 2020 Sep 15;129:110380. Epub 2020 Jun 15.

College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China. Electronic address:

Baoyuan Jiedu (BYJD for short) decoction, a traditional Chinese medicine formula, is composed of Astragalus, Ginseng, Aconite root, Honeysuckle, Angelica, Licorice, which has the functions of nourishing qi and blood, enhancing immune function, improving quality of life and prolonging survival time of tumor patients. The present study aimed to investigate the effect and mechanism of BYJD decoction on reversing the pre-metastatic niche. We showed that BYJD decoction could prolong the survival time of 4T1 tumor-bearing mice. Moreover, we found that the BYJD decoction inhibited the formation of lung pre-metastatic niche and inhibited recruitment of myeloid derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and genes expression of TGF-β, Smad2, Smad3, p-Smad2/3, Smad4, CCL9 in the TGF-β/CCL9 signaling pathway were suppressed by BYJD decoction. In line with the above findings, our results confirm that BYJD decoction inhibits the accumulation of MDSC in pre-metastatic niche of lung via TGF-β/CCL9 pathway.
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http://dx.doi.org/10.1016/j.biopha.2020.110380DOI Listing
September 2020

Protective effects of cardiac resynchronization therapy in a canine model with experimental heart failure by improving mitochondrial function: a mitochondrial proteomics study.

J Interv Card Electrophysiol 2020 Jun 2. Epub 2020 Jun 2.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.

Purpose: Cardiac resynchronization therapy (CRT) is well acknowledged as an effective treatment for dyssynchronous heart failure. However, the molecular mechanism is unclear to date. Mitochondrial dysfunction and impaired energetic metabolism are two important mechanisms that lead to heart failure. Therefore, we aim to screen the changes of mitochondria-associated proteins and signaling pathways involved in heart failure and CRT treatment.

Methods: A total of 24 beagle dogs were randomly assigned into control (CON), heart failure (HF), or CRT group. Myocardial mitochondria from the free wall of left ventricle was extracted for isobaric tags for relative and absolute quantitation (iTRAQ) labeling coupled with two-dimensional liquid chromatography tandem mass spectrometry analysis (2DLC-MS/MS).

Results: A total of 2190 proteins were identified, among which 234 proteins were differentially expressed in HF compared with CON group, 151 proteins were differentially expressed in CRT compared with HF group. A total of 192 of the 234 differentially expressed proteins in HF group were changed oppositely by CRT treatment, and 128 of the 151 CRT-induced differentially expressed proteins showed opposite trend of expression to HF/CON. Gene Ontology analysis of the 128 proteins revealed that 16 were localized in mitochondria, 17 were associated with calcium signaling, and 7 could be secreted extracellularly for cell-to-cell signaling. Calpain-1 (CAPN1), which is localized to mitochondria and related to calcium signaling, was upregulated in HF and downregulated after CRT treatment. CRT treatment also improved mitochondrial morphology and function and reduced collagen areas of both interstitial and perivascular fibrosis.

Conclusions: CRT treatment significantly improved cardiac function, reduced myocardial fibrosis, and enhanced mitochondrial function in the failing heart through CAPN1 downregulation.
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http://dx.doi.org/10.1007/s10840-020-00768-0DOI Listing
June 2020

HIF-1α-upregulated lncRNA-H19 regulates lipid droplet metabolism through the AMPKα pathway in hepatic stellate cells.

Life Sci 2020 Aug 20;255:117818. Epub 2020 May 20.

Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address:

Activation of hepatic stellate cells (HSCs) is a central event in the pathogenesis of liver fibrosis and is characterized by the disappearance of lipid droplets. Although the exogenous supplementation of lipid droplet content can effectively reverse the activation of HSCs, the underlying molecular mechanisms are largely unknown. In our current study, we sought to investigate the role of lncRNA-H19 in the process of lipid droplets disappearance and to further examine the underlying molecular mechanisms. We found that the lncRNA-H19 level was increased in CCl-induced fibrotic liver, which activated HSCs. Further research showed that hypoxia inducible factor-1α (HIF-1α) significantly increased lncRNA-H19 expression by binding to the lncRNA-H19 promoter at two hypoxia response element (HRE) sites located at 492-499 and 515-522 bp. Importantly, lncRNA-H19 knockdown markedly inhibited HSC activation and alleviated liver fibrosis, indicating that lncRNA-H19 may be a potential target for anti-fibrosis therapeutic approaches. Moreover, lncRNA-H19 knockdown could reverse the lipid droplet phenotype of activated HSCs, inhibiting the phosphorylated AMPKα-mediated lipid oxidation signaling pathway. The AMPK agonist AICAR promoted AMPKα phosphorylation and abrogated lipid droplets restoration in HSCs transfected with the lncRNA-H19 knockdown plasmid. Experimental molecular analysis showed that lncRNA-H19 triggered AMPKα to interact with LKB1 and resulted in AMPKα phosphorylation, which accelerating lipid droplets degradation and lipid oxidation. Taken together, our results highlighted the role of lncRNA-H19 in the metabolism of lipid droplets in HSCs, and revealed a new molecular target for alleviating liver fibrosis.
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http://dx.doi.org/10.1016/j.lfs.2020.117818DOI Listing
August 2020

Blockade of periostin-dependent migration and adhesion by curcumol via inhibition of nuclear factor kappa B signaling in hepatic stellate cells.

Toxicology 2020 07 25;440:152475. Epub 2020 Apr 25.

Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, China. Electronic address:

Objectives: Curcumol, a guaiane-type sesquiterpenoid hemiketal extracted from the herb Rhizoma Curcumae, exhibits multiple-pharmacological activities. We previously reported that curcumol ameliorated hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. In this study, we aimed to investigate the effect of curcumol on HSC migration and adhesion, and reveal its regulation mechanisms.

Materials And Methods: Cellular viability was determined by Cell Counting Kit-8. Cell migration was detected by boyden chamber and cell scratch experiment. Recombinant human periostin (rh POSTN) and adeno-associated viral (AAV)-GFP-periostin were used to achieve POSTN overexpression in vitro and in vivo, respectively. Nuclear factor kappa B (NF-κB)-p65 overexpression was achieved by using plasmid. ELISA was conducted to detect POSTN level. Immunohistochemistry, qRT-PCR, Western blotting, and immunofluorescence were performed to assess associated factor expression.

Results: Curcumol suppressed HSC migration and adhesion, and reduced the secretion and expression of POSTN. By gain of function POSTN in HSCs, using rh POSTN, we found that the inhibition of HSC migration and adhesion by curcumol depended on the decrease of POSTN. Besides, curcumol protection against chronic CCl-caused hepatic fibrosis could be impaired by POSTN overexpression. Moreover, we showed that curcumol repressed NF-κB signaling and the production of pro-inflammatory factor. Importantly, curcumol down-regulation of POSTN was rescued by knock-in of NF-κB, as well as the inhibition of HSC migration and adhesion.

Conclusion: These findings reveal the molecular mechanism of curcumol-reduced HSC migration and adhesion, by which points to the possibility of using curcumol based on NF-κB dependent POSTN for the treatment of fibrogenesis.
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http://dx.doi.org/10.1016/j.tox.2020.152475DOI Listing
July 2020

Zi Shen Huo Luo Formula Enhances the Therapeutic Effects of Angiotensin-Converting Enzyme Inhibitors on Hypertensive Left Ventricular Hypertrophy by Interfering With Aldosterone Breakthrough and Affecting Caveolin-1/Mineralocorticoid Receptor Colocalization and Downstream Extracellular Signal-Regulated Kinase Signaling.

Front Pharmacol 2020 3;11:383. Epub 2020 Apr 3.

College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.

Left ventricular hypertrophy (LVH) is an important characteristic of hypertensive heart disease. Renin-angiotensin system (RAS) blockers have been shown to be effective drugs for the reversal of LVH. Clinical and experimental studies have shown that Zi Shen Huo Luo Formula (ZSHLF) can improve the efficacy of perindopril in the treatment of hypertensive LVH, but its mechanism is unclear. This study aimed to investigate the possible mechanism to improve the efficacy of perindopril. First, we identified 23 compounds in ZSHLF by ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis, among which ferulic acid, caffeic acid, vanillic acid, berberine, rutin, quercetin, kaempferol, stachydrine, and tiliroside have been reported to reduce blood pressure and exhibit cardioprotective effects. Second, we treated spontaneously hypertensive rats (SHRs) with perindopril and ZSHLF for 12 continuous weeks and found that chronic use of perindopril could increase the aldosterone (ALD) levels and cause aldosterone breakthrough (ABT). ZSHLF combined with perindopril reduced the ALD levels, interfered with ABT, decreased blood pressure, improved left ventricular diastolic dysfunction, and decreased the collagen volume fraction; these effects were superior to those of perindopril alone. In vitro experiments, ALD-induced cardiomyocytes (H9c2 cells) and cardiac fibroblasts were treated with ZSHLF-containing serum, which suppressed ALD-induced cardiomyocyte hypertrophy and cardiac fibroblast proliferation, increased mineralocorticoid receptor (MR) and Cav-1 colocalization and decreased phosphorylated epidermal growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase (pERK) protein expression the cells. In conclusion, ZSHLF can interfere with ABT and affect the pathological role of ALD by affecting MR and Cav-1 interactions and EGFR/ERK signaling pathway. These effects represent a possible mechanism by which ZSHLF improves the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) in hypertensive LVH treatment. However, the major bioactive components or metabolites responsible for the effects and the implications of these findings in patients need further verification.
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http://dx.doi.org/10.3389/fphar.2020.00383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147343PMC
April 2020