Publications by authors named "Wang Wang"

217 Publications

Spinal microglial activation promotes perioperative social defeat stress-induced prolonged postoperative pain in a sex-dependent manner.

Brain Behav Immun 2021 Nov 19;100:88-104. Epub 2021 Nov 19.

Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China. Electronic address:

Prolonged postsurgical pain, which is associated with multiple risk factors in the perioperative stage, is a common medical and social problem worldwide. Suitable animal models should be established to elucidate the mechanisms underlying the perioperative prolonged postsurgical pain. In this study, standard and modified social defeat stress mice models, including chronic social defeat stress (CSDS), chronic nondiscriminatory social defeat stress (CNSDS) and vicarious social defeat stress (VSDS), were applied to explore the effect of perioperative social defeat stress on postsurgical pain in male and female mice. Our results showed that exposure to preoperative CSDS could induce prolonged postsurgical pain in defeated mice regardless of susceptibility or resilience differentiated by the social interaction test. Similar prolongation of incision-induced mechanical hypersensitivity was also observed in both sexes upon exposing to CNSDS or VSDS in the preoperative period. Moreover, we found that using the modified CNSDS or VSDS models at different recovery stages after surgery could still promote abnormal pain without sex differences. Further studies revealed the key role of spinal microglial activation in the stress-induced transition from acute to prolonged postoperative pain in male but not female mice. Together, these data indicate that perioperative social defeat stress is a vital risk factor for developing prolonged postoperative pain in both sexes, but the promotion of stress-induced prolonged postoperative pain by spinal microglial activation is sexually dimorphic in mice.
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http://dx.doi.org/10.1016/j.bbi.2021.11.010DOI Listing
November 2021

Untargeted GC-MS-Based Metabolomics for Early Detection of Colorectal Cancer.

Front Oncol 2021 4;11:729512. Epub 2021 Nov 4.

Department of Anorectal Medicine, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China.

Background: Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers in the world with a 5-year survival rate of approximately 68%. Although researchers accumulated many scientific studies, its pathogenesis remains unclear yet. Detecting and removing these malignant polyps promptly is the most effective method in CRC prevention. Therefore, the analysis and disposal of malignant polyps is conducive to preventing CRC.

Methods: In the study, metabolic profiling as well as diagnostic biomarkers for CRC was investigated using untargeted GC-MS-based metabolomics methods to explore the intervention approaches. In order to better characterize the variations of tissue and serum metabolic profiles, orthogonal partial least-square discriminant analysis was carried out to further identify significant features. The key differences in t-m/z pairs were screened by the S-plot and VIP value from OPLS-DA. Identified potential biomarkers were leading in the KEGG in finding interactions, which show the relationships among these signal pathways.

Results: Finally, 17 tissue and 13 serum candidate ions were selected based on their corresponding retention time, p-value, m/z, and VIP value. Simultaneously, the most influential pathways contributing to CRC were inositol phosphate metabolism, primary bile acid biosynthesis, phosphatidylinositol signaling system, and linoleic acid metabolism.

Conclusions: The preliminary results suggest that the GC-MS-based method coupled with the pattern recognition method and understanding these cancer-specific alterations could make it possible to detect CRC early and aid in the development of additional treatments for the disease, leading to improvements in CRC patients' quality of life.
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http://dx.doi.org/10.3389/fonc.2021.729512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599589PMC
November 2021

Recent Progress in Oleanolic Acid: Structural Modification and Biological Activity.

Curr Top Med Chem 2021 Nov 4. Epub 2021 Nov 4.

Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016. China.

Natural products have been proven as the main source of biologically active compounds, which are potentially useful for drug development. As one of the most studied pentacyclic triterpenes, oleanolic acid (OA) exhibits a broad range of biological activities and serves as a good scaffold for the development of novel derivatives that could be vital in drug discovery for various ailments. Up to now, many of its derivatives with multiple bioactivities have been prepared through chemical modification. This review summarizes the recent reports of OA derivatives (2016-present) and their biological effects and action mechanisms in vitro and in vivo models, and discusses the design of novel and potent derivatives.
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http://dx.doi.org/10.2174/1568026621666211105101231DOI Listing
November 2021

Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants.

Nat Commun 2021 11 2;12(1):6304. Epub 2021 Nov 2.

Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.
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http://dx.doi.org/10.1038/s41467-021-26539-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563728PMC
November 2021

Recent progress in andrographolide derivatization: structural modification and biological activity.

Mini Rev Med Chem 2021 Oct 22. Epub 2021 Oct 22.

Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016. China.

Natural products have remarkable structural diversity and biological characteristics, providing researchers with more possibilities to develop novel drugs for disease therapeutics. Andrographolide, an ent-labdane diterpenoid from traditional Chinese medicines, Andrographis paniculata, exhibits a broad range of biological activities, which has been a hot area of research for several years. Up to now, lots of its derivatives with multiple bioactivities have been prepared through chemical modification. This review summarizes andrographolide derivatives prepared in the last ten years (2006-present), classifies them by different biological activities, and provides some discussion about the design of novel and potent derivatives.
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http://dx.doi.org/10.2174/1389557521666211022150032DOI Listing
October 2021

The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress.

Nat Metab 2021 10 18;3(10):1357-1371. Epub 2021 Oct 18.

Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Key Laboratory of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The multifunctional roles of metabolic enzymes allow for the integration of multiple signals to precisely transduce external stimuli into cell fate decisions. Elevation of 3-phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for de novo serine biosynthesis, is broadly associated with human cancer development; although how PHGDH activity is regulated and its implication in tumorigenesis remains unclear. Here we show that glucose restriction induces the phosphorylation of PHGDH by p38 at Ser371, which promotes the translocation of PHGDH from the cytosol into the nucleus. Concurrently, AMPK phosphorylates PHGDH-Ser55, selectively increasing PHGDH oxidation of malate into oxaloacetate, thus generating NADH. In the nucleus, the altered PHGDH activity restricts NAD level and compartmentally repressed NAD-dependent PARP1 activity for poly(ADP-ribosyl)ation of c-Jun, thereby leading to impaired c-Jun transcriptional activity linked to cell growth inhibition. Physiologically, nuclear PHGDH sustains tumour growth under nutrient stress, and the levels of PHGDH-Ser371 and PHGDH-Ser55 phosphorylation correlate with p38 and AMPK activity, respectively, in clinical human pancreatic cancer specimens. These findings illustrate a previously unidentified nutrient-sensing mechanism with the critical involvement of a non-canonical metabolic effect of PHGDH and underscore the functional importance of alternative PHGDH activity in tumorigenesis.
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http://dx.doi.org/10.1038/s42255-021-00456-xDOI Listing
October 2021

Biomimetic Elastin Fiber Patch in Rat Aorta Angioplasty.

ACS Omega 2021 Oct 28;6(40):26715-26721. Epub 2021 Sep 28.

Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Zhengzhou, Henan 450001, China.

Vascular grafts significantly contribute to advances in vascular surgery, but none of the currently available prosthetic grafts have elastin fibers similar to native arteries. We hypothesized that a novel elastin patch could be produced after a rat decellularized thoracic aorta elastin fiber scaffold is implanted subcutaneously in rats; we tested this novel elastin patch in a rat aortic arterioplasty model. Sprague-Dawley rats (200 g) were used. Rat thoracic aortae were decellularized and sectioned at a thickness of 30 μm. A single elastin fiber scaffold was fabricated as a net (5 × 5 mm), and then a three-layer scaffold was constructed to make a new patch. The hyaluronic acid-sodium alginate (HA/SA) hydrogel was fabricated by reacting sodium SA, HA, and CaCO, and then the hydrogel was added to the patch to secure the elastin fibers. The patches were implanted subcutaneously in rats and harvested at day 14. The elastin patches were then implanted into the same rat's aorta and harvested at day 14; a decellularized rat thoracic aorta (TA) patch was used as a control. Sections of the retrieved patches were stained by immunohistochemistry and immunofluorescence. The elastin fibers could be secured by the hydrogel. After 14 days, the subcutaneously implanted elastin patch was incorporated into the rat tissue, and H&E staining showed that new tissue had formed around the elastin patch with almost no hydrogel left. After implantation into the rat aorta and then retrieval on day 14, H&E staining showed that there was neointima and adventitia formation in both the TA and elastin patch groups. Both patches showed a similar histological structure after implantation, and immunofluorescence showed that there were CD34- and nestin-positive cells in the neointima. In both groups, the endothelial cells expressed the arterial identity markers Ephrin-B2 and dll-4; almost one-third of the cells in the neointima were PCNA-positive with rare cleaved caspase-3-positive cells. We demonstrated a novel approach to making elastin fiber scaffold hydrogel patches (elastin patches) and tested them in a rat aorta arterioplasty model. This patch showed a similar healing process as the decellularized TA patch; it also showed potential applications in large animals and may be a substitute for prosthetic grafts in vascular surgery.
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http://dx.doi.org/10.1021/acsomega.1c04170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515827PMC
October 2021

The application of tissue-engineered fish swim bladder vascular graft.

Commun Biol 2021 10 5;4(1):1153. Epub 2021 Oct 5.

Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Henan, China.

Small diameter (< 6 mm) prosthetic vascular grafts continue to show very low long-term patency, but bioengineered vascular grafts show promising results in preclinical experiments. To assess a new scaffold source, we tested the use of decellularized fish swim bladder as a vascular patch and tube in rats. Fresh goldfish (Carassius auratus) swim bladder was decellularized, coated with rapamycin and then formed into patches or tubes for implantation in vivo. The rapamycin-coated patches showed decreased neointimal thickness in both the aorta and inferior vena cava patch angioplasty models. Rapamycin-coated decellularized swim bladder tubes implanted into the aorta showed decreased neointimal thickness compared to uncoated tubes, as well as fewer macrophages. These data show that the fish swim bladder can be used as a scaffold source for tissue-engineering vascular patches or vessels.
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http://dx.doi.org/10.1038/s42003-021-02696-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492661PMC
October 2021

HIF1α stabilization in hypoxia is not oxidant-initiated.

Elife 2021 10 1;10. Epub 2021 Oct 1.

Burke Neurological Institute, White Plains, New York, United States.

Hypoxic adaptation mediated by HIF transcription factors requires mitochondria, which have been implicated in regulating HIF1α stability in hypoxia by distinct models that involve consuming oxygen or alternatively converting oxygen into the second messenger peroxide. Here, we use a ratiometric, peroxide reporter, HyPer to evaluate the role of peroxide in regulating HIF1α stability. We show that antioxidant enzymes are neither homeostatically induced nor are peroxide levels increased in hypoxia. Additionally, forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Moreover, decrease in lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD, failed to influence HIF1α protein stability. These data show that mitochondrial, cytosolic or lipid ROS were not necessary for HIF1α stability, and favor a model where mitochondria contribute to hypoxic adaptation as oxygen consumers.
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http://dx.doi.org/10.7554/eLife.72873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530508PMC
October 2021

IL-17 stimulates neutrophils to release S100A8/A9 to promote lung epithelial cell apoptosis in Mycoplasma pneumoniae-induced pneumonia in children.

Biomed Pharmacother 2021 Nov 22;143:112184. Epub 2021 Sep 22.

Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China. Electronic address:

Mycoplasma pneumoniae-induced pneumonia (MPP) is a common cause of community-acquired respiratory tract infections, increasing risk of morbidity and mortality, in children. However, diagnosing early-stage MPP is difficult owing to the lack of good diagnostic methods. Here, we examined the protein profile of bronchoalveolar lavage fluid (BALF) and found that S100A8/A9 was highly expressed. Enzyme-linked immunosorbent assays used to assess protein levels in serum samples indicated that S100A8/A9 concentrations were also increased in serum obtained from children with MPP, with no change in S100A8/A9 levels in children with viral or bacterial pneumonia. In vitro, S100A8/A9 treatment significantly increased apoptosis in a human alveolar basal epithelial cell line (A549 cells). Bioinformatics analyses indicated that up-regulated S100A8/A9 proteins participated in the interleukin (IL)-17 signaling pathway. The origin of the increased S100A8/A9 was investigated in A549 cells and in neutrophils obtained from children with MPP. Treatment of neutrophils, but not of A549 cells, with IL-17A released S100A8/A9 into the culture medium. In summary, we demonstrated that S100A8/A9, possibly released from neutrophils, is a new potential biomarker for the clinical diagnosis of children MPP and involved in the development of this disease through enhancing apoptosis of alveolar basal epithelial cells.
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http://dx.doi.org/10.1016/j.biopha.2021.112184DOI Listing
November 2021

HCG18 Participates in Vascular Invasion of Hepatocellular Carcinoma by Regulating Macrophages and Tumor Stem Cells.

Front Cell Dev Biol 2021 30;9:707073. Epub 2021 Aug 30.

Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, China.

Objectives: To identify key genes involved in vascular invasion in hepatocellular carcinoma (HCC), to describe their regulatory mechanisms, and to explore the immune microenvironment of HCC.

Methodology: In this study, the genome, transcriptome, and immune microenvironment of HCC were assessed by using multi-platform data from The Cancer Genome Atlas ( = 373) and GEO data (GSE149614). The key regulatory networks, transcription factors and core genes related to vascular invasion and prognosis were explored based on the CE mechanism. Survival analysis and gene set enrichment were used to explore pathways related to vascular invasion. Combined with single-cell transcriptome data, the distribution of core gene expression in various cells was observed. Cellular communication analysis was used to identify key cells associated with vascular invasion. Pseudo-temporal locus analysis was used to explore the regulation of core genes in key cell phenotypes. The influence of core genes on current immune checkpoint therapy was evaluated and correlations with tumor stem cell scores were explored.

Results: We obtained a network containing 1,249 pairs of CE regulatory relationships, including 579 differential proteins, 28 non-coding RNAs, and 37 miRNAs. Three key transcription factors, ILF2, YBX1, and HMGA1, were identified, all regulated by HCG18 lncRNA. ScRNAseq showed that HCG18 co-localized with macrophages and stem cells. CIBERSORTx assessed 22 types of immune cells in HCC and found that HCG18 was positively correlated with M0 macrophages, while being negatively correlated with M1 and M2 macrophages, monocytes, and dendritic cells. Cluster analysis based on patient prognosis suggested that regulating phenotypic transformation of macrophages could be an effective intervention for treating HCC. At the same time, higher expression of HCG18, HMGA1, ILF2, and YBX1 was associated with a higher stem cell score and less tumor differentiation. Pan cancer analysis indicated that high expression of HCG18 implies high sensitivity to immune checkpoint therapy.

Conclusion: HCG18 participates in vascular invasion of HCC by regulating macrophages and tumor stem cells through three key transcription factors, YBX1, ILF2, and HMGA1.
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http://dx.doi.org/10.3389/fcell.2021.707073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435853PMC
August 2021

Naringin promotes osteogenesis and ameliorates osteoporosis development by targeting JAK2/STAT3 signalling.

Clin Exp Pharmacol Physiol 2021 Sep 15. Epub 2021 Sep 15.

Department of Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Osteoporosis is a systemic bone metabolism disorder, which increases the risk of fractures, and in severe cases it may cause disability or even death. An important factor contributing to osteoporosis is the imbalance between bone formation and resorption. Naringin was reported to promote osteoblast differentiation, thus enhancing bone formation and alleviating osteoporosis development. However, the signalling pathways related to the regulatory mechanism of naringin in osteoporosis development are not clear. Proliferation of bone mesenchymal stem cells (BMSCs) treated with naringin in vitro was detected by CCK-8. An osteogenesis differentiation medium supplemented with naringin was applied to explore the effects of naringin on BMSC osteogenic differentiation, as detected by Alizarin red staining. Ovariectomy (OVX)-induced postmenopausal osteoporosis (PMOP) rats were orally administered with naringin. Dual-energy X-ray absorptiometry (DEXA) and micro-CT were applied to measure bone mineral density (BMD), bone volume/total volume (BV/TV), trabecula thickness (Tb.Th), trabecula number (Tb.N), trabecular separation (Tb.Sp) and bone surface/bone volume (BS/BV). H&E staining was performed to show pathological changes of the femur in PMOP rats after naringin treatment. Bone metabolism indicators were assessed by ELISA. We found that naringin suppressed the activation of the JAK2/STAT3 pathway. Naringin promoted BMSC proliferation and osteogenic differentiation. Furthermore, naringin alleviates bone loss and improves abnormal bone metabolism of PMOP rats. Collectively, naringin promotes BMSC osteogenic differentiation to ameliorate osteoporosis development by targeting JAK2/STAT3 signalling.
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http://dx.doi.org/10.1111/1440-1681.13591DOI Listing
September 2021

Spectroscopic and computational studies on the binding interaction between gallic acid and Pin1.

Luminescence 2021 Dec 10;36(8):2014-2021. Epub 2021 Oct 10.

Key Laboratory of Bio-resources and Eco-environment of the Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.

Gallic acid (GA) is a natural ingredient in functional foods, which has various health-promoting and antitumour effects. Peptidyl-prolyl cis/trans isomerase Pin1 plays an important role in preventing the development of some malignant tumours. However, whether there was an interaction between Pin1 and GA remains unknown. In this work, the binding information of GA and Pin1 was investigated systematically using multiple spectral and computational methods. GA bound to Pin1 directly with moderate binding affinity in the order of 10  mol/L, therefore decreasing the activity of Pin1. Also, the binding process of GA to Pin1 was driven through weak van der Waals forces, hydrogen bonds, and electrostatic forces. In addition, the important residues Lys63, Arg68, and Arg69 played a significant role in maintaining the binding stability between Pin1 and GA. Interestingly, GA reduced the activity of Pin1 by affecting its conformational characteristics. Our present work showed that GA binds to Pin1 and inhibits its activity, affecting its structural and functional properties, which may contribute to the therapy of Pin1-related diseases.
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http://dx.doi.org/10.1002/bio.4138DOI Listing
December 2021

Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators.

RSC Med Chem 2021 Aug 8;12(8):1402-1413. Epub 2021 Jul 8.

Department of Chemistry, University of Alberta 11227 Saskatchewan Drive NW Edmonton Alberta T6G 2G2 Canada

High blood pressure and consequential cardiovascular diseases are among the top causes of death worldwide. The apelinergic (APJ) system has emerged as a promising target for the treatment of cardiovascular issues, especially prevention of ischemia reperfusion (IR) injury after a heart attack or stroke. However, rapid degradation of the endogenous apelin peptides limits their use as therapeutic agents. Here, we study the effects of simple homologue substitutions, incorporation of non-canonical amino acids l-cyclohexylalanine (l-Cha) and l-homoarginine (l-hArg), on the proteolytic stability of pyr-1-apelin-13 and apelin-17 analogues. The modified 13-mers display up to 40 times longer plasma half-life than native apelin-13 and in preliminary assay show moderate blood pressure-lowering effects. The corresponding apelin-17 analogues show pronounced blood pressure-lowering effects and up to a 340-fold increase in plasma half-life compared to the native apelin-17 isoforms, suggesting their potential use in the design of metabolically stable apelin analogues to prevent IR injury.
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http://dx.doi.org/10.1039/d1md00120eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372210PMC
August 2021

Immune checkpoint programmed death-1 mediates abdominal aortic aneurysm and pseudoaneurysm progression.

Biomed Pharmacother 2021 Oct 30;142:111955. Epub 2021 Jul 30.

Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, 450052 Henan, China; Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, 450002 Henan, China. Electronic address:

Purpose: The causes and pathogenetic mechanisms underlying abdominal aortic aneurysms (AAAs) and pseudoaneurysms are not fully understood. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease AAA and pseudoaneurysm formation in mouse and rat models.

Methods: Human AAA samples were examined in conjunction with an adventitial calcium chloride (CaCl) application mouse model and an aortic patch angioplasty rat model. Single-dose PD-1 antibody (4 mg/kg) or BMS-1 (PD-1 inhibitor-1) (1 mg/kg) was administered by intraperitoneal (IP) or intraluminal injection. In the intramural injection group, PD-1 antibody was injected after CaCl incubation. The rats were divided into three groups: (1) the control group was only decellularized without other special treatment, (2) the PD-1 antibody-coated patch group, and (3) the BMS-1 coated patch group. Patches implanted in the rat abdominal aorta were harvested on day 14 after implantation and analyzed.

Results: Immunohistochemical analysis showed PD-1-positive cells, PD-1 and CD3, PD-1 and CD68, and PD-1 and α-actin co-expressed in the human AAA samples. Intraperitoneal (IP) injection or intraluminal injection of PD-1antibody/BMS-1 significantly inhibited AAA progression. PD-1 antibody and BMS-1 were each successfully conjugated to decellularized rat thoracic artery patches, respectively, by hyaluronic acid. Patches coated with either humanized PD-1 antibody or BMS-1 can also inhibit pseudoaneurysm progression and inflammatory cell infiltration.

Conclusion: PD-1 pathway inhibition may be a promising therapeutic strategy for inhibiting AAA and pseudoaneurysm progression.
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http://dx.doi.org/10.1016/j.biopha.2021.111955DOI Listing
October 2021

UHPLC-MS-based metabolomics and chemoinformatics study reveals the neuroprotective effect and chemical characteristic in Parkinson's disease mice after oral administration of Wen-Shen-Yang-Gan decoction.

Aging (Albany NY) 2021 08 2;13(15):19510-19528. Epub 2021 Aug 2.

Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Parkinson's disease (PD), the typical neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, no therapeutic agent used currently could slow down neuronal cell loss so as to decelerate or halt the progression of PD. Traditional Chinese medicine (TCM) has been utilized to treat the dysfunction of the autonomic nervous system. Wen-Shen-Yang-Gan decoction (WSYGD) has a good effect on the clinical treatment of PD with constipation. However, it is not clear which ingredients and what mechanism are responsible for the therapeutic effect. In this study, the pharmacodynamic study of WSYGD in PD mice was applied. Concurrently, a novel method for the identification of metabolic profiles of WSYGD has been developed. Finally, we found that WSYGD could protect the PD mice induced by rotenone. The underlying mechanism of the protective effect may be related to the reduction of the DA neurons apoptosis via reducing inflammatory reaction. By virtue of UPLC-MS and chemoinformatics method, 35 prototype compounds and 27 metabolites were filtered out and tentatively characterized. In conclusion, this study provides an insight into the metabolism of WSYGD to enable understanding of the metabolic process and therapeutic mechanism of PD.
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http://dx.doi.org/10.18632/aging.203361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386550PMC
August 2021

A non-RBM targeted RBD specific antibody neutralizes SARS-CoV-2 inducing S1 shedding.

Biochem Biophys Res Commun 2021 09 20;571:152-158. Epub 2021 Jul 20.

Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400010, China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing, 400010, China. Electronic address:

Potent neutralizing antibodies (Abs) have been proven with therapeutic efficacy for the intervention against SARS-CoV-2. Majority of these Abs function by directly interfering with the virus entry to host cells. Here, we identified a receptor binding domain (RBD) specific monoclonal Ab (mAb) 82A6 with efficient neutralizing potency against authentic SARS-CoV-2 virus. As most Abs targeting the non-receptor binding motif (RBM) region, 82A6 was incapable to block the RBD-ACE2 interaction. In particular, it actively promoted the S1 subunit shedding from the S protein, which may lead to effective reduction of intact SARS-CoV-2 viruses. Importantly, it could block potential syncytia formation associated with post-infectious cell surface expression of S proteins. Our study evidenced a RBD specific Ab with unique beneficial efficacy against SARS-CoV-2 infection, which might bring informative significance to understand the collective effects of neutralizing Abs elicited in COVID-19 patients.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289697PMC
September 2021

Mechanical Overloading Induced-Activation of mTOR Signaling in Tendon Stem/Progenitor Cells Contributes to Tendinopathy Development.

Front Cell Dev Biol 2021 12;9:687856. Epub 2021 Jul 12.

MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States.

Despite the importance of mechanical loading in tendon homeostasis and pathophysiology, the molecular responses involved in the mechanotransduction in tendon cells remain unclear. In this study, we found that mechanical loading activated the mammalian target of rapamycin (mTOR) in rat patellar tendon stem/progenitor cells (TSCs) in a stretching magnitude-dependent manner. Application of rapamycin, a specific inhibitor of mTOR, attenuated the phosphorylation of S6 and 4E-BP1 and as such, largely inhibited the mechanical activation of mTOR. Moreover, rapamycin significantly decreased the proliferation and non-tenocyte differentiation of PTSCs as indicated by the reduced expression levels of LPL, PPARγ, SOX-9, collagen II, Runx-2, and osteocalcin genes. In the animal studies, mice subjected to intensive treadmill running (ITR) developed tendon degeneration, as evidenced by the formation of round-shaped cells, accumulation of proteoglycans, and expression of SOX-9 and collagen II proteins. However, daily injections of rapamycin in ITR mice reduced all these tendon degenerative changes. Collectively, these findings suggest that mechanical loading activates the mTOR signaling in TSCs, and rapamycin may be used to prevent tendinopathy development by blocking non-tenocyte differentiation due to mechanical over-activation of mTOR in TSCs.
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http://dx.doi.org/10.3389/fcell.2021.687856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311934PMC
July 2021

Albiflorin alleviates cognitive dysfunction in STZ-induced rats.

Aging (Albany NY) 2021 07 28;13(14):18287-18297. Epub 2021 Jul 28.

Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.

Background: To explore the effect of albiflorin (AL) on streptozotocin (STZ)-induced Alzheimer's disease (AD) in rats.

Methods: A mouse model of diabetic encephalopathy was established by intraperitoneal injection of 1%STZ. Step down test and water maze test were used to test the cognitive function of rats. Congo Red Staining was used to detect the distribution of Aβ plaques in the hippocampus of rats. Cytokine levels in serum and hippocampus were measured using ELISA. Serum insulin, oral glucose tolerance (OGTT), serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured by commercial kits. And the content of Nrf-2/HO-1/HMGB1/NF-kB in the hippocampus of diabetic rats were detected by western blot.

Results And Conclusion: Compared with the STZ model group, the average escape latency of rats in the AL group in the Morris water maze test was significantly shortened, and the average number of platform crossings and the ratio of distance/total swimming distance in the target quadrant were increased significantly. Staining of tissue sections and ELISA showed a decrease in Aβ plaque density in the hippocampus of rats in the AL group. And serum insulin levels of rats in the ALgroup were significantly reduced and OGTT was improved. In addition, AL could also regulate the Nrf-2/HO-1/HMGB1/NF-kB signal pathway in the hippocampus. Therefore, AL may ameliorate STZ-induced cognitive impairment in rats by regulating oxidative stress and inflammation in the brain.
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http://dx.doi.org/10.18632/aging.203274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351685PMC
July 2021

Identification of Cross-Reactive CD8 T Cell Receptors with High Functional Avidity to a SARS-CoV-2 Immunodominant Epitope and Its Natural Mutant Variants.

Genes Dis 2021 Jun 29. Epub 2021 Jun 29.

Department of Immunology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, PR China.

Despite the growing knowledge of T cell responses in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Here, with a predicted peptide library from SARS-CoV-2 S and N proteins, restricted to three of the most prominent HLA-A alleles in the Asian population, we found that specific CD8 T cell responses were identified in over 75% of COVID-19 convalescent patients (15/20). A total of 15 SARS-CoV-2 epitopes from the S and N proteins were identified, and among them, 3 dominant epitopes were further characterized. We found that an epitope from the N protein, N (KTFPPTEPK), was the most dominant epitope from our selected peptide library. Importantly, we discovered 2 N-specific T cell receptors (TCRs) with high functional avidity that were independent of the CD8 co-receptor. These TCRs exhibited complementary cross-reactivity to several presently reported N mutant variants, as to the wild-type epitope. Further, the natural functions of these TCRs in the cytotoxic immunity against SARS-CoV-2 were determined with dendritic cells (DCs) and the lung organoid model. We found that the N epitope could be normally processed and endogenously presented by these different types of antigen presenting cells, to elicit successful activation and effective cytotoxicity of CD8 T cells . Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, and illuminated potential ways of viral clearance in COVID-19 patients. These results indicate that utilizing CD8-independent TCRs against SARS-CoV-2-associated antigens may provide functional superiority that is beneficial for the adoptive cell immunotherapies based on natural or genetically engineered T cells. Additionally, this information is highly relevant for the development of the next-generation vaccines with protections against continuously emerged SARS-CoV-2 mutant strains.
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http://dx.doi.org/10.1016/j.gendis.2021.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240504PMC
June 2021

Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer.

Acta Pharm Sin B 2021 Jun 13;11(6):1513-1525. Epub 2021 May 13.

State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Ministry of Education of China, Zhengzhou 450001, China.

Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. Here, we showed , a new JDA derivative, inhibited the growth of gastric cancer cells. Subsequently, we discovered for the first time that induced ferroptosis. Importantly, compound decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of . Furthermore, we demonstrated that caused ferrous iron accumulation through the autophagy pathway, prevention of which rescued induced ferrous iron elevation and cell growth inhibition. Moreover, exhibited more potent anti-cancer activity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models. Patient-derived tumor xenograft models from different patients displayed varied sensitivity to , and GPX4 downregulation indicated the sensitivity of tumors to . Finally, exhibited well pharmacokinetic characteristics. Overall, our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of , and will hopefully serve as a promising compound for gastric cancer treatment.
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http://dx.doi.org/10.1016/j.apsb.2021.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245858PMC
June 2021

A highly efficient regeneration, genetic transformation system and induction of targeted mutations using CRISPR/Cas9 in Lycium ruthenicum.

Plant Methods 2021 Jul 3;17(1):71. Epub 2021 Jul 3.

Beijing Key Laboratory of Ornamental Plants Germplasm Innovation & Molecular Breeding; National Engineering Research Center for Floriculture; Beijing Laboratory of Urban and Rural Ecological Environment; Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants of Ministry of Education; College of Landscape Architecture, Beijing Forestry University, Beijing, 100083, China.

Background: CRISPR/Cas9 is a rapidly developing genome editing technology in various biological systems due to its efficiency, portability, simplicity and versatility. This editing technology has been successfully applied in in several important plants of Solanaceae such as tomato, tobacco, potato, petunia and groundcherry. Wolfberry ranked the sixth among solanaceous crops of outstanding importance in China following potato, tomato, eggplant, pepper and tobacco. To date, there has been no report on CRISPR/Cas9 technology to improve Lycium ruthenicum due to the unknown genome sequencing and the lack of efficient regeneration and genetic transformation systems.

Results: In this study, we have established an efficientregeneration and genetic transformation system of Lycium ruthenicum. We have used this system to validate target sites for fw2.2, a major fruit weight quantitative trait locus first identified from tomato and accounted for 30% of the variation in fruit size. In our experiments, the editing efficiency was very high, with 95.45% of the transgenic lines containing mutations in the fw2.2 target site. We obtained transgenic wolfberry plants containing four homozygous mutations and nine biallelic mutations in the fw2.2 gene.

Conclusions: These results suggest that CRISPR-based gene editing is effective for the improvement of black wolfberry traits, and we expect this approach to be routinely applied to this important economic fruit.
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http://dx.doi.org/10.1186/s13007-021-00774-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254353PMC
July 2021

IL-21 Optimizes the CAR-T Cell Preparation Through Improving Lentivirus Mediated Transfection Efficiency of T Cells and Enhancing CAR-T Cell Cytotoxic Activities.

Front Mol Biosci 2021 4;8:675179. Epub 2021 Jun 4.

Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing, China.

Adoptive immunotherapy using CAR-T cells is a promising curative treatment strategy for hematological malignancies. Current manufacture of clinical-grade CAR-T cells based on lentiviral/retrovirus transfection of T cells followed by anti-CD3/CD28 activation supplemented with IL-2 has been associated with low transfection efficiency and usually based on the use of terminally differentiated effector T cells. Thus, improving the quality and the quantity of CAR-T cells are essential for optimizing the CAR-T cell preparation. In our study, we focus on the role of IL-21 in the γ cytokine conditions for CAR-T cell preparation. We found for the first time that the addition of IL-21 in the CAR-T preparation improved T cell transfection efficiency through the reduction of IFN-γ expression 24-48 h after T cell activation. We also confirmed that IL-21 enhanced the enrichment and expansion of less differentiated CAR-T cells. Finally, we validated that IL-21 improved the CAR-T cell cytotoxicity, which was related to increased secretion of effector cytokines. Together, these findings can be used to optimize the CAR-T cell preparation.
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http://dx.doi.org/10.3389/fmolb.2021.675179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220804PMC
June 2021

Programmed death-1 mediates venous neointimal hyperplasia in humans and rats.

Aging (Albany NY) 2021 06 24;13(12):16656-16666. Epub 2021 Jun 24.

School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold Technology, Ministry of Education, Zhengzhou University, Henan, China.

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness ( < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.
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http://dx.doi.org/10.18632/aging.203185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266332PMC
June 2021

p38 inhibition enhances TCR-T cell function and antagonizes the immunosuppressive activity of TGF-β.

Int Immunopharmacol 2021 Sep 11;98:107848. Epub 2021 Jun 11.

Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, China. Electronic address:

The efficacy of adoptive cell therapy (ACT) relies on the abilities of T cells in self-expansion, survival and the secretion of effector molecules. Here, we presented an optimized method to generate T cells with improved functions by supplementing the culture medium with p38 inhibitor and the combination of IL-7 and IL-15 or IL-2 alone. The addition of p38 inhibitor, Doramapimod or SB202190, to IL-7 and IL-15 culture largely increased the capacity of T cells in the proliferation with enrichment of the naïve-like subsets and expression of CD62L. Importantly, we found this regimen has generated complete T cell resistance to TGF-β-induced functional suppression, with sustained levels of the IFN-γ and Granzyme-B productions. Such findings were also validated in the melanoma-associated antigen recognized by T cells (MART-1) specific T cell receptor (TCR) engineered T cells, which were expanded in Doramapimod and IL-7 + IL-15 added media. In conclusion, we have established and optimized a protocol with the combination of p38 inhibitor, IL-7 and IL-15, rather than IL-2, for the generation of functionally enhanced T cells applicable for ACT.
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http://dx.doi.org/10.1016/j.intimp.2021.107848DOI Listing
September 2021

Identification and analysis of NAC transcription factors and an expression analysis of OsNAC7 subfamily members.

PeerJ 2021 26;9:e11505. Epub 2021 May 26.

Beijing Key Laboratory of Ornamental Plants Germplasm Innovation & Molecular Breeding, National Engineering Research Center for Floriculture, Beijing, China.

NAC (NAM, ATAF1-2, and CUC2) transcription factors (TFs) play a vital role in plant growth and development, as well as in plant response to biotic and abiotic stressors (Duan et al., 2019; Guerin et al., 2019). Chrysanthemum is a plant with strong stress resistance and adaptability; therefore, a systematic study of NAC TFs in chrysanthemum is of great significance for plant breeding. In this study, 153 putative NAC TFs were identified based on the genome. According to the NAC family in Arabidopsis and rice, a rootless phylogenetic tree was constructed, in which the 153 CnNAC TFs were divided into two groups and 19 subfamilies. Moreover, the expression levels of 12 CnNAC TFs belonging to the OsNAC7 subfamily were analyzed in under osmotic and salt stresses, and different tissues were tested during different growth periods. The results showed that these 12 OsNAC7 subfamily members were involved in the regulation of root and stem growth, as well as in the regulation of drought and salt stresses. Finally, we investigated the function of the gene, and the results showed that could confer improved salt and low temperature resistance, enhance ABA sensitivity, and lead to early flowering in tobacco. It was proved that members of the OsNAC7 subfamily have dual functions including the regulation of resistance and the mediation of plant growth and development. This study provides comprehensive information on analyzing the function of CnNAC TFs, and also reveals the important role of OsNAC7 subfamily genes in response to abiotic stress and the regulation of plant growth. These results provide new ideas for plant breeding to control stress resistance and growth simultaneously.
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http://dx.doi.org/10.7717/peerj.11505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164415PMC
May 2021

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma.

Mol Cancer 2021 06 5;20(1):84. Epub 2021 Jun 5.

Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China.

Background: Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche.

Methods: Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer.

Results: We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation.

Conclusions: Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.
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http://dx.doi.org/10.1186/s12943-021-01380-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178856PMC
June 2021

Synthesis, SAR study, and bioactivity evaluation of a series of Quinoline-Indole-Schiff base derivatives: Compound 10E as a new Nur77 exporter and autophagic death inducer.

Bioorg Chem 2021 08 23;113:105008. Epub 2021 May 23.

School of Pharmaceutical Sciences and School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address:

We previously reported 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole- 2-carbohydrazide derivatives as new Nur77 modulators. In this study, we explored whether the 8-methoxy-2-methylquinoline moiety and bicyclic aromatic rings at the N'-methylene position were critical for their antitumor activity against hepatocellular carcinoma (HCC). For this purpose, a small library of 5-substituted 1H-indole-2-carbohydrazide derivatives was designed and synthesized. We found that the 8-methoxy-2-methylquinoline moiety was a fundamental structure for its biological function, while the introduction of the bicyclic aromatic ring into the N'-methylene greatly improved its anti-tumor effect. We found that the representative compound 10E had a high affinity to Nur77. The K values were in the low micromolar (2.25-4.10 μM), which were coincident with its IC values against the tumor cell lines (IC < 3.78 μM). Compound 10E could induce autophagic cell death of liver cancer cells by targeting Nur77 to mitochondria while knocking down Nur77 greatly impaired anti-tumor effect. These findings provide an insight into the structure-activity relation of Quinoline-Indole-Schiff base derivatives and further demonstrate that antitumor agents targeting Nur77 may be considered as a promising strategy for HCC therapy.
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http://dx.doi.org/10.1016/j.bioorg.2021.105008DOI Listing
August 2021

Application of the Tissue-Engineered Plant Scaffold as a Vascular Patch.

ACS Omega 2021 May 23;6(17):11595-11601. Epub 2021 Apr 23.

School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold Technology (Ministry of Education), Zhengzhou University, Zhengzhou, Henan 450001, China.

Tissue-engineered plant scaffolds have shown promising applications in in vitro studies. To assess the applicability of natural plant scaffolds as vascular patches, we tested decellularized leaf and onion cellulose in a rat inferior vena cava patch venoplasty model. The leaf was decellularized, and the scaffold was loaded with polylactic--glycolic acid (PLGA)-based rapamycin nanoparticles (nanoparticles). Nanoparticle-perfused leaves showed decreased neointimal thickness after implantation on day 14; there were also fewer CD68-positive cells and PCNA-positive cells in the neointima in the nanoparticle-perfused patches than in the control patches. Onion cellulose was decellularized, coated with rapamycin nanoparticles, and implanted in the rat; the nanoparticle-coated onion cellulose patches also showed decreased neointimal thickness. These data show that natural plant-based scaffolds may be used as novel scaffolds for tissue-engineered vascular patches. However, further modifications are needed to enhance patch strength for artery implantations.
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http://dx.doi.org/10.1021/acsomega.1c00804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154004PMC
May 2021

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder.

Oncologist 2021 08 8;26(8):e1395-e1405. Epub 2021 Jun 8.

Department of Urology, Peking University First Hospital, Beijing, People's Republic of China.

Background: Different genomic characterization in urothelial carcinoma (UC) by site of origin may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity.

Materials And Methods: We prospectively sequenced 118 tumors and matched blood DNA from Chinese patients with UC using next-generation sequencing techniques, including 45 UTUC and 73 UCB. Two hundred twenty-six patients with UTUC and 350 patients with UCB for The Cancer Genome Atlas were acquired from the cbioportal.

Results: There were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared with UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. Patients with UTUC had lower PD-L1 than those with UCB. There was no significant difference in the number of DDR mutations, copy number variation counts, and tumor mutational burden between UTUC and UCB.

Conclusion: UTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.

Implications For Practice: This study's findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.
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http://dx.doi.org/10.1002/onco.13839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342585PMC
August 2021
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