Publications by authors named "Junjun Li"

206 Publications

Transcytosis-enabled active extravasation of tumor nanomedicine.

Adv Drug Deliv Rev 2022 Aug 8;189:114480. Epub 2022 Aug 8.

Key Laboratory of Smart Biomaterials of Zhejiang Province and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China; Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address:

Extravasation is the first step for nanomedicines in circulation to reach targeted solid tumors. Traditional nanomedicines have been designed to extravasate into tumor interstitium through the interendothelial gaps previously assumed rich in tumor blood vessels, i.e., the enhanced permeability and retention (EPR) effect. While the EPR effect has been validated in animal xenograft tumor models, accumulating evidence implies that the EPR effect is very limited and highly heterogeneous in human tumors, leading to highly unpredictable and inefficient extravasation and thus limited therapeutic efficacy of nanomedicines, including those approved in clinics. Enabling EPR-independent extravasation is the key to develop new generation of nanomedicine with enhanced efficacy. Transcytosis of tumor endothelial cells can confer nanomedicines to actively extravasate into solid tumors without relying on the EPR effect. Here, we review and prospectthe development of transcytosis-inducing nanomedicines, in hope of providing instructive insights for design of nanomedicines that can undergo selective transcellular transport across tumor endothelial cells, and thus inspiring the development of next-generation nanomedicines for clinical translation.
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http://dx.doi.org/10.1016/j.addr.2022.114480DOI Listing
August 2022

Disruption of Functional Brain Networks Underlies the Handwriting Deficit in Children With Developmental Dyslexia.

Front Neurosci 2022 18;16:919440. Epub 2022 Jul 18.

CAS Key Laboratory of Behavioral Science, Center for Brain Science and Learning Difficulties, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.

Developmental dyslexia (DD) is a neurological-based learning disorder that affects 5-17.5% of children. Handwriting difficulty is a prevailing symptom of dyslexia, but its neural mechanisms remain elusive. Using functional magnetic resonance imaging (fMRI), this study examined functional brain networks associated with handwriting in a copying task in Chinese children with DD ( = 17) and age-matched children ( = 36). We found that dyslexics showed reduced network connectivity between the sensory-motor network (SMN) and the visual network (VN), and between the default mode network (DMN) and the ventral attention network (VAN) during handwriting, but not during drawing geometric figures. Moreover, the connectivity strength of the networks showing group differences was correlated with handwriting speed, reading and working memory, suggesting that the handwriting deficit in DD is linked with disruption of a large-scale brain network supporting motoric, linguistic and executive control processes. Taken together, this study demonstrates the alternations of functional brain networks that underly the handwriting deficit in Chinese dyslexia, providing a new clue for the neural basis of DD.
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http://dx.doi.org/10.3389/fnins.2022.919440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339653PMC
July 2022

Personality traits modulate the neural responses to handwriting processing.

Ann N Y Acad Sci 2022 Jul 27. Epub 2022 Jul 27.

Center for Brain Disorders and Cognitive Sciences, School of Psychology, Shenzhen University, Shenzhen, China.

Handwriting is a vital skill for everyday human activities. It has a wealth of information about writers' characteristics and can hint toward underlying neurological conditions, such as Parkinson's disease, autism, dyslexia, and attention-deficit/hyperactivity disorder (ADHD). Many previous studies have reported a link between personality and individual differences in handwriting, but the evidence for the relationship tends to be anecdotal in nature. Using functional magnetic resonance imaging (fMRI), we examined whether the association between personality traits and handwriting was instantiated at the neural level. Results showed that the personality trait of conscientiousness modulated brain activation in the left premotor cortex and right inferior/middle frontal gyrus, which may reflect the impact of personality on orthography-to-grapheme transformation and executive control involved in handwriting. Such correlations were not observed in symbol-drawing or word-reading tasks, suggesting the specificity of the link between conscientiousness and handwriting in these regions. Moreover, using a connectome-based predictive modeling approach, we found that individuals' conscientiousness scores could be predicted based on handwriting-related functional brain networks, suggesting that the influence of personality on handwriting may occur within a broader network. Our findings provide neural evidence for the link between personality and handwriting processing, extending our understanding of the nature of individual differences in handwriting.
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http://dx.doi.org/10.1111/nyas.14871DOI Listing
July 2022

Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for Δ160E-Induced Cardiomyopathy.

Circ Genom Precis Med 2022 Jul 12:101161CIRCGEN121003522. Epub 2022 Jul 12.

Department of Cardiovascular Medicine (T.K., M.S., S.K., T.T., H.I., S. Okuno, S. Ogawa, Y.K., J.-K.L., S. Hikoso, Y.S.).

Background: The Δ160E mutation in , which encodes troponin T, is a rare pathogenic variant identified in patients with hypertrophic cardiomyopathy and is associated with poor prognosis. Thus, a convenient human model recapitulating the pathological phenotype caused by Δ160E is required for therapeutic development.

Methods: We identified a heterozygous in-frame deletion mutation (c.478_480del, p.Δ160E) in in a patient with familial hypertrophic cardiomyopathy showing progressive left ventricular systolic dysfunction, leading to advanced heart failure. To investigate the pathological phenotype caused by Δ160E, we generated a set of isogenic induced pluripotent stem cells carrying the heterozygous Δ160E, homozygously corrected or homozygously introduced Δ160E using genome editing and differentiated them into cardiomyocytes (Hetero-Δ160E-, WT-, and Homo-Δ160E-induced pluripotent stem cells [iPSC]-derived cardiomyocytes [iPSC-CMs]).

Results: Hetero-Δ160E-iPSC-CMs exhibited prolonged calcium decay, relaxation impairment, and hypertrophy compared to WT-iPSC-CMs. Notably, these phenotypes were further exacerbated in Homo-Δ160E-iPSC-CMs. Overexpression of R-GECO-fused Δ160E mutant troponin T prolonged decay time and time to peak of the myofilament-localized calcium transient in iPSC-CMs, indicating that sarcomeric calcium retention with Δ160E may affect intracellular calcium concentration. High-content imaging analysis detected remarkable nuclear translocation of NFATc1, especially in Homo-Δ160E-iPSC-CMs, indicating that the Δ160E mutation promotes hypertrophic signaling pathway in a dose-dependent manner. Increased phosphorylation of CaMKIIδ (calcium/calmodulin-dependent protein kinase IIδ) and phospholamban at Thr17 was observed in Homo- and Hetero-Δ160E-iPSC-CMs. Epigallocatechin-3-gallate, a calcium desensitizing compound, shortened prolonged calcium decay and relaxation duration in Δ160E-iPSC-CMs.

Conclusions: Isogenic iPSC-CMs recapitulate the prolonged calcium decay, relaxation impairment, and subsequent calcium-regulated signaling pathways caused by the Δ160E mutation and can serve as a human model for therapeutic development to prevent hypertrophic cardiomyopathy pathology.
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http://dx.doi.org/10.1161/CIRCGEN.121.003522DOI Listing
July 2022

Cu-based Organic-Inorganic Composite Materials for Electrochemical CO2 Reduction.

Chem Asian J 2022 Jul 20. Epub 2022 Jul 20.

Tianjin University, Department of Chemistry, 92, Weijin Road, Nankai District, Tianjin, 300072, Tianjin, CHINA.

Electrochemical CO2 reduction reaction (CO2RR) is an attractive pathway to convert CO2 into value-added chemicals and fuels. Copper (Cu) is the most effective monometallic catalyst for converting CO2 into multi-carbon products, but suffers from high overpotentials and poor selectivity. Therefore, it is essential to design efficient Cu-based catalyst to improve the selectivity of specific products. Due to the combination of advantages of organic and inorganic composite materials, organic-inorganic composites exhibit high catalytic performance towards CO2RR, and have been extensively studied. In this review, the research advances of various Cu-based organic-inorganic composite materials in CO2RR, i.e., organic molecular modified-metal Cu composites, Cu-based molecular catalyst/carbon carrier composites, Cu-based metal organic framework (MOF) composites, and Cu-based covalent organic framework (COF) composites are systematically summarized. Particularly, the synthesis strategies of Cu-based composites, structure-performance relationship, and catalytic mechanisms are discussed. Finally, the opportunities and challenges of Cu-based organic-inorganic composite materials in CO2RR are proposed.
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http://dx.doi.org/10.1002/asia.202200624DOI Listing
July 2022

Rapid titration of recombinant baculoviruses based on NanoLuc secretion in early infection.

J Virol Methods 2022 Sep 18;307:114565. Epub 2022 Jun 18.

Department of Biopharmacy, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China. Electronic address:

The baculovirus expression vector system has become a powerful tool for recombinant protein production and gene delivery. However, existing titration methods for baculovirus are not economical in terms of test time and cost. A titration method based on NanoLuc secretion that allows for titration of recombinant baculoviruses at 4 h post infection (hpi) is described. In the assay, the envelop protein GP64 signal peptide-guided NanoLuc was secreted into the culture medium in proportion to the virus amount during early infection under combined control by the homologous region 5 (hr5) enhancer and the promoter of immediate early gene 1 (ie1) plus L21. Two timepoint standard curves of luciferase activity to virus titers of 5-9 logs were established with excellent linearity and correlation coefficients (slope = 1.050, R ≥ 0.9969) using a secretory Nanoluc (secrNluc) - inserted standard baculovirus. Through the assay, the titers of three recombinant viruses prepared independently were calculated by directly measuring luciferase activity in the supernatant at 4 and 6 hpi, with greater accuracy compared to the endpoint dilution assay. These results show the efficacy of this proposed method as a streamlined assay for rapidly titrating recombinant baculoviruses.
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http://dx.doi.org/10.1016/j.jviromet.2022.114565DOI Listing
September 2022

E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2.

Med Oncol 2022 Jun 18;39(9):124. Epub 2022 Jun 18.

Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China.

Both pro-oncogenic and anti-oncogenic effects of E2F2 have been revealed in different malignancies. However, the precise role of E2F2 in pancreatic cancer, in particular in relation to therapeutic intervention with gemcitabine, remains unclear. In this study, the effect of E2F2 on the proliferation and cell cycle modulation of pancreatic cancer cells, and whether E2F2 plays a role in the treatment of pancreatic cancer cells by gemcitabine, were investigated. The expression of E2F2 in pancreatic cancer was assessed by various methods including bioinformatics prediction, Western blotting, and real-time PCR. The effect of E2F2 on the proliferation and cell cycling of pancreatic cancer cells was analyzed by tissue culture and flow cytometry. In addition, the effect of E2F2 on the intervention of pancreatic cancer by gemcitabine was investigated using both in vitro and in vivo approaches. The expression of E2F2 was found to be significantly increased in pancreatic cancer tissues and cell lines. The pathogenic capacity of E2F2 lied in the fact that this transcription factor promoted the transformation of pancreatic cancer cell cycle from G1-phase to S-phase, thus enhancing the proliferation of pancreatic cancer cells. Furthermore, the expression of E2F2 was increased in pancreatic cancer cells in the presence of gemcitabine, and the augmented expression of E2F2 upregulated the gemcitabine resistance-related gene RRM2 and its downstream signaling molecule deoxycytidine kinase (DCK). The resistance of pancreatic cancer cells to gemcitabine was confirmed using both in vitro and in vivo models. In this study, E2F2 has been demonstrated for the first time to play a pro-oncogenic role in pancreatic cancer by promoting the transition of the cell cycle from G1-phase to S-phase and, therefore, enhancing the proliferation of pancreatic cancer cells. E2F2 has also been demonstrated to enhance the chemotherapy resistance of pancreatic cancer cells to gemcitabine by upregulating the expression of RRM2 and DCK that is downstream of RRM2.
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http://dx.doi.org/10.1007/s12032-022-01715-xDOI Listing
June 2022

One-Step Formation of Low Work-Function, Transparent and Conductive MgF O Electron Extraction for Silicon Solar Cells.

Adv Sci (Weinh) 2022 Aug 17;9(23):e2202400. Epub 2022 Jun 17.

Institute of Photovoltaics, Southwest Petroleum University, Chengdu, 610500, China.

The development of high-performance dopant-free silicon solar cells is severely bottlenecked by opaque electron selective contact. In this paper, high transmittance (80.5% on glass) and low work function (2.92 eV) lithium fluoride (LiF )/MgF O electron contact stack by tailoring the composition of MgF O hybrid film is reported. This hybrid structure exhibits a high conductivity (2978.4 S cm ) and a low contact resistivity (2.0 mΩ cm ). The element profile of LiF /MgF O contact is measured and the reaction kinetics is analyzed. As a proof-of-concept, this electron selective contact is applied for dopant-free silicon solar cells. An impressive efficiency of 21.3% is achieved on dopant-free monofacial solar cell with molybdenum oxide (MoO )/zinc-doped indium oxide (IZO) hole contact. An efficiency bifaciality of 71% is obtained for dopant-free bifacial solar cell with full-area LiF /MgF O /ITO (tin-doped indium oxide) transparent electron contact. It is the highest efficiency bifaciality so far for dopant-free bifacial solar cells to the best knowledge. Both cell configurations with LiF /MgF O contacts show excellent environment stability. The cell efficiency maintains more than 95% of its initial value after keeping in air for 1500 h. This work provides a new idea to achieve transparent electron contact, showing a great potential for high-efficiency and low-cost optoelectronic devices.
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http://dx.doi.org/10.1002/advs.202202400DOI Listing
August 2022

Serum Nardilysin as a Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma.

J Clin Med 2022 May 30;11(11). Epub 2022 May 30.

Department of Abdominal Oncology, West China Hospital of Sichuan University, Chengdu 610041, China.

Background: Nardilysin, (N-arginine dibasic convertase, NRDC) has been reported to play an important role in cancer progression, and is associated with tumor proliferation signals and inflammatory signals, such as tumor necrosis factor-a (TNF-a) and heparin-binding epidermal growth factor-like growth factor (HB-EGF), through the activation of disintegrin and metalloproteinase (ADAM) proteases. NRDC has recently been revealed to be involved in the tumorigenesis of various types of cancer, including intrahepatic cholangiocarcinoma, malignant cerebral infarction, esophageal squamous cell carcinoma, and gastric cancer. However, the expression profiles and biological relevance of NRDC in pancreatic ductal adenocarcinoma have rarely been reported.

Methods: We analyzed the NRDC expression profile in pancreatic ductal adenocarcinoma by enzyme-linked immunosorbent assay (ELISA) and identified NRDC as a circulating biomarker in the serum of 112 pancreatic ductal adenocarcinoma patients. The diagnostic value of NRDC was analyzed by the area under the curve (AUC) and the receiver operating characteristic (ROC) test.

Results: Our results demonstrated that the clinical prognosis significance of NRDC with the clinical characteristics in pancreatic ductal adenocarcinoma (PDAC). NRDC was notably decreased in PDAC patient serum compared with the control group ( < 0.001). Furthermore, the present study found that the NRDC expression level was correlated with T grade ( < 0.001), metastasis( < 0.001), differentiation( < 0.001), and TNM stage ( = 0.011). Further bioinformatics analysis revealed that NRDC correlated with proliferation and migration pathways; in particular, it mediated cell-matrix adhesion-dependent activation in pancreatic ductal adenocarcinoma.

Conclusions: Serum NRDC may play a useful diagnostic biomarker to evaluate the aggressive clinical features in PAAD patients.
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http://dx.doi.org/10.3390/jcm11113101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181681PMC
May 2022

Development and evaluation of a novel xeno-free culture medium for human-induced pluripotent stem cells.

Stem Cell Res Ther 2022 06 3;13(1):223. Epub 2022 Jun 3.

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.

Background: Human-induced pluripotent stem cells (hiPSCs) are considered an ideal resource for regenerative medicine because of their ease of access and infinite expansion ability. To satisfy the sizable requirement for clinical applications of hiPSCs, large-scale, expansion-oriented, xeno-free, and cost-effective media are critical. Although several xeno-free media for hiPSCs have been generated over the past decades, few of them are suitable for scalable expansion of cultured hiPSCs because of their modest potential for proliferation and high cost.

Methods: In this study, we developed a xeno-free ON2/AscleStem PSC medium (ON2) and cultured 253G1 hiPSCs on different matrices, including iMatrix-511 and gelatin nanofiber (GNF) in ON2. Over 20 passages, we evaluated cell proliferation by doubling times; pluripotency by flow cytometry, immunofluorescence staining and qRT-PCR; and differentiation ability by three germ layer differentiation in vitro and teratoma formation in severe combined immunodeficiency mice, followed by histological analysis. In addition, we compared the maintenance effect of ON2 on hiPSCs with StemFit® AK02 (AK02N) and Essential 8™ (E8). Besides 253G1 hiPSCs, we cultivated different hiPSC lines, including Ff-l01 hiPSCs, ATCC® ACS-1020™ hiPSCs, and Down's syndrome patient-specific ATCC® ACS-1003™ hiPSCs in ON2.

Results: We found that 253G1 hiPSCs in ON2 demonstrated normal morphology and karyotype and high self-renewal and differentiation abilities on the tested matrices for over 20 passages. Moreover, 253G1 hiPSCs kept on GNF showed higher growth and stemness, as verified by the shorter doubling time and higher expression levels of pluripotent markers. Compared to AK02N and E8 media, 253G1 hiPSCs grown in ON2 showed higher pluripotency, as demonstrated by the increased expression level of pluripotent factors. In addition, all hiPSC lines cultivated in ON2 were able to grow for at least 10 passages with compact clonal morphology and were positive for all detected pluripotent markers.

Conclusions: Our xeno-free ON2 was compatible with various matrices and ideal for long-term expansion and maintenance of not only healthy-derived hiPSCs but also patient-specific hiPSCs. This highly efficient medium enabled the rapid expansion of hiPSCs in a reliable and cost-effective manner and could act as a promising tool for disease modeling and large-scale production for regenerative medicine in the future.
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http://dx.doi.org/10.1186/s13287-022-02879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166585PMC
June 2022

Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901).

Oncologist 2022 03;27(2):e116-e125

The Second Department of Thoracic Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People's Republic of China.

Background: Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers.

Methods: We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis.

Results: Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC.

Conclusion: We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.
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http://dx.doi.org/10.1093/oncolo/oyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895731PMC
March 2022

Cdh1 Deficiency Sensitizes TNBC Cells to PARP Inhibitors.

Genes (Basel) 2022 Apr 30;13(5). Epub 2022 Apr 30.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China.

Triple-negative breast cancer (TNBC) is a type of breast tumor that currently lacks options for targeted therapy. Tremendous effort has been made to identify treatment targets for TNBC. Here, we report that the expression level of anaphase promoting complex (APC) coactivator Cdh1 in TNBC is elevated compared to that in the adjacent healthy tissues, and high levels of Cdh1 expression are correlated with poor prognoses, suggesting that Cdh1 contributes to the progression of TNBC. Interfering with the function of Cdh1 can potentiate the cytotoxic effects of PARP inhibitors against BRCA-deficient and BRCA-proficient TNBC cells through inducing DNA damage, checkpoint activation, cell cycle arrest, and apoptosis. Further investigation reveals that Cdh1 promotes BRCA1 foci formation and prevents untangled DNA entering mitosis in response to PARP inhibition (PARPi) in TNBC cells. Collectively, these results suggest that APC/Cdh1 is a potential molecular target for PARPi-based therapies against TNBCs.
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http://dx.doi.org/10.3390/genes13050803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9141497PMC
April 2022

Insight into the effects of the crystal phase of Ru over ultrathin [email protected] core-shell nanosheets for methanol electrooxidation.

Nanoscale 2022 Jun 9;14(22):8096-8102. Epub 2022 Jun 9.

Department of Chemistry, School of Science, Tianjin University & Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin 300072, China.

Coating a second metal on the surface of ultrathin 2D nanosheets (NSs) could induce lattice strain and modify the electronic structure, thereby changing the surface reactivity. Herein, we report the effects of different crystal phases of Ru on the electrocatalytic performance of ultrathin [email protected] core-shell NSs for the methanol oxidation reaction (MOR). Importantly, Ru with a novel face-centered-cubic phase was found to have more effect on the electronic structure of Pt than Ru with a conventional hexagonal close-packed phase, thereby leading to improved electrocatalytic activity toward the MOR under acidic and basic conditions. It is believed that the strategy presented here would offer a new approach to the construction of bimetallic core-shell nanostructures with various promising applications.
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http://dx.doi.org/10.1039/d2nr01602hDOI Listing
June 2022

Potential role of selenium in alleviating obesity-related iron dyshomeostasis.

Crit Rev Food Sci Nutr 2022 May 16:1-15. Epub 2022 May 16.

Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China.

Obesity is a serious health problem in modern life and increases the risk of many comorbidities including iron dyshomeostasis. In contrast to malnourished anemia, obesity-related iron dyshomeostasis is mainly caused by excessive fat accumulation, inflammation, and disordered gut microbiota. In obesity, iron dyshomeostasis also induces disorders associated with gut microbiota, neurodegenerative injury, oxidative damage, and fat accumulation in the liver. Selenium deficiency is often accompanied by obesity or iron deficiency, and selenium supplementation has been shown to alleviate obesity and overcome iron deficiency. Selenium inhibits fat accumulation and exhibits anti-inflammatory activity. It regulates gut microbiota, prevents neurodegenerative injury, alleviates oxidative damage to the body, and ameliorates hepatic fat accumulation. These effects theoretically meet the requirements for the inhibition of factors underlying obesity-related iron dyshomeostasis. Selenium supplementation may have a potential role in the alleviation of obesity-related iron dyshomeostasis. This review verifies this hypothesis in theory. All the currently reported causes and results of obesity-related iron dyshomeostasis are reviewed comprehensively, together with the effects of selenium. The challenges and strategies of selenium supplementation are also discussed. The findings demonstrate the possibility of selenium-containing drugs or functional foods in alleviating obesity-related iron dyshomeostasis.
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http://dx.doi.org/10.1080/10408398.2022.2074961DOI Listing
May 2022

Qiangjing tablets repair of blood-testis barrier dysfunction in rats via regulating oxidative stress and p38 MAPK pathway.

BMC Complement Med Ther 2022 May 14;22(1):133. Epub 2022 May 14.

TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, The People's Republic of China.

Background: The blood-testis barrier (BTB) is a physical barrier of the testis to prevent various exogenous substrates from entering apical compartments and provides immune privilege for spermatogenesis, which is essential for normal spermatogenic function of testis. It has been shown that oxidative stress can damage BTB by activating the p38 MAPK pathway. In Traditional Chinese Medicine, Qiangjing tablets (QJT) improve spermatogenesis and increase pregnancy rates. Previous studies have confirmed that QJT can improve sperm quality and have obvious antioxidant effects. In this study, we explore whether QJT contributes to recovery from BTB dysfunction in rats.

Methods: BTB dysfunction was induced in rats by 1% Cyclophosphamide (CP). The CP-induced rats in the treatment group were given a dose of QJT (0.45 g/kg·d) by gavage. Testis tissues were collected for histopathological and biochemical analysis, and the testis weight was estimated. Levels of BTB-related proteins and antioxidant enzyme were analyzed in the testis tissues.

Results: QJT resolved the pathological injury of rats testis induced by CP. Furthermore, MDA levels were significantly reduced, and the levels of SOD markedly increased in the testicular tissue after QJT treatment. In addition, QJT down-regulated the expression of p38 protein in rat testis and up-regulated the expressions of key proteins ZO-1, occludin and F-actin in BTB.

Conclusion: These results demonstrate that QJT exerts protective effects on CP-induced rats with BTB dysfunction, likely by regulating the oxidative stress-mediated p38 MAPK pathway.
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http://dx.doi.org/10.1186/s12906-022-03615-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107122PMC
May 2022

Diagnosis and treatment of multiple myeloma in Hunan Province.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2022 Apr;47(4):497-504

Department of Hematology, Second Xiangya Hospital, Central South University, Changsha 410011, China.

Objectives: There is less clinical data on multiple myeloma (MM) in China, and the aim of this study was to collect and analyze the clinical data of newly diagnosed multiple myeloma (NDMM) patients in Hunan Province during 1 year, to understand the real clinical features and treatment outcome for Hunan Province patients with MM, and to strengthen the understanding of the standardized diagnosis process and treatment plan of MM.

Methods: The clinical data of 529 patients with NDMM in 12 large-scale general hospitals in Hunan Province from January 1 to December 31, 2019 were collected and analyzed, including baseline data, treatment regimens, duration of treatment, and adverse reactions. The clinical characteristics, treatment, and safety of patients were analyzed by SPSS 21.0.

Results: Among the 529 NDMM patients, the age was 33-90 (median 64) years and the male-female ratio was 1.38꞉1. The clinical features ranged from high to low were as follows: Bone pain (77.7%), anemia (66.8%), renal insufficiency (40.6%), hypercalcemia (15.1%). Typing: IgG 46.5%, IgA 24.6%, IgD 2.6%, IgM 0.8%, light chain 15.7%, double clone 3.0%, no secretion 0.6%, absence 6.2%. Staging: Durie-Salmon stage I, II, and III were 4.5%, 10.6%, 77.3%, respectively, and 40 cases (7.6%) missed this data. International Staging System (ISS) stage I, II, and III were 10.4%, 24.4%, and 47.6%, respectively, and 93 cases (17.6%) were missing. Revised International Staging System (R-ISS) stage I, II, and III were 5.5%, 27.0%, 23.1%, respectively, and 235 cases (44.4%) missed this data. Among the 98 NDMM patients in the Third Xiangya Hospital, Central South University, Durie-Salmon (DS) stage missing 2.0%, ISS stage missing 12.3%, and R-ISS stage missing 12.3%.Treatment: Among the 529 patients,475 received treatment, the rate of treatment was 89.8%; 67.4% of the patients were able to complete four courses of chemotherapy at induction phase, 90.3% of the patients received proteasome inhibitor based combination chemotherapy regimen more than once, 67.2% received immunomodulator based regimen more than once, and 59.8% of the patients received proteasome inhibitor and immunomodulator based combination chemotherapy regimen more than once. Curative: Overall response rate (ORR) and high quality response rate (HQR) of the 4-course group were better than those of the 2-course group (ORR: 85% vs 65%, =0.006; HQR: 68.3% vs 24.0%, <0.001). The HQR of the standard chemotherapy group was better than that of the non-standard chemotherapy group (65.1% vs 48.2%, =0.035). Adverse reactions during treatment included hematologic toxicity (17.5%), peripheral neuropathy (24.8%), gastrointestinal adverse events (23.8%), pulmonary infection (25.9%), herpes zoster (4.6%), and venous thrombotic events (1.7%).

Conclusions: In 2019, the missed diagnosis rate of MM patients was high, the medium age of diagnosis was older, and the accuracy of patient diagnosis was not high. There is a great difference among medical centers, especially in the stage and risk stratified, nearly half of NDMM patients are not diagnosed with R-ISS stage; the lack of cytogenetic data needs to be supplemented by follow-up studies. A high proportion of patients with NDMM present with bone pain and anemia.Patients received treatment have higher use of chemotherapy regimens containing proteasome inhibitors and/or immunomodulators, but there is a significant gap among different medical centers, and standardized treatment needs to be strengthened. The safety during chemotherapy is controllable.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2022.210555DOI Listing
April 2022

Engineered three-dimensional cardiac tissues maturing in a rotating wall vessel bioreactor remodel diseased hearts in rats with myocardial infarction.

Stem Cell Reports 2022 05 14;17(5):1170-1182. Epub 2022 Apr 14.

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Electronic address:

A rotating wall vessel (RWV) bioreactor was constructed for growing massive functional cardiac constructs to recover the function of a distressed rat heart. Three-dimensional cardiac tissues were engineered by seeding human-induced pluripotent stem cell-derived cardiomyocytes on poly(lactic-co-glycolic acid) fiber sheets (3D-hiPSC-CTs) and cultured in the RWV bioreactor (RWV group) or under static conditions (control group). The tissues were transplanted into a myocardial infarction nude rat model, and cardiac performance was evaluated. In the RWV group, cell viability and contractile and electrical properties significantly improved, mature cardiomyocytes were observed, and mechanical stress-related mediators of mammalian target of rapamycin signaling were upregulated compared with those of the control. Four weeks post-transplantation, tissue survival and left ventricular ejection fraction significantly improved in the RWV group. Hence, dynamic culture in an RWV bioreactor could provide a superior culture environment for improved performance of 3D-hiPSC-CTs, providing a means for functional cardiomyogenesis in myocyte-loss heart failure.
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http://dx.doi.org/10.1016/j.stemcr.2022.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133656PMC
May 2022

Zerumbone, a humulane sesquiterpene from Syringa pinnatifolia, attenuates cardiac fibrosis by inhibiting of the TGF-β1/Smad signaling pathway after myocardial infarction in mice.

Phytomedicine 2022 Jun 31;100:154078. Epub 2022 Mar 31.

State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address:

Background: Zerumbone (ZER) is a humulane sesquiterpene isolated from Syringa pinnatifolia Hemsl., a representative Mongolian herbal medicine that is used to treat cardiovascular diseases. Cardiac fibrosis is a common pathological process in cardiovascular disease that results from the excessive accumulation of extracellular matrix (ECM), and the transforming growth factor (TGF)-β/Smad pathway is a canonical signaling pathway that directly induces expressions of ECM-related genes. Currently, the cardioprotective effect and underlying mechanisms of ZER on the inhibition of cardiac fibrosis are not well known.

Purpose: To explore the cardioprotective properties and pharmacological mechanism of ZER against cardiac fibrosis via the TGF-β1/Smad signaling pathway.

Methods: Myocardial infarction (MI) model was induced by ligation of the left anterior descending coronary artery in ICR mice. The mice were randomly divided into six groups: sham, model, low-dose ZER (ZER-L), medium-dose ZER (ZER-M), high-dose ZER (ZER-H) and fosinopril. Mice in each group were intragastrically administered treatments for 21 days, and cardiac function was evaluated by 2D echocardiography. The pathological structure of the heart was examined by hematoxylin and eosin (HE) and Masson staining. Content of collagen I and collagen III were assessed by immunofluorescence methods. The inhibitory effect of ZER on TGF-β1 protein expression was predicted by molecular docking technology. Reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting were used to measure the levels of genes and proteins expressed in the TGF-β1/Smad signaling pathway and MMPs. TGF-β1-treated cardiac fibroblasts (CFs) of neonatal SD rats were adopted for in vitro studies.

Results: Cardiac ejection fraction (EF) and fractional shortening (FS) in the model group were markedly decreased compared with those in the sham group, indicating that the MI model was successfully established. ZER and fosinopril elevated EF and FS values, suggesting cardioprotective effects. Pathological staining and immunofluorescence analysis showed that the content of collagen I and collagen III increased in the cardiac tissue of mice in model group, while ZER treatment obviously reduced collagen levels. The molecular docking simulations predicted the hydrophobic interactions between ZER and TGF-β1. In addition, the expression of TGF-β1, p-Smad2/3 and MMPs in the ZER treatment group was significantly decreased compared with the model group. In vitro studies further confirmed that α-smooth muscle actin (α-SMA) and p-Smad2/3 increased markedly in cardiac fibroblasts after incubation with TGF-β1, and treatment with ZER suppressed the expression of α-SMA and TGF-β1 downstream proteins in cardiac fibroblasts.

Conclusion: ZER rescues cardiac function by attenuating cardiac fibrosis, and the antifibrotic effect may be mediated by blocking the TGF-β1/Smad pathway.
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http://dx.doi.org/10.1016/j.phymed.2022.154078DOI Listing
June 2022

Suppression of RPL34 Inhibits Tumor Cell Proliferation and Promotes Apoptosis in Glioblastoma.

Appl Biochem Biotechnol 2022 Aug 4;194(8):3494-3506. Epub 2022 Apr 4.

Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.

Accumulating evidence indicates Ribosomal protein 34 (RPL34) promotes tumor malignance and its expression is associated with poor prognosis in multiple cancer cells. However, the physiological role and biological mechanism of RPL34 in glioblastoma (GBM) remain unclear. Hence, this study aimed to investigate the expression and the role of RPL34 in GBM. A total of 59 glioma samples and 12 normal brains for epilepsy surgery were used to determine the underlying mechanisms and the biological behaviors of RPL34 in GBM. In this study, we identified that RPL34 expression was significantly (p < 0.05) enriched in GBM tumors compared with low-grade glioma and normal brain, and its expression was associated with poor survival. Additionally, RPL34 was functionally required for tumor proliferation in vitro. Mechanically, inhibition of RPL34 induced glioma cell apoptosis by activation of Bad/Caspase7/PARP signaling pathway. The RPL34 promotes cell survival in GBM and could be a potential therapeutic target for GBM.
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http://dx.doi.org/10.1007/s12010-022-03857-0DOI Listing
August 2022

Satellite Cells are Activated in a Rat Model of Radiation-Induced Muscle Fibrosis.

Radiat Res 2022 06;197(6):638-649

Graduate Collaborative Training of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Department of Head and Neck Surgery, Central laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.

Radiation-induced muscle fibrosis is a long-term side effect of radiotherapy that significantly affects the quality of life and even reduces the survival of cancer patients. We have demonstrated that radiation induces satellite cell (SC) activation at the molecular level; however, cellular evidence in a rat model of radiation-induced muscle fibrosis was lacking. In this study, we evaluated SC activation in vivo and investigated whether radiation affects the proliferation and differentiation potential of SCs in vitro. For in vivo studies, Sprague-Dawley rats were randomly divided into six groups (n = 6 per group): non-irradiated controls, 90 Gy/1 week-, 90 Gy/2 weeks-, 90 Gy/4 weeks-, 90 Gy/12 weeks- and 90 Gy/24 weeks-postirradiation groups. Rats received a single dose of radiation in the left groin area and rectus femoris tissues were collected in the indicated weeks. Fibrosis, apoptosis, and autophagy were evaluated by Masson's trichrome staining, TUNEL staining, and electron microscopy, respectively. SC activation and central nuclear muscle fibers were evaluated by immunofluorescence staining and hematoxylin and eosin staining. IL-1β concentrations in serum and irradiated muscle tissue samples were determined by ELISA. For in vitro studies, SCs were isolated from rats with radiation-induced muscle fibrosis and their proliferation and differentiation were evaluated by immunofluorescence staining. In vivo, fibrosis increased over time postirradiation. Apoptosis and autophagy levels, IL-1β concentrations in serum and irradiated skin tissues, and the numbers of SCs and central nuclear muscle fibers were increased in the irradiated groups when compared with the control group. In vitro, cultured SCs from irradiated muscle were positive for the proliferation marker Pax7, and differentiated SCs were positive for the myogenic differentiation marker MyHC. This study provided cellular evidence of SC activation and proliferation in rats with radiation-induced muscle fibrosis.
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http://dx.doi.org/10.1667/RADE-21-00183.1DOI Listing
June 2022

Programmed death-ligand 1 signaling and expression are reversible by lycopene via PI3K/AKT and Raf/MEK/ERK pathways in tongue squamous cell carcinoma.

Genes Nutr 2022 Feb 14;17(1). Epub 2022 Feb 14.

Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410073, Changsha, People's Republic of China.

Background: Cancer therapy targeting programmed death receptor-1 (PD-1 or CD279) or programmed death-ligand 1 (PD-L1 or CD274) gives hope to Tongue Squamous Cell Carcinoma (TSCC) treatment. However, the tumor-intrinsic mechanism of PD-L1 is not fully elucidated in TSCC. On the other hand, lycopene showed antitumor effects and chemotherapy/radiotherapy-enhancing effects by mechanisms closely correlated with PD-L1.

Purpose: We aimed to explore whether the mechanisms of PD-L1 signaling and regulation are reversible by lycopene treatment in TSCC.

Methods: We collected TSCC tissues and normal tissues for assessment of PD-L1 expression by immunohistochemical technique and western blotting. We measured the expression of PD-L1 in three TSCC cell lines and constructed cell lines with knockdown and overexpression of PD-L1. Then, we measured the proliferation by CCK-8 assay, migration and invasion by Transwell assay, and apoptosis by TUNEL assay in five groups with treatment of blank control, negative control with vector transfection, PD-L1 knockdown/overexpression, 4 μM lycopene, and combined 4 μM lycopene and PD-L1 knockdown/overexpression. We also systematically analyzed the PD-L1 constitutive signaling pathways and their effect EMT pathways. In order to bring out the mechanism underlying PI3K/AKT depressing Raf/MEK/ERK, we used PI3K inhibitor LY294002.

Results: We detected significant PD-L1 upregulation in biopsies by western blot and immunohistochemistry. Our study demonstrated that PD-L1 upregulation elevated IGF-1R to activate the PI3K/AKT pathway but inactivated the Raf/MEK/ERK pathway in TSCC cell line CAL27, while PD-L1 knockdown decreased IGF-1R to inactivate both PI3K/AKT and Raf/MEK/ERK pathways in cell line SCC9, to increase/decrease p-FOXOs and decrease/increase p-GSK-3β, producing further changes in EMT, proliferation, migration, invasion, and apoptosis. Lycopene reversed PD-L1 signaling and expression by mechanisms opposite to PD-L1 upregulation but similar to PD-L1 knockdown.

Conclusion: Taken together, this study firstly confirmed PD-L1 expression and signaling are reversible by lycopene via PI3K/AKT and Raf/MEK/ERK pathways in TSCC. Our study provides a sounder basis for comprehending PD-L1 signaling and expression and prevention and treatment of TSCC.
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http://dx.doi.org/10.1186/s12263-022-00705-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903509PMC
February 2022

Correlative analysis of lung CT findings in patients with Birt-Hogg-Dubé Syndrome and the occurrence of spontaneous pneumothorax: a preliminary study.

BMC Med Imaging 2022 02 7;22(1):22. Epub 2022 Feb 7.

Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.

Background: The diagnosis of patients with Birt-Hogg-Dubé (BHD) syndrome is always delayed (even for more than 10 years). Improving the understanding and diagnosis of this disease is vital for clinicians and radiologists. In this study we presented the chest computed tomography (CT) findings of BHD syndrome and offered suggestions for BHD cases with spontaneous pneumothorax.

Methods: Twenty-six BHD patients from 11 families (10 men, 16 women; mean age: 46 ± 12 years, 20-68 years) were included. The clinical features of the patients included pneumothorax, renal lesions, and skin lesions. Twenty-three patients underwent chest CT imaging. The cyst condition of each patient derived from reconstructed chest CT imaging was recorded, including the cyst number, size, volume, pattern, and distribution.

Results: Pneumothorax occurred in 54% (14/26) of patients. Among them, 43% (6/14) had pneumothorax more than twice. However, typical skin and renal lesions were absent. Four patients had renal hamartoma. CT showed that 23 (100%) patients had lung cysts. Pulmonary cysts were bilateral and multiple, round, irregular, or willow-like. And 93.6% of the large cysts (long-axis diameter ≥ 20 mm) were under the pleura, and near the mediastinum and spine. The long-axis diameter, short-axis diameter and volume of the largest cysts were associated with the occurrence of pneumothorax (all P < 0.05).

Conclusions: Chest CT imaging can reveal some characteristic features of BHD syndrome. The occurrence of pneumothorax in BHD patients is closely related to their pulmonary cystic lesions.
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http://dx.doi.org/10.1186/s12880-022-00743-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819866PMC
February 2022

Grazing exclusion had greater effects than nitrogen addition on soil and plant community in a desert steppe, Northwest of China.

BMC Plant Biol 2022 Feb 3;22(1):60. Epub 2022 Feb 3.

School of Life Sciences, Lanzhou University, No. 222, Southern Tianshui Road, Lanzhou, 730000, China.

Background: The impacts of increasing nitrogen (N) deposition and overgrazing on terrestrial ecosystems have been continuously hot issues. Grazing exclusion, aimed at restoration of grassland ecosystem function and service, has been extensively applied, and considered a rapid and effective vegetation restoration method. However, the synthetic effects of exclosure and N deposition on plant and community characteristics have rarely been studied. Here, a 4-year field experiment of N addition and exclusion treatment had been conducted in the desert steppe dominated by Alhagi sparsifolia and Lycium ruthenicum in northwest of China, and the responses of soil characteristics, plant nutrition and plant community to the treatments had been analyzed.

Results: The grazing exclusion significantly increased total N concentration in the surface soil (0-20 cm), and increased plant height, coverage (P < 0.05) and aboveground biomass. Specifically, A. sparsifolia recovered faster both in individual and community levels than L. ruthenicum did after exclusion. There was no difference in response to N addition gradients between the two plants.

Conclusions: Our findings suggest that it is exclusion rather than N addition that has greater impacts on soil properties and plant community in desert steppe. Present N deposition level has no effect on plant community of desert steppe based on short-term experimental treatments.
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http://dx.doi.org/10.1186/s12870-021-03400-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812004PMC
February 2022

Nanocasting of fibrous morphology on a substrate for long-term propagation of human induced pluripotent stem cells.

Biomed Mater 2022 02 18;17(2). Epub 2022 Feb 18.

Institute for Integrated Cell-Material Science, Kyoto University, Kyoto 606-8501, Japan.

Human-induced pluripotent stem cells (hiPSCs) can be self-renewed for many generations on nanofibrous substrates. Herein, a casting method is developed to replicate the nanofibrous morphology into a thin layer of polymethylsiloxane (PDMS). The template is obtained by electrospinning and chemical crosslinking of gelatin nanofibers on a glass slide. The replicas of the template are surface-functionalized by gelatin and used for propagation of hiPSCs over tenth generations. The performance of the propagated hiPSCs is checked by immunofluorescence imaging, flowcytometry, and RT-PCR, confirming the practicability of this method. The results are also compared to those obtained using electrospun nanofiber substrates. Inherently, the PDMS replica is of low stiffness and can be reproduced easily. Compared to other patterning techniques, casting is more flexible and cost-effective, suggesting that this method might find applications in cell-based assays that rely on stringent consideration of both substrate stiffness and surface morphology.
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http://dx.doi.org/10.1088/1748-605X/ac51b8DOI Listing
February 2022

Extraordinary p-d Hybridization Interaction in Heterostructural Pd-PdSe Nanosheets Boosts C-C Bond Cleavage of Ethylene Glycol Electrooxidation.

Angew Chem Int Ed Engl 2022 Apr 7;61(16):e202200899. Epub 2022 Feb 7.

Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Department of Chemistry, School of Science, Tianjin University & Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300072, P. R. China.

Advanced electrocatalysts for complete oxidation of ethylene glycol (EG) in direct EG fuel cells are strongly desired owing to the higher energy efficiency. Herein, Pd-PdSe heterostructural nanosheets (Pd-PdSe HNSs) have been successfully fabricated via a one-step approach. These Pd-PdSe HNSs feature unique electronic and geometrical structures, in which unconventional p-d hybridization interactions and tensile strain effect co-exist. Compared with commercial Pd/C and Pd NSs catalysts, Pd-PdSe HNSs display 5.5 (6.6) and 2.5 (2.6) fold enhancement of specific (mass) activity for the EG oxidation reaction (EGOR). Especially, the optimum C1 pathway selectivity of Pd-PdSe HNSs reaches 44.3 %, illustrating the superior C-C bond cleavage ability. Electrochemical in situ FTIR spectroscopy and theoretical calculations demonstrate that the extraordinary p-d hybridization interaction and tensile strain effect could effectively reduce the activation energy of C-C bond breaking and accelerate CO* oxidation, boosting the complete oxidation of EG and improving the catalytic performance.
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http://dx.doi.org/10.1002/anie.202200899DOI Listing
April 2022

miR-140-3p attenuated the tumorigenesis of multiple myeloma via attenuating BZW2.

Hematology 2022 Dec;27(1):173-180

Department of Hematology, The 1st Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, People's Republic of China.

Background: Among B-cell lymphoma, multiple myeloma (MM) is an incurable malignancy. miR-140-3p was known to be an inhibitor in malignant tumors. However, the function of miR-140-3p in MM remains unclear.

Methods: qRT-PCR was performed to determine the expressions of miR-140-3p and BZW2 mRNA. The protein level of BZW2 was determined by the western blot. Cell viability or cell apoptosis was detected by the MTT assay or flow cytometry, respectively. Binding between miR-140-3p and BZW2 was validated using the dual luciferase assay. Xenograft model was applied to verify the results of study.

Results: The level of miR-140-3p was significantly downregulated in MM. Overpexression of miR-140-3p impaired the proliferation of MM cell lines and induced apoptosis in MM cells. miR-140-3p was validated to target BZW2 and inhibit the expression of BZW2. BZW2 was involved in the regulation of miR-140-3p on MM cell vitality and apoptosis. In vivo study revealed that miR-140-3p impeded tumorigenesis of MM cell line in nude mice.

Conclusion: Our present study revealed that miR-140-3p served as a suppressor in MM by negatively regulating BZW2. Thus, miR-140-3p could act as a new target for treating MM.
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http://dx.doi.org/10.1080/16078454.2021.2009644DOI Listing
December 2022

Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes.

Stem Cell Reports 2022 02 20;17(2):337-351. Epub 2022 Jan 20.

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation. After monolayer differentiation, plakophilin-2 deficiency led to reduced contractility, disrupted intercalated disc structures, and impaired desmosome assembly in iPSC-CMs. Allele-specific fluorescent labeling of endogenous DSG2 encoding desmoglein-2 in the generated isogenic lines enabled real-time desmosome-imaging under an adjusted dose of plakophilin-2. Adeno-associated virus-mediated gene replacement of PKP2 recovered contractility and restored desmosome assembly, which was sequentially captured by desmosome-imaging in plakophilin-2-deficient iPSC-CMs. Our isogenic set of iPSC-CMs recapitulates AC pathology and provides a rapid and convenient cellular platform for therapeutic development.
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http://dx.doi.org/10.1016/j.stemcr.2021.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828557PMC
February 2022

miR-378d suppresses malignant phenotype of ESCC cells through AKT signaling.

Cancer Cell Int 2021 Dec 22;21(1):702. Epub 2021 Dec 22.

Department of Pathology, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272029, Shandong, China.

Background: Post-resistance progress in paclitaxel (PTX) treatment remains a major challenge in tumor treatment. A high dose of PTX was used for cell lines to analyze the changes in molecular expression. The miR-378d was sharply reduced in surviving cells, but the role of miR-378d in Esophageal squamous cell carcinoma (ESCC) remained unclear.

Methods: We analyzed the relationship between miR-378d expression and the clinicopathological features of ESCC. We constructed miR-378d silent expression cell lines to study phenotypes and molecular mechanisms.

Results: The miR-378d expression was associated with good prognosis in patients with ESCC. miR-378d inhibition promoted chemo-resistance, monoclonal formation, EMT, migration, invasion, stemness, and metastasis of ESCC cells. miR-378d can target downregulated AKT1.

Conclusions: Therefore, miR-378d expression is a good prognostic factor of patients with ESCC and regulates the malignant phenotype of tumor cells through AKT.
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http://dx.doi.org/10.1186/s12935-021-02403-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8697470PMC
December 2021

T3 Promotes Glioma Cell Senescence and Apoptosis via THRA and THRB.

J Environ Pathol Toxicol Oncol 2021 ;40(4):1-9

Institute of Neuroscience, Kunming Medical University, Kunming, Yunnan, China.

Glioma is one of the most common types of primary intracranial tumors. The relationship between triiodothyronine (T3) and glioma is not clear. This study aimed to investigate the effect of T3 on the proliferation of glioma cells and its mechanism. Cell viability was analyzed by cell counting kit 8 assay. Flow cytometry analysis was used to detect cell apoptosis and cell cycle. Thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) were silenced by transfecting si-THRA and si-THRB plasmids into HS683 and A172 glioma cells. Western blot was performed to assess the protein expressions. The results indicated that triiodothyronine (T3) affected the viability, apoptosis and cell cycle of HS683 and A172 glioma cells. Cell apoptosis was significantly inhibited in si-THRA and si-THRB experimental groups. Moreover, knockdown of THRA and THRB reversed the G1 and G2 phase arrest led by T3 and induced an up-regulation of cyclin D1 expression. The phosphorylated extracellular signal-regulated kinase (p-ERK), p-AKT, and phosphorylated signal transducer and activator of transcription (p-STAT3) proteins were markedly increased by inhibiting THRA and THRB in HS683 and A172 glioma cells. T3 affected apoptosis and cell cycle of glioma cells through regulating THRA and THRB expressions. THRA and THRB may affect glioma development through regulating, at least partially, the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways.
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http://dx.doi.org/10.1615/JEnvironPatholToxicolOncol.2021038740DOI Listing
January 2022

Qishen granule (QSG) exerts cardioprotective effects by inhibiting NLRP3 inflammasome and pyroptosis in myocardial infarction rats.

J Ethnopharmacol 2022 Mar 16;285:114841. Epub 2021 Nov 16.

College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Qishen granule (QSG) is a traditional Chinese medicine formulation that is widely used in clinical practice for the treatment of myocardial infarction (MI), and its efficacy and safety have been well approved. However, the underlying mechanism by which QSG alleviates inflammation and cell pyroptosis remains unknown.

Aim Of The Study: The aim of this study was to clarify whether QSG ameliorated MI by inhibiting inflammasome activation and cell pyroptosis.

Materials And Methods: In vivo, SD male rats were subjected to the left anterior ascending branch (LAD) ligation to construct MI model. And in vitro, OGD/R, ISO, Ang II and LPS-ATP were used to induce H9C2 cell injury. Cell viability and ROS were detected by CCK8 and DCFH-DA dye respectively. Western blots were applied to detect the expression of inflammasome-related proteins. Cell pyroptosis was evaluated by Calcein-AM/PI staining, Hoechst/PI staining and NT-GSDMD expression.

Results: QSG administration improved the cardiac function, as well as reduced inflammatory cell infiltration and collagen deposition. In H9C2 cells, OGD/R failed to induce inflammasome activation, while ISO, Ang II and LPS-ATP successfully induced inflammasome activation and cell pyroptosis, as evidenced by increased Caspase-1(P20) and NT-GSDMD. In LPS-ATP induced H9C2 model, ROS production and cell pyroptosis were suppressed when treated with QSG. Furthermore, QSG significantly decreased the protein levels of P65-NF-κB, NLRP3, ASC, Caspase-1 (P20), Cleaved IL-18, Cleaved IL-1β and NT-GSDMD.

Conclusion: This study is the first to demonstrate that QSG has cardioprotective effects by inhibiting inflammasome activation and pyroptosis, which are considered as promising therapeutic targets for MI.
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http://dx.doi.org/10.1016/j.jep.2021.114841DOI Listing
March 2022
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