Publications by authors named "Yu Ren"

328 Publications

Mining the prognostic significance and immune infiltration of family members in human breast cancer by bioinformatics analysis.

Gland Surg 2022 Apr;11(4):720-741

Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Growing evidence proved that signal transducer and activators of transcription () proteins are cytoplasmic transcription factors known to play key roles in many cellular biological processes and may be prognostic predictors of some cancers. However, the role of each family members in breast cancer (BRCA) is diverse and controversial. This study aimed to systematic mine the prognostic significance and immune infiltration of family member in human BRCA.

Methods: Based on The Cancer Genome Atlas (TCGA) database, we used the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA) and The Human Protein Atlas to analyze the expression of family members in normal human breast and tumor tissues. The Kaplan-Meier Plotter, GEPIA and PrognoScan were utilized to assess the prognostic value of different in BRCA. Then we used the cBioPortal, STRING, GeneMANIA and Metascape to make further mutation analysis, protein-protein interaction (PPI) analysis and subsequent functional enrichment analysis. Finally, the "ESTIMATE" and "ggcorrplot" package of R 17 software were used for immune infiltration analysis.

Results: [P<0.01, hazard ratio (HR) =1.23, 95% confidence interval (CI): 1.07-1.42] and (P=0.018, HR =0.69, 95% CI: 0.51-0.94) could be an independent risk factor for predicting overall survival (OS). could be used as an independent predictor of distant metastasis-free survival in BRCA based on both GSE19615 (P=0.021, HR =0.21, 95% CI: 0.06-0.79) and GSE2034 (P=0.015, HR =0.57, 95% CI: 0.37-0.90) datasets. Meanwhile, , and also have been shown to independently predict the prognosis of BRCA. Additionally, the functional mechanisms of co-expressed genes were mainly focused on immune-related pathways and its expression was associated with immune checkpoint-associated genes and immunomodulators in BRCA.

Conclusions: Our study mined the prognostic significance of family members in BRCA and their correlation with immune infiltration. The results suggest that individual , except , may act as a prognostic biomarker for BRCA and provide a reference for further potential immunotherapies.
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http://dx.doi.org/10.21037/gs-22-189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068537PMC
April 2022

MCC950 ameliorates the dementia symptom at the early age of line M83 mouse and reduces hippocampal α-synuclein accumulation.

Biochem Biophys Res Commun 2022 Apr 20;611:23-30. Epub 2022 Apr 20.

CAS Key Laboratory of Receptor Research, Center for Neurological and Psychiatric Research and Drug Discovery (CNPRDD), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. Electronic address:

Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia after Alzheimer's disease (AD). Neuroinflammation plays an important role in neurodegenerative diseases. It is urgent to unravel the pathogenesis of DLB and find potential therapeutic drugs. Here, we investigated the pharmacological effects of the NLRP3 inflammasome inhibitor MCC950 in A53T α-synuclein transgenic line M83 mice aged 4 months. The behavioral tests including Y-maze, Barnes maze, nest building and Rotarod showed that MCC950 significantly improved the cognitive dysfunction symptom without affecting the motor coordination after consecutive intragastric administration every day for 5 weeks. Furthermore, immunostaining or immunoblotting experiments on the hippocampal tissue were performed, and the results suggested that MCC950 not only inhibited the expression of NLRP3, and suppressed the activation of astrocytes and microglia, but also promoted the mTOR-mediated autophagy pathway to reduce human α-synuclein accumulation. Our findings further demonstrate that line M83 mice may be used as an animal model for DLB research, and can provide preclinical evidences for the development of MCC950 as a promising therapeutic drug.
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http://dx.doi.org/10.1016/j.bbrc.2022.04.076DOI Listing
April 2022

hUC-MSCs lyophilized powder loaded polysaccharide ulvan driven functional hydrogel for chronic diabetic wound healing.

Carbohydr Polym 2022 Jul 28;288:119404. Epub 2022 Mar 28.

College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address:

In this study, we used the polysaccharide ulvan from the green macroalgae Ulva fenestrata to prepare the hydrogel for chronic diabetic wound healing. A natural polysaccharide-based hydrogel matrix (UC-DPA-Ag hydrogel) was prepared using ulvan dialdehyde, chitosan, dopamine (DPA) and silver nanoparticles (Ag NPs). Human umbilical cord mesenchymal stem cell lyophilized powder (hUC-MSCs) was loaded into the hydrogel to develop a novel chronic diabetic wound healing material ([email protected]). The resulting hydrogel features adequate mechanical properties, swelling capability, adhesiveness, antioxidant, antibacterial ability, and promoting cell proliferation and migration. In vivo wound healing in type II diabetic mellitus mouse wound model showed that hUC-MSCs loaded UC-DPA-Ag hydrogel could accelerate wound healing effectively. This advanced hydrogel provides a facile and effective way for diabetic chronic wound management. Furthermore, it offers a new route for the utilizing Ulva as a valuable biomaterial for the global and large-scale production of valued added biomaterials.
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http://dx.doi.org/10.1016/j.carbpol.2022.119404DOI Listing
July 2022

Development of Early-Life Gastrointestinal Microbiota in the Presence of Antibiotics Alters the Severity of Acute DSS-Induced Colitis in Mice.

Microbiol Spectr 2022 Apr 19:e0269221. Epub 2022 Apr 19.

Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.

Early-life gastrointestinal microbiota development is crucial for physiological development and immunological homeostasis. In the current study, perinatal microbiota and the development of gastrointestinal microbiota in different early-life periods (perinatal, lactation, and postweaning nutrition periods) were explored by using an antibiotic-interfered mouse model and a dextran sulfate sodium-induced colitis mouse model. Gut microbiota samples were collected from mother mice and litters. The results of 16S rRNA gene sequences suggested that microbiota in the gastrointestinal system were present in prenatal fetal mice, and microbiota structures in different parts of the gastrointestinal system of the fetal mice were similar to those in the corresponding gut parts of maternal mice. Microbiota in mucus samples from different regions exhibited higher diversity at birth than at other periods and varied substantially over time with diet change. Moreover, antibiotic treatment in early life affected the composition and diversity of gastrointestinal microbiota in adult mice and enhanced susceptibility to experimental colitis in mice, particularly in the lactation period. This approach of exploring gut microbiota evolution is hoped to provide an enhanced view of how resident microbiota develop in early life, which in turn might facilitate understanding of gut microbiota and related diseases. This study investigated resident microbiota in the whole gastrointestinal (GI) tract to explore gut microbiota development in early life and found that early-life antibiotic exposure exacerbated alterations in gut microbiota and murine dextran sulfate sodium (DSS)-induced colitis. Furthermore, the presence of bacteria in the GI tract of mice before birth and the importance of the lactation period in GI microbiota development were confirmed.
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http://dx.doi.org/10.1128/spectrum.02692-21DOI Listing
April 2022

Differentially expressed microRNAs during the differentiation of muscle-derived stem cells into insulin-producing cells, a promoting role of microRNA-708-5p/STK4 axis.

PLoS One 2022 8;17(4):e0266609. Epub 2022 Apr 8.

Reproductive Medicine Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, China.

Objective: Stem cell therapy is a promising approach for diabetes via promoting the differentiation of insulin-producing cells (IPCs). This study aimed to screen the differentially expressed miRNAs (DEmiRNAs) during the differentiation of muscle-derived stem cells (MDSCs) into IPCs, and uncover the underlying function and mechanism of a specific DEmiRNA, miR-708-5p.

Methods: MDSCs were successfully isolated from the leg muscle of rats, and were induced for IPCs differentiation through a five-stage protocol. miRNA microarray assay was performed for screening DEmiRNAs during differentiation. The features of MDSCs-derived IPCs were identified by qRT-PCR, flow cytometry, and immunofluorescence staining. The targeting of STK4 by miR-708-5p was examined by luciferase assay. The protein expression of STK4, YAP1, and p-YAP1 was determined by Western blot and immunofluorescence staining.

Results: MDSCs were successfully isolated and differentiated into IPCs. A total of 12 common DEmiRNAs were obtained during five-stage differentiation. Among them, miR-708-5p that highly expressed in MDSCs-derived IPCs was selected. Overexpression of miR-708-5p upregulated some key transcription factors (Pdx1, Ngn3, Nkx2.2, Nkx6.1, Gata4, Gata6, Pax4, and Pax6) involving in IPCs differentiation, and increased insulin positive cells. In addition, STK4 was identified as the target gene of miR-708-5p. miR-708-5p overexpression downregulated the expression of STK4 and the downstream phosphorylated YAP1.

Conclusions: There were 12 DEmiRNAs involved in the differentiation of MDSCs into IPCs. miR-708-5p promoted MDSCs differentiation into IPCs probably by targeting STK4-mediated Hippo-YAP1 signaling pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266609PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8992996PMC
April 2022

Analysis of COVID-19 Collective Irrationalities Based on Epidemic Psychology.

Authors:
Hua Luo Yu Ren

Front Psychol 2022 21;13:825452. Epub 2022 Mar 21.

Department of Pharmacy, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China.

As the SARS-CoV-2 virus swept the world in late 2019, it has brought widespread fear, some suspicion, and degrees of stigma. In the shadow of the COVID-19 pandemics, a series of collective irrationalities such as panic buying, protest marches against vaccines, and pandemic stigma occurred. This phenomenon is inseparable from the spread of rumors about the epidemic. The advent of social media has radically changed the way we consume information and form opinions and made a flood of digital misinformation becoming ubiquitous. The diffusion of false rumors affects the public's perception of reality and disrupts the prevention of the epidemic. This paper analyzes the COVID-19 collective irrationalities from epidemic psychology to provide a new reference view for overcoming psychological problems related to COVID-19.
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http://dx.doi.org/10.3389/fpsyg.2022.825452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977506PMC
March 2022

FMNL2 suppresses cell migration and invasion of breast cancer: a reduction of cytoplasmic p27 via RhoA/LIMK/Cofilin pathway.

Cell Death Discov 2022 Apr 4;8(1):155. Epub 2022 Apr 4.

Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, P.R. China.

Formin-like protein 2 (FMNL2) belongs to a highly conserved family of cytoskeletal remodeling proteins that have been reported to be implicated in various actin-dependent physiological and cancer-associated processes. In this study, we mainly investigated the effects of FMNL2 on breast cancer cell migration and invasion, and the underlying mechanisms involved. We found that FMNL2 reduced cell migration and invasion of breast cancer in vitro and in vivo. Further, FMNL2 disrupted actin cytoskeleton rearrangement and hampered the RhoA/LIMK/Cofilin pathway in breast cancer cells. Critically, both Rho inhibitor ZOL and LIMK inhibitor BMS3 significantly abrogated these migration-promoting effects in FMNL2-silencing MDA-MB-231 and BT549 cells. RhoA/LIMK/Cofilin pathway was involved in FMNL2 silencing-induced actin cytoskeleton rearrangement in MDA-MB-231 and BT549 cells. More importantly, cytoplasmic p27 promoted FMNL2-mediated cell migration and invasion through RhoA/LIMK/Cofilin pathway in MCF7 and MDA-MB-231 cells. In addition, the expression and prognosis of FMNL2 were associated with ER in breast cancer. Furthermore, ERα overexpression reduced the protein levels of FMNL2 in breast cancer cells, which were reversed by MG132. In conclusion, FMNL2 suppressed cell migration and invasion of breast cancer by inhibiting RhoA/LIMK/Cofilin pathway through a reduction of cytoplasmic p27. This finding implies that the interference of FMNL2-mediated RhoA/LIMK/Cofilin pathway involving the cytoplasmic p27 may be a promising strategy for ameliorating breast cancer metastasis and prognosis.
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http://dx.doi.org/10.1038/s41420-022-00964-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980084PMC
April 2022

Feeding of L-Leucine Improves Antioxidative Capacity and Spleen Weight and Changes Amino Acid Concentrations in Broilers After Chronic Thermal Stress.

Front Vet Sci 2022 18;9:862572. Epub 2022 Mar 18.

Research Center for Livestock Environmental Control and Smart Production, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.

L-Leucine (L-Leu) was demonstrated to confer thermotolerance by feeding in broiler chicks and chickens in our previous studies. However, the L-Leu-mediated roles in recovering from the detrimental effects of heat stress in broilers are still unknown. This study aimed to investigate the effects of L-Leu feeding on the growth performance, relative weight of organs, serum metabolites and antioxidant parameters, and gene expression profiles in broiler chickens after chronic heat stress. Fertilized broiler eggs (Ross 308) were subjected to feeding of sterile water (0.5 mL/egg) or L-Leu (69 μmol/0.5 mL/egg) on embryonic day 7. After hatching, the male chicks were separated and used for the current study. All chickens were subjected to thermal stress exposure from 21 to 39 days of age and 1 week of recovery from 40 to 46 days of age. The results showed that feeding of L-Leu did not affect the body weight gain or relative weight of organs under chronic heat stress; however, the serum glutathione peroxidase was significantly increased and serum malondialdehyde was significantly decreased by L-Leu at 39 days of age. After 1 week of recovery, feeding of L-Leu significantly improved the relative spleen weight at 46 days of age. Subsequent RNA-seq analysis in the spleen showed that a total of 77 significant differentially expressed genes (DEGs) were identified, including 62 upregulated DEGs and 15 downregulated DEGs. Aspartic-type endopeptidase and peptidase activities were upregulated after recovery in the L-Leu group. The expression of genes related to B cell homeostatic proliferation and vestibular receptor cell differentiation, morphogenesis and development was downregulated in the L-Leu group. Moreover, the concentrations of serum catalase, total antioxidative capacity, isoleucine and ammonia were significantly decreased by L-Leu feeding after recovery. These results suggested that L-Leu feeding promoted the recovery of antioxidative status after chronic heat stress in broiler chickens.
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http://dx.doi.org/10.3389/fvets.2022.862572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971722PMC
March 2022

PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK.

Int J Biol Sci 2022 28;18(5):2032-2046. Epub 2022 Feb 28.

Department of breast surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

The progressive, multifactorial and multistep dynamic process of metastasis is the primary cause of breast cancer (BC) lethality. PROX1 (Prospero-related homeobox 1), as a type of transcription factor that plays a key role in the formation of lymphatic vessels in animal embryonic development, has been proven to promote or suppress cancer in a variety of malignant tumors. However, molecular mechanisms behind PROX1 induced breast cancer metastases remain elusive. Changes of PROX1 expression and clinical significance of PROX1 in BC were evaluated by BC tissue, as well as public database. The functional role of PROX1 in metastases BC was analyzed by transwell assay , and by lung metastases model of nude mice via lentivirus mediated knockdown assays. Mechanism studies were performed by public database screening, western blot and PCR assay, immunoprecipitation, immunofluorescence staining and luciferase promoter assays. In this study, we found that PROX1 was upregulated in breast cancer tissues; increased PROX1 expression in breast cancer was associated with tumor size, lymph node metastasis, ER and PR status. Meanwhile, PROX1 can promote breast cancer invasion and metastasis and . Furthermore, PROX1 can interact with hnRNPK to activate WNT/β-catenin signaling in breast cancer cells. Moreover, the interaction of PROX1 and hnRNPK inhibits the ubiquitination of hnRNPK, and subsequently activates WNT pathway to promote the invasion and metastasis of breast cancer. In conclusion, our findings indicated PROX1 contributes to breast cancer EMT and metastasis and serves as a candidate diagnostic biomarker and promising therapeutic target for breast cancer.
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http://dx.doi.org/10.7150/ijbs.68960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935233PMC
April 2022

Nanoarchitectonics of Illite-Based Materials: Effect of Metal Oxides Intercalation on the Mechanical Properties.

Nanomaterials (Basel) 2022 Mar 18;12(6). Epub 2022 Mar 18.

Key Laboratory of Karst Georesources and Environment, Ministry of Education, College of Resources and Environmental Engineering, Guizhou University, Guiyang 550025, China.

Clay minerals inevitably interact with colloidal oxides (mainly iron and aluminum oxides) in the evolution of natural geomaterials. However, the interaction between the clay minerals and the colloidal oxides affecting the stability and the strength of geotechnical materials remains poorly understood. In the present work, the interaction between the clay minerals and the colloidal oxides was investigated by reaction molecular dynamics simulations to explore the mechanical properties of illite-based materials. It was found that the metal atoms of the intercalated amorphous iron and aluminum oxides interact with oxygen atoms of the silica tetrahedron at the interface generating chemical bonds to enhance the strength of the illite-based materials considerably. The deformation and failure processes of the hybrid illite-based structures illustrated that the Al-O bonds were more favorable to the mechanical properties' improvement of the hybrid system compared with Fe-O bonds. Moreover, the anisotropy of illite was greatly improved with metal oxide intercalation. This study provides new insight into the mechanical properties' improvement of clay-based materials through metal oxides intercalation.
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http://dx.doi.org/10.3390/nano12060997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8951239PMC
March 2022

Targeting the Erk1/2 and autophagy signaling easily improved the neurobalst differentiation and cognitive function after young transient forebrain ischemia compared to old gerbils.

Cell Death Discov 2022 Feb 26;8(1):87. Epub 2022 Feb 26.

Medical College, Institute of Translational Medicine, Department of Neurology, Affiliated Hospital of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou University, Yangzhou, 225001, PR China.

The hippocampal neurogenesis occurs constitutively throughout adulthood in mammalian species, but declines with age. In this study, we overtly found that the neuroblast proliferation and differentiation in the subgranular zone and the maturation into fully functional and integrated neurons in the granule-cell layer in young gerbils following cerebral ischemia/reperfusion was much more than those in old gerbils. The neurological function and cognitive and memory-function rehabilitation in the young gerbils improved faster than those in the old one. These results demonstrated that, during long term after cerebral ischemia/reperfusion, the ability of neurogenesis and recovery of nerve function in young animals were significantly higher than that in the old animals. We found that, after 14- and 28-day cerebral ischemia/reperfusion, the phosphorylation of MEK1/2, ERK1/2, p90RSK, and MSK1/2 protein levels in the hippocampus of young gerbils was significantly much higher than that of old gerbils. The levels of autophagy-related proteins, including Beclin-1, Atg3, Atg5, and LC3 in the hippocampus were effectively maintained and elevated at 28 days after cerebral ischemia/reperfusion in the young gerbils compared with those in the old gerbils. These results indicated that an increase or maintenance of the phosphorylation of ERK1/2 signal pathway and autophagy-related proteins was closely associated with the neuroblast proliferation and differentiation and the process of maturation into neurons. Further, we proved that neuroblast proliferation and differentiation in the dentate gyrus and cognitive function were significantly reversed in young cerebral ischemic gerbils by administering the ERK inhibitor (U0126) and autophagy inhibitor (3MA). In brief, following experimental young ischemic stroke, the long-term promotion of the neurogenesis in the young gerbil's hippocampal dentate gyrus by upregulating the phosphorylation of ERK signaling pathway and maintaining autophagy-related protein levels, it overtly improved the neurological function and cognitive and memory function.
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http://dx.doi.org/10.1038/s41420-022-00888-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882190PMC
February 2022

Intraoperative vancomycin powder to reduce surgical site infections after posterior spine surgery: a systematic review and meta-analysis.

EFORT Open Rev 2022 Feb 15;7(2):109-121. Epub 2022 Feb 15.

Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China.

The purpose of the study was to evaluate the effect of local application of vancomycin powder (VP) to prevent surgical site infections (SSIs) after posterior spine surgery. A comprehensive search of Web of Science, EMBASE, Pubmed, Ovid, and Cochrane Library databases for articles published was performed to collect comparative studies of intrawound vancomycin in posterior spine surgery before March 2021. Two reviewers independently screened eligible articles based on the inclusion and exclusion criteria, assessed the study quality, and extracted the data. Revman 5.4 software was used for data analysis. A total of 22 articles encompassing 11 555 surgical patients were finally identified for meta-analysis. According to the information provided by the included literature, the combined odds ratio showed that topical use of VP was effective for reducing the incidence of SSIs (P< 0.00001) after posterior spine surgery without affecting its efficacy in the treatment of deep infections (P< 0.00001). However, there is no statistical significance in superficial infections. In a subgroup analysis, VP at a dose of 1, 2, and 0.5-2 g reduced the incidence of spinal SSIs. The result of another subgroup analysis suggested that local application of VP could significantly reduce the risk of SSIs, whether it was administered after posterior cervical surgery or thoracolumbar surgery. Moreover, the percentage of SSIs due to gram-positive germs (P< 0.00001) and MRSA (P< 0.0001) could reduce after intraoperative VP was used, but did not significantly reduce to gram-negative germs. The local application of VP appears to protect against SSIs, gram-positive germs, and MRSA (methicillin-resistant Staphylococcus aureus) infections after the posterior spinal operation.
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http://dx.doi.org/10.1530/EOR-21-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897567PMC
February 2022

A53T α-synuclein induces neurogenesis impairment and cognitive dysfunction in line M83 transgenic mice and reduces the proliferation of embryonic neural stem cells.

Brain Res Bull 2022 05 17;182:118-129. Epub 2022 Feb 17.

CAS Key Laboratory of Receptor Research, Center for Neurological and Psychiatric Research and Drug Discovery (CNPRDD), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, Jiangsu, People's Republic of China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan road, Beijing 100049, China. Electronic address:

Dementia with Lewy body (DLB) is the second most common degenerative dementia after Alzheimer's disease. There is no therapeutic drug for DLB currently. It's urgent for us to understand the pathological mechanism of dementia mediated by α-synuclein, as the main component of Lewy body. Here, we found that the A53T α-synuclein transgenic mice showed decreased nesting behavior starting from the age of 1 month. The results in Morris water maze test suggested that the 6-month-old mice had learning memory deficits. Golgi staining indicated that the apical neuronal dendritic spines of hippocampal CA1 neurons were significantly reduced in 6-month-old homozygotes and heterozygotes, although MAP2 protein expression revealed no significant difference in the hippocampus among wild-type mice, homozygotes and heterozygotes. In vitro, we proved mutant A53T α-synuclein decreased the dendritic branches and dendrite spines on the embryonic mice hippocampal neurons. Furthermore, Ki67 immunofluorescence staining identified that the Ki67-positive cells of the hippocampal dentate gyrus and subventricular zone were significantly reduced in 6-month-old homozygotes and heterozygotes, compared with age-matched wild-type mice. Similarly, when 6-month-old mice were injected with BrdU for one day, the immunostaining results also confirmed that BrdU-positive cells were significantly reduced in homozygous and heterozygous mice. Lastly, we transfected primary embryonic hippocampal neural stem cells with lentivirus vector expressing A53T α-synuclein in vitro. Both BrdU staining and Western blotting showed that A53T α-synuclein significantly decreased the proliferation of embryonic neural stem cells. Taken together, these data suggest that A53T α-synuclein can induce adult neurogenesis impairment and cognitive dysfunction. The A53T α-synuclein transgenic mice may be used as an animal model for DLB. Promoting adult neurogenesis may be a promising approach to treat DLB pathogenesis.
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http://dx.doi.org/10.1016/j.brainresbull.2022.02.010DOI Listing
May 2022

Effects of high-intensity interval training on improving arterial stiffness in Chinese female university students with normal weight obese: a pilot randomized controlled trial.

J Transl Med 2022 02 2;20(1):60. Epub 2022 Feb 2.

Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhouyuan Road, Shanghai, 201318, China.

Background: High intensity interval training (HIIT) has been reported to exert better effects on cardiovascular fitness in obesity, but little known about the arterial stiffness (AS) in female university students with normal weight obesity (NWO). Thus, this study aimed to investigate the effects of HIIT on the body composition, heart rate (HR), blood pressure (BP), blood lipids metabolism as well as the novel parameters of propensity for AS (arterial velocity pulse index [AVI], arterial pressure volume index [API]) for female university students with NWO.

Methods: Forty female university students with NWO were randomly assigned to control group (n = 20) and HIIT group (3 bouts of 9‑min intervals at 90% of the maximal heart rate [HR], interspersed by 1 min rest, 5 days a week, n = 20). Tests were performed before and after 4 weeks of training. Repeated measures ANOVA and simple effect test analysis were used to analyze dependent variable changes.

Results: After 4 weeks HIIT statistically significantly improved the body composition by decreasing the body mass index, body fat percent, total body fat mass (BFM), BFM of left arm, measured circumference of left arm, and obesity degree, and increasing the total body skeletal muscle mass, protein content, total body water, fat free mass, body cell mas, and InBody score. HIIT also statistically significantly decreased the HR and BP. As for the lipid profile, HIIT obviously ameliorated the blood lipids metabolism by decreasing the levels of total cholesterol (TC), triglyceride, low-density lipoprotein, and TC/HDL, and increasing the levels of high-density lipoprotein (HDL). In addition, the AVI and API were markedly decreased via HIIT intervention.

Conclusions: HIIT produced significant and meaningful benefits for body composition, HR, BP, and blood lipids metabolism, and could decrease AS in female university students with NWO. This suggests that HIIT may effectively reduce the risk of arteriosclerosis and protect the cardiovascular function for female university students with NWO. Trial registration ChiCTR2100050711. Registered 3 September 2021. Retrospectively registered.
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http://dx.doi.org/10.1186/s12967-022-03250-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809004PMC
February 2022

Mesenchyme homeobox 2 has a cancer-inhibiting function in breast carcinoma via affection of the PI3K/AKT/mTOR and ERK1/2 pathways.

Biochem Biophys Res Commun 2022 02 7;593:20-27. Epub 2022 Jan 7.

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

A cancer-inhibiting role of mesenchyme homeobox 2 (MEOX2) has been observed in several malignancies. However, the association between MEOX2 and breast carcinoma has not been addressed. This research focused on investigating the possible relevance of MEOX2 in breast carcinoma. Initial expression analysis by TCGA data uncovered low levels of MEOX2 in breast carcinoma. We then confirmed that MEOX2 was poorly expressed in clinical tumor specimens of breast carcinoma by real-time quantitative PCR and immunoblotting assays. Moreover, low levels of MEOX2 in breast carcinoma patients were found to be correlated with reduced overall survival. A series of cellular function assays showed that the forced expression of MEOX2 had anticancer effects, including the inhibition of cell proliferation, the induction of G0-G1 phase arrest, the restraint of metastatic potential, and the enhancement of chemosensitivity. Further analysis revealed that MEOX2 negatively modulated the phosphatidyl-inositol-3 kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) and extracellular signal-regulated kinase (ERK1/2) pathways. Reactivation of AKT by a chemical activator reversed MEOX2-mediated anticancer effects. An in vivo xenograft assay validated the anticancer function of MEOX2 in breast carcinoma. Taken together, these data show that MEOX2 exerts a cancer-inhibiting role in breast carcinoma by affecting the PI3K/AKT/mTOR and ERK1/2 pathways. This work suggests MEOX2 as a new contributor for breast carcinoma progression, which may be a candidate target for anticancer therapy development.
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http://dx.doi.org/10.1016/j.bbrc.2022.01.011DOI Listing
February 2022

Changes of groundwater arsenic risk in different seasons in Hetao Basin based on machine learning model.

Sci Total Environ 2022 Apr 11;817:153058. Epub 2022 Jan 11.

The Institute of Hydrogeology and Environmental Geology, Chinese Academy of Geological Science, Shijiazhuang 050061, China; Hebei Cangzhou Groundwater and Land Subsidence National Observation and Research Station, Shijiazhuang, 050061, China.

Arsenic pollution of shallow groundwater is serious in Hetao Basin. At present, there are few studies on the seasonal variation and mechanism of high As groundwater. In order to master the risk difference and influence mechanism of high As groundwater in different seasons, we collected 506 shallow groundwater samples in the Hetao Basin, and used climatic factors, topographic factors, and others (influence of irrigation channels, vegetation index) that are closely distributed with As in groundwater to establish a high-precision random forest model of high As groundwater in the Hetao Basin in summer. We used climate factors as dynamic predictors to predict the distribution of high As risks in winter and established human health risk zones in the Hetao Basin. The results show that from winter to summer, the probability of high As in high risk areas further increases with the influence of factors such as temperature increase, rainfall increase, and enhanced evapotranspiration, while the probability of high As in low risk areas is the opposite and shows a downward trend. The areas with increased probability of high human health risks and stable areas are mainly distributed along the drainage canals and concentrated in the middle of the basin. From winter to summer, as the local residents' demand for groundwater increases, the probability of high As has increased and stabilized in high risk areas. The number of threatened populations reached 246,000 and 108,000, respectively. Therefore, we need to focus on them. The results of this research explored the changing trend and mechanism of high As groundwater risks under the influence of climate, further enriching the regional high As groundwater research system, and can also be provided as a reference for similar research in other regions.
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http://dx.doi.org/10.1016/j.scitotenv.2022.153058DOI Listing
April 2022

Crystallization Behavior and Electrical Properties of Nanoparticle-Reinforced Poly(lactic Acid)-Based Films.

Polymers (Basel) 2022 Jan 2;14(1). Epub 2022 Jan 2.

Department of Mechanical System Engineering, Gyeongsang National University, Tongyeong-si 53064, Korea.

Graphene oxide (GO) and multiwalled carbon nanotubes with silver particles (MWNT-Ag) of different concentrations were used as nanofillers to prepare poly(lactic acid) (PLA) nanoparticle films through the solvent casting method. In this study, the effects of nanoparticles on the crystallization behavior, relationships between the dispersion and electrical properties, and hydrolytic degradation behaviors were investigated for the PLA/MWNT-Ag and PLA/rGO films. Differential scanning calorimetry was used to evaluate the crystallization behaviors of the PLA/MWNT-Ag and PLA/reduced GO (rGO) films. Electron probe microanalysis was performed to characterize the dispersion of MWNT-Ag, and X-ray diffraction and Raman spectroscopy were used to determine the degree of dispersion of rGO in the PLA matrix. The results showed that nanoparticles enhanced the crystallization kinetics of PLA as well as the hydrolytic degradation rate. From the measurement of electrical properties, the electrical conductivity of PLA/MWNT-Ag 1.0 wt% was much higher than that of the pure PLA and PLA/rGO films, showing that MANT and Ag nanoparticles contribute greatly to enhancing the electrical conductivity of the PLA/MWNT-Ag films.
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http://dx.doi.org/10.3390/polym14010177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8747221PMC
January 2022

Inhibition of HMGB1 Ameliorates the Maternal-Fetal Interface Destruction in Unexplained Recurrent Spontaneous Abortion by Suppressing Pyroptosis Activation.

Front Immunol 2021 23;12:782792. Epub 2021 Dec 23.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.

Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the mechanisms are unclear. Our previous studies have found that high mobility group box 1 (HMGB1) molecules are highly expressed at the maternal-fetal interface of unexplained recurrent spontaneous abortion (URSA) patients. The purpose of this study was to further detect the expression of HMGB1 and pyroptosis in decidual tissue of URSA patients, and explore the potential mechanism of the protective role of HMGB1 in URSA patients and mouse model. The decidua tissues of 75 URSA patients and 75 women who actively terminated pregnancy were collected, and URSA mouse models were established and treated with HMGB1 inhibitor-aspirin. The expression of HMGB1, and their receptors (RAGE, TLR2, TLR4), pyroptosis-associated proteins (NLRP-3, caspase-1, GSDMD) and NF-κB was examined at the maternal-fetal interface of human and mouse. Our study found that HMGB1, NLRP-3, Caspase-1, GSDMD, RAGE, TLR2 and TLR4 were highly expressed and NF-κB signaling pathway were activated in the decidua tissue of URSA group. Moreover, immune cell disorder and co-localization of HMGB1 and macrophages were found at the maternal-fetal interface of URSA mice. However, HMGB1, TLR2, TLR4, NF-κB, and pyroptosis-associated proteins can be down-regulated by administering low-dose aspirin. These data may indicate that highly expressed HMGB1 was actively secreted by macrophages and then activated pyroptosis through the TLR2/TLR4-NF-κB pathway to cause aseptic inflammation, leading to the occurrence and development of URSA. Moreover, low-dose aspirin can reduce HMGB1 protein levels of serum and decidual in URSA.
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http://dx.doi.org/10.3389/fimmu.2021.782792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8732860PMC
February 2022

Increases in groundwater arsenic concentrations and risk under decadal groundwater withdrawal in the lower reaches of the Yellow River basin, Henan Province, China.

Environ Pollut 2022 Mar 22;296:118741. Epub 2021 Dec 22.

Institute of Hydrogeology and Environmental Geology, Chinese Academy of Geological Sciences, Shijiazhuang, 050061, PR China; National Observation and Research Station on Groundwater and Land Subsidence in Beijing-Tianjin-Hebei Plain, Shijiazhuang, 050061, PR China.

The spatiotemporal variability in groundwater arsenic concentrations following extensive groundwater extractions over decades was rarely studied on a large scale. To fill this gap, variations in groundwater arsenic concentrations in the North Henan Plain in China from 2010 to 2020 were investigated. The possibility of high-arsenic groundwater (>10 μg/L) was higher than 40% in aquifers within a distance of 100 m from paleochannels. This may be due to the fact that deposits in paleochannels were rich in organic matter and suitable for arsenic enrichment. Following groundwater withdrawal over ten years from 2010 to 2020, nearly half of groundwater samples (44%) were elevated in groundwater arsenic concentrations, and the proportion of high arsenic groundwater increased from 24% in 2010 to 26% in 2020. These may be related to enhanced Fe(III) oxide reduction under decadal groundwater withdrawal. However, around 56% groundwater samples were decreases in arsenic concentrations because of increased NO levels in these samples in 2020. Furthermore, extensive groundwater withdrawal decreased groundwater tables averagely by 4.6 m from 2010 to 2020, which induced the intrusion of high-arsenic groundwater from shallow aquifers into deeper ones. More importantly, the long-term groundwater pumping has perturbed groundwater flow dynamics and redistributed high-arsenic groundwater in the plain, leading to 18% more areas and 33.8% more residents being potentially at risk. This study suggests that the threat of groundwater overexploitation may be much more severe than previously expected.
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http://dx.doi.org/10.1016/j.envpol.2021.118741DOI Listing
March 2022

Crosstalk between autophagy and microbiota in cancer progression.

Mol Cancer 2021 12 11;20(1):163. Epub 2021 Dec 11.

Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.

Autophagy is a highly conserved catabolic process seen in eukaryotes and is essentially a lysosome-dependent protein degradation pathway. The dysregulation of autophagy is often associated with the pathogenesis of numerous types of cancers, and can not only promote the survival of cancer but also trigger the tumor cell death. During cancer development, the microbial community might predispose cells to tumorigenesis by promoting mucosal inflammation, causing systemic disorders, and may also regulate the immune response to cancer. The complex relationship between autophagy and microorganisms can protect the body by activating the immune system. In addition, autophagy and microorganisms can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses involved in cancer progression. Various molecular mechanisms, correlating the microbiota disorders and autophagy activation, control the outcomes of protumor or antitumor responses, which depend on the cancer type, tumor microenvironment and disease stage. In this review, we mainly emphasize the leading role of autophagy during the interaction between pathogenic microorganisms and human cancers and investigate the various molecular mechanisms by which autophagy modulates such complicated biological processes. Moreover, we also highlight the possibility of curing cancers with multiple molecular agents targeting the microbiota/autophagy axis. Finally, we summarize the emerging clinical trials investigating the therapeutic potential of targeting either autophagy or microbiota as anticancer strategies, although the crosstalk between them has not been explored thoroughly.
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http://dx.doi.org/10.1186/s12943-021-01461-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665582PMC
December 2021

Retraction Note: Radiation-induced glucocorticoid receptor promotes CD44 + prostate cancer stem cell growth through activation of SGK1-Wnt/β-catenin signaling.

J Mol Med (Berl) 2022 01;100(1):149

Department of Radiation Oncology, University of Rochester School, of Medicine and Dentistry, Rochester, NY, 14642, USA.

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http://dx.doi.org/10.1007/s00109-021-02173-0DOI Listing
January 2022

Research on the cutoff tumor size of omitting radiotherapy for BCSS after breast conserving surgery in women aged 65 years or oder with low-risk invasive breast carcinoma: Results based on the SEER database.

Breast 2021 Dec 22;60:287-294. Epub 2021 Nov 22.

Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd., Xi'an, 710061, Shaanxi Province, China. Electronic address:

Background: Radiotherapy after breast-conserving surgery (BCS) is not always necessary in older women staged T1N0M0 with low-risk invasive breast cancer, but few studies have concluded the detailed tumor size as a reference for avoiding radiotherapy. The study was conducted to explore and identify the optimal cutoff tumor size.

Methods: The study population was from the Surveillance, Epidemiology, and End Results (SEER) database in 2010-2016. Propensity score matching was used to balance the confounders between groups. Predictors associated with survival were analyzed by Kaplan-Meier, X-tile, Cox proportional hazards model and competing risk model.

Results: A total of 52049 women and 3846 deaths were included in the cohort with a median follow-up of 34 months. Based on the cutoff value determined by X-tile analysis, the study population were divided into small tumor group (≤14 mm in diameter) and large tumor group (>14 mm in diameter). Small tumors and radiotherapy were correlated with better breast cancer-specific survival (BCSS). In subgroup analysis, the absolute benefit of BCSS in 6 years attributed to radiotherapy was only 0.90% (RT vs. non- RT:98.77% vs. 97.87%) for patients with small tumors but up to 3.33% (RT vs. non- RT:97.10% vs. 93.77%) for those with large tumors.

Conclusion: Small tumors and adjuvant radiotherapy were associated with improved long-term prognosis, and 14 mm in diameter was the cutoff tumor size of omitting radiotherapy for patients aged 65 or older with T1N0M0 stage, ER+ and HER2-breast carcinoma after BCS.
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http://dx.doi.org/10.1016/j.breast.2021.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714502PMC
December 2021

Alterations in mitochondrial function and energy metabolism-related properties in thyroid cancer stem cells.

Acta Biochim Pol 2021 Nov;69(1):11-17

Scientific Research Department Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia Autonomous Region, 010017, China.

Increasing evidence indicates that cancer stem cells (CSCs) are initiators of the occurrence, development, and recurrence of malignant tumors. Mitochondria are important organelles in eukaryotic cells, not only responsible for converting part of energy released during nutrients oxidation into the energy-yielding molecule adenosine triphosphate (ATP) to fuel the activities of cell, but also play essential roles in processes such as cell apoptosis and cellular proliferation. The mitochondrial-related abnormalities have also been considered to have an important role in the origin and development of tumors. This study aimed at testing the abnormalities in mitochondrial function and energy/metabolism-related phenotypes in thyroid cancer stem cells (TCSCs). TCSCs were isolated and identified from MDA-T32 thyroid carcinoma cell line. The mitochondrial mass and mitochondrial arrangement, amount of mitochondrial DNA (mtDNA), mitochondrial membrane potential (MMP), oxygen/glucose consumption, and intracellular concentrations of reactive oxygen species (ROS) and ATP levels were examined. Perinuclear mitochondrial distribution, low amount of mtDNA and oxygen/glucose consumption, high MMP, and low intracellular ROS and ATP concentrations were observed in TCSCs. Alterations in mitochondrial function and cellular energy metabolism may be used as novel indicators of thyroid cancer.
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http://dx.doi.org/10.18388/abp.2020_5370DOI Listing
November 2021

ARHGEF19 promotes the growth of breast cancer in vitro and in vivo by the MAPK pathway.

Physiol Int 2021 Nov 23. Epub 2021 Nov 23.

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

Objective: To assess the expression of ARHGEF19 in human breast cancer, investigate its role in breast cancer, and clarify the mechanism.

Methods: Bioinformatics analysis, immunoblot, quantitative PCR, and immunohistochemical (IHC) assays were performed to assess ARHGEF19 expression in breast cancer. CCK-8 and Edu assays were conducted to reveal its role in breast cancer cell proliferation. Flow cytometry (FCM) assays and immunoblot were performed to confirm its effects on breast cancer apoptosis. Immunoblot was also performed to clarify the mechanism. Finally, tumor growth assays were aimed to confirm the role of ARHGEF19 in mice.

Results: We observed that ARHGEF19 was highly expressed in human breast cancer. ARHGEF19 promoted breast cancer cell growth in vitro, and suppressed apoptosis. In addition, we found that ARHGEF19 could activate the MAPK pathway in breast cancer cells. Our findings further confirmed that ARHGEF19 contributed to breast cancer growth in mice.

Conclusion: We observed that ARHGEF19 promoted the growth of breast cancer in vitro and in vivo via MAPK pathway, and presume it could serve as a breast cancer therapeutic target.
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http://dx.doi.org/10.1556/2060.2021.00187DOI Listing
November 2021

Preparation of chitosan crosslinked with metal-organic framework (MOF-199)@aminated graphene oxide aerogel for the adsorption of formaldehyde gas and methyl orange.

Int J Biol Macromol 2021 Dec 16;193(Pt B):2243-2251. Epub 2021 Nov 16.

College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, PR China. Electronic address:

Chitosan crosslinked with metal-organic framework (MOF-199)@aminated graphene oxide aerogel ([email protected]/CS) were prepared to adsorb formaldehyde and methyl orange. The prepared [email protected]/CS aerogel was well characterized via SEM, EDX, FT-IR, XRD and XPS to reveal the microstructure and composition. Besides, the mechanical property and the stability of [email protected]/CS aerogel were investigated. The results showed that [email protected]/CS aerogel had good stability in water, compression resilience and thermostability. The study on the ability to adsorb formaldehyde gas and methyl orange showed that the adsorption capacity of [email protected]/CS aerogel was related to the pore size and the surface functional groups of [email protected]/CS aerogel. When the pore size is moderate, as the amino group and MOF-199 on the aerogel increased, the adsorption capacity of formaldehyde gas (197.89 mg/g) and methyl orange (412 mg/g) can reach the maximum. Furthermore, the adsorption process at equilibrium followed the Freundlich isotherm model. The kinetic behavior was well fitted by the pseudo-second-order model, indicating chemisorption as the rate-determining step. This work can provide a reliable basis for the adsorbent to remove pollutants in different forms at the same time, and has potential application in simultaneously adsorbing liquid pollutants and gas pollutants.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.11.056DOI Listing
December 2021

A Novel Cerium(IV)-Based Metal-Organic Framework for CO Chemical Fixation and Photocatalytic Overall Water Splitting.

ChemSusChem 2022 Jan 6;15(1):e202102368. Epub 2021 Dec 6.

College of Materials Science and Engineering, Changsha University of Science and Technology, Changsha, Hunan 410114, P. R. China.

Cerium (IV)-based metal-organic frameworks (MOFs) are highly desirable due to their unique potential in fields such as redox catalysis and photocatalysis. However, due to the high reduction potential of Ce species in solution, it is still a great challenge to synthesize Ce -MOFs with novel structures, which are extremely dominated by the hexanuclear Ce-O cluster inorganic building units (IBUs). Herein, a Ce-O IBU chain containing Ce -MOF, CSUST-3 (CSUST: Changsha University of Science and Technology), was successfully prepared using the kinetic stabilization study of UiO-66(Ce)-NDC (H NDC=2,6-naphthalenedicarboxylic acid). Furthermore, owing to the superior redox activity, Lewis acidity and semiconductor-like behavior owing to Ce , activated CSUST-3 was demonstrated to be an excellent catalyst for CO chemical fixation. One-pot synthesis of styrene carbonate from styrene and CO was achieved under mild conditions (1 atm CO , 80 °C, and solvent free). Moreover, activated CSUST-3 was shown to be a remarkable co-catalyst-free photocatalyst for overall water splitting (OWS), rendering 59 μmol g  h of H and 22 μmol g  h of O under simulated sunlight irradiation (Na S-Na SO as sacrificial agent).
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http://dx.doi.org/10.1002/cssc.202102368DOI Listing
January 2022

Clinical Value and Potential Mechanisms of Oxysterol-Binding Protein Like 3 (OSBPL3) in Human Tumors.

Front Mol Biosci 2021 19;8:739978. Epub 2021 Oct 19.

Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Cancer remains one of the top culprits causing disease-related deaths. A lack of effective multi-cancer therapeutic targets has limited the prolongation of cancer patients' survival. Therefore, it is important to explore novel oncogenic genes or versatile targets and perform a comprehensive analysis to assess their roles in the process of tumorigenesis. OSBPL3 protein is an intracellular lipid receptor of the oxysterol-binding protein superfamily, which participates in some pathological and physiological processes in tumor progression. However, its clinical roles and potential mechanisms in cancers remain unknown. Thus, we aimed to systematic explore the potential oncogenic roles of OSBPL3 across thirty-three tumors using multiple web-based and publicly available tools, including the Cancer Genome Atlas, Gene Expression Omnibus, Genotype-Tissue Expression, cBioPortal, and Human Protein Atlas database. OSBPL3 is highly expressed in major subtypes of cancers, distinctly associated with the prognosis of tumor patients. We observed X676_splice/V676G alteration in the oxysterol domain and frequent mutations of OSBPL3 involve cell survival in skin cutaneous melanoma. We also first presented that the expression of OSBPL3 was associated with tumor mutational burden (TMB) in nine cancer types. Additionally, OSBPL3 shows an enhanced phosphorylation level at S426, S251, and S273 loci within the pleckstrin homology domain in multiple tumors, such as breast cancer or lung adenocarcinoma. And OSBPL3 expression was associated with active immune cells (CD8 T cells) and cancer-associated fibroblasts in breast cancer, colon adenocarcinoma, and kidney renal clear cell carcinoma and immune checkpoint genes in more than 30 tumors, but weakly associated with immune suppressive cells (myeloid-derived suppressor cells, T regulatory cells). Moreover, protein processing and mRNA metabolic signaling pathways were involved in the functional mechanisms of OSBPL3. Our study first demonstrated that a novel agent OSBPL3 plays an important role in tumorigenesis from the perspective of publicly available databases and clinical tumor samples in various cancers, which comprehensively provide insights into its biological functions and may be helpful for further investigation.
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http://dx.doi.org/10.3389/fmolb.2021.739978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560696PMC
October 2021

PD-L2 glycosylation promotes immune evasion and predicts anti-EGFR efficacy.

J Immunother Cancer 2021 10;9(10)

Department of Maxillofacial and Otorhinolaryngology Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China

Background: Combination therapy has been explored for advanced head and neck squamous cell carcinoma (HNSCC) owing to the limited efficacy of anti-epidermal growth factor receptor (EGFR) therapy. Increased expression and glycosylation of immune checkpoint molecules in tumors are responsible for cetuximab therapy refractoriness. The role of programmed death ligand 2 (PD-L2), a ligand of PD-1, in the immune function is unclear. Here, we examined the regulatory mechanism of PD-L2 glycosylation and its role in antitumor immunity and cetuximab therapy.

Methods: Single-cell RNA sequencing and immunohistochemical staining were used to investigate PD-L2 expression in cetuximab-resistant/sensitive HNSCC tissues. The mechanism of PD-L2 glycosylation regulation was explored in vitro. The effects of PD-L2 glycosylation on immune evasion and cetuximab efficacy were verified in vitro and using mice bearing orthotopic SCC7 tumors.

Results: The PD-L2 levels were elevated and -glycosylated in patients with cetuximab-resistant HNSCC. Glycosylated PD-L2 formed a complex with EGFR, which resulted in the activation of EGFR/signal transducer and activator of transcription 3 (STAT3) signaling and decreased the cetuximab binding affinity to EGFR. The -glycosyltransferase fucosyltransferase (FUT8), a transcriptional target of STAT3, was required for PD-L2 glycosylation. Moreover, glycosylation modification stabilized PD-L2 by blocking ubiquitin-dependent lysosomal degradation, which consequently promoted its binding to PD-1 and immune evasion. Inhibition of PD-L2 glycosylation using Stattic, a specific STAT3 inhibitor, or PD-L2 mutation blocking its binding to FUT8, increased cytotoxic T lymphocyte activity and augmented response to cetuximab.

Conclusions: Increased expression and glycosylation of PD-L2 in tumors are an important mechanism for cetuximab therapy refractoriness. Thus, the combination of PD-L2 glycosylation inhibition and cetuximab is a potential therapeutic strategy for cancer.
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http://dx.doi.org/10.1136/jitc-2021-002699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547513PMC
October 2021

Development and Validation of an IL6/JAK/STAT3-Related Gene Signature to Predict Overall Survival in Clear Cell Renal Cell Carcinoma.

Front Cell Dev Biol 2021 29;9:686907. Epub 2021 Sep 29.

Shaoxing People's Hospital, Shaoxing, China.

Traditional clinicopathological features (TNM, pathology grade) are often insufficient in predictive prognosis accuracy of clear cell renal cell carcinoma (ccRCC). The IL6-JAK-STAT3 pathway is aberrantly hyperactivated in many cancer types, and such hyperactivation is generally associated with a poor clinical prognosis implying that it can be used as a promising prognosis indicator. The relation between the IL6-JAK-STAT3 pathway and ccRCC remains unknown. We evaluated the levels of various cancer hallmarks and filtered out the promising risk hallmarks in ccRCC. Subsequently, a prognosis model based on these hallmark-related genes was established weighted correlation network analysis and Cox regression analysis. Besides, we constructed a nomogram based on the previous model with traditional clinicopathological features to improve the predictive power and accuracy. The IL6-JAK-STAT3 pathway was identified as the promising risk hallmarks in ccRCC, and the pathway-related prognosis model based on five genes was built. Also, the nomogram we developed demonstrated the strongest and most stable survival predictive ability. Our study would provide new insights for guiding individualized treatment of ccRCC patients.
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http://dx.doi.org/10.3389/fcell.2021.686907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511427PMC
September 2021

Mechanism of miR-30b-5p-Loaded PEG-PLGA Nanoparticles for Targeted Treatment of Heart Failure.

Front Pharmacol 2021 30;12:745429. Epub 2021 Sep 30.

Cardiology Department, Inner Mongolia People's Hospital, Hohhot, China.

Exploring the effectiveness of miR-30b-5p-loaded PEG-PLGA nanoparticles (NPs) for the treatment of heart failure and the underlying mechanism. PEG-PLGA characteristics with different loading amounts were first examined to determine the loading, encapsulation, and release of miR-30b-5p from NPs. The effects of miR-30b-5p NPs on cardiac function and structure were assessed by immunofluorescence, echocardiography, HE/Masson staining, and TUNEL staining. The effects of NPs on the expression of factors related to cardiac hypertrophy and inflammation were examined by RT-PCR and western blotting, and the mechanism of miR-30b-5p treatment on heart failure was explored by dual luciferase reporter assay and RT-PCR. The size of PEG-PLGA NPs with different loading amounts ranged from 200 to 300 nm, and the zeta potential of PEG-PLGA NPs was negative. The mean entrapment efficiency of the NPs for miR-30b-5p was high (81.8 ± 2.1%), and the release rate reached 5 days with more than 90% release. Distribution experiments showed that NPs were mainly distributed in the heart and had a protective effect on myocardial injury and cardiac function. Compared with a rat model of cardiac failure and miR-30b-5p-non-loaede NP groups, the expression of cardiac hypertrophy markers (ANP, BNPβ-MHC) and inflammatory factors (IL-1β, IL-6) were significantly decreased. Dual luciferase reporter assay assays indicated that miR-30b-5p exerted its effects mainly by targeting TGFBR2. PEG-PLGA NPs loaded with miR-30b-5p improved cardiac function, attenuated myocardial injury, and regulated the expression of factors associated with cardiac hypertrophy and inflammation by targeting TGFBR2.
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http://dx.doi.org/10.3389/fphar.2021.745429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514665PMC
September 2021
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