Publications by authors named "Bing Feng"

204 Publications

Application of artificial intelligence in preoperative imaging of hepatocellular carcinoma: Current status and future perspectives.

World J Gastroenterol 2021 Aug;27(32):5341-5350

Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor in China. Preoperative diagnosis of HCC is challenging because of atypical imaging manifestations and the diversity of focal liver lesions. Artificial intelligence (AI), such as machine learning (ML) and deep learning, has recently gained attention for its capability to reveal quantitative information on images. Currently, AI is used throughout the entire radiomics process and plays a critical role in multiple fields of medicine. This review summarizes the applications of AI in various aspects of preoperative imaging of HCC, including segmentation, differential diagnosis, prediction of histopathology, early detection of recurrence after curative treatment, and evaluation of treatment response. We also review the limitations of previous studies and discuss future directions for diagnostic imaging of HCC.
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http://dx.doi.org/10.3748/wjg.v27.i32.5341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409162PMC
August 2021

Identification of Dysregulated Mechanisms and Potential Biomarkers in Ischemic Stroke Onset.

Int J Gen Med 2021 22;14:4731-4744. Epub 2021 Aug 22.

Department of Neurology, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530022, People's Republic of China.

Objective: Ischemic stroke (IS) is a major cause of severe disability. This study aimed to identify potential biomarkers closely related to IS diagnosis and treatment.

Methods: Profiles of gene expression were obtained from datasets GSE16561, GSE22255, GSE112801 and GSE110993. Differentially expressed mRNAs between IS and controls were then subjected to weighted gene co-expression network analysis as well as multiscale embedded gene co-expression network analysis. The intersection of the two sets of module genes was subjected to analyses of functional enrichment and of microRNAs (miRNAs) regulation. Then, the area under receiver operating characteristic curves (AUC) was calculated to assess the ability of genes to discriminate IS patients from controls. IS diagnostic signatures were constructed using least absolute shrinkage and selection operator regression.

Results: A total of 234 common co-expression network genes were found to be potentially associated with IS. Enrichment analysis found that these genes were mainly associated with inflammation and immune response. The aberrantly expressed miRNAs (hsa-miR-651-5p, hsa-miR-138-5p, hsa-miR-9-3p and hsa-miR-374a-3p) in IS had regulatory effects on IS-related genes and were involved in brain-related diseases. We used the criterion AUC > 0.7 to screen out 23 hub genes from IS-related genes in the GSE16561 and GSE22255 datasets. We obtained an 8-gene signature (ADCY4, DUSP1, ATP5F1, DCTN5, EIF3G, ELAVL1, EXOSC7 and PPIE) from the training set of GSE16561 dataset, which we confirmed in the validation set of GSE16561 dataset and in the GSE22255 dataset. The genes in this signature were highly accurate for diagnosing IS. In addition, the 8-gene signature significantly correlated with infiltration by immune cells.

Conclusion: These findings provide new clues to molecular mechanisms and treatment targets in IS. The genes in the signature may be candidate markers and potential gene targets for treatments.
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http://dx.doi.org/10.2147/IJGM.S327594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390889PMC
August 2021

Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders.

Front Cell Dev Biol 2021 3;9:686820. Epub 2021 Aug 3.

Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.

Metabolic disorders include metabolic syndrome, obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. Due to unhealthy lifestyles such as high-calorie diet, sedentary and physical inactivity, the prevalence of metabolic disorders poses a huge challenge to global human health, which is the leading cause of global human death. Mitochondrion is the major site of adenosine triphosphate synthesis, fatty acid β-oxidation and ROS production. Accumulating evidence suggests that mitochondrial dysfunction-related oxidative stress and inflammation is involved in the development of metabolic disorders. Mitophagy, a catabolic process, selectively degrades damaged or superfluous mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial function. It is considered to be one of the major mechanisms responsible for mitochondrial quality control. Growing evidence shows that mitophagy can prevent and treat metabolic disorders through suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. In the past decade, in order to expand the range of pharmaceutical options, more and more phytochemicals have been proven to have therapeutic effects on metabolic disorders. Many of these phytochemicals have been proved to activate mitophagy to ameliorate metabolic disorders. Given the ongoing epidemic of metabolic disorders, it is of great significance to explore the contribution and underlying mechanisms of mitophagy in metabolic disorders, and to understand the effects and molecular mechanisms of phytochemicals on the treatment of metabolic disorders. Here, we investigate the mechanism of mitochondrial dysfunction in metabolic disorders and discuss the potential of targeting mitophagy with phytochemicals for the treatment of metabolic disorders, with a view to providing a direction for finding phytochemicals that target mitophagy to prevent or treat metabolic disorders.
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http://dx.doi.org/10.3389/fcell.2021.686820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369426PMC
August 2021

Combination Treatment With Inhibitors of ERK and Autophagy Enhances Antitumor Activity of Betulinic Acid in Non-small-Cell Lung Cancer and .

Front Pharmacol 2021 29;12:684243. Epub 2021 Jun 29.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Aberrant activation of the Ras-ERK signaling pathway drives many important cancer phenotypes, and several inhibitors targeting such pathways are under investigation and/or approved by the FDA as single- or multi-agent therapy for patients with melanoma and non-small-cell lung cancer (NSCLC). Here, we show that betulinic acid (BA), a natural pentacyclic triterpenoid, inhibits cell proliferation, and induces apoptosis and protective autophagy in NSCLC cells. Thus, the cancer cell killing activity of BA is enhanced by autophagy inhibition. Mitogen-activated protein kinases, and especially ERK that facilitates cancer cell survival, are also activated by BA treatment. As such, in the presence of ERK inhibitors (ERKi), lung cancer cells are much more sensitive to BA. However, the dual treatment of BA and ERKi results in increased protective autophagy and AKT phosphorylation. Accordingly, inhibition of AKT has a highly synergistic anticancer effect with co-treatment of BA and ERKi. Notably, autophagy inhibition by hydroxychloroquine (HCQ) increases the response of lung cancer cells to BA in combination with ERKi. , the three-drug combination (BA, ERKi, and HCQ), resulted in superior therapeutic efficacy than single or dual treatments in the xenograft mouse model. Thus, our study provides a combined therapy strategy that is a highly effective treatment for patients with NSCLC.
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http://dx.doi.org/10.3389/fphar.2021.684243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275840PMC
June 2021

Targeting Long Non-Coding RNAs in Hepatocellular Carcinoma: Progress and Prospects.

Front Oncol 2021 25;11:670838. Epub 2021 Jun 25.

Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Hepatocellular carcinoma is the fifth-ranked cancer worldwide with a relatively low five-year survival rate. Long non-coding RNAs are a group of RNAs with remarkable aberrant expression which could act on multiple bioprocesses and ultimately impact upon tumor proliferation, invasion, migration, metastasis, apoptosis, and therapy resistance in cancer cells including hepatocellular carcinoma cells. In recent years, long non-coding RNAs have been reported to be indispensable targets in clinical target therapy to stop the growth of cancer and prolong the lifespan of patients with hepatocellular carcinoma. In this review, we enumerate the signaling pathways and life activities affected by long non-coding RNAs in hepatocellular carcinoma cells to illustrate the role of long non-coding RNAs in the development and therapy resistance of hepatocellular carcinoma.
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http://dx.doi.org/10.3389/fonc.2021.670838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267409PMC
June 2021

Kun-Dan Decoction Ameliorates Insulin Resistance by Activating AMPK/mTOR-Mediated Autophagy in High-Fat Diet-Fed Rats.

Front Pharmacol 2021 28;12:670151. Epub 2021 May 28.

Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.

Metabolic syndrome is characterized by central obesity, hyperglycemia and hyperlipidemia. Insulin resistance is the leading risk factor for metabolic syndrome. Kun-Dan decoction (KD), a traditional Chinese medicine, has been applied to treat patients with metabolic syndrome for over ten years. It is increasingly recognized that autophagy deficiency is the key cause of metabolic syndrome. Therefore, we aimed to explore whether KD can activate autophagy to improve metabolic syndrome. Network pharmacology was used to explore the underlying mechanism of KD in the treatment of metabolic syndrome. The high-fat diet-fed rats and oleic acid-induced LO2 cells were employed in our study. Oral glucose tolerance test and insulin tolerance test, obesity and histological examination, serum cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity in high-fat diet-fed rats were analyzed. Furthermore, the protein expressions of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), phospho-AMPK, mammalian target of rapamycin (mTOR), phospho-mTOR, p62, autophagy related protein (Atg) 5, Atg7, Atg12, Atg13, Atg16L1 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-Ⅱ/Ⅰ were examined in rats and LO2 cells. Moreover, autophagy activator rapamycin and inhibitor 3-methyladenine, and small interfering RNA against Atg7 were utilized to verify the role of autophagy in the treatment of metabolic syndrome by KD in oleic acid-induced LO2 cells. Results from network pharmacology indicated that targeted insulin resistance might be the critical mechanism of KD in the treatment of metabolic syndrome. We found that KD significantly suppressed obesity, serum cholesterol, triglyceride and LDL-C levels and increased serum HDL-C level in high-fat diet-fed rats. Furthermore, KD enhanced insulin sensitivity and attenuated HOMA-IR in high-fat diet-fed rats. Western blot showed that KD could enhance autophagy to increase the insulin sensitivity of high-fat diet-fed rats and oleic acid-induced LO2 cells. Furthermore, 3-methyladenine and small interfering RNA against Atg7 could reverse the protective effect of KD on LO2 cells. However, rapamycin could cooperate with KD to enhance autophagic activation to increase insulin sensitivity in LO2 cells. The induction of autophagy may be the major mechanism for KD to improve insulin resistance and metabolic syndrome.
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http://dx.doi.org/10.3389/fphar.2021.670151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193673PMC
May 2021

Metabolic reprogramming of terminally exhausted CD8 T cells by IL-10 enhances anti-tumor immunity.

Nat Immunol 2021 06 24;22(6):746-756. Epub 2021 May 24.

Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8 tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8 tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.
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http://dx.doi.org/10.1038/s41590-021-00940-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610876PMC
June 2021

Hypoxia-inducible factor-1α-mediated upregulation of CD99 promotes the proliferation of placental mesenchymal stem cells by regulating ERK1/2.

World J Stem Cells 2021 Apr;13(4):317-330

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.

Background: As human placenta-derived mesenchymal stem cells (hP-MSCs) exist in a physiologically hypoxic microenvironment, various studies have focused on the influence of hypoxia. However, the underlying mechanisms remain to be further explored.

Aim: The aim was to reveal the possible mechanisms by which hypoxia enhances the proliferation of hP-MSCs.

Methods: A hypoxic cell incubator (2.5% O) was used to mimic a hypoxic microenvironment. Cell counting kit-8 and 5-ethynyl-20-deoxyuridine incorporation assays were used to assay the proliferation of hP-MSCs. The cell cycle was profiled by flow cytometry. Transcriptome profiling of hP-MSCs under hypoxia was performed by RNA sequencing. CD99 mRNA expression was assayed by reverse transcription-polymerase chain reaction. Small interfering RNA-mediated hypoxia-inducible factor 1α (HIF-1α) or CD99 knockdown of hP-MSCs, luciferase reporter assays, and the ERK1/2 signaling inhibitor PD98059 were used in the mechanistic analysis. Protein expression was assayed by western blotting; immunofluorescence assays were conducted to evaluate changes in expression levels.

Results: Hypoxia enhanced hP-MSC proliferation, increased the expression of cyclin E1, cyclin-dependent kinase 2, and cyclin A2, and decreased the expression of p21. Under hypoxia, CD99 expression was increased by HIF-1α. CD99-specific small interfering RNA or the ERK1/2 signaling inhibitor PD98059 abrogated the hypoxia-induced increase in cell proliferation.

Conclusion: Hypoxia promoted hP-MSCs proliferation in a manner dependent on CD99 regulation of the MAPK/ERK signaling pathway .
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http://dx.doi.org/10.4252/wjsc.v13.i4.317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080541PMC
April 2021

Unprecedented high selectivity of -hexane dehydroaromatization to benzene over metal-free phosphorus-doped activated carbon catalysts.

Chem Commun (Camb) 2021 Apr;57(34):4166-4169

Green Chemical Engineering Technology Research Center, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.

Phosphorus-doped activated carbon is reported for the first time as a highly selective catalyst for n-hexane dehydroaromatization to benzene and hydrogen with 100% n-hexane conversion and 97% benzene selectivity. The weak/medium-strength acidic centres composed of (CO)(C)-P(O)(OH) units on the catalyst surface would be the catalytic active sites. This work provides a new alternative in the preparation of metal-free catalysts for the highly selective functionalization of C-H bonds of n-alkanes.
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http://dx.doi.org/10.1039/d1cc00396hDOI Listing
April 2021

Human placenta mesenchymal stem cell-derived exosomes delay HO-induced aging in mouse cholangioids.

Stem Cell Res Ther 2021 03 22;12(1):201. Epub 2021 Mar 22.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.

Background: Cholangiocyte senescence is an important pathological process in diseases such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Stem cell/induced pluripotent stem cell-derived exosomes have shown anti-senescence effects in various diseases. We applied novel organoid culture technology to establish and characterize cholangiocyte organoids (cholangioids) with oxidative stress-induced senescence and then investigated whether human placenta mesenchymal stem cell (hPMSC)-derived exosomes exerted a protective effect in senescent cholangioids.

Methods: We identified the growth characteristics of cholangioids by light microscopy and confocal microscopy. Exosomes were introduced concurrently with HO into the cholangioids. Using immunohistochemistry and immunofluorescence staining analyses, we assessed the expression patterns of the senescence markers p16, p21, and senescence-associated β-galactosidase (SA-β-gal) and then characterized the mRNA and protein expression levels of chemokines and senescence-associated secretory phenotype (SASP) components.

Results: Well-established cholangioids expressed cholangiocyte-specific markers. Oxidative stress-induced senescence enhanced the expression of the senescence-associated proteins p16, p21, and SA-β-gal in senescent cholangioids compared with the control group. Treatment with hPMSC-derived exosomes delayed the cholangioid aging progress and reduced the levels of SASP components (i.e., interleukin-6 and chemokine CC ligand 2).

Conclusions: Senescent organoids are a potential novel model for better understanding senescence progression in cholangiocytes. hPMSC-derived exosomes exert protective effects against senescent cholangioids under oxidative stress-induced injury by delaying aging and reducing SASP components, which might have therapeutic potential for PSC or PBC.
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http://dx.doi.org/10.1186/s13287-021-02271-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983269PMC
March 2021

Immunosuppressive effect of mesenchymal stem cells on lung and gut CD8 T cells in lipopolysaccharide-induced acute lung injury in mice.

Cell Prolif 2021 May 19;54(5):e13028. Epub 2021 Mar 19.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China.

Objectives: Acute lung injury (ALI) not only affects pulmonary function but also leads to intestinal dysfunction, which in turn contributes to ALI. Mesenchymal stem cell (MSC) transplantation can be a potential strategy in the treatment of ALI. However, the mechanisms of synergistic regulatory effects by MSCs on the lung and intestine in ALI need more in-depth study.

Materials And Methods: We evaluated the therapeutic effects of MSCs on the murine model of lipopolysaccharide (LPS)-induced ALI through survival rate, histopathology and bronchoalveolar lavage fluid. Metagenomic sequencing was performed to assess the gut microbiota. The levels of pulmonary and intestinal inflammation and immune response were assessed by analysing cytokine expression and flow cytometry.

Results: Mesenchymal stem cells significantly improved the survival rate of mice with ALI, alleviated histopathological lung damage, improved intestinal barrier integrity, and reduced the levels of inflammatory cytokines in the lung and gut. Furthermore, MSCs inhibited the inflammatory response by decreasing the infiltration of CD8 T cells in both small-intestinal lymphocytes and Peyer's patches. The gut bacterial community diversity was significantly altered by MSC transplantation. Furthermore, depletion of intestinal bacterial communities with antibiotics resulted in more severe lung and gut damages and mortality, while MSCs significantly alleviated lung injury due to their immunosuppressive effect.

Conclusions: The present research indicates that MSCs attenuate lung and gut injury partly via regulation of the immune response in the lungs and intestines and gut microbiota, providing new insights into the mechanisms underlying the therapeutic effects of MSC treatment for LPS-induced ALI.
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http://dx.doi.org/10.1111/cpr.13028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088466PMC
May 2021

Insights Into circRNAs: Functional Roles in Lung Cancer Management and the Potential Mechanisms.

Front Cell Dev Biol 2021 9;9:636913. Epub 2021 Feb 9.

Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.

Lung cancer is the most prevalent cancer globally. It is also the leading cause of cancer-related death because of the late diagnosis and the frequent resistance to therapeutics. Therefore, it is impending to identify novel biomarkers and effective therapeutic targets to improve the clinical outcomes. Identified as a new class of RNAs, circular RNAs (circRNAs) derive from pre-mRNA back splicing with considerable stability and conservation. Accumulating research reveal that circRNAs can function as microRNA (miRNA) sponges, regulators of gene transcription and alternative splicing, as well as interact with RNA-binding proteins (RBPs), or even be translated into proteins directly. Currently, a large body of circRNAs have been demonstrated differentially expressed in physiological and pathological processes including cancer. In lung cancer, circRNAs play multiple roles in carcinogenesis, development, and response to different therapies, indicating their potential as diagnostic and prognostic biomarkers as well as novel therapeutics. In this review, we summarize the multi-faceted functions of circRNAs in lung cancer and the underlying mechanisms, together with the possible future of these discoveries in clinical application.
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http://dx.doi.org/10.3389/fcell.2021.636913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900409PMC
February 2021

Mesenchymal stem cell-mediated immunomodulation of recruited mononuclear phagocytes during acute lung injury: a high-dimensional analysis study.

Theranostics 2021 1;11(5):2232-2246. Epub 2021 Jan 1.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China.

Acute lung injury (ALI)-recruited mononuclear phagocytes play a pivotal role in lung injury and repair. This study investigated the types of recruited mononuclear phagocytes and the immunotherapeutic effects of allograft mesenchymal stem cells (MSCs) in a mouse model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 mice were orotracheally instilled with LPS (20 mg/kg). Compact bone-derived MSCs were administered orotracheally 4 h after LPS inhalation. Mononuclear phagocytes recruited in the lung tissues were characterized at different timepoints by high-dimensional analysis including flow cytometry, mass cytometry, and single-cell RNA sequencing. Eight mononuclear phagocyte subsets recruited to LPS-challenged lungs were precisely identified. On day 3 after LPS administration, both Ly6CCD38 and Ly6CCD38 monocytes were recruited into acutely injured lungs, which was associated with increased secretion of neutrophil chemokines. Ly6CCD38 monocytes differentiated into M1 macrophages on day 3, and subsequently differentiated into CD38 monocyte-derived dendritic cells (mo-DCs) on day 7, while Ly6CCD38 monocytes differentiated into CD11bCD38 DCs on day 7. When ALI mice were treated with MSCs, the mortality significantly reduced. Notably, MSCs reduced the amount of M1 macrophages and reduced the secretion of neutrophil chemokines on day 3. Furthermore, MSCs reduced the number of CD38 mo-DCs and CD11bCD38 DCs on day 7, suppressing the antigen presentation process. Recruited mononuclear phagocyte subsets with a high level of CD38 exhibited an activated phenotype and could secrete higher levels of cytokines and chemokines. This study characterized the dynamic functions and phenotypes of recruited mononuclear phagocytes in ALI mice and MSC-treated ALI mice.
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http://dx.doi.org/10.7150/thno.52514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797670PMC
August 2021

Mesenchymal stem cell-mediated immunomodulation of recruited mononuclear phagocytes during acute lung injury: a high-dimensional analysis study.

Theranostics 2021 1;11(5):2232-2246. Epub 2021 Jan 1.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China.

Acute lung injury (ALI)-recruited mononuclear phagocytes play a pivotal role in lung injury and repair. This study investigated the types of recruited mononuclear phagocytes and the immunotherapeutic effects of allograft mesenchymal stem cells (MSCs) in a mouse model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 mice were orotracheally instilled with LPS (20 mg/kg). Compact bone-derived MSCs were administered orotracheally 4 h after LPS inhalation. Mononuclear phagocytes recruited in the lung tissues were characterized at different timepoints by high-dimensional analysis including flow cytometry, mass cytometry, and single-cell RNA sequencing. Eight mononuclear phagocyte subsets recruited to LPS-challenged lungs were precisely identified. On day 3 after LPS administration, both Ly6CCD38 and Ly6CCD38 monocytes were recruited into acutely injured lungs, which was associated with increased secretion of neutrophil chemokines. Ly6CCD38 monocytes differentiated into M1 macrophages on day 3, and subsequently differentiated into CD38 monocyte-derived dendritic cells (mo-DCs) on day 7, while Ly6CCD38 monocytes differentiated into CD11bCD38 DCs on day 7. When ALI mice were treated with MSCs, the mortality significantly reduced. Notably, MSCs reduced the amount of M1 macrophages and reduced the secretion of neutrophil chemokines on day 3. Furthermore, MSCs reduced the number of CD38 mo-DCs and CD11bCD38 DCs on day 7, suppressing the antigen presentation process. Recruited mononuclear phagocyte subsets with a high level of CD38 exhibited an activated phenotype and could secrete higher levels of cytokines and chemokines. This study characterized the dynamic functions and phenotypes of recruited mononuclear phagocytes in ALI mice and MSC-treated ALI mice.
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http://dx.doi.org/10.7150/thno.52514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797670PMC
August 2021

Knockdown of OsSAE1a affects the growth and development and phosphate homeostasis in rice.

J Plant Physiol 2020 Dec 6;255:153275. Epub 2020 Sep 6.

College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China; Soil Ecology Lab, College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, 210095, China. Electronic address:

SUMOylation is a post-translational modification process that comprises a tandem enzymatic cascade, i.e., maturation, activation, conjugation, and ligation of a small ubiquitin-like modifier, which triggers the modulated activities and transport of the cellular proteins to other areas of the cell. In Oryza sativa (rice), OsSIZ1/2 encoding E3 SUMO ligase exerts regulatory influences on Pi homeostasis and developmental responses. However, the role of OsSAE1a, SUMO E1 activating enzyme, in regulating phosphate (Pi) utilization and/or growth and development is not known in rice and was thus investigated in this study. The qRT-PCR assay revealed a constitutive and variable spatiotemporal expression pattern of OsSAE1a in the vegetative and reproductive tissues and was comparable in the root and shoot grown under different Pi regimes. RNAi-mediated suppression of OsSAE1a exerted variable effects on the concentrations of Pi and total P in different tissues, uptake and distribution of Pi, and relative expression levels of several genes that play pivotal roles in the maintenance of Pi homeostasis. The effects of the mutation in OsSAE1a were also evident in the vegetative and reproductive traits of rice during growth in a hydroponic system and pot soil, respectively. Overall, these results suggest a broad-spectrum role of OsSAE1a in the maintenance of Pi homeostasis and regulating growth and development.
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http://dx.doi.org/10.1016/j.jplph.2020.153275DOI Listing
December 2020

Novel Targets in Glucose Homeostasis and Obesity-Lesson from Rare Mutations.

Curr Diab Rep 2020 10 31;20(11):66. Epub 2020 Oct 31.

Pennington Biomedical Research Center, Brain Glycemic And Metabolism Control Department, Louisiana State University, 6400 Perkins Rd, Basic Science Building L2024, Baton Rouge, LA, 70808, USA.

Purpose Of Review: Obesity and diabetes have already become the second largest risk factor for cardiovascular disease. During the last decade, remarkable advances have been made in understanding the human genome's contribution to glucose homeostasis disorders and obesity. A few studies on rare mutations of candidate genes provide potential genetic targets for the treatment of diabetes and obesity. In this review, we discussed the detailed findings of these studies and the possible causalities between specific genetic variations and dysfunctions in energy or glucose homeostasis. We are optimistic that novel therapeutic strategies targeting these specific mutants for treating and preventing diabetes and obesity will be developed in the near future.

Recent Findings: Studies on rare genetic mutation-caused obesity or diabetes have identified potential genetic targets to decrease body weight or reduce the risk of diabetes. Rare mutations observed in lipodystrophy, obese, or diabetic human patients are promising targets in the treatment of diabetes and obesity.
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http://dx.doi.org/10.1007/s11892-020-01351-7DOI Listing
October 2020

Clinical characteristics of familial schizophrenia.

Asia Pac Psychiatry 2021 Jun 14;13(2):e12422. Epub 2020 Oct 14.

Department of Psychiatry, Xijing Hospital, Xi'an, China.

Introduction: A family history of psychiatric disorders is one of the strongest risk factors for schizophrenia. The characteristics of patients with a family history of psychiatric disorders have not been systematically evaluated.

Methods: This multicenter study (26 centers, 2425 cases) was performed in a Chinese population to examine the sociodemographic and clinical characteristics of schizophrenia patients with a family history of psychotic disorders in comparison with those of patients with sporadic schizophrenia.

Results: Nineteen percent of patients had a family history of mental disease. Multiple logistic regression analysis revealed that ≥4 hospitalizations (OR = 1.78, P = .004), tobacco dependence (OR = 1.48, P = .006), alcohol dependence (OR = 1.74, P = .013), and physical illness (OR = 1.89, P = .001) were independently and significantly associated with a family history of mental disease.

Conclusion: Patients with a family history of mental disorders present different demographics and clinical features than patients without a family history of psychiatric disorders.
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http://dx.doi.org/10.1111/appy.12422DOI Listing
June 2021

The role of Aurora-A in human cancers and future therapeutics.

Am J Cancer Res 2020 1;10(9):2705-2729. Epub 2020 Sep 1.

Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University Nanjing, China.

Aurora-A is a mitotic serine/threonine-protein kinase and an oncogene. In normal cells, Aurora-A appears from G2 phase and localizes at the centrosome, where it participates in centrosome replication, isolation and maturation. Aurora-A also maintains Golgi apparatus structure and spindle assembly. Aurora-A undergoes ubiquitination-mediated degradation after the cell division phase. Aurora-A is abnormally expressed in tumor cells and promotes cell proliferation by regulating mitotic substrates, such as PP1, PLK1, TPX2, and LAST2, and affects other molecules through a non-mitotic pathway to promote cell invasion and metastasis. Some molecules in tumor cells also indirectly act on Aurora-A to regulate tumor cells. Aurora-A also mediates resistance to chemotherapy and radiotherapy and is involved in tumor immunotherapy. Clinical trials of Aurora-A molecular inhibitors are currently underway, and clinical transformation is just around the corner.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539775PMC
September 2020

Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C CD8 T cells.

Cell Death Dis 2020 10 6;11(10):829. Epub 2020 Oct 6.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China.

Systemic inflammatory processes, including alveolar injury, cytokine induction, and neutrophil accumulation, play key roles in the pathophysiology of acute lung injury (ALI). The immunomodulatory effects of mesenchymal stem cells (MSCs) can contribute to the treatment of inflammatory disorders. In previous studies, the focus was on innate immune cells and the effects of MSCs on ALI through CD8 T cells remain unclear. In the present study, lipopolysaccharide (LPS) was used to induce ALI in mice. ALI mice were treated with MSCs via intratracheal instillation. Survival rate, histopathological changes, protein levels, total cell count, cytokine levels, and chemokine levels in alveolar lavage fluid were used to determine the efficacy of MSCs. Mass cytometry and single-cell RNA sequencing (scRNA-seq) were used to characterize the CD8 T cells in the lungs. Ly6C CD8 T cells are prevalent in normal mice, whereas a specialized effector phenotype expressing a high level of Ly6C is predominant in advanced disease. MSCs significantly mitigated ALI and improved survival. MSCs decreased the infiltration of CD8 T cells, especially Ly6C CD8 T cells into the lungs. Mass cytometry revealed that CD8 T cells expressing high Ly6C and CXCR3 levels caused tissue damage in the lungs of ALI mice, which was alleviated by MSCs. The scRNA-seq showed that Ly6C CD8 T cells exhibited a more activated phenotype and decreased expression of proinflammatory factors that were enriched the most in immune chemotaxis after treatment with MSCs. We showed that CD8 T cells play an important role in MSC-mediated ALI remission, and both infiltration quantity and proinflammatory function were inhibited by MSCs, indicating a potential mechanism for therapeutic intervention.
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http://dx.doi.org/10.1038/s41419-020-03036-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538431PMC
October 2020

Immunosuppressive effects of mesenchymal stem cells on lung B cell gene expression in LPS-induced acute lung injury.

Stem Cell Res Ther 2020 09 25;11(1):418. Epub 2020 Sep 25.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Rd, Hangzhou City, 310003, China.

Background: Immune system disorders play important roles in acute lung injury (ALI), and mesenchymal stem cell (MSC) treatment can reduce inflammation during ALI. In this study, we compared the changes in lung B cells during MSC treatment.

Methods: We investigated the effects of MSCs on lung B cells in a mouse model of lipopolysaccharide (LPS)-induced ALI. MSCs were administered intratracheally 4 h after LPS. As vehicle-treated controls, mice were treated with phosphate-buffered saline (PBS) containing 2% C57BL/6 (PBS group). Histopathological changes, survival rate, inflammatory factor levels, and the number of neutrophils in bronchoalveolar lavage fluid (BALF) were determined. Single-cell RNA sequencing (scRNA-Seq) analysis was performed to evaluate the transcriptional changes in lung B cells between the PBS, LPS, and LPS/MSC groups on days 3 and 7.

Results: MSC treatment ameliorated LPS-induced ALI, as indicated by the reductions in mortality, the levels of chemokines and cytokines in BALF, and the severity of lung tissue histopathology in ALI mice. Lung B cells in the PBS group remained undifferentiated and had an inhibitory phenotype. Based on our scRNA-Seq results, the differentially expressed genes (DEGs) in lung B cells in both the PBS group and LPS group were involved in chemotaxis processes and some proinflammatory pathways. MSC treatment inhibited the expression of chemokine genes that were upregulated by LPS and were related to the recruitment of neutrophils into lung tissues. Immunoglobulin-related gene expression was decreased in lung B cells of mice treated with LPS/MSC for 7 days. The DEGs regulated by MSCs were enriched in biological processes, including humoral immune response and apoptotic signaling.

Conclusions: Lung B cells played an important role in the effects of treatment of ALI with MSCs. These observations provide new insights into the mechanisms underlying the effects of MSC treatment for ALI.
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http://dx.doi.org/10.1186/s13287-020-01934-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517809PMC
September 2020

ICAT acts as a Coactivator in Regulating PPARγ Transcriptional Activity in Mesangial Cells.

Exp Clin Endocrinol Diabetes 2021 May 16;129(5):365-373. Epub 2020 Sep 16.

Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Aims: Our study aims to explore the role of β-catenin interaction protein-1(ICAT) in regulating peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity in mesangial cells. The abnormal ICAT expression in mesangial cells under high glucose(HG) contributes to the development of diabetes and its complications such as diabetic nephropathy (DN).

Methods: Human mesangial cells (HMCs) were cultured in either 5.5 (normal control) or 30 (high glucose) mmol/L glucose medium. Overexpression and knock-down of ICAT or β-catenin were carried out by transient transfection. PPARγ transcriptional activity was evaluated by luciferase assay. Protein-protein interactions were tested by Coimmunoprecipitation and GST-pull down assay. Cell phenotype transition of HMCs was detected by the expression level of α-SMA and fibronectin, as well as MTT assay.

Results: High β-catenin protein expression but low ICAT was accompanied by low PPARγ transcriptional activity in HMCs cultured in HG. By using bioinformatics prediction, protein-protein and protein-DNA interaction experimental methods, ICAT and β-catenin were confirmed to act as coactivators in regulating PPARγ transcriptional activity. Overexpression of ICAT could mitigate the decrease of PPARγ transcriptional activity and partly relieve cell phenotype transition in HMCs.

Conclusions: β-catenin and ICAT interact as coactivator to modulate PPARγ transcriptional activation. In HMCs cultured in HG, the low expression of ICAT leads to low PPARγ transcriptional activation.
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http://dx.doi.org/10.1055/a-0879-1846DOI Listing
May 2021

The functional role of long non-coding RNAs and their underlying mechanisms in drug resistance of non-small cell lung cancer.

Life Sci 2020 Nov 29;261:118362. Epub 2020 Aug 29.

Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, China; Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China. Electronic address:

Background: Non-small cell lung cancer (NSCLC) is the most commonly diagnosed solid cancer and the main origin of cancer-related deaths worldwide. Current strategies to treat advanced NSCLC are based on a combined approach of targeted therapy and chemotherapy. But most patients will eventually get resistance to either chemotherapy or targeted therapy, leading to the poor prognosis. The mechanism of NSCLC drug resistance is inconclusive and is affected by multiple factors. Long non-coding RNAs (LncRNAs) are non-coding RNAs (ncRNAs) longer than 200 nucleotides. Recent studies show that lncRNAs are involved in many cellular physiological activities, including drug resistance of NSCLC. It is of great clinical significance to understand the specific mechanisms and the role of lncRNAs in it.

Conclusions: Herein, we focus on the functional roles and the underlying mechanisms of lncRNAs in acquired drug resistance of NSCLC. LncRNAs have potential values as novel prognostic biomarkers and even therapeutic targets in the clinical management of NSCLC.
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http://dx.doi.org/10.1016/j.lfs.2020.118362DOI Listing
November 2020

The Impact of Entrepreneurial Passion on Psychology and Behavior of Entrepreneurs.

Authors:
Bing Feng Min Chen

Front Psychol 2020 21;11:1733. Epub 2020 Jul 21.

Academy of Financial Research, School of Business, Wenzhou University, Wenzhou, China.

In order to study the influence of entrepreneurial passion on entrepreneurs' psychology and behavior, based on the theory of self-efficacy, a model of relationship between entrepreneurial passion and entrepreneurs' psychology and behavior was constructed, relevant hypotheses were proposed, and the promotion mechanism of entrepreneurial passion on entrepreneurial behavior and enterprise performance was analyzed. A survey of 300 entrepreneurs from Hangzhou, Wenzhou, Jiaxing, Shaoxing, and Huzhou was conducted to verify the reliability of the questionnaire through statistical description and analysis. Then exploratory factor analysis and confirmatory factor analysis (CFA) were conducted to test the correlation between variables. Finally, the structural equation was simulated to verify the correctness of the proposed hypothesis and model. The results show that the designed questionnaire has good reliability [the correction item total correlation coefficients (CITC) of all scales are greater than 0.3, values of Cronbach's α are higher than 0.6], the validity (all inventory accumulation explanation degree are higher than 50%) and the fitting (χ/df values of all scales are less than 3, comparative fitness index (CFI), goodness of fitness index (GFI), and incremental fitness index (IFI) are greater than 0.9, root-mean-square error of approximation (RMSEA) value is less than 0.08). The direct effect of harmonious passion on entrepreneurial persistence and enterprise performance is not significant, while the direct effect of compulsive passion on entrepreneurial persistence and enterprise performance is significant. Harmonious passion ( < 0.001) and compulsive passion ( < 0.01) are significantly correlated with entrepreneurial self-efficacy, and self-efficacy plays a mediating role between entrepreneurial passion and entrepreneur psychology and behavior ( < 0.05), and the hypothesis proposed is basically valid. Therefore, entrepreneurial passion can positively guide the entrepreneurial persistence of entrepreneurs, and at the same time promote the performance of enterprises by stimulating the positive emotions of entrepreneurs. In addition, entrepreneurs can enhance their entrepreneurial role identity, maintain a positive attitude, stimulate creativity, and innovation, to enhance their sense of energy efficiency. The government can also promote successful business cases to build an inclusive and innovative social environment and stimulate the entrepreneurial passion of entrepreneurs. This study reveals the relationship between entrepreneurial passion, self-efficacy, and entrepreneur psychology and behavior, and extends the application of entrepreneurial passion in the field of entrepreneurship.
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http://dx.doi.org/10.3389/fpsyg.2020.01733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385187PMC
July 2020

Development of fundamental power couplers for 166.6 MHz superconducting quarter-wave beta = 1 proof-of-principle cavities.

Rev Sci Instrum 2020 Jun;91(6):063301

Accelerator Division, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.

Superconducting 166.6 MHz β = 1 cavities of quarter-wave geometry have been chosen for a high energy photon source, a 6 GeV diffraction-limited synchrotron light source currently under construction in Beijing. Five cavities will provide the required 5.4 MV radio frequency (rf) voltage and 900 kW beam power. Each cavity will be equipped with one fundamental power coupler (FPC), delivering a minimum rf power of 180 kW to the beam. A 50 Ω coaxial structure with one planar warm window was employed. Its location was carefully selected to avoid electron bombardments on the ceramic window due to potential cavity field emission while preserving the required strong coupling. Focusing on optimized heat loads, a compact geometry was pursued to allow assembly with the cavity in a class 10 clean room, thus minimizing contamination. Two prototype FPCs have been fabricated and examined with high power on room-temperature test stands. The couplers were tested up to 50 kW continuous wave (cw) limited by the available solid-state amplifier. The rf conditioning was conducted initially in travelling-wave mode and later in a standing-wave setup with the variable phase of the reverse wave. All rf surfaces were thus exposed to a high field equivalent to 200 kW cw traveling wave. Being the most critical component, the window-inner-conductor assembly was conditioned up to 150 kW at 650 MHz on a hybrid test stand. Multipacting barriers were encountered as predicted and can be processed by rf conditioning. The design, fabrication, and high-power tests of the first 166.6 MHz FPCs are presented.
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http://dx.doi.org/10.1063/5.0001540DOI Listing
June 2020

Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa.

FASEB J 2020 08 14;34(8):10146-10167. Epub 2020 Jun 14.

Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA.

Rhodopsin mutation and misfolding is a common cause of autosomal dominant retinitis pigmentosa (RP). Using a luciferase reporter assay, we undertook a small-molecule high-throughput screening (HTS) of 68, 979 compounds and identified nine compounds that selectively reduced the misfolded P23H rhodopsin without an effect on the wild type (WT) rhodopsin protein. Further, we found five of these compounds, including methotrexate (MTX), promoted P23H rhodopsin degradation that also cleared out other misfolded rhodopsin mutant proteins. We showed MTX increased P23H rhodopsin degradation via the lysosomal but not the proteasomal pathway. Importantly, one intravitreal injection (IVI) of 25 pmol MTX increased electroretinogram (ERG) response and rhodopsin level in the retinae of Rho knock-in mice at 1 month of age. Additionally, four weekly IVIs increased the photoreceptor cell number in the retinae of Rho mice compared to vehicle control. Our study indicates a therapeutic potential of repurposing MTX for the treatment of rhodopsin-associated RP.
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http://dx.doi.org/10.1096/fj.202000282RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688577PMC
August 2020

Inclusion of purified dietary fiber during gestation improved the reproductive performance of sows.

J Anim Sci Biotechnol 2020 12;11:47. Epub 2020 May 12.

Key Laboratory for Animal Disease-Resistant Nutrition of the Ministry of Education of China, and Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, Wenjiang, Chengdu, 611130 People's Republic of China.

Background: This study aimed to investigate the impacts of guar gum and cellulose as the source of dietary fiber during gestation on the reproductive performance of sows.

Methods: A total of 210 sows (parities 3-6) were randomly allocated into six diets ( = 35) throughout gestation to feed graded levels of dietary fiber (DF), including a corn-soybean meal-based control diet with no wheat bran inclusion (CON, 12.5% DF), a wheat bran-rich diet (DF1, 17.4% DF), and another 4 diets (DF2, 17.7% DF; DF3, 18.1% DF; DF4, 18.4% DF; DF5, 18.8% DF) in which wheat bran were equally substituted by 1%, 2%, 3% and 4% purified FIBER MIX (guar gum and cellulose, 1:4). All sows received similar DE and other nutrients throughout gestation.

Results: DF treatment during gestation resulted in normal fecal score (1 to 5 with 1 = dry and 5 = watery) in sows compared with those received the CON diet ( <  0.05). The number of total born piglets had a tendency to be affected by dietary treatment ( = 0.07), and correlation analysis revealed a linear response of total born to dietary fiber levels during gestation ( 0.01). Sows received the DF2, DF3, and DF5 diets during gestation had a greater ADFI during lactation compared with those in the CON group ( 0.05) without affecting the daily body weight gain of suckling piglets. Gut microbiota compositions were dramatically changed by the gestation stage and some of those were changed by DF inclusion. Fecal acetate, propionate, and butyrate of sows were markedly increased in late gestation, and butyrate contents in feces of gestating sows were significantly affected by DF levels ( 0.01). Serum concentrations of pro-inflammatory TNF-α were decreased and anti-inflammatory IL-10 was increased on day 30 of gestation by DF levels ( 0.05).

Conclusions: In summary, increasing dietary fiber levels by guar gum and cellulose during gestation improved the reproductive performance of sows, which might be related to changes in immunity and gut microbiota of sows.
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http://dx.doi.org/10.1186/s40104-020-00450-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216585PMC
May 2020

Ginkgolic acid inhibits the growth of renal cell carcinoma cells via inactivation of the EGFR signaling pathway.

Exp Ther Med 2020 Apr 27;19(4):2949-2956. Epub 2020 Feb 27.

Department of Urology, 900th Hospital of The Joint Logistics Support Force (People's Liberation Army), Fuzhou, Fujian 350000, P.R. China.

Renal cell carcinoma (RCC) is one of the most common urological malignancies occurring in adult human kidneys worldwide. Recent research on antitumor drugs has focused on plant extracts, a class of compounds that play critical roles in cancer treatment. The present study aimed to investigate the potential antitumor effect of ginkgolic acid (GA) in RCC. Transwell invasion assay, cell counting kit-8 assay and flow cytometry were used to measure cell migration, cell viability and apoptosis, respectively. A network pharmacology approach was applied to identify pathway information, combining molecular docking techniques to screen for key target information. In the present study, GA inhibited the viability and proliferation of RCC cells (786-O and A498), both and , via G arrest. GA also reduced RCC cell invasion and migration. In addition, the epidermal growth factor receptor (EGFR) was identified as a critical target protein of GA, which significantly inactivated EGFR signaling in RCC (P<0.05). Collectively, the present study provided evidence that GA exerts its anticancer function by directly targeting the EGFR signaling pathway, revealing the potential of GA therapy for RCC.
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http://dx.doi.org/10.3892/etm.2020.8570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086188PMC
April 2020

Corrigendum: Non-coding RNAs: Emerging Regulators of Sorafenib Resistance in Hepatocellular Carcinoma.

Front Oncol 2020;10:277. Epub 2020 Mar 3.

Department of Medical Oncology, Nanjing School of Clinical Medicine, Jinling Hospital, Southern Medical University, Nanjing, China.

[This corrects the article DOI: 10.3389/fonc.2019.01156.].
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http://dx.doi.org/10.3389/fonc.2020.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063857PMC
March 2020

The Clinical Efficacy and Safety of Stem Cell Therapy for Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Aging Dis 2020 Feb 1;11(1):141-153. Epub 2020 Feb 1.

1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Diabetes mellitus (DM) is a chronic metabolic disease with high morbidity and mortality. Recently, stem cell-based therapy for DM has shown considerable promise. Here, we undertook a systematic review and meta-analysis of published clinical studies to evaluate the efficacy and safety of stem cell therapy for both type 1 DM (T1DM) and type 2 DM (T2DM). The PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and ClinicalTrials.gov databases were searched up to November 2018. We employed a fixed-effect model using 95% confidence intervals (CIs) when no statistically significant heterogeneity existed. Otherwise, a random-effects statistical model was used. Twenty-one studies met our inclusion criteria: ten T1DM studies including 226 patients and eleven T2DM studies including 386 patients. Stem cell therapy improved C-peptide levels (mean difference (MD), 0.41; 95% CI, 0.06 to 0.76) and glycosylated hemoglobin (HbA1c; MD, -3.46; 95% CI, -6.01 to -0.91) for T1DM patients. For T2DM patients, stem cell therapy improved C-peptide levels (MD, 0.33; 95% CI, 0.07 to 0.59), HbA1c (MD, -0.87; 95% CI, -1.37 to -0.37) and insulin requirements (MD, -35.76; 95% CI, -40.47 to -31.04). However, there was no significant change in fasting plasma glucose levels (MD, -0.52; 95% CI, -1.38 to 0.34). Subgroup analyses showed significant HbA1c and C-peptide improvements in patients with T1DM treated with bone marrow hematopoietic stem cells (BM-HSCs), while there was no significant change in the mesenchymal stem cell (MSC) group. In T2DM, HbA1c and insulin requirements decreased significantly after MSC transplantation, and insulin requirements and C-peptide levels were significantly improved after bone marrow mononuclear cell (BM-MNC) treatment. Stem cell therapy is a relatively safe and effective method for selected individuals with DM. The data showed that BM-HSCs are superior to MSCs in the treatment of T1DM. In T2DM, MSC and BM-MNC transplantation showed favorable therapeutic effects.
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http://dx.doi.org/10.14336/AD.2019.0421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961772PMC
February 2020

Molecular mechanism underlying the difference in proliferation between placenta-derived and umbilical cord-derived mesenchymal stem cells.

J Cell Physiol 2020 10 28;235(10):6779-6793. Epub 2020 Jan 28.

State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.

The placenta and umbilical cord are pre-eminent candidate sources of mesenchymal stem cells (MSCs). However, placenta-derived MSCs (P-MSCs) showed greater proliferation capacity than umbilical cord-derived MSCs (UC-MSCs) in our study. We investigated the drivers of this proliferation difference and elucidated the mechanisms of proliferation regulation. Proteomic profiling and Gene Ontology (GO) functional enrichment were conducted to identify candidate proteins that may influence proliferation. Using lentiviral or small interfering RNA infection, we established overexpression and knockdown models and observed changes in cell proliferation to examine whether a relationship exists between the candidate proteins and proliferation capacity. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence assays were conducted to elucidate the mechanisms underlying proliferation. Six candidate proteins were selected based on the results of proteomic profiling and GO functional enrichment. Through further validation, yes-associated protein 1 (YAP1) and β-catenin were confirmed to affect MSCs proliferation rates. YAP1 and β-catenin showed increased nuclear colocalization during cell expansion. YAP1 overexpression significantly enhanced proliferation capacity and upregulated the expression of both β-catenin and the transcriptional targets of Wnt signaling, CCND1, and c-MYC, whereas silencing β-catenin attenuated this influence. We found that YAP1 directly interacts with β-catenin in the nucleus to form a transcriptional YAP/β-catenin/TCF4 complex. Our study revealed that YAP1 and β-catenin caused the different proliferation capacities of P-MSCs and UC-MSCs. Mechanism analysis showed that YAP1 stabilized the nuclear β-catenin protein, and also triggered the Wnt/β-catenin pathway, promoting proliferation.
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http://dx.doi.org/10.1002/jcp.29572DOI Listing
October 2020
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