Research articles

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  • PAQR3 silencing promotes skin wound healing and angiogenesis, enhanced macrophage M2 polarization and elevated expression of PPARγ in diabetic mice. PAQR3 silencing in macrophages also enhances migration of HaCaT cells and tube formation of HUVECs in vitro. The promotion of diabetic wound healing through M2 macrophage polarization and angiogenesis by PAQR3 silencing is mediated by the inhibition of STUB1-mediated PPARγ protein ubiquitination and degradation.

    • Jian Qiu
    • Chang Shu
    • Wei-Chang Zhang
    Article
  • The authors propose a new role for ADAR1, an RNA editing enzyme, in nonalcoholic fatty liver disease (NAFLD). Overexpression of ADAR1 ameliorates high-fat diet-induced liver injury and significantly abolishes NLRP3 inflammasome activation in THP-1 cells. Inhibition of ADAR1 expression causes a dramatic enhancement in NLRP3 inflammasome activation. Therefore, ADAR1 is a potential NAFLD suppressor through regulation of NLRP3 inflammasomes.

    • Rong Xiang
    • Yuxing Liu
    • Fang Wang
    Article
  • The replacement and desmoplastic histopathological growth patterns (HGP) were studied in patients with uveal melanoma liver metastases (MUM). L1CAM and laminin vascular network were detected at the advancing front of the high-risk replacement HGP but not in the more prognostically favorable desmoplastic HGP. Any percentage of replacement HGP (rHGP), predominant rHGP, or pure rHGP in MUM had a significant adverse effect on metastasis-specific overall survival (p = 0.038; (p = 0.0058); p = 0.0064

    • Raymond Barnhill
    • Steven van Laere
    • Claire Lugassy
    Article
  • Smurf1 is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and NAFLD mode mice. Smurf1 promotes p53 ubiquitynation via stabilizing mouse double minute 2 (MDM2). An decrease in p53 enhances lipogenesis by inducing SREBP-1c, and inhibits lipolysis via repressing malonyl-CoA decarboxylase (MCD) or Lipin1. Overall, Smurf1 deficiency attenuates liver steatosis via the MDM-p53 pathway.

    • Wenjun Lin
    • Xin Zhang
    • Wei An
    Article
  • The presence of visceral obesity or type 2 diabetes mellitus is a major risk factor and potential therapeutic target for non-alcoholic fatty liver disease (NAFLD). A new murine NAFLD model established in this study had obesity and insulin resistance, and rapidly develop steatohepatitis and fibrosis. This model could be useful as preclinical models for drug development of NAFLD.

    • Takafumi Sakuma
    • Masato Nakamura
    • Naoya Kato
    Article
  • Characterization of macrophage polarization into different functional phenotypes is valuable for further investigation of gout pathogenesis, as well as for a better disease management. In this study the authors found that altered macrophage polarization exists in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at an early stage and into M2 at later stages while the macrophages in chronic gout were generally polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.

    • Li Zhao
    • Wenjing Ye
    • Yu Xue
    Article
  • The antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) has shown activity in breast cancer with low levels of HER2 expression. The historical/conventional assays for HER2 were designed separate high levels of HER2 from intermediate levels and show no expression in the low range. In this study, we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then design a quantitative assay to stratify HER2 expression in unamplified cases. Assessment of HER2 protein in the optimal dynamic range will ultimately help select the optimal patients for T-DXd and this work can serve as a model for other assays for ADCs where pathology reads may be less accurate that protein measurements.

    • Myrto Moutafi
    • Charles J. Robbins
    • David L. Rimm
    Article
  • Apolipoprotein B100 (apoB100) is the structural protein of several of the lipoprotein cholesterol carriers and accumulates in extracellular deposits in the systemic disease atherosclerosis, and the neurodegenerative blinding disease, age-related macular degeneration. Herein, the authors characterized the retinal pathology of transgenic mice expressing mouse apoB100, in order to catalog their functional and morphological ocular phenotypes, as a function of age, and establish measurable endpoints for their use as a pre-clinical mouse model to test potential therapies.

    • Mayur Choudhary
    • Faryan Tayyari
    • Goldis Malek
    Article
  • GTSE1 performs oncogenic functions in various tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Here, the authors found that GTSE1 is overexpressed in ccRCC, and its high expression was positively relation with advanced clinical stages and worse prognosis. In additional, GTSE1 knockdown inhibited ccRCC cell malignant phenotype in vitro and vivo. Mechanistically, GTSE1 promotes ccRCC malignance progression by attenuating KLF4 expression.

    • Weihao Chen
    • Hanfeng Wang
    • Xu Zhang
    Article
  • Current treatments, which mostly aim to restore bowel habits, are ineffective for intestinal pain in irritable bowel syndrome (IBS). Abnormal gut-derived serotonin metabolism and mucosal neurite outgrowth are linked to visceral hypersensitivity. Enhanced mucosal innervation dependent on 5-HT7 contributes to hyperalgesia in two IBS-like mouse models. A positive-feedback loop between serotonin and neurotrophin is involved in intensifying nerve fiber elongation. A novel 5-HT7 receptor antagonist may be administered orally as an intestinal analgesic for IBS-related pain.

    • Wen-Ying Chang
    • Yi-Ting Yang
    • Linda Chia-Hui Yu
    Article Open Access
  • Targeting Siglec-15 may be an effective alternative therapy for patients that do not respond to PD-1/PD-L1 inhibition. In this study, the authors show broad expression of this potential immune modulatory target in a wide range of cancer types. These data may inform future clinical development and show potential for future companion diagnostic tests for Siglec-15 therapeutics.

    • Saba Shafi
    • Thazin Nwe Aung
    • David L. Rimm
    Article
  • In nasopharyngeal carcinoma (NPC) CREB1 and SRGN are increased while miR-148a-5p is decreased. Silencing of SRGN and CREB1, and miR-148a-5p overexpression represses NPC tumor progression. The authors show that CREB1 promotes SRGN expression by targeting its promoter. In NPC, FoxO1 binds to miR-148a-5p, and miR-148a-5p targets CREB1. FoxO1 knockdown abolishes the downregulation of CREB1 and SRGN induced by STAT3 silencing. In summary, STAT3 regulates SRGN and promotes the growth and metastasis of NPC through the FoxO1-miR-148a-5p-CREB1 axis.

    • Yong-Li Wang
    • Dan Ren
    • Shen-Hong Qu
    Article
  • The expression of circRTN4 is significantly enhanced in lupus nephritis. Downregulation of circRTN4 expression alleviates extracellular matrix deposition by targeting the miR-513a-5p/FN axis in cultured human renal mesangial cells and pristane-induced BALB/c mice or MRL/lpr mice. In addition, monocyte circRTN4 participates in mesangial cell dysfunction in an exosome-dependent manner. Exosomal circRTN4 mzytherefore be an effective biomarker for lupus nephritis detection and a novel therapeutic target.

    • Xinyan Miao
    • Yuexin Tian
    • Shuxia Liu
    Article Open Access
  • When skeletal muscles undergo ischemia/reperfusion injury, fibroblast growth factor 21 (FGF21), a stress regulator, is upregulated and reduces Drp1 levels, which consequently alleviates abnormal mitochondrial fission and apoptosis. This work provides new insight into relationship between FGF21 and mitochondria and provides a possible therapeutic target for amelioration of muscle ischemia/reperfusion injury.

    • Baoxiang Li
    • Limin Liu
    Article
  • The authors carried out a comparative genetic and histopathological study of 15 patient-derived xenografts (PDX) that were newly established from patients with various types of aggressive non-Hodgkin lymphomas. We have demonstrated that despite keeping the same genetic profiles the PDX models do not recapitulate microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research.

    • Radek Jakša
    • Jana Karolová
    • Pavel Klener
    Article Open Access
  • WISP-2, a recently identified adipokine, plays a role in modulating the turnover of extracellular matrix in the cartilage, and its downregulation may detrimentally alter the inflammatory environment in osteoarthritic cartilage. The authors also show the participation of Wnt/β-catenin signaling pathway in these processes. Thus, targeting WISP-2 might represent a potential therapeutical approach for degenerative and/or inflammatory diseases of musculoskeletal system, such as osteoarthritis.

    • Clara Ruiz-Fernández
    • María González-Rodríguez
    • Oreste Gualillo
    Article
  • This study describes how HOTAIRM1 transferred by alveolar epithelial cell (AEC)-derived Exos promotes proliferation and transdifferentiation of lung fibroblasts. The authors reveal the mechanism by which HOTAIRM1 competitively binds to miR-30d-3p and YY1 to upregulate the expression of HSF1. Furthermore, AEC-Exosomes harboring HOTAIRM1 accelerates interstitial pulmonary fibrosis through disrupting miR-30d-3p-mediated HSF1 inhibition and inducing HSF1.

    • Lin Chen
    • Yang Yang
    • XiaoBo Huang
    Article
  • Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rats are members of the zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators and are highly expressed in mature osteoclasts, and enhance the expression of Bcl-xl mRNA. OCZF overexpression significantly promotes bone loss in ovariectomy-induced osteolytic mice. Protein levels of RNA binding splicing regulator of Bcl-x mRNA and Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mouse-derived osteoclasts, suggesting that OCZF promotes osteoclast survival via Sam68.

    • Xianghe Xu
    • Takeo Shobuike
    • Akiko Kukita
    Article
  • Siglec-15 is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. The aim of this study was to develop an immunohistochemical assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, the authors created and validated an assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. This study may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.

    • Saba Shafi
    • Thazin Nwe Aung
    • David L. Rimm
    Technical Report
  • Circular RNAs (circRNAs) play important roles in many lung diseases. This study investigated the role of circHECTD1 in acute lung injury (ALI). circHECTD1 attenuates the apoptosis of alveolar epithelial cells in lipopolysaccharide-induced ALI through the miR-320a/PIK3CA and miR-136/Sirt1 pathways, indicating a novel therapeutic target for ALI.

    • Hongbin Li
    • Xiaoxuan Niu
    • Min Gao
    Article