Cell Mol Gastroenterol Hepatol
November 2024
Background & Aims: Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells and hepatic stellate cells in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis.
Methods: Liver fibrosis was induced by carbon tetrachloride in wild-type and SphK1 mice to study the recruitment and polarization of macrophages.
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme.
View Article and Find Full Text PDFSphingosine kinase 1 (SphK1) plays critical roles in the activation of hepatic stellate cells (HSCs) and liver fibrosis. Our previous study found that polydatin ameliorates chronic liver injury and fibrosis by inhibiting oxidative stress. However, whether polydatin exerts an anti-fibrotic effect on liver fibrosis dependent on SphK1 signaling is unknown.
View Article and Find Full Text PDFBackground And Aims: Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease.
View Article and Find Full Text PDFObjective: Glucose disposal by insulin-responsive tissues maintains the body glucose homeostasis and insulin resistance leads to a risk of developing type 2 diabetes (T2DM). Insulin stimulates the translocation of glucose transporter isoform 4 (GLUT4) vesicles from intracellular compartments to the plasma membrane to facilitate glucose uptake. However, the underlying mechanisms of GLUT4 vesicle translocation are not well defined.
View Article and Find Full Text PDFPurpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.
Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASi, CDK4/6i, and anti-programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models and , and their effects on downstream signaling were examined.
Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody-drug conjugates, is a viable alternative.
View Article and Find Full Text PDFThere is a compelling need for new therapeutic strategies for glioblastoma multiforme (GBM). Preclinical target and therapeutic discovery for GBMs is primarily conducted using cell lines grown in serum-containing media, such as U-87 MG, which do not reflect the gene expression profiles of tumors found in GBM patients. To address this lack of representative models, we sought to develop a panel of patient-derived GBM models and characterize their genomic features, using RNA sequencing (RNA-seq) and growth characteristics, both when grown as neurospheres in culture, and grown orthotopically as xenografts in mice.
View Article and Find Full Text PDFSichuan Da Xue Xue Bao Yi Xue Ban
May 2019
Objective: To determine the effect of Huntingtin-associated protein 1 ( 1) on fibroblast proliferation.
Methods: 1 knockout ( 1 ) primary fibroblasts were isolated and cultured . The proliferation of 1 fibroblasts was detected by EdU proliferation assay and cell flow assay.
Liver Cholestasis is a widespread disease of broad etiologies and ultimately results in fibrosis, which is still lacking effective therapeutic strategies. Activation of hepatic stellate cells (HSCs) is the key event of liver fibrosis. Here, we aimed to investigate the effect and mechanism of the Slit2 signaling in cholestasis-induced liver fibrosis.
View Article and Find Full Text PDFChronic restraint stress (CRS) can affect hypothalamic-pituitary-adrenal (HPA) axis activity and increase glucocorticoid levels. Glucocorticoids are stress hormones that regulate multiple aspects of energy homeostasis. Stress also impairs glucose tolerance.
View Article and Find Full Text PDFBackground & Aims: Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen.
Methods: Fourteen-day-old Nox1 mice, Nox4 mice, Nox1Nox4 (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months.
Liver fibrosis is characterized by activated hepatic stellate cells (HSC) and extracellular matrix accumulation. Blocking the activation of HSC and the inflammation response are two major effective therapeutic strategies for liver fibrosis. In addition to the long history of using andrographolide (Andro) for inflammatory disorders, we aimed at elucidating the pharmacological effects and potential mechanism of Andro on liver fibrosis.
View Article and Find Full Text PDFUnlabelled: Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) leads to liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the sphingosine kinase (SphK)1-dependent effect on liver fibrosis. The levels of expression and activity of SphK1 were significantly increased in fibrotic livers compared with the normal livers in human.
View Article and Find Full Text PDFActivation of hepatic stellate cells (HSCs) is an essential event in the initiation and progression of liver fibrosis. HSCs are believed to be the major source of collagen-producing myofibroblasts in fibrotic livers. A key feature in the pathogenesis of liver fibrosis is fibrillar Collagen I (Col 1) deposition.
View Article and Find Full Text PDFChronic high-salt diet-associated renal injury is a key risk factor for the development of hypertension. However, the mechanism by which salt triggers kidney damage is poorly understood. Our study investigated how high salt (HS) intake triggers early renal injury by considering the 'gut-kidney axis'.
View Article and Find Full Text PDFDiabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated.
View Article and Find Full Text PDFThe non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway.
View Article and Find Full Text PDF5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5.
View Article and Find Full Text PDFThe pathogenesis of Alzheimer's disease (AD), a type of neurodegenerative disease characterized by learning and memory impairment, is often associated with pathological features, such as amyloid-beta (Aβ) accumulation and insulin resistance. The transgenic mouse, APPswePS1dE9 (APP/PS1), is one of the most commonly used animal models in pathogenesis studies of AD. The purpose of this study is to investigate the sex differences between APP/PS1 mice in the pathogenesis of AD.
View Article and Find Full Text PDFProfiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications.
View Article and Find Full Text PDFMultiple therapeutic agonists of death receptor 5 (DR5) have been developed and are under clinical evaluation. Although these agonists demonstrate significant anti-tumor activity in preclinical models, the clinical efficacy in human cancer patients has been notably disappointing. One possible explanation might be that the current classes of therapeutic molecules are not sufficiently potent to elicit significant response in patients, particularly for dimeric antibody agonists that require secondary cross-linking via Fcγ receptors expressed on immune cells to achieve optimal clustering of DR5.
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