The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes.
View Article and Find Full Text PDFBackground: Newborns can be exposed to inorganic arsenic (iAs) through contaminated drinking water, formula, and other infant foods. Epidemiological studies have demonstrated a positive association between urinary iAs levels and the risk of developing nonalcoholic fatty liver disease (NAFLD) among U.S.
View Article and Find Full Text PDFThe impacts of microplastics (MPs) prevalent in soil on the transport of pollutants were urged to be addressed, which has important implications for ecological risk assessment. Therefore, we investigated the influence of virgin/photo-aged biodegradable polylactic acid (PLA) and non-biodegradable black polyethylene (BPE) mulching films MPs on arsenic (As) transport behaviors in agricultural soil. Results showed that both virgin PLA (VPLA) and aged PLA (APLA) enhanced the adsorption of As(Ⅲ) (9.
View Article and Find Full Text PDFInsulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis.
View Article and Find Full Text PDFBackground & Aims: Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related steatohepatitis, all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as activating transcription factor 4 (ATF4), to HCC and their underlying mechanisms of action remained unknown.
Methods: Hepatocyte-specific ATF4-deficient MUP-uPA mice (MUP-uPA/Atf4) and control MUP-uPA/Atf4 mice were fed a high-fat diet to induce NASH-related HCC, and Atf4 and Atf4 mice were injected with diethylnitrosamine to model carcinogen-induced HCC.
Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support or restrain the progression of PDAC and may impede blood supply and nutrient availability. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood.
View Article and Find Full Text PDFSterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis.
View Article and Find Full Text PDFMany cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation.
View Article and Find Full Text PDFAs a promising genome editing platform, the CRISPR/Cas9 system has great potential for efficient genetic manipulation, especially for targeted integration of transgenes. However, due to the low efficiency of homologous recombination (HR) and various indel mutations of non-homologous end joining (NHEJ)-based strategies in non-dividing cells, in vivo genome editing remains a great challenge. Here, we describe a homology-mediated end joining (HMEJ)-based CRISPR/Cas9 system for efficient in vivo precise targeted integration.
View Article and Find Full Text PDFDespite rapid progresses in the genome-editing field, in vivo simultaneous overexpression of multiple genes remains challenging. We generated a transgenic mouse using an improved dCas9 system that enables simultaneous and precise in vivo transcriptional activation of multiple genes and long noncoding RNAs in the nervous system. As proof of concept, we were able to use targeted activation of endogenous neurogenic genes in these transgenic mice to directly and efficiently convert astrocytes into functional neurons in vivo.
View Article and Find Full Text PDFUnlabelled: Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of CCl .
View Article and Find Full Text PDFPrecisely targeted genome editing is highly desired for clinical applications. However, the widely used homology-directed repair (HDR)-based genome editing strategies remain inefficient for certain in vivo applications. We here demonstrate a microhomology-mediated end-joining (MMEJ)-based strategy for precisely targeted gene integration in transfected neurons and hepatocytes in vivo with efficiencies up to 20%, much higher (up to 10 fold) than HDR-based strategy in adult mouse tissues.
View Article and Find Full Text PDFTargeted integration of transgenes can be achieved by strategies based on homologous recombination (HR), microhomology-mediated end joining (MMEJ) or non-homologous end joining (NHEJ). The more generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining (HMEJ)-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and ∼800 bp of homology arms, and the targeted genome.
View Article and Find Full Text PDFRechnitz window group represents a Cordilleran-style metamorphic core complex, which is almost entirely located within nearly contemporaneous Neogene sediments at the transition zone between the Eastern Alps and the Neogene Pannonian basin. Two tectonic units are distinguished within the Rechnitz metamorphic core complex (RMCC): (1) a lower unit mainly composed of Mesozoic metasediments, and (2) an upper unit mainly composed of ophiolite remnants. Both units are metamorphosed within greenschist facies conditions during earliest Miocene followed by exhumation and cooling.
View Article and Find Full Text PDFWe describe the structure, microstructures, texture and paleopiezometry of quartz-rich phyllites and marbles along N-trending Moutsounas shear zone at the eastern margin of the Naxos metamorphic core complex (MCC). Fabrics consistently indicate a top-to-the-NNE non-coaxial shear and formed during the main stage of updoming and exhumation between ca. 14 and 11 Ma of the Naxos MCC.
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