Evaluation of the efficacy of gastric lymphoma treated with non-surgical therapy using oral and double contrast-enhanced gastric ultrasonography.

AIM: To investigate the feasibility of assessing the ecacy of non-surgical treatment for gastric lymphoma using oral contrast-enhanced ultrasound (OCEUS) and double contrast-enhanced ultrasound (DCEUS). MATERIAL AND METHODS: A total of 27 patients with gastric lymphoma treated nonoperatively were included in this retrospective study. The ecacy was evaluated using OCEUS and CT, respectively, and the results were tested for kappa concordance. Sixteen of the 27 patients underwent multiple DCEUS examinations before and after treatment. Micro-perfusion of the lesion in DCEUS is represented by the Echo Intensity Ratio (EIR), (echo intensity of the lymphoma lesion/echo intensity of the normal gastric wall), and one-way ANOVA was used to compare the differences between groups in EIR values before and after treatment. RESULTS: OCEUS and CT were highly consistent in assessing the efficacy of gastric lymphoma, with a Kappa value of 0.758. During a median follow-up of 8.8 months, there was no statistical difference between the complete remission rate obtained by OCEUS and that obtained by endoscopic and CT (25.93% vs. 44.44%, p=0.154; 25.93% vs. 33.33%, p=0.766). There was also no statistical difference in the time to achieve complete remission using OCEUS assessment and endoscopy and CT (4.71±1.03 months vs. 6.01±2.14 months, p=0.088; 4.47±1.84 months vs. 6.01±2.14 months p=0.143). The difference in EIR between the groups before treat-ment and after different numbers of treatments was statistically signifficant (p<0.05), and post hoc analysis revealed this dif-ference as early as after the second treatment (p<0.05). CONCLUSIONS: Transabdominal OCEUS and CT are comparable in the assessment of gastric lymphoma treatment ecacy. DCEUS is a noninvasive, cost-effective, and widely available method for gastric lymphoma therapeutic effect evaluation. Therefore, transabdominal OCEUS and DCEUS have the potential to be used for the early assessment of the ecacy of the non-surgical treatment of gastric lymphoma.

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis (NASH). G protein-coupled receptor 35 (GPR35) is involved in metabolic stresses, but its role in NAFLD is unknown. We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis. Specifically, we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of GPR35 had the opposite effect. Administration of the GPR35 agonist kynurenic acid (Kyna) suppressed HFCF diet-induced steatohepatitis in mice. Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4 (STARD4) through the ERK1/2 signaling pathway, ultimately resulting in hepatic cholesterol esterification and bile acid synthesis (BAS). The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1, promoting the conversion of cholesterol to bile acid. The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice. STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice. Our findings indicate that the GPR35-STARD4 axis is a promising therapeutic target for NAFLD.

Manganese Prussian blue nanozymes with antioxidant capacity prevent acetaminophen-induced acute liver injury.

As one of the leading cases of acute liver failure triggered by excessive Acetaminophen (APAP), breakdown of the antioxidant system, inflammatory response, and inescapable apoptosis following overaccumulation of reactive oxygen species (ROS) play crucial roles in the mechanisms of APAP-induced liver injury (AILI). Therefore, cutting off ROS overproduction at the source is considered promising. Here, manganese Prussian blue nanozymes (MPBZs) with superior antioxidant enzyme-like activity are prepared as an effective strategy for hepatocyte protection, in which MPBZs accumulated in the liver show anti-oxidation properties by scavenging superfluous ROS. Importantly, in addition to alleviating oxidative stress, bioactive MPBZs with abundant variable valence states as a natural antioxidant enzymes mediated the responses of multi-biological signaling pathways in vitro and in vivo, including Nrf2-Keap1, NF-κB, and mitochondrial-induced apoptosis signaling pathways, enhancing tolerance for imminent AILI. Taking nanomedicine, hepatology, and catalytic chemistry into consideration, the revealed superior performance of AILI prevention suggests that MPBZ-based nano-detoxification therapy may offer an effective alternative against AILI.

An effective spatial relational reasoning networks for visual question answering.

Visual Question Answering (VQA) is a method of answering questions in natural language based on the content of images and has been widely concerned by researchers. The existing research on the visual question answering model mainly focuses on the point of view of attention mechanism and multi-modal fusion. It only pays attention to the visual semantic features of the image in the process of image modeling, ignoring the importance of modeling the spatial relationship of visual objects. We are aiming at the existing problems of the existing VQA model research. An effective spatial relationship reasoning network model is proposed, which can combine visual object semantic reasoning and spatial relationship reasoning at the same time to realize fine-grained multi-modal reasoning and fusion. A sparse attention encoder is designed to capture contextual information effectively in the semantic reasoning module. In the spatial relationship reasoning module, the graph neural network attention mechanism is used to model the spatial relationship of visual objects, which can correctly answer complex spatial relationship reasoning questions. Finally, a practical compact self-attention (CSA) mechanism is designed to reduce the redundancy of self-attention in linear transformation and the number of model parameters and effectively improve the model's overall performance. Quantitative and qualitative experiments are conducted on the benchmark datasets of VQA 2.0 and GQA. The experimental results demonstrate that the proposed method performs favorably against the state-of-the-art approaches. Our best single model has an overall accuracy of 71.18% on the VQA 2.0 dataset and 57.59% on the GQA dataset.

Hepatocyte-specific deletion of cellular repressor of E1A-stimulated genes 1 exacerbates alcohol-induced liver injury by activating stress kinases.

Alcohol-associated liver disease (ALD) encompasses a wide range of pathologies from simple steatosis to cirrhosis and hepatocellular carcinoma and is a global health problem. Currently, there are no effective pharmacological treatments for ALD. We have previously demonstrated that aging exacerbates the pathogenesis of ALD, but the underlying mechanisms are still poorly understood. Cellular repressor of E1A-stimulated genes 1 protein (CREG1) is a recently identified small glycoprotein that has been implicated in aging process by promoting cellular senescence and activating stress kinases. Thus, the current study aimed to explore the role of aging associated CREG1 in ALD pathogenesis and CREG1 as a potential therapeutic target. Hepatic and serum CREG1 protein levels were elevated in ALD patients. Elevation of hepatic CREG1 protein and mRNA was also observed in a mouse model of Gao-binge alcohol feeding. Genetic deletion of the Creg1 gene in hepatocytes (Creg1∆hep ) markedly exacerbated ethanol-induced liver injury, apoptosis, steatosis and inflammation. Compared to wild-type mice, Creg1∆hep mice had increased phosphorylation of hepatic stress kinases such as apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38 but not TGF-ß-activated kinase 1 (TAK1) or extracellular signal-regulated kinase (ERK) after alcohol feeding. In vitro, ethanol treatment elevated the phosphorylation of ASK1, JNK, and p38 in mouse hepatocyte AML-12 cells. This elevation was further enhanced by CREG1 knockdown but alleviated by CREG1 overexpression. Last, treatment with an ASK1 inhibitor abolished ethanol-induced liver injury and upregulated hepatic lipogenesis, proinflammatory genes and stress kinases in Creg1∆hep mice. Taken together, our data suggest that CREG1 protects against alcoholic liver injury and inflammation by inhibiting the ASK1-JNK/p38 stress kinase pathway and that CREG1 is a potential therapeutic target for ALD.

Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration.

Nuclear receptor corepressor 1 (NCoR1) is a corepressor of the epigenetic regulation of gene transcription that has important functions in metabolism and inflammation, but little is known about its role in alcohol-associated liver disease (ALD). In this study, we developed mice with hepatocyte-specific NCoR1 knockout (NCoR1Hep-/-) using the albumin-Cre/LoxP system and investigated the role of NCoR1 in the pathogenesis of ALD and the underlying mechanisms. The traditional alcohol feeding model and NIAAA model of ALD were both established in wild-type and NCoR1Hep-/- mice. We showed that after ALD was established, NCoR1Hep-/- mice had worse liver injury but less steatosis than wild-type mice. We demonstrated that hepatocyte-specific loss of NCoR1 attenuated liver steatosis by promoting fatty acid oxidation by upregulating BMAL1 (a circadian clock component that has been reported to promote peroxisome proliferator activated receptor alpha (PPARα)-mediated fatty ß-oxidation by upregulating de novo lipid synthesis). On the other hand, hepatocyte-specific loss of NCoR1 exacerbated alcohol-induced liver inflammation and oxidative stress by recruiting monocyte-derived macrophages via C-C motif chemokine ligand 2 (CCL2). In the mouse hepatocyte line AML12, NCoR1 knockdown significantly increased ethanol-induced CCL2 release. These results suggest that hepatocyte NCoR1 plays distinct roles in controlling liver inflammation and steatosis, which provides new insights into the development of treatments for steatohepatitis induced by chronic alcohol consumption.