Adenosine 2A receptor (A2AR) exerts protective roles in endotoxin‐ and/or ischemia‐induced tissue damage. However, the role for A2AR in nonalcoholic fatty liver disease (NAFLD) remains largely ...unknown. We sought to examine the effects of global and/or myeloid cell‐specific A2AR disruption on the aspects of obesity‐associated NAFLD and to elucidate the underlying mechanisms. Global and/or myeloid cell–specific A2AR‐disrupted mice and control mice were fed a high‐fat diet (HFD) to induce NAFLD. In addition, bone marrow–derived macrophages and primary mouse hepatocytes were examined for inflammatory and metabolic responses. Upon feeding an HFD, both global A2AR‐disrupted mice and myeloid cell–specific A2AR‐defcient mice revealed increased severity of HFD‐induced hepatic steatosis and inflammation compared with their respective control mice. In in vitro experiments, A2AR‐deficient macrophages exhibited increased proinflammatory responses, and enhanced fat deposition of wild‐type primary hepatocytes in macrophage–hepatocyte cocultures. In primary hepatocytes, A2AR deficiency increased the proinflammatory responses and enhanced the effect of palmitate on stimulating fat deposition. Moreover, A2AR deficiency significantly increased the abundance of sterol regulatory element‐binding protein 1c (SREBP1c) in livers of fasted mice and in hepatocytes upon nutrient deprivation. In the absence of A2AR, SREBP1c transcription activity was significantly increased in mouse hepatocytes. Conclusion: Taken together, our results demonstrate that disruption of A2AR in both macrophage and hepatocytes accounts for increased severity of NAFLD, likely through increasing inflammation and through elevating lipogenic events due to stimulation of SREBP1c expression and transcription activity. (Hepatology 2018;68:48‐61).
Person re-identification (ReID) is one of the commonly used criminal investigation methods in reconnaissance. Although the current ReID has achieved robust results on single domains, the focus of ...researches has shifted to cross-domain in recent years, which is caused by domain bias between different datasets. Generative Adversarial Networks (GAN) is used to realize the image style transfer of different datasets to alleviate the effect of cross-domain. However, the existing GAN-based models ignore complete expressions and occlusion of pedestrian characteristics, resulting in low accuracy in feature extraction. To address these issues, we introduce a cross domain model based on feature fusion (FFGAN) to fuse global, local and semantic features to extract more delicate pedestrian features. Before extracting pedestrian features, we preprocess feature maps with a feature erasure block to solve an occlusion issue. Finally, FFGAN enables a more complete visual description of pedestrian characteristics, thereby improving the accuracy of FFGAN in identifying pedestrians. Experimental results show that the effect of FFGAN is significantly improved compared with some advanced cross-domain ReID algorithms.
Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and ...non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice.
Mice with disruption of Tmem173 (STINGgt) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD; 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; an activator of STING) or cyclic guanosine monophosphate–adenosine monophosphate (cGAMP). Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (by oil red O staining after incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry.
Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than cells of liver tissues from patients without NAFLD. STINGgt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis after the HFD or MCD than control mice. Levels of phosphorylated c-Jun N-terminal kinase and p65 and mRNAs encoding tumor necrosis factor and interleukins 1B and 6 (markers of inflammation) were significantly lower in liver tissues from STINGgt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STINGgt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STINGgt, mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STINGgt macrophages in the presence of DMXAA or incubated with the medium collected from these macrophages had decreased fat deposition and markers of inflammation compared with hepatocytes or stellate cells incubated with control macrophages.
Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.
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Adipose tissue hypoxia occurs early in obesity and is associated with increased tissue macrophages and systemic inflammation that impacts muscle insulin responsiveness. We investigated how hypoxia ...interacted with adipocyte-macrophage crosstalk and inflammatory cytokine release, using co-culture and conditioned media (CM). Murine primary adipocytes from lean or obese mice were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions. RAW264.7 macrophages were incubated under normoxic or hypoxic conditions with or without adipocyte conditioned media. Macrophage and adipocyte-macrophage co-culture CM were also collected. We found hypoxia did not elicit direct cytokine release from macrophages. However, adipocyte CM or adipocyte co-culture, synergistically stimulated TNFα and MCP-1 release from macrophages that was not further impacted by hypoxia. Exposure of muscle cells to elevated cytokines led to reduced insulin and muscle stress/inflammatory signaling. We conclude hypoxia or obesity induces release of inflammatory TNFα and MCP-1 from mice primary adipocytes but the two environmental conditions do not synergize to worsen macrophage signal transduction or insulin responsiveness.
•Hypoxic adipocytes induced macrophages inflammation to secret TNFα and MCP-1.•CMs from inflammatory macrophages rendered muscle cells insulin resistant.•CMs from inflammatory macrophages activated S6K and JNK.•TNFα and MCP-1 may cause muscle cells insulin resistance induced by inflammatory macrophages-derived CM.
Recent evidence suggests that adenosine 2A receptor (A2AR) exerts a protective role in NAFLD. However, the role of the A2AR in macrophages in NAFLD pathophysiology remains unknown. In the present ...study, hepatic inflammation and fat deposition were examined in myeloid cell-specific A2AR-deficient mice and control mice fed a HFD for 12 weeks. In addition, bone marrow cells were isolated from global and/or myeloid cell-specific A2AR-deficient mice and differentiated into macrophages (BMDM) for inflammatory analysis and for macrophage-hepatocyte co-cultures. Upon HFD feeding, the activity of JNK p46 and NFκB p65 and the mRNA levels of proinflammatory cytokines such as TNFα, IL-1β, and IL-6 in livers of myeloid cell-specific A2AR-defcient mice were significantly higher than their respective levels in livers of control mice. These increases were accompanied with increased severity of diet-induced hepatic steatosis, indicated by the results from liver histology and by elevated levels of liver triglycerides. When BMDM were analyzed for inflammatory activation, the phosphorylation states of JNK p46 and NFκB p65 and the production of proinflammatory cytokines in A2AR-deficient BMDM were significantly higher than their respective levels in control BMDM. Moreover, in macrophage-hepatocyte co-culture systems, hepatocytes co-cultured with A2AR-deficient BMDM revealed significant increases in TNFα, IL-1β, and IL-6 mRNAs in relative to hepatocytes co-cultured with control BMDM. Additionally, hepatocytes co-cultured with A2AR-deficient BMDM accumulated much more fat upon palmitate stimulation than hepatocytes co-cultured with control BMDM. Taken together, these results suggest that the inflammatory status of macrophages can be altered by A2AR in a manner to critically determine the development of NAFLD. Moreover, targeting A2AR to suppress inflammation may be a viable preventive and/or therapeutic approach for inflammation-associated diseases including NAFLD.
Disclosure
J. Zhou: None. H. Li: None. X. Luo: None. L. Ma: None. C. Wu: None.
Adenosine 2A receptor (A2AR) exerts anti-inflammatory effects. However, the role of A2AR in obesity-associated adipose tissue inflammation remains to be elucidated. The present study examined the ...expression of A2AR in adipose tissue of mice with diet-induced obesity and determined the effect of A2AR disruption on the status of obesity-associated adipose tissue inflammation. WT C57BL/6J mice and A2AR-disrupted mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and adipose tissue inflammation. In vitro, bone marrow-derived macrophages from A2AR-disrupted mice and WT control mice were treated with palmitate and examined for macrophage proinflammatory activation. Compared with that of low-fat diet (LFD)-fed WT mice, A2AR expression in adipose tissue of HFD-fed WT mice was increased significantly and was present predominantly in adipose tissue macrophages. The increase in adipose tissue A2AR expression in HFD-fed mice was accompanied with increased phosphorylation states of c-Jun N-terminal kinase 1 p46 and nuclear factor kappa B p65 and mRNA levels of interleukin (Il)-1beta, Il6 and tumor necrosis factor alpha. In A2AR-disrupted mice, HFD feeding induced significant increases in adipose tissue inflammation, indicated by enhanced proinflammatory signaling and increased proinflammatory cytokine expression, and adipose tissue insulin resistance, indicated by a decrease in insulin-stimulated Akt phosphorylation relative to those in WT mice. Lastly, A2AR disruption enhanced palmitate-induced macrophage proinflammatory activation. Taken together, these results suggest that A2AR plays a protective role in obesity-associated adipose tissue inflammation, which is attributable to, in large part, A2AR suppression of macrophage proinflammatory activation.
Pancreatic cancer is a highly dismal malignancy and has a poor response to major treatments. Patients with pancreatic cancer usually have poor prognosis. Precision therapy has a great potential to ...improve the outcome of pancreatic cancer. Over 25% of patients have druggable targets, which mainly involve in KRAS mutation status, homologous recombination repair deficiency, gene fusions, and immunotherapy related pathways. Patients with familial or personal history of malignancy, younger patients, or patients with acinar cell carcinoma may benefit from precision therapy. However, only 4% of patients have received precision therapy, and thus precision therapy is still not a major therapeutic method for pancreatic cancer. It is common that genetic/molecular reports are lack of critical information, such as KRAS mutation status, tumor cell content, fusions and germline mutations. It is necessary to promote precision therapy from streamlet towards mainstream by formulating detection technique, establishing expertise team and stressing cooperation to accumulate evidence, thereby providing benefits for the patients. Recent reports have shown that precision treatments could improve the outcome and survival of patients with pancreatic cancer. In 2019, The New England Journal of Medicine published the POLO study which investigated olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), in patients with metastatic pancreatic cancer and BRCA1 or BRCA2 germline mutation. This is the first clinical trial of precision therapy based on therapeutic targets in pancreatic cancer. In 2020, Pishvaian et al. from the University of Texas MD Anderson Cancer Center published the results of “Know Your Tumor (KYT)”. In this study, among 1 856 patients with pancreatic cancer, patients with actionable molecular alterations who received a matched therapy (n = 46, 2.58 years) had longer median overall survival than did those patients who only received unmatched therapies n = 143; 1.51 years; hazard ratio (HR) was 0.42, P = 0.004. The patients who received a matched therapy also had longer overall survival compared with the patients who did not have an actionable molecular alteration (n=488; 1.32 years; HR was 0.34, P<0.000 1). This real-world study indicates that matched treatments for patients with pancreatic cancer and actionable molecular alterations could prolong the overall survival of patients for more than one year. To date, therapeutic targets in pancreatic cancer include KRAS mutation status (KRAS wild-type and KRAS G12C mutation), homologous recombination repair deficiency (BRCA1/2, PALB2, ATM/ATR/ATRX, CHEK2, CDK12, RAD51, NBN, BLM, FANC, RAD51/51C, RAD50, BAP1, BARD1, BRIP1, MRE11), gene fusions (NTRK, NRG1, ALK, RAF, RET, MET, FGFR2/3, ROS), immunotherapy related pathways MSI-H, TMB, MMR-D (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2, POLE, EPCAM) and others BRAF, human epidermal growth factor receptor 2 (HER2). It is necessary to establish specialized team which focuses on precision treatments in pancreatic cancer for the reasons that only limited proportion of patients have therapeutic targets which are widely distributed. The overall survival of patients with pancreatic cancer is poor. It is hard to acquire tumor specimens from advanced pancreatic cancer. As great importance has been attached, we believe that there will be a bright future for the precision treatment in pancreatic cancer.
Pancreatic cancer is a highly malignant tumor of the digestive tract. Given the lack of appropriate screening and diagnosis methods, the deep location of the pancreas, difficulty in a tissue biopsy, ...rapid tumor progression and low response rate to radiotherapy or chemotherapy, its morbidity is almost similar to the mortality. Approximately 80% of patients with pancreatic cancer have advanced disease at the time of diagnosis, and the average survival time is less than 1 year. The extremely aggressive nature of pancreatic cancer and the low survival rate make it a heavy global burden. With the advancement of many basic and clinical studies, new progress has been made in the pathogenesis of pancreatic cancer, diagnostic methods, preoperative treatment, radiotherapy techniques and systemic treatment of advanced diseases during the last year. These results further enrich the treatment options for patients with pancreatic cancer and improve the prognosis. The present review summarized the important findings in pancreatic cancer research in 2021.
Energy sources identify metabolic phenotypes n pancreatic cancer Chen Liang Yi Qin Bo Zhang Shunrong Ji Si Shi Wenyan Xu Jiang Liu Jinfeng Xiang Dingkong Liang Qiangsheng Hu Liang Liu Chen Liu Guopei Luo Quanxing Ni Jin xu Xianjun Yu
生物化学与生物物理学报：英文版,
2016, Letnik:
48, Številka:
11
Journal Article
Recenzirano
Metabolic reprogramming is one of the emerging hallmarks of cancers. As a highly malignant tumor, pancreatic ductal adenocarcinoma （PDA） is not only a metabolic disease but also a hetero- geneous ...disease. Heterogeneity induces PDA dependence on distinct nutritive substrates, thereby inducing different metabolic phenotypes. We stratified PDA into four phenotypes with distinct types of energy metabolism, including a Warburg phenotype, a reverse Warburg phenotype, a glutaminolysis phenotype, and a lipid-dependent phenotype. The four phenotypes possess dis- tinct metabolic features and reprogram their metabolic pathways to adapt to stress. The metabolic type present in PDA should prompt differential imaging and serologic metabolite detection for diagnosis and prognosis. The targeting of an individual metabolic phenotype with corresponding metabolic inhibitors is considered a promising therapeutic approach and, in combination with chemotherapy, is expected to be a novel strategy for PDA treatment.
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