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    • Besides MPO the infiltrated neutrophils in IR injured

    2019-04-19

    Besides MPO, the infiltrated neutrophils in IR injured liver can produce INFγ to enhance TLR4 signaling, stimulate KCs activation, and induce Th1 inflammation responses. Subsequently, M1/Th1 acetylcholine chloride produce INFγ to enhance neutrophil infiltration in the process of hepatic and renal IR injury. In IR liver injury, INFγ is an important mediator to regulate the crosstalk between KCs and neutrophils. Interestingly, we found that 14-day DcR3a supplement inhibited the IR-elevated hepatic INFγ and TLR4 signals as well as KCs and neutrophils crosstalk, therefore protecting our DcR3a + IR-Zucker (HS) rats from IR steatotic liver injury. In obese animals, the visceral adipose tissue-derived TNFα (Th1 cytokine) and IL-1 seem to contribute to M1 phenotype KCs activation, which results in the neutrophil infiltration of the steatotic liver. In our IR-Zucker (HS) rats, the significant increase in serum TNFα levels, hepatic Th1 cytokines, KCs accumulation and M1 polarization were associated with increased hepatic neutrophil infiltration. These results support the concepts that TNFα release from activated KCs increase neutrophil infiltration and aggravate the severity of steatotic liver IR injury. M2 macrophages have poor antigen-presenting capacity but can produce factors that promote tissue remodeling. Mechanisms induced by M2/Th2 activation are able to protect kidney from IR injury. In our DcR3a + IR-Zucker (HS) rats, 14-day DcR3a supplement-related inhibition of TNFα and IL-1β levels reduced M1/Th1 and enhanced M2/Th2 KCs polarization, and thus limited hepatic IR damage. In conclusion, this study suggested that 14-day DcR3a supplement protected steatotic livers from hepatic IR injury by downregulating hepatic TL1A/Fas-L and TLR4/NFκB signals, by suppressing hepatic M1 polarization of KCs, by reducing hepatic neutrophil infiltration to decrease oxidative injury and microcirculatory failure, and by ameliorating hepatic inflammation, apoptosis, and necrosis (Fig. 4). Our parallel in vitro studies in primary isolated KCs supported the in vivo beneficial effects of DcR3a supplement and pinpointed the mechanisms by which this occurs during IR steatotic liver injury. Our findings strongly suggested that 14-day DcR3a supplement was likely to provide a meaningful approach to the management of IR injury in steatotic livers.
    Introduction In Asia, the predominant histological type of esophageal cancer is squamous cell carcinoma, accounting for over 90% of all cancers of the esophagus. Most squamous cell carcinomas are located in the midportion of the esophagus, with early local invasion and regional lymph node spreading. Because the early symptoms of esophageal cancer are subtle and nonspecific, patients usually present with obvious difficulty swallowing and body weight loss, which indicate advanced disease. Only a minority of affected patients have a tumor confined to the mucosa, requiring treatment by surgical management alone. Multidisciplinary modalities should be considered to achieve a higher local control and overall survival in the treatment of advanced esophageal cancer. From 1981 to 1999, there were over 46 nonrandomized clinical trials that analyzed over 2700 patients with advanced esophageal cancer who were treated by neoadjuvant chemoradiotherapy. Taken together, the results suggested that the overall survival and local control of advanced esophageal cancer could be improved by neoadjuvant chemoradiotherapy followed by surgery. At least two randomized clinical trials and two meta-analyses demonstrated the benefits of neoadjuvant chemoradiotherapy in improving the overall survival of patients with advanced esophageal cancer. The most popular chemotherapy regimens investigated in previous studies of neoadjuvant chemoradiotherapy contained 5-fluorouracil (5-FU) and cisplatin. One of the severe side effects of cisplatin is renal function impairment. Oxaliplatin, a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane carrier ligand, has shown in vitro and in vivo efficacy against many tumor cell lines, including some that are resistant to cisplatin and carboplatin. Oxaliplatin also lacks ototoxicity and nephrological toxicities that are caused by cisplatin. Preclinical studies have shown that oxaliplatin is a radiation-sensitizing agent and is synergistic with 5-FU. Furthermore, oxaliplatin in combination with capecitabine resulted in a 35% tumor response rate and acceptable toxicities in a Phase II study when used as a first-line therapy for metastatic esophageal cancer. To maximize the treatment effect without compromising the general condition of patients before surgery, we designed this Phase II study to assess the efficacy and safety of one cycle of loading chemotherapy plus preoperative concurrent chemoradiotherapy (CCRT) with oxaliplatin and 5-FU/leucovorin followed by surgery, if possible, in patients with locally advanced esophageal cancer.