Background: The poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the need for novel strategies against this disease. Our previous study suggested the involvement of CCL2 and tumor associated macrophages (TAMs) in esophageal carcinogenesis. Despite the recognition of TAMs as a promising target for cancer treatment, mechanisms underlying its infiltration, activation and tumor-promotive function in ESCC remain unknown. Methods: Human esophageal tissue array and TCGA database were used to evaluate the clinical relevance of CCL2 and TAMs in ESCC. F344 rats and C57BL/6 mice were treated with N-nitrosomethylbenzylamine (NMBA) to establish orthotopic models of esophageal carcinogenesis. CCL2/CCR2 gene knockout mice and macrophage-specific PPARG gene knockout mice were respectively used to investigate the role of infiltration and polarization of TAMs in ESCC. CCL2-mediated monocyte chemotaxis was estimated in malignantly transformed Het-1A cells. THP-1 cells were used to simulate TAMs polarization in vitro. RNA-sequencing was performed to uncover the mechanism. Results: Increasing expression of CCL2 correlated with TAMs accumulation in esophageal carcinogenesis, and they both predicts poor prognosis in ESCC cohort. Animal studies show blockade of CCL2-CCR2 axis strongly reduces tumor incidence by hindering TAMs recruitment and thereby potentiates the antitumor efficacy of CD8 + T cells in the tumor microenvironment. More importantly, M2 polarization increases PD-L2 expression in TAMs, resulting in immune evasion and tumor promotion through PD-1 signaling pathway. Conclusion: This study highlights the role of CCL2-CCR2 axis in esophageal carcinogenesis. Our findings provide new insight into the mechanism of immune evasion mediated by TAMs in ESCC, suggesting the potential of TAMstargeted strategies for ESCC prevention and immunotherapy.

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trans-Resveratrol (resveratrol) has been shown to have beneficial effects on the cardiovascular system in a number of studies. It is, however, unclear whether this naturally occurring compound can protect against cardiac hypertrophy. The aim of the present study was to investigate the effects of resveratrol on cardiac hypertrophy in vivo and the potential underlying mechanisms involving endothelin (ET), angiotensin (Ang) II and nitric oxide (NO) in partially nephrectomized rats. Animal models bearing cardiac hypertrophy were replicated in male Sprague-Dawley rats following partial nephrectomy (PNX). Resveratrol (10 or 50 mg/kg) was administered to rats by gavage for 4 weeks. Simultaneous PNX and sham operation controls were simultaneously established in the present study. The systolic blood pressure (SBP) of rats was measured at baseline and, along with heart weight, after 4 weeks treatment. Serum ET-1, AngII and NO concentrations were determined. In the present study, it was shown that, compared with rats in the sham-operated group, rats in the PNX group had significantly higher SBP (154.1 +/- 22.7 mmHg), heart weight (1.69 +/- 0.24 g) and serum ET-1 (125.70 +/- 26.27 pg/mL) and AngII serum concentrations (743.63 +/- 86.50 pg/mL), whereas serum NO concentrations were lower (21.1 +/- 6.9 micromol/L; all P < 0.05). These values in the sham control group were 114 +/- 10 mmHg, 1.28 +/- 0.13 g, 52.44 +/- 21.85 pg/mL, 528.7 +/- 158.5 pg/mL and 53.21 +/- 23.87 micromol/L, respectively. After 4 weeks treatment with 50 mg/kg resveratrol, SBP, heart weight and ET-1 and AngII concentrations had decreased to 135.4 +/- 15.8 mmHg, 1.39 +/- 0.15 g, 97.11 +/- 26.74 pg/mL and 629.64 +/- 116.18 pg/mL, respectively. However, the serum NO concentration had increased to 40.1 +/- 14.6 micromol/L. These values were significantly different from those obtained for the PNX group. In conclusion, trans-resveratrol appears to be able to protect against the increase in SBP and subsequent cardiac hypertrophy in vivo and the mechanisms responsible may involve, at least in part, modulation of NO, AngII and ET-1 production.

Milk protein concentrate was pretreated either by microwave irradiation or by ultrasound before initiation of 3-h enzymatic hydrolysis. The duration of pretreatment ranged from 1 to 8 min at a power level of 800 W, with the control not being subjected to any pretreatment, and five enzymes (Alcalase, Trypsin, Neutrase, Alkaline Protease and Flavourzyme) were employed. The effects of microwave and ultrasound pretreatments on the kinetics and degree of hydrolysis, protein solubility, bitterness and angiotensinconverting enzyme inhibitory activity were evaluated. Pretreatments increased the degree of hydrolysis and stabilised the solubility of the hydrolysates but could not significantly reduce bitterness of the hydrolysates The angiotensin-converting enzyme inhibitory activity of the hydrolysates were improved with 5-min ultrasound-pretreated Neutrase hydrolysates giving IC 50 value of 0.23 mg mL À1 . Kinetic parameters showed improved catalytic efficiencies. Pretreatments of milk protein concentrates with either microwave or ultrasound significantly improve the bioactivity and functional characteristics of the resulting hydrolysates. Enzyme hydrolysis of MPC H. Uluko et al. Enzyme hydrolysis of MPC H. Uluko et al. Enzyme hydrolysis of MPC H. Uluko et al. 2254 Enzyme hydrolysis of MPC H. Uluko et al. 2255 Enzyme hydrolysis of MPC H. Uluko et al. Enzyme hydrolysis of MPC H. Uluko et al.

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Lactobacillus casei AST18 was screened as an antifungal lactic acid bacteria which we have reported before. In this research, the antifungal properties of cell-free culture filtrate (CCF) from L. casei AST18 were detected, and the antifungal compounds of CCF were prepared by ultrafiltration, and semi-preparative HPLC, and then determined by GC-MS. CCF was sensitive to pH and heat treatment but it was not affected by the treatment of trypsin and pepsin. Through the treatment of ultrafiltration and semi-preparative HPLC there were two parts of CCF which showed antifungal activities: part 1 and part 4. Lactic acid was identified as the main antifungal compound in part 1. In part 4, three small molecular substances were detected with GC-MS. The three potential antifungal substances were cyclo-(Leu-Pro), 2,6-diphenyl-piperidine, and 5,10-diethoxy-2,3,7,8-tetrahydro-1H,6H-dipyrrolo[1,2-a;1',2'-d]pyrazine. The antifungal activity of L. casei AST18 was a synergistic effect of lactic acid and cyclopeptides.

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Autolysis of lactic acid bacteria (LAB) plays a vital role in dairy processing. During cheese making, autolysis of LAB affects cheese flavor development through release of intracellular enzymes and restricts the proliferation of cells in yogurt fermentation and probiotics production. In order to explore the mechanism of autolysis, the gene for the autolytic enzymes of L. bulgaricus, N-acetylmuramidase (mur), was cloned and sequenced (GenBank accession number: KF157911). Mur gene overexpression and gene knockout vectors were constructed based on pMG76e and pUC19 vectors. Recombinant plasmids were transformed into L. bulgaricus ljj-6 by electroporation, then three engineered strains with pMG76e-mur vector and fifteen engineered strains with pUC19-mur::EryBII were screened. The autolysis of the mur knockout strain was significantly lower and autolysis of the mur overexpressed strain was significantly higher compared with that of the wild type strain ljj-6. This result suggested that the mur gene played an important role in autolysis of L. bulgaricus. On the other hand, autolytic activity in a low degree was still observed in the mur knockout strain, which implied that other enzymes but autolysin encoded by mur were also involved in autolysis of L. bulgaricus.