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The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated. CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G0/G1 cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells. CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells.

The treatment of human colorectal cancer (CRC) cells through suppressing the abnormal survival signaling pathways has recently become a significant area of focus. In this study, our results demonstrated that decyl caffeic acid (DC), one of the novel caffeic acid derivatives, remarkedly suppressed the growth of CRC cells both in vitro and in vivo. The inhibitory effects of DC on CRC cells were investigated in an in vitro cell model and in vivo using a xenograft mouse model. CRC cells were treated with DC at various dosages (0, 10, 20 and 40 μM), and cell survival, the apoptotic index and the autophagy level were measured using an MTT assay and flow cytometry analysis, respectively. The signaling cascades in CRC were examined by Western blot assay. The anti-cancer effects of DC on tumor growth were examined by using CRC HCT-116 cells implanted in an animal model. Our results indicated that DC differentially suppressed the growth of CRC HT-29 and HCT-116 cells through an enhancement of cell-cycle arrest at the S phase. DC inhibited the expression of cell-cycle regulators, which include cyclin E and cyclin A proteins. The molecular mechanisms of action were correlated to the blockade of the STAT3 and Akt signaling cascades. Strikingly, a high dosage of DC prompted a self-protection action through inducing cell-dependent autophagy in HCT-116 cells. Suppression of autophagy induced cell death in the treatment of DC in HCT-116 cells. DC seemed to inhibit cell proliferation of CRC differentially, and the therapeutic advantage appeared to be autophagy dependent. Moreover, consumption of DC blocked the tumor growth of colorectal adenocarcinoma in an experimental animal model. In conclusion, our results suggested that DC could act as a therapeutic agent through the significant suppression of tumor growth of human CRC cells.

This study investigated the effects of l-glutamine (Gln) and/or l-leucine (Leu) administration on sepsis-induced skeletal muscle injuries. C57BL/6J mice were subjected to cecal ligation and puncture to induce polymicrobial sepsis and then given an intraperitoneal injection of Gln, Leu, or Gln plus Leu beginning at 1 h after the operation with re-injections every 24 h. All mice were sacrificed on either day 1 or day 4 after the operation. Blood and muscles were collected for analysis of inflammation and oxidative damage-related biomolecules. Results indicated that both Gln and Leu supplementation alleviated sepsis-induced skeletal muscle damage by reducing monocyte infiltration, calpain activity, and mRNA expression levels of inflammatory cytokines and hypoxia-inducible factor-1α. Furthermore, septic mice treated with Gln had higher percentages of blood anti-inflammatory monocytes and muscle M2 macrophages, whereas Leu treatment enhanced the muscle expressions of mitochondrion-related genes. However, there were no synergistic effects when Gln and Leu were simultaneously administered. These findings suggest that both Gln and Leu had prominent abilities to attenuate inflammation and degradation of skeletal muscles in the early and/or late phases of sepsis. Moreover, Gln promoted the switch of leukocytes toward an anti-inflammatory phenotype, while Leu treatment maintained muscle bioenergetic function.

Inflammatory bowel disease (IBD) is associated with loss of immune tolerance to antigens originating from the diet and from the gut microflora. T cells play crucial roles in the pathogenesis of IBD. Chlorpyrifos (CPF) is one of the most ubiquitous organophosphate pesticides in the world. The aim of the study was to investigate the effects of dietary exposure to CPF on T-cell populations in C57BL/6 mice with dextran sulfate sodium (DSS)-induced colitis. Mice received distilled water containing 3% DSS for 6 days to induce acute colitis, which was then replaced with distilled water for 21 days, allowing progression to chronic inflammation. During the experimental period, mice were given either an AIN-93-based control diet or a CPF diet-containing 7, 17.5, or 35 ppm of CPF. Results showed that dietary exposure to CPF significantly increased circulating neutrophils in colitic mice. CPF-exposed groups had lower percentages of blood and spleen T cells without altering the proportions of CD4+ and CD8+ T-cell subsets. The percentage of blood regulatory T (Treg) cells, as well as splenic expressions of Treg-related genes, were suppressed in CPF-exposed mice. CPF upregulated the colonic gene expression of tumor necrosis factor-α. Meanwhile, plasma haptoglobin, colon weights, and luminal immunoglobulin G levels were higher in CPF-exposed groups. Histopathological analyses also observed that colon injury was more severe in all CPF-exposed mice. These results suggest that dietary exposure to CPF aggravated tissue injuries in mice with DSS-induced chronic colitis by suppressing T-cell populations and Treg polarization.

Purpose Diabetes is a chronic inflammatory disorder resulting in endothelial dysfunction which contributes to peripheral arterial disease and limb ischemia. Leukocytes play critical roles in vascular and tissue remodelling after ischemia. This study investigated the effects of dietary glutamine (GLN) supplementation on immune cell polarization in diabetic mice subjected to limb ischemia. Methods Diabetes was induced by an intraperitoneal injection of streptozotocin for 5 consecutive days in C57BL/6J mice. Diabetic mice were fed the AIN-93 diet or an AIN-93 diet in which a part of the casein was replaced by GLN. After 3 weeks of the dietary intervention, mice were subjected to unilateral femoral artery ligation to induce limb ischemia. Results GLN supplementation enhanced the proportion of anti-inflammatory monocytes and regulatory T cells in the blood. Expression of C-C motif chemokine receptor 5 by activated CD4 + T cells was promoted and prolonged in the GLN-supplemented group. GLN downregulated the percentage of M1 macrophages in muscle tissues which was correlated with lower levels of C-C motif chemokine ligand 2 in plasma. The muscle M1/M2 ratio was also reduced in the GLN group. Gene expression of interleukin-6 was suppressed by GLN supplementation, while expression levels of the peroxisome proliferator-activated receptor γ and myogenic differentiation 1 genes were elevated in post-ischemic muscles. Histological findings also indicated that muscle regeneration was accelerated in the GLN group. Conclusions GLN supplementation in diabetic mice may exert more-balanced polarization of CD4 + T cells, monocytes, and macrophages, thus attenuating inflammatory responses and contributing to muscle regeneration after limb ischemia.

This study investigated whether the administration of L-Arginine, the precursor of nitric oxide, increases the percentages of blood endothelial progenitor cells and protects against ischemia/reperfusion induced inflammatory response in a mouse model of hind-limb IR injury. C57 BL/6 mice were randomized to one normal-control and four ischemia/reperfusion groups. The normal-control group did not undergo an ischemia/reperfusion procedure but mice in the ischemia/reperfusion groups were subjected to 150 min of unilateral hind-limb ischemia. The ischemia/reperfusion groups were subjected to either intravenous saline or L-Arginine (300 mg/kg body weight) administration before reperfusion and then sacrificed at either 24 h or 48 h after reperfusion. Blood and muscle tissues were collected for analysis. Ischemia/reperfusion injury led to a significant decrease in the percentage of blood endothelial progenitor cells and plasma nitric oxide concentration but plasma interleukin-6 levels and gene expression of inflammatory cytokines in injured muscle tissue were elevated. In contrast to the saline groups, those with L-Arginine administration were able to maintain a normal level of blood endothelial progenitor cells. In addition, after reperfusion, concentrations of nitric oxide, matrix metallopeptidase-9, and vascular endothelial growth factor in plasma were upregulated but keratinocyte-derived chemokine and monocyte chemoattractant protein-1 messenger RNA expressions in muscle were attenuated 48 h after reperfusion. Histologic findings also demonstrated a significant reduction of ischemia/reperfusion-induced muscle injury when L-Arginine was administered. A single dose of L-Arginine administration before reperfusion increases the percentage of endothelial progenitor cells and reduces the inflammatory reaction locally and systemically after ischemia/reperfusion injury.

The liver is the main organ responsible for bacterial and endotoxin clearance. Pyroptosis is a form of proinflammatory programmed cell death activated by caspase-1/11 and gasdermin D (GadD). Pyroptosis protects the host against bacterial infection; however, overactive pyroptosis can lead to organ injury. Glutamine (GLN) is a specific amino acid with anti-inflammatory and immunomodulatory properties. This study investigated the effects of GLN pretreatment on liver pyroptosis in a mouse model of polymicrobial sepsis. Mice were assigned to sham, sepsis control (Sepsis-C), and sepsis GLN (Sepsis-G) groups. The sham and Sepsis-C groups were fed the AIN-93G diet. The Sepsis-G group was provided with identical diet components except that part of the casein was replaced by GLN. After feeding the respective diets for 2 weeks, a cecal ligation and puncture (CLP) procedure was performed in the sepsis groups. An antibiotic was administered after CLP. Mice were sacrificed at either 24 or 72 h after CLP. The results showed that sepsis resulted in upregulated liver caspase-1/11 expression. Compared to the Sepsis-C group, the Sepsis-G group had higher liver caspase-11 and NLRP3 gene expressions at 24 h and lower active caspase-1/11 and cleaved GadD protein levels at 72 h after sepsis. Additionally, liver inflammatory cytokine gene expressions had decreased by 72 h post-CLP. The findings suggest that prophylactic administration of GLN initially upregulated liver pyroptosis to eradicate pathogens, yet the process of pyroptosis was suppressed in the late phase of sepsis. This may have beneficially attenuated liver inflammation and injury in an antibiotic-treated septic condition.

Epidemiological studies have indicated that impaired glucose metabolism may increase the risk of squamous cell carcinoma of the head and neck (SCCHN). AMP-activated protein kinase (AMPK) regulates glucose and lipid metabolism via the phosphorylation and subsequent inactivation of its downstream target acetyl-CoA carboxylase (ACC).Thus, we analyzed the expression of pAMPK and its downstream target phosphorylated acetyl-CoA carboxylase (pACC), as well as their impact on the survival of patients with resected SCCHN. One hundred eighteen patients with surgically resected SCCHN were enrolled. Immunohistochemical (IHC) staining for pAMPK and pACC was performed using tissue microarrays of operative specimens of SCCHN. The expression was divided into two or three groups according to the IHC score [pAMPK: negative (0), positive (1-3); pACC: negative (0), low expression (1, 2), and high expression (3)]. Statistical analysis was performed to determine the association of pAMPK expression with clinicopathological features and pACC and pErk expression. The positive rates of pAMPK and pACC expression were 64.4% (76/118) and 68.6% (81/118), respectively. pAMPK was significantly higher in patients aged younger than 60 years (P = 0.024; χ2 test) and those with early-stage (T1/T2; P = 0.02; χ2 test) and oral cavity (P = 0.026; Fisher's exact test) tumors. In multivariate analysis, pAMPK expression was not significantly correlated with overall survival (OS) (adjusted hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.35-1.23), whereas high pACC expression was independently associated with worse OS in node-positive patients (adjusted HR: 17.58; 95% CI: 3.50-88.18). Strong expression of pACC was found to be an independent prognostic marker for patients with node-positive SCCHN. Our results suggest that pACC may play a role in tumor progression of SCCHN and may help to identify patient subgroups at high risk for poor disease outcome.

This study investigated the influence of intravenous arginine (Arg) administration on alteration of circulating proangiogenic cells and remote lung injury in a model of polymicrobial sepsis. Mice were assigned to one normal control group (NC) and two sepsis groups that were induced by cecal ligation and puncture (CLP). One of the sepsis groups was injected with saline (SS), whereas the other (SA) was administered with a single bolus of 300 mg Arg/kg body weight via the tail vein 1 h after CLP. Septic mice were sacrificed at either 24 or 48 h after CLP, with their blood and lung tissues collected for analysis. Results showed that septic groups had higher proangiogenic cells releasing factors and proangiogenic cells percentage in blood. Also, concentration of inflammatory cytokines and expression of angiopoietin (Angpt)/Tie-2 genes in lung tissues were upregulated. Arg administration promoted mobilization of circulating proangiogenic cells while it downregulated the production of inflammatory cytokines and expression of Angpt/Tie-2 genes in the lung. The results of this investigation suggested that intravenous administration of Arg shortly after the onset of sepsis enhanced the mobilization of circulating proangiogenic cells, maintained the homeostasis of the Angpt/Tie-2 axis, and attenuated remote organ injury in polymicrobial sepsis.

Sixty male Wistar rats were fed a control or an ethanol-containing diet in groups C or E. The fat compositions were adjusted with 25% or 57% fish oil substituted for olive oil in groups CF25, CF57, EF25, and EF57. Hepatic thiobarbituric acid-reactive substance (TBARS) levels, cytochrome P450 2E1 protein expression, and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 levels, as well as intracellular adhesion molecule (ICAM)-1 levels were significantly elevated, whereas plasma adiponectin level was significantly reduced in group E (p<0.05). Hepatic histopathological scores of fatty change and inflammation, in group E were significantly higher than those of group C (p<0.05). Hepatic TBARS, plasma ICAM-1, and hepatic TNF-α, IL-1β, and IL-10 levels were significantly lower, and plasma adiponectin levels were significantly higher in groups EF25 and EF57 than those in group E (p<0.05). The immunoreactive area of the intestinal tight junction protein, ZO-1, showed no change between groups C and E. Only group CF57 displayed a significantly higher ZO-1 immunoreactive area compared to group C (p=0.0415). 25% or 57% fish oil substituted for dietary olive oil could prevent ethanol-induced liver damage in rats, but the mechanism might not be related to intestinal tight junction ZO-1 expression.