Glycine Alleviated Intestinal Injury by Inhibiting Ferroptosis in Piglets Challenged with Diquat.

The purpose of this research was to examine the impact of glycine on intestinal injury caused by oxidative stress in piglets. A 2 × 2 factorial experiment with diets (basic diet vs. 1% glycine diet) and oxidative stress (saline vs. diquat) was conducted on 32 weanling piglets. On day 21, all piglets received an injection of either saline or diquat. After 7 days, all pigs were slaughtered and intestinal samples were collected. Dietary glycine supplementation improved intestinal mucosal morphology, increased the activities of disaccharidases and enhanced intestinal mucosal antioxidant capacity, while regulating the expression of ferroptosis mediators in the piglets under oxidative stress. These findings suggested that dietary glycine supplementation improved the morphology and function of the intestinal mucosa, which was involved in regulating antioxidant capacity and ferroptosis.

Polyphenols Sourced from Ilex latifolia Thunb. Relieve Intestinal Injury via Modulating Ferroptosis in Weanling Piglets under Oxidative Stress.

Polyphenols sourced from Ilex latifolia Thunb. (PIT) contain high levels of phenolic acids, tannic acids, triterpenoids and so on, which play important roles in antioxidant function. This study was conducted to investigate the effects of PIT against intestinal injury in piglets under oxidative stress. Thirty-two weanling piglets were arranged by a 2 × 2 factorial experiment with diets (basal diet vs. PIT diet) and oxidative stress (saline vs. diquat). All piglets were injected with saline or diquat on d 21, respectively. After 7 days, all pigs were slaughtered and intestinal samples were collected. PIT enhanced jejunal villus heights and crypt depth in the piglets under oxidative stress. PIT increased the activities of intestinal mucosal lactase, sucrase and maltase in the challenged piglets. PIT also increased the jejunal ratio of protein to DNA and ileal protein content. PIT increased the jejunal activities of GSH-PX and GSH content and reduced the ileal MDA amounts. Furthermore, PIT regulated the expression of ferroptosis mediators, such as TFR1, HSPB1, SLC7A11 and GPX4. These results indicate that dietary PIT supplementation enhances the histological structure and function of the intestinal mucosa, which is involved in modulating antioxidant capacity and ferroptosis.

Glycine alleviated diquat-induced hepatic injury via inhibiting ferroptosis in weaned piglets.

OBJECTIVE: The beneficial effects of glycine were tested in piglets with diquat-induced hepatic injury. METHODS: Thirty-two piglets were assigned by a 2×2 factorial experimental design including glycine supplementation and diquat challenge. After 3 weeks of feeding with a basic diet or a 1% glycine supplemented diet, piglets were challenged with diquat or saline. After 1 week later, the piglets were slaughtered and samples were collected. RESULTS: Our results indicated that glycine alleviated diquat induced morphological hepatic injury, decreased the activities of plasma alanine aminotransferase, aspartate aminotransferase and glutamyl transpeptidase in the piglets under diquat challenge, and increased total antioxidant capacity and antioxidative enzyme activity significantly. Adding glycine enhanced the concentrations of hepatic adenosine triphosphate and adenosine diphosphate. Transmission electron microscope observation showed that diquat induced clear hepatocytes ferroptosis and its effect could be alleviated by glycine to a certain degree. Moreover, glycine significantly affected mRNA and protein expression of ferroptosis-related signals in the liver. CONCLUSION: These results demonstrated that glycine attenuated liver damage via inhibiting ferroptosis.

SPARC regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma.

BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.

Holly polyphenols alleviate intestinal inflammation and alter microbiota composition in lipopolysaccharide-challenged pigs.

The effect of holly polyphenols (HP) on intestinal inflammation and microbiota composition was evaluated in a piglet model of lipopolysaccharide (LPS)-induced intestinal injury. A total of twenty-four piglets were used in a 2 × 2 factorial design including diet type and LPS challenge. After 16 d of feeding with a basal diet supplemented with or without 250 mg/kg HP, pigs were challenged with LPS (100 µg/kg body weight) or an equal volume of saline for 4 h, followed by analysis of disaccharidase activities, gene expression levels of several representative tight junction proteins and inflammatory mediators, the SCFA concentrations and microbiota composition in intestinal contents as well as proinflammatory cytokine levels in plasma. Our results indicated that HP enhanced intestinal disaccharidase activities and reduced plasma proinflammatory cytokines including TNF-α and IL-6 in LPS-challenged piglets. Moreover, HP up-regulated mRNA expression of intestinal tight junction proteins such as claudin-1 and occludin. In addition, bacterial 16S rRNA gene sequencing showed that HP altered hindgut microbiota composition by enriching Prevotella and enhancing SCFA production following LPS challenge. These results collectively suggest that HP is capable of alleviating LPS-triggered intestinal injury by improving intestinal disaccharidase activities, barrier function and SCFA production, while reducing intestinal inflammation.

Holly (Ilex latifolia Thunb.) Polyphenols Extracts Alleviate Hepatic Damage by Regulating Ferroptosis Following Diquat Challenge in a Piglet Model.

Background: Holly (Ilex latifolia Thunb.) polyphenols extracts (HPE) contain high amounts of polyphenols, including phenolic acids, triterpenoids, tannic acids, and so on, which have strong antioxidant function. This experiment was aimed to explore the protective effect and mechanism of HPE against hepatic injury induced by diquat. Methods: Thirty-two weaned piglets were allotted by a 2 × 2 factorial experiment design with diet type (basal diet vs. HPE diet) and diquat challenge (saline vs. diquat). On the 21st day, piglets were injected with diquat or saline. One week later, blood samples were collected. Then all piglets were slaughtered and hepatic samples were collected. Results: Dietary HPE supplementation improves hepatic morphology, the activities of plasma aspartate aminotransferase, alanine aminotransferase, and glutamyl transpeptidase, and enhances hepatic anti-oxidative capacity, while it regulates the expression of ferroptosis mediators (transferrin receptor protein 1, heat shock protein beta 1, solute carrier family 7 member 11, and glutathione peroxidase 4) in diquat-challenged piglets. Conclusion: These results indicate that dietary HPE supplementation enhances hepatic morphology and function, which is involved in modulating antioxidant capacity and ferroptosis.

Development and Testing of an Intelligent Pain Management System (IPMS) on Mobile Phones Through a Randomized Trial Among Chinese Cancer Patients: A New Approach in Cancer Pain Management.

BACKGROUND: Cancer has become increasingly prevalent in China over the past few decades. Among the factors that determine the quality of life of cancer patients, pain has commonly been recognized as a most critical one; it could also lead to the ineffective treatment of the cancer. Driven by the need for better pain management for cancer patients, our research team developed a mobile-based Intelligent Pain Management System (IPMS). OBJECTIVE: Our objective was to design, develop, and test the IPMS to facilitate real-time pain recording and timely intervention among cancer patients with pain. The system's usability, feasibility, compliance, and satisfaction were also assessed. METHODS: A sample of 46 patients with cancer pain symptoms were recruited at the Oncology Center of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch (hereinafter referred to as "the Oncology Center"). In a pretest, participants completed a pain management knowledge questionnaire and were evaluated using the baseline cancer pain assessment and Karnofsky Performance Status (KPS) evaluation. The participants were then randomly assigned into two groups (the trial group and the control group). After a 14-day trial period, another round of cancer pain assessment, KPS evaluation and pain management knowledge assessment were repeated. In the trial group, the data were fully automatically collected by the IPMS. In the control group, the data were collected using conventional methods, such as phone interviews or door-to-door visits by physicians. The participants were also asked to complete a satisfaction questionnaire on the use of the IPMS. RESULTS: All participants successfully completed the trial. First, the feasibility of IPMS by observing the number of daily pain assessments recorded among patients was assessed. Second, the users' satisfaction, effectiveness of pain management, and changes in the quality of their lives were evaluated. All the participants gave high satisfaction score after they used IMPS. Both groups reported similar pain scores and KPS scores at the baseline. At the end of the trial, the mean pain score of the trial group was significantly lower than of the control group (P<.001). The ending KPS score of the trial group was significantly higher than of the control group (P<.001). The improvement of pain management knowledge score in the trial group was more pronounced than that in the control group (P<.001). CONCLUSIONS: This study provided preliminary data to support the potentials of using IPMS in cancer pain communication between patients and doctors and to provide real-time supportive intervention on a convenient basis at a low cost. Overall, the IPMS can serve as a reliable and effective approach to control cancer pain and improve quality of life for patients with cancer pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT02765269; http://clinicaltrials.gov/ct2/show/NCT02765269 (Archived by WebCite at http://www.webcitation.org/6rnwsgDgv).

MicroRNA-153 promotes Wnt/ß-catenin activation in hepatocellular carcinoma through suppression of WWOX.

Persistent activation of Wnt/ß-catenin signaling plays crucial roles in the development of human cancers, including hepatocellular carcinoma (HCC). Here, we performed a MicroRNA-based genetic screen, which revealed a novel diversion in ß-catenin signaling triggered by MicroRNA-153 (miR-153). Overexpression of miR-153 was able to promote ß-catenin transcriptional activity, leading to cell-cycle progression, proliferation and colony formation of HCC cells. Additionally, systemic administration of miR-153 antigomir suppressed hepatocellular carcinogenesis in a murine liver cancer model. At the molecular level, we found that miR-153 inhibited protein level of WWOX, a tumor suppressor and inhibitor of ß-catenin signaling, through targeting its 3'-untranslated region. Therefore, our study highlights the importance of MicroRNA-153/WWOX/ß-catenin regulatory axis in the HCC tumorigenesis.

Re-sensitization of 5-FU resistance by SPARC through negative regulation of glucose metabolism in hepatocellular carcinoma.

Secreted protein, acidic and rich in cysteine (SPARC), a calcium-binding matricellular glycoprotein, is implicated in the progression of many cancers. Currently, there is growing evidence for important functions of SPARC in a variety of cancers and its role in cancer depends on tumor types. In this study, we reported SPARC negatively regulated glucose metabolism in hepatocellular carcinoma (HCC). Overexpression of SPARC inhibited glucose uptake and lactate product through downregulation of key enzymes of glucose metabolism. On the other hand, knock down of SPARC reversed the phenotypes. Meanwhile, exogenous expression of SPARC in HepG2 cells resulted in tolerance to low glucose and was correlated with AMPK pathway. Interestingly, the 5-fluorouracil (5-FU)-resistant HepG2 cells showed increased glucose metabolism and downregulated SPARC levels. Finally, we reported the overexpression of SPARC re-sensitize 5-FU-resistant cells to 5-FU through inhibition of glycolysis both in vitro and in vivo. Our study proposed a novel function of SPARC in the regulation of glucose metabolism in hepatocellular carcinoma and will facilitate the development of therapeutic strategies for the treatments of liver tumor patients.

Netrin-1 promoted pancreatic cancer cell proliferation by upregulation of Mdm2.

Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to result from the ability of netrin-1 secretions to stimulate survival when bound to associated receptors. The objective of this study was to determine the role of netrin-1 in pancreatic cancer cell proliferation in vitro. Our results revealed that netrin-1 overexpression promoted while its silence inhibited two pancreatic cancer cell lines. At the molecular level, we found that netrin-1 promoted cell proliferation by upregulation of murine double minute 2 (Mdm2). As a result, p53 protein contents were reduced in cells overexpressing netrin-1. Therefore, our data suggests the presence of a previously unknown network in the proliferation and progression of pancreatic cancer cells.

MiR-199a suppresses the hypoxia-induced proliferation of non-small cell lung cancer cells through targeting HIF1α.

Deregulated microRNAs (miRNAs) are small noncoding RNAs that are involved in the carcinogenesis of various cancers, including lung cancer. HIF1a has been suggested to be a master regulator of hypoxia-induced cell proliferation. The relationship between HIF1a expression and the progression of non-small cell lung cancer (NSCLC) is not fully understood, and whether HIF1a expression is regulated by miRNAs in this process remains unclear. In this study, we found that the upregulation of HIF1a expression and the reduction in miR-199a levels were highly associated with NSCLC progression. NSCLC cells derived from cancer tissues with low miR-199a levels showed high HIF1a expression and high proliferation capacity. Moreover, HIF1a and glycolysis inhibitors suppress the proliferation of NSCLC cells. MiR-199a overexpression suppressed the hypoxia-induced proliferation of NSCLC cells through targeting elevated HIF1a and blocking the downstream upregulation of PDK1 without affecting AKT activation. Together, these results indicate that downregulation of miR-199a is essential for hypoxia-induced proliferation through derepressing the expression of HIF1a expression and affecting HIF1a mediated glycolytic pathway in NSCLC progression.

Comprehensive assessment of the association between DNA repair gene XRCC3 rs861539 C/T polymorphism and lung cancer risk.

A few case-control studies were performed to assess the association between X-ray repair cross-complementing group 3 (XRCC3) rs861539 C/T polymorphism and lung cancer susceptibility, but no consistent finding was reported. In the present study, we performed a meta-analysis of 14 case-control studies with a total of 7,869 lung cancer cases and 10,778 controls to provide a comprehensive assessment of the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk. Pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs) were calculated to assess the strength of the association. Overall, there was no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models [OR (95 % CI) for T versus C, 1.00 (0.89-1.13), P = 0.99; OR (95 % CI) for TT versus CC, 1.07 (0.81-1.41), P = 0.62; OR (95 % CI) for TT/CT versus CC, 0.95 (0.84-1.07), P = 0.39; OR (95 % CI) for TT versus CT/CC, 1.10 (0.86-1.39), P = 0.62]. In the subgroup analyses of both Asians and Caucasians, there was still no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models (All P values were more than 0.05). However, there was an obvious association between XRCC3 rs861539 C/T polymorphism and decreased risk of lung cancer in the subgroup analysis of the mixed population (All P values were less than 0.05). In addition, there was some risk of publication bias in the meta-analysis, and there was obvious discrepancy in the findings between studies with large sample size and studies with small sample size in the meta-analysis. The meta-analysis indicates that the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk is still uncertain owing to the obvious discrepancy in the findings between studies with large sample size and studies with small sample size. More studies with large sample size are needed to further assess the association.

HIF1-regulated ATRIP expression is required for hypoxia induced ATR activation.

The ATR-ATRIP protein kinase complex plays a crucial role in the cellular response to replication stress and DNA damage. Recent studies found that ATR could be activated in response to hypoxia and be involved in hypoxia-induced genetic instability in cancer cells. However, the underlying mechanisms for ATR activation in response to hypoxic stress are still not fully understood. We reported that ATRIP is a direct target of HIF-1. Silencing the expression of HIF-1α in cancer cells by RNA interference abolished hypoxia-induced ATRIP expression. Silencing the expression of ATRIP by RNA interference abolished hypoxia induced ATR activation and CHK1 phosphorylation in cancer cells. Taken together, these data shed novel insights on the mechanism of hypoxia-induced activation of the ATR pathway.