Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Physical activity as a proxy to ameliorate inflammation in patients with type 2 diabetes and periodontal disease at high cardiovascular risk

While the beneficial impact of physical activity has been ascertained in a variety of pathological scenarios, including diabetes and low-grade systemic inflammation, its potential remains still putative for periodontal health. Periodontal disease has been associated with inflammatory systemic alterations, which share a common denominator with type 2 diabetes mellitus and cardiovascular disease. Physical exercise, along with nutritional counseling, is a cornerstone in the treatment and prevention of type 2 diabetes, also able to reduce the prevalence of periodontal disease and cardiovascular risk. In addition, considering the higher incidence of periodontitis in patients with type 2 diabetes compared to healthy controls, the fascinating research question would be whether physical activity could relieve the inflammatory pressure exerted by the combination of these two diseases. This multi-disciplinary viewpoint discusses available literature in order to argument the hypothesis of a “three–way relationship” linking diabetes, periodontitis, and physical activity.     

Anti-inflammatory activity of herb products from Licania rigida Benth.

PurposeThe objective of the present study was to evaluate the systemic anti-inflammatory activity of the hydroalcoholic extract of the leaves of Licania rigida Benth (EHFLR) on models of systemic inflammation in mice.MethodsThe quantitative chemical profiles of phenolic acids and flavonoids were performed by High-Performance Liquid Chromatography (HPLC). Systemic anti-inflammatory activity was determined from carrageenan and dextran-induced paw edema models and the animals were orally treated (p.o.) with EHFLR at doses of 25, 50, 100 mg/kg, indomethacin (10 mg/kg) for carrageenan-induced paw edema and promethazine (6 mg/kg) for dextran-induced paw edema. The possible mechanisms involved in the anti-inflammatory action of the extract were evaluated by the paw edema models induced by histamine and arachidonic acid, and by the model of carrageenan-induced peritonitis, where vascular permeability and leukocyte migration to the peritoneal cavity were evaluated.ResultsThe results of the HPLC identified the presence of phenolic acids and flavonoids, with chlorogenic acid (1.16%) and Caempferol (0.81%) as the main constituents. From the results, it was concluded that the extract has an LD₅₀ ≥5000 mg/kg when administered orally in mice as this dose did not trigger deaths in any of the observed groups. EHFLR (25 mg/kg) showed a significant antiderematogenic effect on histamine and arachidonic acid-induced paw edema at the third hour of the tests, with a percentage of inhibition of 46.64% and 18.33%, respectively. The extract (25 mg/kg, p.o.) also significantly reduced vascular permeability and leukocyte migration in the peritoneal cavity.ConclusionsIt is concluded that EHFLR exerts a systemic anti-inflammatory action, which seems to depend, at least in part, on the inhibition of arachidonic acid metabolism and the action of vasoactive amines. In addition, the extract reduced the leukocyte migration in the peritoneal cavity, indicating that its action may be linked to the inhibition of pro-inflammatory cytokines.     

Bile acid indices as biomarkers for liver diseases I: Diagnostic markers

BACKGROUNDHepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis.AIMTo discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile.METHODSWe analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases.RESULTSTotal and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases.CONCLUSIONBA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.     

不同氮源对丹参和藏丹参毛状根有效成分积累的影响

目的氮素是中药材有效成分积累的重要影响元素,为探讨不同氮源对丹参Salviamiltiorrhiza和藏丹参Salvia castanea毛状根生长和活性成分积累的影响。方法分别采用硝酸铵、水解乳蛋白、蛋白胨、牛肉浸膏、酪蛋白和酵母提取物6种氮源处理对丹参和藏丹参毛状根的影响,分析毛状根生长及活性成分积累的变化。结果硝酸铵最有利于2种丹参毛状根的生长。水解乳蛋白能够显著促进丹酚酸类成分的积累,与硝酸铵对照相比,丹参迷迭香酸和丹酚酸B含量分别提高了2.94倍和3.27倍,藏丹参二者含量分别提高了13.74倍和2.01倍。酵母提取物对2种丹参毛状根二氢丹参酮Ι和隐丹参酮积累的促进效果最为显著,水解乳蛋白能显著促进丹参根中丹参酮IIA的积累,牛肉浸膏则对藏丹参中丹参酮IIA积累的促进作用最为显著。结论硝酸铵是2种丹参毛状根生长的最佳氮源,水解乳蛋白是丹酚酸积累的最佳氮源,不同氮源对4种丹参酮的影响不一致,丹参和藏丹参对不同氮源的响应也不一致。该研究不仅对丹参毛状根规模化培养及活性成分工业化生产具有一定指导意义,也对藏丹参资源的开发利用提供了借鉴作用。     

Efficacy of n-3 fatty acids supplementation on the prevention of pregnancy induced-hypertension or preeclampsia: A systematic review and meta-analysis

The efficacy of n-3 fatty acids supplementation on the prevention of pregnancy-induced hypertension or preeclampsia remains unclear. The aim of study was to examine the effect of supplementation with EPA, and/or DHA, and/or ALA during pregnancy on the pregnancy-induced hypertension or preeclampsia. A systematic search was performed on Scopus, PubMed, Web of Science (WoS), Cochrane Library, and Google scholar, which covered the period between 1991 and 2018. The clinical trials with any control groups (i.e. placebo or other supplementation) were selected. The whole process of meta-analysis and data analysis was done using Comprehensive Meta-Analysis (Version 2.0, Biostat). The searched keywords were: “Fatty Acids, Omega-3”, “n-3 Polyunsaturated Fatty Acid” “Eicosapentaenoic Acid”, “Docosahexaenoic Acids”, “n-3 Polyunsaturated Fatty Acid”, “n-3 PUFAs”, “alpha-Linolenic Acid”, “fish oil”, “Nuts”, “nutrient”, or their synonyms “pregnancy induced hypertension” and preeclampsia. In addition, some key journals, according to Scopus report and the references of the original and review articles, were manually searched for possible related studies. The meta-analysis of the 14 comparisons demonstrated that n-3 fatty acids supplementation played a protective role against the risk of preeclampsia (RR, 0.82; 95% CI, 0.70–0.97; p = 0.024; I2 = 19.0%). The analysis of the 10 comparisons revealed that n-3 fatty acid supplements for pregnant women did not mitigate the risk of pregnancy-induced hypertension (RR, 0.98; 95% CI, 0.90–1.07; p = 0.652; I2 = 0%). The n-3 fatty acid supplements are an effective strategy to prevent the incidence of preeclampsia in women with low-risk pregnancies.