Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was th...Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer;These DNA alterations may have? been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.展开更多
The NLRP3-IL-1β pathway plays an important role in adipose tissue(AT)-induced inflammation and the development of obesityassociated comorbidities.We aimed to determine the impact of NLRP3 on obesity and its associate...The NLRP3-IL-1β pathway plays an important role in adipose tissue(AT)-induced inflammation and the development of obesityassociated comorbidities.We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix(ECM)remodeling.Samples obtained from 98 subjects were used in a case-control study.The expression of different components of the inflammasome as well as their main effectors and inflammation-and ECM remodeling-related genes were analyzed.The impact of blocking NLRP3 using siRNA in lipopolysaccharide(LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated.We demonstrated that obesity(P<0.01),obesity-associated T2D(P<0.01)and NAFLD(P<0.05)increased the expression of different com ponents of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT.We also found that obese patients with T2D exhibited increased(P<0.05)hepatic gene expression levels of NLRP3,IL1B and IL18.We showed that NLRP3,but not NLRP1,is regulated by inflammation and hypoxia in visceral adipocytes.We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked(P<0.01)LPS-induced inflammation by downregulating the mRNA levels of CCL2,IL1B,IL6,IL8,S100A8,S100A9,TLR4 and TNF as well as inhibiting(P<0.01)the secretion of IL1-β into the culture medium.Furthermore,blocking NLRP3 attenuated(P<0.01)the LPS-induced expression of important molecules involved in AT fibrosis(COL1A1,COL4A3,COL6A3 and MMP2).These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.展开更多
Patients with liver cirrhosis,irrespective of etiology,have increased risk of liver-related and all-cause mortality(1).Also,the severity of cirrhosis determines health outcomes.For instance,patients with compensated c...Patients with liver cirrhosis,irrespective of etiology,have increased risk of liver-related and all-cause mortality(1).Also,the severity of cirrhosis determines health outcomes.For instance,patients with compensated cirrhosis have a nearly five-fold increased risk of death,while those with decompensated cirrhosis have approximately a 10-fold increased risk compared with the general population(1).Furthermore,the median survival time of patients with compensated cirrhosis is 12 years,while it is only 1.8 years in those with decompensated cirrhosis(2).Moreover,the presence of intercurrent conditions,such as sarcopenia(loss of skeletal muscle mass and function)may also compromise the prognosis of patients with cirrhosis(3).展开更多
A catabolic state develops following surgical trau-ma.including weight loss and muscle wasting,whichleads to an increased loss of nitrogen in the urineThere is a decrease in muscle protein synthesis and anincreased tr...A catabolic state develops following surgical trau-ma.including weight loss and muscle wasting,whichleads to an increased loss of nitrogen in the urineThere is a decrease in muscle protein synthesis and anincreased translocation of amino acids from muscle tothe splanchnic area.This results in an impoverish-ment of muscle free amino acids.mainly GLN,andeventually impairment of muscle function which can-not be counteracted by conventional TPN.However,TPN supplemented with GLN improves nitrogen bal-展开更多
Despite our many advances in deconstructing and understanding cellular and biomolecular machineries,the homochirality of life remains an enigma.Since our earliest ancestors,the central dogma has operated solely on D-DNA
A sedentary lifestyle and obesity are important risk factors for severe COVID-19 complications and death[1,2].Excessive adipose tissue(AT)might contribute to more extensive viral spread with increased shedding,immune ...A sedentary lifestyle and obesity are important risk factors for severe COVID-19 complications and death[1,2].Excessive adipose tissue(AT)might contribute to more extensive viral spread with increased shedding,immune activation,and cytokine amplification[3].Several factors secreted by contracting muscle,termed myokines,mediate the beneficial effects of exercise in a wide range of diseases,including obesity[4].Thus,we conducted a study to explore the potential role of myokines of the fibronectin type III domain-containing family,FNDC4 and FNDC5,in mechanisms underlying the increased susceptibility to COVID-19 complications in obesity.展开更多
基金Supported in parts by grants from the Swedish Cancer Society(CAN 2010/255),the Swedish Research Council(08712),Tore Nilson Foundation,Assar Gabrielsson Foundation(AB Volvo),Jubileumskliniken Foundation,IngaBritt&Arne Lundberg Research Foundation,Swedish and Gothenburg Medical Societies and the Medical Faculty,University of Gothenburg,VGR 19/00,1019/00.
文摘Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer;These DNA alterations may have? been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.
基金supported by Plan Estatal I+D+I from the Spanish Institute de Salud Carlos Ⅲ-Subdirecci6n General de Evaluacion y Fomento de la investigacion-FEDER(grants num ber PI16/01217,PI17/02183 and PI17/02188)by the Gobierno de Navarra(10/2018)by CIBEROBN,ISCⅢ,Spain.
文摘The NLRP3-IL-1β pathway plays an important role in adipose tissue(AT)-induced inflammation and the development of obesityassociated comorbidities.We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix(ECM)remodeling.Samples obtained from 98 subjects were used in a case-control study.The expression of different components of the inflammasome as well as their main effectors and inflammation-and ECM remodeling-related genes were analyzed.The impact of blocking NLRP3 using siRNA in lipopolysaccharide(LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated.We demonstrated that obesity(P<0.01),obesity-associated T2D(P<0.01)and NAFLD(P<0.05)increased the expression of different com ponents of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT.We also found that obese patients with T2D exhibited increased(P<0.05)hepatic gene expression levels of NLRP3,IL1B and IL18.We showed that NLRP3,but not NLRP1,is regulated by inflammation and hypoxia in visceral adipocytes.We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked(P<0.01)LPS-induced inflammation by downregulating the mRNA levels of CCL2,IL1B,IL6,IL8,S100A8,S100A9,TLR4 and TNF as well as inhibiting(P<0.01)the secretion of IL1-β into the culture medium.Furthermore,blocking NLRP3 attenuated(P<0.01)the LPS-induced expression of important molecules involved in AT fibrosis(COL1A1,COL4A3,COL6A3 and MMP2).These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.
文摘Patients with liver cirrhosis,irrespective of etiology,have increased risk of liver-related and all-cause mortality(1).Also,the severity of cirrhosis determines health outcomes.For instance,patients with compensated cirrhosis have a nearly five-fold increased risk of death,while those with decompensated cirrhosis have approximately a 10-fold increased risk compared with the general population(1).Furthermore,the median survival time of patients with compensated cirrhosis is 12 years,while it is only 1.8 years in those with decompensated cirrhosis(2).Moreover,the presence of intercurrent conditions,such as sarcopenia(loss of skeletal muscle mass and function)may also compromise the prognosis of patients with cirrhosis(3).
文摘A catabolic state develops following surgical trau-ma.including weight loss and muscle wasting,whichleads to an increased loss of nitrogen in the urineThere is a decrease in muscle protein synthesis and anincreased translocation of amino acids from muscle tothe splanchnic area.This results in an impoverish-ment of muscle free amino acids.mainly GLN,andeventually impairment of muscle function which can-not be counteracted by conventional TPN.However,TPN supplemented with GLN improves nitrogen bal-
文摘Despite our many advances in deconstructing and understanding cellular and biomolecular machineries,the homochirality of life remains an enigma.Since our earliest ancestors,the central dogma has operated solely on D-DNA
基金This work was supported by Fondo de Investigación Sanitaria-FEDER(FIS PI19/00785 and PI19/00990)the Instituto de Salud Carlos III and the Department of Health of the Gobierno de Navarra(exp.0011-3638-2020-000002).
文摘A sedentary lifestyle and obesity are important risk factors for severe COVID-19 complications and death[1,2].Excessive adipose tissue(AT)might contribute to more extensive viral spread with increased shedding,immune activation,and cytokine amplification[3].Several factors secreted by contracting muscle,termed myokines,mediate the beneficial effects of exercise in a wide range of diseases,including obesity[4].Thus,we conducted a study to explore the potential role of myokines of the fibronectin type III domain-containing family,FNDC4 and FNDC5,in mechanisms underlying the increased susceptibility to COVID-19 complications in obesity.
