BACKGROUND & AIMS
The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The NAD+-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT controls hepatic steatosis in mice.
Mice with liver-specific disruption of Sirt1 (SIRT1 LKO mice) and their wild-type littermates (controls) were divided into groups that were placed on normal chow diets, fasted for 24 hrs, or fasted for 24 hrs and then fed for 6 hrs. Liver tissues were collected and analyzed by histologic, gene expression profile, and real-time PCR assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and assessed by mitochondrial oxidation and immunoblot analyses. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry.
Fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting upregulated FGF21 in livers of control, but not SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased transcriptional activity of the FGF21 promoter (–2070/+117) and levels of FGF21 mRNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased expression of genes that regulate fatty acid oxidation, decreased fasting-induced steatosis, reduced obesity, increased energy expenditure, and promoted browning of white adipose tissue.
SIRT1-mediated activation of FGF21 prevents liver steatosis caused by fasting. This hepatocyte-derived endocrine signaling appears to regulate expression of genes that control a brown fat-like program in white adipose tissue, energy expenditure, and adiposity. Strategies to activate SIRT1 or FGF21 might be used to treat fatty liver disease and obesity.
liver-specific disruption of Sirt1; hepatocyte-derived hormone; metabolic homeostasis; obesity
We identified in the transcriptome analysis of patients with alcoholic hepatitis (AH) osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, Western blotting and ELISA. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH compared to normal livers and other types of chronic liver diseases and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and MMP-7) and cleaved-OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C SNP of the OPN gene compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by LPS and stimulated inflammatory actions in hepatic stellate cells.
Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target.
alcoholic liver disease; translational research; cytokines; liver fibrosis
We have previously demonstrated that chronic plus binge ethanol feeding acts synergistically to induce liver injury in mice; however, the mechanisms underlying this phenomenon remain unclear. In the current study, we show that chronic plus binge ethanol feeding synergistically upregulated the hepatic expression of IL-1β and TNF-α and induced neutrophil accumulation in the liver compared to chronic or binge feeding alone. The in vivo depletion of neutrophils through the administration of an anti-Ly6G antibody markedly reduced chronic-binge ethanol feeding-induced liver injury. Real-time PCR analyses revealed that hepatic E-selectin expression was upregulated 10-fold, whereas the expression of other neutrophil infiltration-related adhesion molecules (such as P-selectin, ICAM-1, and VCAM-1) was slightly upregulated or downregulated in this chronic-binge model. The genetic deletion of E-selectin prevented chronic-binge ethanol-induced hepatic neutrophil infiltration and the elevation of serum transaminases without affecting ethanol-induced steatosis. In addition, E-selectin-deficient mice showed reduced hepatic expression of several proinflammatory cytokines, chemokines, and adhesion molecules compared to wild-type mice after chronic-binge ethanol feeding. Finally, the expression of E-selectin was highly upregulated in human alcoholic fatty livers but not in alcoholic cirrhosis.
Chronic-binge ethanol feeding upregulates the expression of proinflammatory cytokines, followed by the induction of E-selectin. Elevated E-selectin plays an important role in hepatic neutrophil infiltration and injury in mice induced by chronic-binge feeding, and may also contribute to the pathogenesis of early stages of human alcoholic liver disease.
Adhesion molecules; alcoholic liver injury; inflammation
To simplify the architecture of a neuromorphic system, it is extremely desirable to develop synaptic cells with the capacity of low operation power, high density integration, and well controlled synaptic behaviors. In this study, we develop a resistive switching device (ReRAM)-based synaptic cell, fabricated by the CMOS compatible nano-fabrication technology. The developed synaptic cell consists of one vertical gate-all-around Si nano-pillar transistor (1T) and one transition metal-oxide based resistive switching device (1R) stacked on top of the vertical transistor directly. Thanks to the vertical architecture and excellent controllability on the ON/OFF performance of the nano-pillar transistor, the 1T1R synaptic cell shows excellent characteristics such as extremely high-density integration ability with 4F2 footprint, ultra-low operation current (<2 nA), fast switching speed (<10 ns), multilevel data storage and controllable synaptic switching, which are extremely desirable for simplifying the architecture of neuromorphic system.
The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity.
autoimmune disease; biliary epithelial cell; hepatocytes; immunity; liver; lymphocytes; tolerance
Reversible control of charge transport and magnetic properties without degradation is a key for device applications of transition metal oxides. Chemical doping during the growth of transition metal oxides can result in large changes in physical properties, but in most of the cases irreversibility is an inevitable constraint. Here we report a reversible control of charge transport, metal-insulator crossover and magnetism in field-effect devices based on ionically gated archetypal oxide system - SrRuO3. In these thin-film devices, the metal-insulator crossover temperature and the onset of magnetoresistance can be continuously and reversibly tuned in the range 90–250 K and 70–100 K, respectively, by application of a small gate voltage. We infer that a reversible diffusion of oxygen ions in the oxide lattice dominates the response of these materials to the gate electric field. These findings provide critical insights into both the understanding of ionically gated oxides and the development of novel applications.
Stem cell therapy has shown promise in treating a variety of pathologies including skin wounds, but practical applications remain elusive. Here we demonstrate that endogenous stem cell mobilization produced by AMD3100 and low-dose Tacrolimus is able to reduce by 25% the time of complete healing of full-thickness wounds created by surgical excision. Equally important, healing was accompanied by reduced scar and regeneration of hair follicles. Searching for mechanisms, we found that AMD3100 combined with low-dose Tacrolimus mobilized increased number of lineage-negative c-Kit+, CD34+ and CD133+ stem cells. Low-dose Tacrolimus also increased the number of SDF-1 bearing macrophages in the wounds sites amplifying the “pull” of mobilized stem cells into the wound. Lineage tracing demonstrated the critical role of CD133 stem cells in enhanced capillary and hair follicle neogenesis contributing to more rapid and perfect healing. Our findings offer a significant therapeutic approach to wound healing and tissue regeneration.
Background & Aims
Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure.
We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line.
The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (eg. IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL cells and of primary LPCs from wild-type mice, but not STAT1−/− or IRF-1−/− mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells.
IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.
cytokeratin-19; cytokeratin-7; STAT1; IRF-1; hepatic stellate cells; macrophages
Alpha-Galactosylceramide (α-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from α-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of α-Galcer induces mild hepatitis with a rapid elevation in the levels of IL-4 and a delayed elevation in the levels of IFN-γ, and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, genetic deletion of both IL-4 and IFN-γ aggravated, rather than abolished, α-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL-4, the IL-4 receptor, or its downstream signaling molecule STAT6 ameliorated α-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN-γ, the IFN-γ receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated α-Galcer-induced liver injury in wild-type, IL-4 knockout, and IFN-γ knockout mice.
Our results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-γ, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-γ may have the potential to improve the efficacy of α-Galcer in the treatment of liver disease.
liver disease; STAT1; STAT6; α-Galcer
Group A streptococci (GAS) are associated with a variety of mucosal and invasive human infections. Recurrent infections by highly heterologous serotypes indicate that cross-serotype immunity is critical for prevention of GAS infections; however, mechanisms underlying serotype-independent protection are poorly understood. Here we report that intranasal vaccination of mice with Sortase A (SrtA), a conserved cell wall bound protein, reduced colonization of nasal-associated lymphoid tissue (NALT) by heterologous serotypes of GAS. Vaccination significantly increased CD4+ IL-17A+ cells in NALT and depletion of IL-17A by neutralizing antibody prevented GAS clearance from NALT which was dependent on immunization with SrtA. Vaccination also induced high levels of SrtA-specific antibodies; however, immunized, B cell-deficient mice cleared streptococcal challenges as efficiently as wild type mice, indicating that the cross-serotype protection is Th17-biased and antibody-independent. Furthermore, efficient GAS clearance from NALT was associated with a rapid neutrophil influx into NALT of immunized mice. These results suggest that serotype independent immune protection against GAS mucosal infection can be achieved by intranasal vaccination with SrtA and enhanced neutrophil function is critical for anti-GAS defense and might be a target for prevention of GAS infections.
Fungi are an emerging source of peptide antibiotics. With the availability of a large number of model fungal genome sequences, we can expect that more and more fungal defensin-like peptides (fDLPs) will be discovered by sequence similarity search. Here, we report a total of 69 new fDLPs encoded by 63 genes, in which a group of fDLPs derived from dermatophytes are defined as a new family (fDEF8) according to sequence and phylogenetic analyses. In the oleaginous fungus Mortierella alpine, fDLPs have undergone extensive gene expansion. Our work further enlarges the fungal defensin family and will help characterize new peptide antibiotics with therapeutic potential.
peptide antibiotic; gene duplication; exon-intron structure; cysteine-stabilized α-helical and β-sheet motif
Interleukin-22 (IL-22) plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces by binding to the receptors IL-22R1, which is generally thought to be expressed exclusively in epithelial cells, and IL-10R2. Our laboratory previously demonstrated that IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22R1 and IL-10R2. Recently, we have identified high expression levels of IL-22R1 and IL-10R2 in liver progenitor cells and hepatic stellate cells (HSCs). Overexpression of IL-22 in vivo or treatment with IL-22 in vitro promotes proliferation of liver progenitor cells via a signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. IL-22 treatment also prevents HSC apoptosis in vitro and in vivo. Surprisingly, overexpression of IL-22, via either gene targeting or exogenous administration of adenovirus expressing IL-22, reduces liver fibrosis and accelerates the resolution of liver fibrosis during recovery. The anti-fibrotic effects of IL-22 are mediated via the activation of STAT3 in HSCs and subsequent induction of suppressor of cytokine signaling 3, which induces HSC senescence. Taken together, the hepatoprotective, mitogenic, and anti-fibrotic effects of IL-22 are beneficial in ameliorating alcoholic liver injury. Importantly, due to the restricted expression of IL-22R1, IL-22 therapy is expected to have few side effects, thus making IL-22 a potential candidate for treatment of alcoholic liver disease.
hepatic stellate cells; liver fibrosis; liver progenitor cells; senescence
Background: Chronic ethanol consumption induces pancreatic β-cell dysfunction and metabolic syndrome.
Results: Ethanol-induced Atf3 inhibits glucokinase transcriptional activity through direct binding or Atf3/Pdx-1/Hdac1 axis on glucokinase promoter.
Conclusion: ATf3 fosters β-cell dysfunction via Gck down-regulation and triggers T2D, which is ameliorated by in vivo Atf3 silencing.
Significance: The presented data uncover a new role for Atf3 as a potential therapeutic target in treating type 2 diabetes.
Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from −287 to −158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters β-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis.
Gene Expression; Gene Therapy; Glucokinase; Metabolic Disease; Pancreatic Islet; Type 2 Diabetes
fracturing is expanding rapidly in the US to meet increasing
energy demand and requires high volumes of hydrofracking fluid to
displace natural gas from shale. Accidental spills and deliberate
land application of hydrofracking fluids, which return to the surface
during hydrofracking, are common causes of environmental contamination.
Since the chemistry of hydrofracking fluids favors transport of colloids
and mineral particles through rock cracks, it may also facilitate
transport of in situ colloids and associated pollutants in unsaturated
soils. We investigated this by subsequently injecting deionized water
and flowback fluid at increasing flow rates into unsaturated sand
columns containing colloids. Colloid retention and mobilization was
measured in the column effluent and visualized in situ with bright
field microscopy. While <5% of initial colloids were released by
flushing with deionized water, 32–36% were released by flushing
with flowback fluid in two distinct breakthrough peaks. These peaks
resulted from 1) surface tension reduction and steric repulsion and
2) slow kinetic disaggregation of colloid flocs. Increasing the flow
rate of the flowback fluid mobilized an additional 36% of colloids,
due to the expansion of water filled pore space. This study suggests
that hydrofracking fluid may also indirectly contaminate groundwater
by remobilizing existing colloidal pollutants.
The liver lymphocyte population is enriched with natural killer (NK) cells, which play a key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the anti-fibrotic cytokine IFN-γ. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-α treatment enhances, while other factors (e.g., alcohol, TGF-β) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-γ. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed.
viral hepatits; alcoholic liver disease; NKG2D; NAFLD; IFN-gamma
Somatic LKB1 mutations are found in lung adenocarcinomas at different frequencies in Caucasian and East Asian (Japanese and Korean) populations. This study was designed to characterize the frequency of LKB1 mutations, their relationship to EGFR and KRAS mutations, and their associated clinicopathologic characteristics in Chinese patients.
Two hundred thirty-nine lung adenocarcinomas consecutively collected from October 2007 to July 2009 were dissected into 3 to 4 small (3 mm) pieces for histopathological analyses of tumor content. Genomic DNA and/or cDNA from 86 samples with more than 70% tumor content were used for sequencing of LKB1 (exons 1–9), EGFR (exons 18–21), and KRAS (exon 2). LKB1 germline mutation status was determined by sequencing of genomic DNA from matched histologically distant lung tissues that are histologically normal.
6.9% of lung adenocarcinomas harbored LKB1 somatic mutations. A total of 10.5% of patients had an LKB1 germline polymorphism, F354L. Interestingly, in two of these patients, tumors displayed loss of heterozygosity at this allele. EGFR kinase domain and KRAS mutations were found in 66.3% and 2.3% of Chinese lung adenocarcinomas, respectively. Concurrent LKB1 and EGFR somatic mutations were observed in one patient. Both KRAS-mutant tumors harbored LKB1 mutations.
These data provide important clinical and molecular characteristics of lung adenocarcinomas from Chinese patients.
Chinese lung adenocarcinoma; LKB1; EGFR; KRAS; Mutation
The aim of this study was to determine the hemodynamic effects of various support modes of continuous flow left ventricular assist devices (CF-LVADs) on the cardiovascular system using a numerical cardiovascular system model.
Three support modes were selected for controlling the CF-LVAD: constant flow mode, constant speed mode, and constant pressure head mode of CF-LVAD. The CF-LVAD is established between the left ventricular apex and the ascending aorta, and was incorporated into the numerical model. Various parameters were evaluated, including the blood assist index (BAI), the left ventricular external work (LVEW), the energy of blood flow (EBF), pulsatility index (PI), and surplus hemodynamic energy (SHE).
The results show that the constant flow mode, when compared to the constant speed mode and the constant pressure head mode, increases LVEW by 31% and 14%, and EBF by 21% and 15%, respectively, indicating that this mode achieved the best ventricular unloading among the 3 support modes. As BAI is increased, PI and SHE are gradually decreased, whereas PI of the constant pressure head reaches the maximum value.
The study demonstrates that the continuous flow control mode of the CF-LVAD may achieve the highest ventricular unloading. In contrast, the constant rotational speed mode permits the optimal blood perfusion. Finally, the constant pressure head strategy, permitting optimal pulsatility, should optimize the vascular function.
Blood Flow Velocity; Heart Failure; Ventricular Function; Left
Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1). Using IL-1Ratreated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1β signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1β was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1β induced steatosis, increased the inflammatory and prosteatotic chemokine MCP-1 in hepatocytes, and augmented TLR4-dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Casp-1-dependent upregulation of IL-1β and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD.
Germline mutations are responsible for familial cancer syndromes which account for approximately 5–10% of all types of cancers. These mutations mainly occur at tumor suppressor genes or genome stability genes, such as DNA repair genes. Here we have identified a cancer predisposition family, in which eight members were inflicted with a wide spectrum of cancer including one diagnosed with lung cancer at 22 years old. Sequencing analysis of tumor samples as well as histologically normal specimens identified two germline mutations co-existing in the familial cancer syndrome, the mutation of tumor suppressor gene P53 V157D and mismatch repair gene PMS2 R20Q. We further demonstrate that P53 V157D and/or PMS2 R20Q mutant promotes lung cancer cell proliferation. These two mutants are capable of promoting colony formation in soft agar as well as tumor formation in transgenic drosophila system. Collectively, these data have uncovered the important role of co-existing germline P53 and PMS2 mutations in the familial cancer syndrome development.
P53 V157D; PMS2 R20Q; Germline mutation; Familial cancer syndrome; Co-existing
Natural killer (NK) cells are enriched in lymphocytes within the liver and have unique phenotypic features and functional properties, including TRAIL-dependent cytotoxicity and specific cytokine profiles. As a key component of innate immunity in the liver, NK cells perform critical roles in host defense against pathogens and tumors via their natural cytotoxicity and cytokine production, and they also act as regulatory cells by engaging in reciprocal interactions with other types of liver cells through cell-to-cell contact and the production of cytokines. Accumulating evidence from the last decade suggests that NK cells play an important role in controlling viral hepatitis, liver fibrosis, and liver tumorigenesis but also contribute to the pathogenesis of liver injury and inflammation. The characterization of intrahepatic NK cell functions has not only helped us to better understand the pathogenesis of liver disease but has also revealed new therapeutic targets for managing this disease.
viral hepatitis; liver fibrosis; liver tumor; cytokine; NKG2D
Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4–6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (alt) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. this protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. this feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.
We have previously reported that mice with a dominant negative transforming growth factor β receptor restricted to T cells (dnTGFβRII mice) develop an inflammatory biliary ductular disease that strongly resembles human primary biliary cirrhosis (PBC). Furthermore, deletion of the gene encoding interleukin (IL)-12p40 resulted in a strain (IL-12p40−/−dnTGFβRII) with dramatically reduced autoimmune cholangitis. To further investigate the role of the IL-12 cytokine family in dnTGFβRII autoimmune biliary disease, we deleted the gene encoding the IL-12p35 subunit from dnTGFβRII mice, resulting in an IL-12p35−/− dnTGFβRII strain which is deficient in two members of the IL-12 family, IL-12 and IL-35. In contrast to IL-12p40−/− mice, the IL-12p35−/− mice developed liver inflammation and bile duct damage with similar severity but delayed onset as the parental dnTGFβRII mice. The p35−/− mice also demonstrated a distinct cytokine profile characterized by a shift from a Th1 to a Th17 response. Strikingly, liver fibrosis was frequently observed in IL-12p35−/− mice. In conclusion, IL-12p35−/− dnTGFβRII mice, histologically and immunologically, reflect key features of PBC, providing a useful generic model to understand the immunopathology of human PBC.
Primary biliary cirrhosis; murine models; autoimmunity; cholangitis
The ongoing rapid urbanization in China offers rural population opportunities not only for economic improvement but also for substantial health risks. Albeit some researches related to rural-urban difference of metabolic syndrome (MS), there lacks studies focusing on this point in undeveloped provinces in China.
The survey, as part of China National Diabetes and Metabolic disorders Study, was conducted in Shaanxi province from June 2007 to May 2008. A total of 3,297 adults aged 20 years or older were included, of which 1,467 individuals were from urban areas, 839 from semi-urban areas, and 890 from rural areas. The MS was defined according to the 2009 Joint Interim Statement.
The age-standardized prevalence of MS was significant higher in rural residents than in urban counterparts (29.0% vs. 25.9%, P = 0.017), in particular among females (30.2% vs. 24.4%, P = 0.003). After adjusted for the listed risk factors, rural residents had a 27.6% increased risk of having MS than urban residents. With respect to MS components, the crude prevalence of raised fasting glucose and raised blood pressure was significantly greater in rural than in urban participants. However, no significant difference in the prevalence of MS was observed between semi-urban and urban participants.
Rural residents in Shaanxi province, northwest China, were at increased risk of MS, which could be partly explained by sociodemographic and lifestyle differences. In addition, the gap between urban and semi-urban areas seemed to be minimized in related to MS prevalence. Much more attention should be paid to and intervention strategies were needed to address the rural-urban disparities in China.
Metabolic syndrome; Prevalence; Rural; Urban; China; Cross-sectional survey