Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition, candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance, inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.
Inflammatory responses are essential in eliminating harmful substrates from damaged tissue and inducing recovery. Several cytokines participate in and facilitate this response. Certain cytokines such as interleukin (IL)-1β and IL-18 are initially produced in precursor form in response to toll-like receptor (TLR) ligands and undergo maturation by inflammasomes, which are cytosolic multi-protein complexes containing nucleotide-binding oligomerization domain (NOD)-containing protein 2-like receptors (NLRs). Immune modulators targeting inflammasomes have been investigated to control inflammatory diseases such as metabolic syndrome. However, most immune modulators possessing anti-inflammasome properties attenuate production of other cytokines, which are essential for host defense. In this review, we analyzed the effect of anti-inflammasome agents on the production of cytokines which are not regulated by inflammasome and involving in initial immune responses. As a result, the inflammasome inhibitors are put into three categories: non-effector, stimulator, or inhibitor of cytokine production. Even the stimulator of cytokine production ameliorated symptoms resulting from inflammasome activation in mouse models. Thus, we suggest ideal immune modulators targeting inflammasomes in order to enhance cytokine production while inhibiting cytokine maturation.
The present study aimed to develop and optimize chitosan coated solid lipid nanoparticles (chitosan-SLNs) encapsulated with methazolamide. Chitosan-SLNs were successfully prepared by a modified oil-in-water emulsification-solvent evaporation method with glyceryl monostearate as the solid lipid and phospholipid as the surfactant. Systematic screening of formulation factors was carried out. The optimized formula for preparation was screened by orthogonal design as well as Box-Behnken design with entrapment efficiency, particle size and zeta potential as the indexes. The entrapment efficiency of the optimized formulation (methazolamide-chitosan-SLNs) prepared was (58.5±4.5)%, particle size (247.7±17.3) nm and zeta potential (33.5±3.9) mV. Transmission electron microscopy showed homogeneous spherical particles in the nanometer range. A prolonged methazolamide in vitro release profile was obtained in the optimized chitosan-SLNs suspension compared with methazolamide solution. No ocular damages were observed in the susceptibility test on albino rabbits. The results suggest that the combination of orthogonal design and Box-Behnken design is efficient and reliable in the optimization of nanocarriers, and chitosan-SLNs is a potential carrier for ophthalmic administration.
Identifying sensitive and specific biomarkers for early detection of cancer is immensely imperative for early diagnosis and treatment and better clinical outcome of cancer patients. This study aimed to construct a specific DNA methylation pattern of cancer suppressor genes and explore the feasibility of applying cell-free DNA based methylation as a biomarker for early diagnosis of esophageal squamous cell carcinoma (ESCC). We recruited early stage ESCC patients from Yangzhong County, China. The Illumina Infinium 450K Methylation BeadChip was used to construct a genome-wide DNA methylation profile. Then, differentiated genes were selected for the validation study using the Sequenom MassARRAY platform. The frequency of methylation was compared between cancer tissues, matched cell-free DNAs and normal controls. The specific methylation profiles were constructed, and the sensitivity and specificity were calculated. Seven CG sites in three genes CASZ1, CDH13 and ING2 were significantly hypermethylated in ESCC as compared with normal controls. A significant correlation was found between the methylation of DNA extracted from cancer tissues and matched plasma cell-free DNA, either for individual CG site or for cumulative methylation analysis. The sensitivity and specificity reached 100% at an appropriate cut-point using these specific methylation biomarkers. This study revealed that aberrant DNA methylation is a promising biomarker for molecular diagnosis of esophageal cancer. Hypermethylation of CASZ1, CDH13 and ING2 detected in plasma cell-free DNA can be applied as a potential noninvasive biomarker for diagnosis of esophageal cancer.
The highly conserved RNA binding protein PUF (Pumilio/FBF) family is present throughout eukaryotes from yeast to mammals, with critical roles in development, fertility and the nervous system. However, the function of the mammalian PUF family members remains underexplored. Our previous study reported that a gene-trap mutation of Pum2 results in a smaller testis but does not impact fertility and viability. Although the gene-trap mutation disrupted the key functional domain of PUM protein–PUM-HD (Pumilio homology domain), but still produced a chimeric Pum2-β-geo protein containing part of PUM2, raising a question if such a chimeric protein may provide any residual function or contribute to the reproductive phenotype. Here, we report the generation of a conditional PUM2 allele, when knocked out, producing no residual PUM2 and hence a complete loss-of-function allele. We also uncovered small but significant reduction of male fertility and viability in the mutants, suggesting requirement of PUM2 for male fertility and viability.
Non-Hodgkin lymphoma (NHL) is one of the most common cancers affecting men of reproductive age. The high response rate of bendamustine as first-line treatment for NHL, coupled with young age of patients, makes elucidation of the impact of treatment on male reproduction important. Our aim was to determine the effects of bendamustine on male reproduction by animal model. Male mice were treated with bendamustine (40 mg/kg) through tail vein injection while cisplatin was given as a standard (3 mg/kg) through intraperitoneal injection. After 3 weeks, bendamustine induced weight loss and sperm morphology abnormalities were compared to the control. Additionally, sperm with folded tails were the most frequent abnormality in bendamustine-treated mice. But the mechanism of sperm abnormality induced by bendamustine remains to be elucidated. These results indicate bendamustine may affect spermatozoa of patients who have been treated for NHL.
The surgical treatment for aortic diseases remains a challenge for any cardiac surgeon. The use of sutureless ring connector in aortic anastomosis can simplify the procedure and shorten anastomosis time. Therefore, we developed a novel device for sutureless aortic anastomosis. A series of experiments were carried out for tensile and leakproof-capacity assessments to verify the feasibility of the ring connector by using fresh swine aorta samples. In in vivo test, the ring connector was implanted in 6 swine with follow-up of 6 months. Radiographic and pathological studies of the aorta were performed. In the tensile tests, the strength was 32.7±5.9 Newton (N) in the sutureless anastomosis group, compared with 73.3±12.5 N in the control group by traditional manual suture. In the leakproof-capacity assessment, no sign of either leakage or bursting was evident at 280 mmHg of internal pressure in the aorta samples. In in vivo tests, it took 9.47±0.3 minutes for the sutureless anastomosis, compared with 15.58±1.39 minutes for hand-sewn suturing. Insertion was easy and rapid. Radiographic and pathological studies were performed at first month, third month and sixth month after surgery, each time obtained from the two swine, showed patency of the anastomosis and no signs of stenosis, blood leakage, migration or pseudoaneurysm formation, except one paralyzed swine developed of thrombo-occlusion at the site of the sutureless anastomosis. The result indicates that this novel ring connector offers considerable promise for sutureless aortic anastomosis.