The present study indicated that elderly, longer duration of HCV infection, obesity, and history of diabetes mellitus are independent clinical parameters associated with advanced fibrosis, whereas elevated AST, alpha fetoprotein, and presence of grade 2 and 3 steatosis are independent laboratorial parameters associated with stage 3 and 4 fibrosis in patients with CHC.

CHC and ESRD are independently associated with a higher frequency of a history of DM, but lower frequencies of being obese, and having hepatic steatosis, stage III-IV fibrosis, and elevated transaminases. In patients with CHC and ESRD, stage III-IV fibrosis is not associated with a history of DM, but is independently associated with hepatic steatosis and thrombocytopenia.

We previously reported that celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, suppresses growth of human hepatocellular carcinoma (HCC) cells through both COX-2 dependence and independence. Recently, we established COX-2-deleted human HCC cells, C2D-HuH7, and C2D-HuH7-bearing nude mice. Using this novel model, we examined the pharmacological effects and mechanisms of celecoxib on in-vivo growth of HCC xenografts in relation to COX-2 expression. After treatment with celecoxib, the mice bearing HuH7 or C2D-HuH7 xenografts were assessed for the pharmacological effects and mechanisms of celecoxib on HCC xenograft growth in relation to COX-2 expression. Celecoxib resulted in an effective and comparable growth reduction of both COX-2-expressing and COX-2-deleted HuH7 xenografts in association with decreased Ki-67 expression. These results demonstrated celecoxib's COX-2-independent in-vivo anti-HCC effects. Celecoxib increased peroxisome proliferator-activated receptor gamma predominantly in HuH7 xenografts, indicating its COX-2 dependency. Celecoxib reduced p-Rb and DP1/E2F1 complex predominantly via upregulated p21/CDK4 complex in HuH7 xenograft, but p27/CDK4 complex in C2D-HuH7 xenografts. The effects of celecoxib on phosphatase and tensin homolog deleted on chromosome ten/PI3K/Akt signaling were COX-2 independent, but its effects on extracellular-regulated kinase signaling seemed COX-2 dependent. In addition, the effects of celecoxib on AC-H3, AC-H4, and histone deacetylase 2 could be both COX-2 dependent and independent. In conclusion, celecoxib suppresses growth of HuH7 xenografts regardless of COX-2 expression, which may be mediated through different signaling.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with cognitive impairment and later dementia among the elderly. Mounting evidence shows that adverse maternal environments during the fetal development increase the risk of diseases later in life including neurological disorders, and suggests an early origin in the development of AD-related dementia (ADRD) in utero. In the present study, we investigated the impact of antenatal hypoxia and fetal stress on the initiation of AD-related pathology in offspring of 5xFAD mice. We showed that fetal hypoxia significantly reduced brain and body weight in the fetal and the early postnatal period, which recovered in young adult mice. Using spontaneous Y-maze, novel object recognition (NOR), and open field (OF) tasks, we found that antenatal hypoxia exacerbated cognitive decline in offspring of 5xFAD compared with normoxia control. Of interest, fetal hypoxia did not alter intraneuronal soluble amyloid-β (Aβ) oligomer accumulation in the cortex and hippocampus in 5xFAD mouse offspring, indicating that antenatal hypoxia increased the vulnerability of the brain to synaptotoxic Aβ in the disease onset later in life. Consistent with the early occurrence of cognitive decline, we found synapse loss but not neuronal death in the cerebral cortex in 5xFAD but not wild-type (WT) offspring exposed to antenatal hypoxia. Furthermore, we also demonstrated that antenatal hypoxia significantly increased microglial number and activation, and reactive astrogliosis in the cerebral cortex in WT offspring. Moreover, antenatal hypoxia resulted in an exacerbated increase of microgliosis and astrogliosis in the early stage of AD in 5xFAD offspring. Together, our study reveals a causative link between fetal stress and the accelerated onset of AD-related pathology, and provides mechanistic insights into the developmental origin of aging-related neurodegenerative disorders.

C-type natriuretic peptide (CNP) is an important vascular regulator that is present in the brain. Our previous study demonstrated the innate neuroprotectant role of CNP in the neonatal brain after hypoxic-ischemic (HI) insults. In this study, we further explored the role of CNP in cerebrovascular pathology using both in vivo and in vitro models. In a neonatal mouse HI brain injury model, we found that intracerebroventricular administration of recombinant CNP dose-dependently reduces brain infarct size. CNP significantly decreases brain edema and immunoglobulin G (IgG) extravasation into the brain tissue, suggesting a vasculoprotective effect of CNP. Moreover, in primary brain microvascular endothelial cells (BMECs), CNP dose-dependently protects BMEC survival and monolayer integrity against oxygen-glucose deprivation (OGD). The vasculoprotective effect of CNP is mediated by its innate receptors NPR2 and NPR3, in that inhibition of either NPR2 or NPR3 counteracts the protective effect of CNP on IgG leakage after HI insult and BMEC survival under OGD. Of importance, CNP significantly ameliorates brain atrophy and improves neurological deficits after HI insults. Altogether, the present study indicates that recombinant CNP exerts vascular protection in neonatal HI brain injury via its innate receptors, suggesting a potential therapeutic target for the treatment of neonatal HI brain injury.