What is the role of Von Willebrand factor in chronic hepatitis B virus infection to hepatocellular carcinoma: a review article.

Von Willebrand factor (VWF) is a glycoprotein synthesized and secreted by vascular endothelial cells and megakaryocytes, found on plasma surface, endothelial cells, and α-granule of platelets. VWF can be interacted with collagen and platelet membrane glycoproteins GPIb and GPIb-IIa and play an important role in platelet adhesion and aggregation. Growing research evidence suggests that VWF also mediates the prevention or protesting of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients from several clinical studies. While the mechanism of VWF in HCC protection or protest is still unclear, further study is required. This article aims to rationalize the role of VWF in the development of HCC, and the functional domain of VWF in cancer as well as cross-talking with platelets and miRNAs. This article also looks forward to the future development and challenges of VWF research.

Changes in dorsal root ganglion CGRP expression in mouse pinch nerve injury model: Modulation by Somatostatin type-2 receptor.

INTRODUCTION: Our previous work has shown that somatostatin effectively inhibits neuropathic pain by activating its type 2 receptor (SSTR2) in the dorsal root ganglion (DRG) and spinal cord of mice. However, the underlying mechanism of this activation has not been elucidated. METHODS: To explore further mechanisms, we examined pain behavior and the expression of neuropeptides such as calcitonin gene-related peptide (CGRP) in dorsal root ganglion neurons(DRGs) as well as the changes of the number of CGRP-IR DRGs in the mouse model of sciatic pinch nerve injury. RESULTS: In this model, the number of medium and small DRG neurons in ipsilateral CGRP-IR was slightly increased, but not significantly, compared with sham animals at 3, 7, and 9 days after pinch nerve injury. This correlated with the behavioral readouts of hypersensitivity at the same time points. However, the magnitude of the painful behavior (Autotomy) was observed after application of SSTR2 antagonist (CYN154806, 5 mg/kg) in the injured nerve groups compared to the saline-treated injured group as well as the sham-operated group. Following pinch nerve injury, there was a significant decrease in the number of ipsilateral CGRP-IR small and medium DRG neurons in SSTR2 antagonist (anti-SSTR2)- but not saline-treated mice. These data also correlated with painful behavioral readouts where hypersensitivity was significantly increased by anti-SSTR2 but not saline treatment. DISCUSSION/CONCLUSION: In all, application of the SSTR2 antagonist to the pinched sciatic nerve suppressed CGRP expression and aggravated painful behavior, suggesting that CGRP expression in DRG neurons can be an important component of the pain mechanism and an indicator of pain behavior.

Somatostatin Type 2 Receptor Antibody Enhances Mechanical Hyperalgesia in the Dorsal Root Ganglion Neurons after Sciatic Nerve-pinch Injury: Evidence of Behavioral Studies and Bax Protein Expression.

BACKGROUND: Our previous study has indicated that somatostatin potently inhibits neuropathic pain through the activation of its type 2 receptor (SSTR2) in mouse dorsal root ganglion and spinal cord. However, the underlying mechanism of this activation has not been elucidated clearly. OBJECTIVE: The aim of this study is to perform the pharmacological studies on the basis of sciatic nerve-pinch mice model and explore the underlying mechanism involving SSTR2. METHODS: On the basis of a sciatic nerve-pinch injury model, we aimed at comparing the painful behavior and dorsal root ganglion neurons neurochemical changes after the SSTR2 antibody (anti- SSTR2;5µl,1µg/ml) administration in the mouse. RESULTS: After pinch nerve injury, we found that the mechanical hyperalgesia and severely painful behavior (autotomy) were detected after the application of SSTR2 antibody (anti-SSTR2; 5µl, 1µg/ml) on the pinch-injured nerve. The up-regulated phosphorylated ERK (p-ERK) expression and the apoptotic marker (i.e., Bax) were significantly decreased in DRGs after anti-SSTR2 treatment. CONCLUSION: The current data suggested that inhibitory changes in proteins from the apoptotic pathway in anti-SSTR2-treated groups might be taking place to overcome the protein deficits caused by SSTR2 antibody and supported the new therapeutic intervention with SSTR2 antagonist for neuronal degeneration following nerve injury.

Nuclear factor erythroid 2-related factor 2 antibody attenuates thermal hyperalgesia in the dorsal root ganglion: Neurochemical changes and behavioral studies after sciatic nerve-pinch injury.

Oxidative stress is generated in several peripheral nerve injury models.Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated to have a role in antioxidant effect. After nerve injury, the severely painful behavior is also performed. However, little has been explored regarding the function of Nrf2 in this painful process. Therefore, in this study, we compared the effects of Nrf2 antibody administration following sciatic nerve-pinch injury on painful behavior induced in young mice and neurochemical changes in dorsal root ganglion neurons. After pinch nerve injury, we found that the magnitude of the thermal allodynia was significantly decreased after application of Nrf2 antibody (5ul, 1mg/ml) in such injured animals and phosphorylated ERK(p-ERK) as well as the apoptotic protein (i.e., Bcl-6) in DRG neurons were also down-regulated in the anti-Nrf2-treated injured groups compared to the saline-treated groups. Taken collectively, these data suggested that the Nrf2 antibody reduced thermal hyperalgesia via ERK pathway and the down regulation of Bcl-6 protein from the apoptosis pathway might be protecting against the protein deletions caused by anti-Nrf2 effect and suggested the new therapeutic strategy with Nrf2 inhibitor following nerve injury.

Insulin resistance-induced hyperglycemia decreased the activation of Akt/CREB in hippocampus neurons: Molecular evidence for mechanism of diabetes-induced cognitive dysfunction.

Several previous studies have indicated that diabetic have higher risk of suffering from Alzheimer's disease, which severely induced cognitive dysfunction. However, the underlying molecular mechanism and more details on the cognitive deficits induced by hyperglycemia have not been elucidated. Here in our present study, on the basis of Goto-Kakizaki (GK) rats and streptozotocin (STZ)-induced diabetic model, we detected the variation of dendritic spine density in hippocampus as well as the differential expression of some important signal transduction molecules that were of relevance in learning and memory function. We found that the magnitude of escape latency time was significantly increased in such diabetic animals; the phosphorylated Akt/CREB; SYP and BDNF as well as other downstream molecules in hippocampus neurons were also downregulated in both diabetic groups compared to the normal groups. Thus, all of these data indicate the obstacle of neuronal pathology and the Akt/CREB signaling pathway caused by hyperglycemia that may suppress cognitive behavior, which may provide a novel way for the prevention of diabetic encephalopathy and the cognitive deficits of Alzheimer's disease.

Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway.

Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases including Alzheimer's disease (AD), in which dysregulation of double-stranded RNA-dependent protein kinase (PKR)-like ER-resident kinase (PERK) is considered to play a critical role. Allicin, a garlic extract, has been demonstrated a protective role in AD model. The present study was designed to investigate the possible protective effect of allicin on ER stress-induced cognitive deficits and underlying mechanisms in rats. In this study, 72h of lateral ventricular infusion of tunicamycin (TM), an ER stress stimulator, induced significant cognitive deficits. TM increased tau phosphorylation, Aß42 deposit, and oxidative stress, and reduced antioxidative enzymes activity in the hippocampus. TM moderately elevated the expression of PERK and its downstream substrate nuclear factor erythroid-derived 2-like 2 (Nrf2) in the hippocampus. All these impaired changes by TM were significantly improved by allicin pretreatment. Allicin markedly increased PERK and Nrf2 expression in the hippocampus. Thus, our data demonstrate the protective role of allicin in ER stress-related cognitive deficits, and suggest that PERK/Nrf2 antioxidative signaling pathway underlies the action mechanism.

Allicin ameliorates cardiac hypertrophy and fibrosis through enhancing of Nrf2 antioxidant signaling pathways.

AIM: To evaluate the protective effects of allicin on Ang II-induced cardiac hypertrophy. METHODS: Sprague-Dawley male rats were randomized into 3 groups:1)sham group (saline)(n = 12), 2) Ang II group(n = 9), 3) allicin group (Ang II + allicin)(n = 9). They received infusions of either saline or Ang II (250 ng/kg body weight per min) through mini-osmotic pumps implanted subcutaneously for 2 weeks and given a diet containing 180 mg/kg/day of allicin for 8 consecutive weeks. Hemodynamic, morphological, histological, and biochemical changes were evaluated at corresponding time points. RESULTS: Ang II infusion increased blood pressure, heart rate and heart weight to body weight ratio, and resulted in anatomical and functional changes, such as increased LV mass, posterior wall thickness and LV end-diastolic diameter, and decreased fractional shortening and EF compared with sham rats. Nrf2 and HO-1 in the hearts of rats in the Ang II group were moderately elevated at both mRNA and protein levels compared to sham group mice, but NQO1 andγ-GCS were significantly lower. GPx activities, levels of GSH and T-AOC in the hearts of the rats in the Ang II group were also significantly lower, and the levels of TBARS, reactive oxygen species and protein carbonyl were significant increased. Allicin attenuated LV mass, posterior wall thickness and LV end-diastolic diameter (1.10 ± 0.04 vs. 1.37 ± 0.05, 2.26 ± 0.08 vs. 2.96 ± 0.12, 7.27 ± 0.36 vs. 8.56 ± 0.41, respectively; all P < 0.05), and increased fractional shortening and EF (28.30 ± 3.21 vs. 25.40 ± 2.57, 60.27 ± 5.63 vs. 51.30 ± 4.78, respectively; both P < 0.05) in the Ang II-induced hypertrophic rats compared to the untreated Ang II rats. Furthermore, allicin treatment attenuated the accumulation of interstitial collagen and collagen I/III (P < 0.01 vs. the untreated Ang II group), decreased the levels of reactive oxygen species, protein carbonyl and TBARS and increased GPx activities. Moreover, allicin significantly increased mRNA expression and protein levels of Nrf2, NQO1, and γ-GCS ( P < 0.01, P < 0.05 vs. the untreated Ang II group). CONCLUSION: Allicin could prevent the development of cardiac remodeling and the progression of cardiac hypertrophy to cardiac dysfunction caused by enhancing the Nrf2 antioxidant signaling pathways.

Allicin ameliorates cognitive deficits ageing-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways.

Numerous studies have demonstrated that learning and memory abilities in the course of normal aging cognitive abilities tend to decline and Nrf2 expression appears to decline with aging. So, Nrf2 pathway has been identified as a promising therapeutic target for neurodegenerative diseases. The organosulfur compounds, allicin can activate Nrf2, because it has an electrophilic center, which can serve as an attack site for nucleophiles, such as specific protein sulfhydryl groups present on Keap1. However, the influence of allicin on aging-induced cognitive deficits has not been examined. In this study, we assess the effects of allicin on endogenous antioxidant defenses in hippocampus of cognitively impaired aged mouse. Our results indicate that treatment of allicin significantly ameliorated ageing-induced cognitive dysfunction through enhancing of Nrf2 antioxidant signaling pathways. Therefore, allicin could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in aging and Alzheimer's disease.

[Pineal mechanism of danggui shaoyao powder on anti-aging].

OBJECTIVE: To study whether Danggui Shaoyao Powder (DSP) is by way of improving pineal function to realize its anti-aging effects. METHODS: Forty aged rats were randomly divided into the sham operated group (A), the pinealectomized group (B), the sham medicated group (C), the pinealectomized and medicated group (D). The medication given was gastric perfusion of DSP for 3 weeks. Learning and memory ability of rats was observed using Morris water maze and the serum melatonin (MLT) concentration of the rats was measured by radio-immunoassay. RESULTS: The average escape latency in Group B was significantly longer than that in other groups (P <0.05). The times of passing through the platform and the percentage of swimming distance in Group C were significantly higher than those in other groups (P <0.05). The serum MLT was higher at daytime than at night in Group C and D (P <0.05); that at daytime in Group C was higher than Group A (P <0.05) and also higher in Group D than Group B; that at daytime was higher in Group C than Group D; that at night markedly decreased in Group D as compared with Group B (P <0.05). CONCLUSION: DSP could increase the melatonin secretion and improve learning and memory ability. Since its effects reduced after pinealectomy, it could be deduced that improving pineal function should be one of the action mechanisms for anti-aging.

Effects of the aqueous extract of the Chinese medicine Danggui-Shaoyao-San on rat pineal melatonin synthesis.

OBJECTIVES: The purpose of this study is to investigate if the aqueous extract of the Chinese medicine Danggui-Shaoyao-San (DSS) can increase the plasma level of melatonin and enhance the function of the pineal gland of naturally aged rats. METHODS: The rats were treated with DSS at doses of 3ml or same volume of distilled water by oral administration at 11 p.m. for three weeks. The plasma level of melatonin were measured by radioimmunoassay. The function of pineal gland were measured through three parameters: pineal beta adrenergic receptor binding investigated by [3H]DHA binding; pineal expression of NAT mRNA detected by real-time RT-PCR; phosphorylation of CREB (P-CREB) and total level of CREB (T-CREB) measured by western blot analysis. RESULTS: DSS significantly increased melatonin level at night after oral administration for 3 weeks. By measurement of pineal [3H]DHA binding, it was found DSS improved the beta-adrenergic receptors binding in pineals. The stimulatory effect of DSS on the expression of NAT mRNA in the old rat pineal gland has been demonstrated in this study. Western blot analysis showed that DSS significantly increased phosphorylation of CREB. CONCLUSIONS: Our results indicate that a downstream pathway for DSS induction of melatonin synthesis in the rat pineal gland acts via cyclic AMP-dependent cascade and transcription mechanism.