Caffeic acid dimethyl ether alleviates alcohol-induced hepatic steatosis via microRNA-378b-mediated CaMKK2-AMPK pathway.

Alcoholic liver disease (ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Caffeic Acid Dimethyl Ether (CADE) significantly inhibits alcohol-induced hepatic steatosis in vivo through AMP-activated protein kinase (AMPK) pathway, but its in-depth mechanism remains unclear. This work aimed to clarify further mechanism of CADE in improving hepatic lipid accumulation in ALD through the microRNA-378b (miR-378b)-mediated Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-AMPK signaling pathway. Here, we reported that the hepatic or serum triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels were sharply escalated by ethanol while prominently decreased by CADE. Ethanol sharply up-regulated miR-378b expression while CADE effectively prevented the elevation of miR-378b in vivo. And treatment of CADE surely increased mRNA and protein expression of CaMKK2 as a kinase of AMPK and reduced lipid accumulation in the livers of alcohol-fed C57BL/6 mice. MiR-378b escalation exacerbated hepatic steatosis and inhibited CaMKK2-AMPK signaling, while miR-378b deficiency alleviated lipid accumulation and activated the CaMKK2 cascade. Furthermore, CADE alleviated the lipid deposition and reversed the disorder of CaMKK2-AMPK signaling pathway induced by miR-378b over-expression. However, knockdown of miR-378b eliminated the beneficial effect of CADE on lipid metabolism. In brief, our results showed that CADE ultimately improved hepatic lipid deposition by regulating the CaMKK2-AMPK signaling pathway through miR-378b.

Methyl ferulic acid ameliorates alcohol-induced hepatic insulin resistance via miR-378b-mediated activation of PI3K-AKT pathway.

A previous study indicated that microRNA-378b (miR-378b) plays a critical role in controlling hepatic insulin resistance by targeting insulin receptor (IR) and p110α in alcoholic liver disease (ALD). Methyl ferulic acid (MFA), a bioactive ingredient in Securidaca inappendiculata Hassk rhizomes, exhibits multiple pharmacological activities. It has been reported that MFA ameliorates insulin resistance in ALD, whereas the underlying molecular mechanism remains unclear. The objective of study was to evaluate the influence of MFA on insulin sensitivity in ethanol-induced L-02 cells as well as alcohol-fed mice and illuminate the function of miR-378b-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in system. MFA was found to remarkably down-regulate miR-378b level and increase IR and p110α expressions. Furthermore, the effect of MFA on modulating miR-378b/PI3K-AKT pathway to enhance insulin sensitivity was corroborated by overexpressing and inhibiting miR-378b. Taken together, MFA exhibited a positive effect against ALD by attenuating the inhibition of miR-378b on IR/p110α and partly activating the insulin signaling to alleviate alcohol-induced hepatic insulin resistance.

[Upholding Chinese spirit on schistosomiasis control in the new era to accelerate the progress towards schistosomiasis elimination in China].

China is one of the schistosomiasis-endemic countries with the highest burden of disease across the world. Following the control efforts for over 60 years, great successes have been achieved in schistosomiasis control in the country, and the control program is moving towards transmission interruption and elimination. To commemorate the 60th anniversary of publishing Chairman Mao Zedong's two poems entitled "Farewell to the God of Plague", a series of activities that disseminate schistosomiasis control achievements have been conducted in China throughout 2018, including the development of Chinese spirit on schistosomiasis control in the new era. After extensive discussion, collection and screening, and "Integration of all efforts, scientific control, willingness to dedication and swearing to wipe out the 'God of Plague' " was proposed as Chinese spirit on schistosomiasis control in the new era. Integration of all efforts is a summary of administrative policy-making and population participation in Chinese schistosomiasis control programs; scientific control is the refinement of the Chinese national schistosmiasis control strategy that is developed and implemented tailoring to time and circumstances; willingness to dedication is a valuable spiritual wealth and inexhaustible source of power for Chinese schistosomiasis control professionals in the new era; and swearing to wipe out the "God of Plague" is a sacred mission assigned to Chinese professionals participating in the national schistosomiasis control program in the new era. Chinese spirit on schistosomiasis control in the new era will further strengthen our belief in achieving the goal of schistosomiasis elimination in China eventually.

HOTAIR lncRNA SNPs rs920778 and rs1899663 are associated with smoking, male gender, and squamous cell carcinoma in a Chinese lung cancer population.

The abnormal expression of the long noncoding RNA (lncRNA) HOX transcript intergenic antisense RNA (HOTAIR) plays an important role in the development of various cancers; however, single nucleotide polymorphisms (SNPs) in HOTAIR and their association with primary lung cancer susceptibility have not yet been reported. Here, we performed a case-control study including 262 primary lung cancer patients and 451 cancer-free control individuals to investigate the association between four haplotype-tagging SNPs (rs920778, rs12826786, rs4759314, and rs1899663) in the HOTAIR lncRNA and the risk of developing primary lung cancer. We found a significant association between the SNPs rs920778 and rs1899663 in the HOTAIR and primary lung cancer susceptibility (P < 0.05). Moreover, homozygous C/T (C/T + TT) for rs920778 (C > T) sites was significantly associated with gender, smoking history, and pathological type. In addition, linkage disequilibrium and haplotype analysis of HOTAIR gene polymorphisms for susceptibility to lung cancer revealed a high degree of linkage disequilibrium between the rs920778 and rs1899663 loci (D' = 0.86, r2 = 0.52). The population of rs920778, rs1899663, and rs4759314 had a significantly increased risk of lung cancer (P < 0.001). In summary, the present study provides persuasive evidence that SNP rs920778 is closely correlated with susceptibility to primary lung cancer. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in the development of primary lung cancer.

Methyl ferulic acid attenuates ethanol-induced hepatic steatosis by regulating AMPK and FoxO1 Pathways in Rats and L-02 cells.

Methyl ferulic acid (MFA) is a biologically active monomer extracted and purified from the Chinese herbal medicine Securidaca inappendiculata hasskarl. The previously studies showed that MFA improved acute liver injury induced by ethanol. However, the effect of MFA on ethanol-induced hepatic steatosis in alcoholic liver disease (ALD) still remains unclear. The current study was aimed at elucidating the effect of MFA on alcohol-induced hepatic steatosis and the underlying mechanisms. Human hepatocyte L-02 cells exposed to 200 mM ethanol for 24 h to simulate alcoholic steatosis in vitro. SD rats were fed a Lieber-DeCarli diet containing 5% (w/v) alcohol for 16 weeks to induce alcoholic liver disease in vivo. We examined the effect of MFA on ethanol-induced lipid deposition in L-02 cells and SD rats. The results showed that MFA reduced the accumulation of lipid in L-02 cells, improved alcoholic liver injury in rats, alleviated hepatic pathological lesions, and reduced lipid deposition in rat serum and liver. Further studies suggest that MFA reduces lipid synthesis by activating AMPK-ACC/MAPK-FoxO1 pathway. In addition, MFA also promotes lipid oxidation by up-regulating the expression of SIRT1, PPAR-α, and CPT-1α. Taken together, MFA ameliorates ethanol-induced hepatic steatosis by activating AMPK-ACC/MAPK-FoxO1 pathway and up-regulating the expression levels of SIRT1, PPAR-α, and CPT-1α.

NOX4/ROS mediate ethanol­induced apoptosis via MAPK signal pathway in L­02 cells.

The aim of the present study was to assess the molecular mechanism of ethanol­induced oxidative stress­mediated apoptosis in L­02 liver cells in order to elucidate novel pathways associated with alcoholic liver disease. L­02 cells were treated with 400 mM ethanol with or without inhibitors. The cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry and a single­stranded DNA (ssDNA) assay. Intracellular reactive oxygen species (ROS) production of L­02 cells was determined using the 2',7'­dichlorofluorescein­diacetate dye. The protein expression of c­Jun N­terminal kinase (JNK), phosphorylated (p)­JNK, P38, p­P38, NADPH oxidase (NOX)1, NOX4, p22phox, B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein were measured by western blot analysis. The mRNA expression of NOX1, NOX4 and p22phox was measured by reverse transcription polymerase chain reaction analysis. The results indicated that after treatment with various concentrations of ethanol for the indicated durations, L­02 cells were displayed a significant decrease in cell viability in a dose­and time­dependent manner. Ethanol­induced apoptosis and cell death of L­02 cells was accompanied by the generation of ROS, elevated expression of NOX, as well as phosphorylation of JNK and P­38. In addition, increased expression of Bcl­2 was induced by 400 mM ethanol. Furthermore, treatment with NOX inhibitor attenuated the ethanol­induced a decrease in cell viability, and an increase in apoptosis and Bcl­2 expression. In conclusion, ethanol induced apoptosis in the L­02 hepatocyte cell line via generation of ROS and elevated expression of NOX4. This indicated that activation of JNK and p38 in the mitogen­activated protein kinase pathway promotes apoptosis in L­02 cells.

Hepatoprotective effects of Methyl ferulic acid on alcohol-induced liver oxidative injury in mice by inhibiting the NOX4/ROS-MAPK pathway.

AIMS: The present study aimed to investigate the hepatoprotective effects of Methyl ferulic acid (MFA) against oxidative stress and apoptosis as well as inflammation in mice with liver injury induced by alcohol and its underlying mechanisms. METHODS: C57BL/6 mice were divided into a control group,a model group, and Methyl ferulic acid with high dosage (20 mg/kg), moderate dosage (10 mg/kg) and low dosage (5 mg/kg) groups. The general condition and organ index of each group were investigated. Histopathological analysis was performed to determine the degree of hepatic injury. Biochemical analyses of functional liver enzymes, lipid peroxidation enzymes and lipid content in each group. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The mechanisms were investigated by detecting levels of NADPH Oxidase 4 (NOX4),p22phox, cytochrome P4502E1 (CYP2E1),Bax,B-cell lymphoma 2 (Bcl-2),cleaved-caspase 3 and 9 and phosphorylated extracellular regulated protein kinases(ERK),phosphorylated c-Jun N-terminal kinase (JNK), and phosphorylated p38 mitogen-activated protein kinase (MAPK) using real-time polymerase chain reaction (PCR) and Western blotting. RESULTS: MFA treatment significantly decreased serum enzymatic activities of alanine aminotransferase (ALT) and aspartate aminotransaminase (AST). MFA markedly increased levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px) and total antioxidative capacity (T-AOC), and reduced the concentration of malondialdehyde (MDA) and reactive oxygen species (ROS). Histopathological examination of livers showed that MFA reduced cytoplasmic vacuolisation necrosis and inflammatory cell infiltration in alcohol-treated mice. MFA treatment remarkably reduced the levels of trigyceride (TG), total cholesterol (TC) and low-density lipoprotein (LDL), decreasing the levels of high-density lipoprotein (HDL), alcohol dehydrogenase(ADL) and aldehyde dehydrogenase (ALDH). MFA treatment remarkably inhibited the expression of inflammatory factors tumour necrosis factor (TNF)-α, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1ß and IL-6. MFA attenuated both mRNA and protein expression of NOX4,p22phox,CYP2E1,Bax/Bcl-2. In addition, MFA inhibited the activation of caspase 3 and 9 and downregulated the levels of p-JNK,p-p38 MAPK and p-ERK in liver. CONCLUSION: MFA has a protective effect on alcohol-induced liver injury, which may be related to its antioxidant,anti-inflammatory,lipid-eliminating properties and its ability to regulate the NOX4/ROS-MAPK signalling pathway.

How to identify the posterior boundary of No. 8a and the right side group of No. 9 lymph nodes?

As the development of laparoscopic gastrectomy for gastric cancer in recent years, laparoscopic lymphadenectomy becomes more and more feasible and widely accepted. But there're still some issues confuse gastric surgeons, such as the precise extent of the lymph nodes (LN), especially the posterior boundary of No. 8a and the right side group of No. 9 LNs. Here we introduce a reasonable and feasible method to identify the posterior boundary of No. 8a and the right side group of No. 9 LNs and demonstrate the detail procedure.

The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization.

In this study, we examined anti-fungal and anti-inflammatory effects of the synthetic melanocortin peptide (Ac-Cys-Lys-Pro-Val-NH2)2 or (CKPV)2 against Candida albicans vaginitis. Our in vitro results showed that (CKPV)2 dose-dependently inhibited Candida albicans colonies formation. In a rat Candida albicans vaginitis model, (CKPV)2 significantly inhibited vaginal Candida albicans survival and macrophages sub-epithelial mucosa infiltration. For mechanisms study, we observed that (CKPV)2 inhibited macrophages phagocytosis of Candida albicans. Meanwhile, (CKPV)2 administration inhibited macrophage pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) release, while increasing the arginase activity and anti-inflammatory cytokine IL-10 production, suggesting macrophages M1 to M2 polarization. Cyclic AMP (cAMP) production was also induced by (CKPV)2 administration in macrophages. These above effects on macrophages by (CKPV)2 were almost reversed by melanocortin receptor-1(MC1R) siRNA knockdown, indicating the requirement of MC1R in the process. Altogether, our results suggest that (CKPV)2 exerted anti-fungal and anti-inflammatory activities against Candida albicans vaginitis probably through inducing macrophages M1 to M2 polarization and MC1R activation.