Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase

The cardioprotective properties of puerarin, a natural product, have been attributed to the endothelial nitric oxide synthase (eNOS)-mediated production of nitric oxide (NO) in EA.hy926 endothelial cells. However, the mechanism by which puerarin activates eNOS remains unclear. In this study, we sought to identify the intracellular pathways underlying eNOS activation by puerarin. Puerarin induced the activating phosphorylation of eNOS on Ser1177 and the production of NO in EA.hy926 cells. Puerarin-induced eNOS phosphorylation required estrogen receptor (ER)-mediated phosphatidylinositol 3-kinase (PI3K)/Akt signaling and was reversed by AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent kinase II (CaMKII) inhibition. Importantly, puerarin inhibited the adhesion of tumor necrosis factor (TNF)-α-stimulated monocytes to endothelial cells and suppressed the TNF-α induced expression of intercellular cell adhesion molecule-1. Puerarin also inhibited the TNF-α-induced nuclear factor-κB activation, which was attenuated by pretreatment with N^G-nitro-l-arginine methyl ester, a NOS inhibitor. These results indicate that puerarin stimulates eNOS phosphorylation and NO production via activation of an estrogen receptor-mediated PI3K/Akt- and CaMKII/AMPK-dependent pathway. Puerarin may be useful for the treatment or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease.     

Influencing factors of pressure pain hypersensitivity of the upper trapezius in food service workers with nonspecific neck/shoulder myofascial pain: A cross-sectional study

It is unclear which factors contribute to the developing pressure pain hypersensitivity of the upper trapezius, a type of neurophysiological hyperexcitability. The present study investigated the relationship between physical and psychological factors and pressure pain hypersensitivity of the upper trapezius for each sex. In total, 154 individuals with neck/shoulder myofascial pain participated, among 372 food service workers. Participants completed a questionnaire (Beck Depression Inventory, and Borg Rating of Perceived Exertion scale) and were photographed to measure posture. Pressure pain sensitivity, 2 range of motions (cervical lateral bending and rotation), and 4 muscle strengths (serratus anterior, lower trapezius [LT], biceps, and glenohumeral external rotator) were measured by a pressure algometer, iPhone application, and handheld dynamometer, respectively. For each sex, forward multivariate logistic regression was used to test our a priori hypothesis among selected variables that a combination of psychosocial and physical factors contributed to the risk for pressure pain hypersensitivity. In multivariate analyses, LT strength (odds ratio = 0.94, 95% confidence interval = 0.91–0.97, P = .001) was the only significant influencing factor for pressure pain hypersensitivity in men. Dominant painful ipsilateral cervical rotation range of motion (odds ratio = 0.96, 95% confidence interval = 0.92–0.99, P = .037) was the only influencing factor for pressure pain hypersensitivity in women. LT strength and dominant painful ipsilateral cervical rotation range of motion could serve as guidelines for preventing and managing pressure pain hypersensitivity of the upper trapezius in food service workers with nonspecific neck/shoulder myofascial pain.     

Combined differential gene expression profile and pathway enrichment analyses to elucidate the molecular mechanisms of uterine leiomyoma after gonadotropin-releasing hormone treatment

Composite regulatory signature database (CRSD), a self-developed comprehensive Web server for composite regulatory signature discovery, used to compare the published microarray data with our data on patients with uterine leiomyoma treated with or without GnRH analogue (GnRH-a), revealed that the focal adhesion, mitogen-activated protein kinase (MAPK), CXC chemokine receptor 4/stromal-derived factor-1 (CXCR4/SDF-1), T-cell receptor, integrin, vascular endothelial growth factor (VEGF), GnRH, and transforming growth factor-beta (TGF-beta) signaling pathways are highly expressed in uterine leiomyoma and significantly down-regulated after GnRH-a treatment. According to the results these signaling pathways could be involved in inflammation, proliferation, and remodeling processes of leiomyoma development and possibly in the regression of leiomyoma after GnRH-a treatment, which might improve our understanding of the mechanisms of leiomyoma formation and help us to find novel drug targets or specific markers for diagnosis and prognosis in uterine leiomyoma.     

Phthalides from Pittosporum illicioides var. illicioides with inhibitory activity on superoxide generation and elastase release by neutrophils

Six new phthalides, (S)-3-ethyl-7-hydroxy-6-methoxyphthalide (1), (S)-3-ethyl-7-hydroxy-5,6-dimethoxyphthalide (2), (S)-3-ethyl-5,6,7-trimethoxyphthalide (3), (R)-3-ethyl-7-hydroxy-6-methoxyphthalide (4), (Z)-3-ethylidene-7-hydroxy-6-methoxyphthalide (5), and (Z)-3-ethylidene-6,7-dimethoxyphthalide (6), have been isolated from the root of Pittosporum illicioides var. illicioides, together with seven known compounds. The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 1-4 exhibited inhibition (IC50相似文献   

In vitro anti-biofilm activity of macelignan isolated from Myristica fragrans Houtt. against oral primary colonizer bacteria

In early dental plaque formation, oral primary colonizers such as Streptococcus mutans, Streptococcus sanguis and Actinomyces viscosus are initially attached to the pellicle-coated tooth surface to form a biofilm. The study aimed to determine the efficacy of macelignan, isolated from nutmeg (Myristica fragrans Houtt.), in removing each single oral primary biofilm in vitro on a polystyrene 96-well microtiter plate. Four biofilm growth phases (4, 12, 20 and 24 h) were evaluated in this study after treatment with macelignan at various concentrations (0.2, 2 and 10 microg/mL) and exposure times (5, 10 and 30 min). Anti-biofilm activity of macelignan was measured as the percentage of the remaining biofilm absorbance after macelignan treatment in comparison with the untreated control. At 24 h of biofilm growth, S. mutans, A. viscosus and S. sanguis biofilms were reduced by up to 30%, 30% and 38%, respectively, after treatment with 10 microg/mL macelignan for 5 min. Increasing the treatment time to 30 min resulted in a reduction of more than 50% of each of the single primary biofilms. The results indicate that macelignan is a potent natural anti-biofilm agent against oral primary colonizers.