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The TGF-β1/Smad3-signaling pathway and gender differences were investigated in alcoholic liver fibrosis. Mice were divided into female normal, female model, male normal, and male model groups. Liver injury and fibrosis were assessed using histopathology and serology. Western blotting was performed to analyze the expression of relevant factors. HSC-T6 cells were divided into estradiol + saline, estradiol + ethanol, testosterone + saline, and testosterone + ethanol groups, and similar assessments were conducted in vitro. Compared with the female model group, the male model group exhibited significantly increased GPT, GOT, TNF-α, IL-6, and testosterone levels, fibrosis rate, and TGF-β1, Smad3, and PCNA expression, and significantly decreased estradiol levels and Caspase-3 expression. The apoptosis rate was higher in the estradiol + ethanol group than in the testosterone + ethanol group, although the testosterone + ethanol group exhibited significantly increased TNF-α, IL-6, Collagen-I, α-SMA, TGF-β1, Smad3, and PCNA expression, and significantly decreased Caspase-3 expression. Alcoholic liver fibrosis showed significant gender differences associated with the TGF-β1/Smad3-signaling pathway.

Geraniin has been reported to possess potent anti-inflammatory properties and to modulate the macrophage polarization. This study sought to evaluate the protective effects and underlying mechanisms of geraniin on lipopolysaccharide (LPS)-induced neuroinflammation and neurobiological alternations as well as cognitive impairment. Daily intragastrical administration with geraniin (20 mg kg–1day–1) for 14 days significantly prolonged the duration in the target quadrant (26.53 ± 2.03 versus 37.09 ± 3.27%; p< 0.05) and increased crossing-target number (1.93 ± 0.22 versus 3.08 ± 0.17; p< 0.01) in the probe test of LPS-treated mice. Geraniin also ameliorated LPS-elicited neural/synaptic impairments and decreased levels of LPS-induced Aβ generation (p< 0.05), amyloid precursor protein (APP) (p< 0.05) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) (p< 0.05). Furthermore, geraniin suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) (9.85 ± 0.58 versus 5.20 ± 0.52 pg/mg of protein; p< 0.01), interleukin (IL)-1β (16.31 ± 0.67 versus 8.62 ± 0.46 pg/mg of protein; p< 0.01), and IL-6 (12.12 ± 0.45 versus 7.43 ± 0.32 pg/mg of protein; p< 0.05), and inhibited glial cell activation. Moreover, geraniin effectively polarized the microglia toward an anti-inflammatory M2 phenotype. Further study revealed that geraniin targeted toll-like receptor 4 (TLR4)-mediated signaling and decreased the production of pro-inflammatory cytokines in BV-2 microglial cells. These results indicate that geraniin mitigates LPS-elicited neural/synaptic neurodegeneration, amyloidogenesis, neuroinflammation, and cognitive impairment and suggest geraniin as a therapeutic option for neuroinflammation-associated neurological disorders, such as Alzheimer’s disease.

In this work, a novel ratiometric electrochemical aptasensor was designed for prostate specific antigen (PSA) detection based on toehold-mediated strand displacement reaction (TMSDR). For PSA detection, PSA could bind with the aptamer sequence in hairpin probe 1 (HP1), and HP1/PSA complex was obtained. Then, in the presence of S3 DNA, HP1/PSA could trigger two TMSDR processes by hybridizing with Fc-S2/S1 double-stranded DNA, which would generate a large amount of Fc-S2 and recycle HP1/PSA. This enabled the hybridization of Fc-S2 with methylene blue labeled thiolated hairpin probe 2 (MB-HP2) immobilized on the electrode surface, causing MB molecules away from the electrode and Fc close to the electrode. Thus, with the increasing PSA concentrations, the current of MB (IMB) decreased and the current of Fc (IFc) increased. The ratio of IFc/IMBwas shown to be linear with the logarithm of PSA concentration from 1 pg mL−1to 100 ng mL−1, with a detection limit of 0.28 pg mL−1. In addition, the aptasensor had good specificity, reproducibility, repeatability, and stability for PSA detection, and was successfully applied to spiked diluted human serum samples.

Many mutations in the signal peptide and propeptide of factor IX (FIX) cause hemophilia B. A FIX variants database reports 28 unique missense mutations in these regions that lead to FIX deficiency, but the underlying mechanism is known only for the mutations on R43 that interfere with propeptide cleavage. It remains unclear how other mutations result in FIX deficiency and why patients carrying the same mutation have different bleeding tendencies. Here, we modify a cell-based reporter assay to characterize the missense mutations in the signal peptide and propeptide of FIX. The results show that the level of secreted conformation-specific reporter (SCSR), which has a functional γ-carboxyglutamate (Gla) domain of FIX, decreases significantly in most mutations. The decreased SCSR level is consistent with FIX deficiency in hemophilia B patients. Moreover, we find that the decrease in the SCSR level is caused by several distinct mechanisms, including interfering with cotranslational translocation into the endoplasmic reticulum, protein secretion, γ-carboxylation of the Gla domain, and cleavage of the signal peptide or propeptide. Importantly, our results also show that the SCSR levels of most signal peptide and propeptide mutations increase with vitamin K concentration, suggesting that the heterogeneity of bleeding tendencies may be related to vitamin K levels in the body. Thus, oral administration of vitamin K may alleviate the severity of bleeding tendencies in patients with missense mutations in the FIX signal peptide and propeptide regions.

Domoic acid (DA) is one of the best known marine toxins, causative of important neurotoxic alterations. DA effects are documented both in wildlife and experimental assays, showing that this toxin causes severe injuries principally in the hippocampal area. Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress are involved in DA-induced cognitive functional impairment. Therefore, therapeutics targeted to improve mitochondrial function and increase oxidative stress defence could be beneficial. Quercetin, a bioflavanoid, has been reported to have potent neuroprotective effects and anti-oxidative ability, but its preventive effects on DA-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. In this study, we evaluated the effects of quercetin on DA-induced cognitive deficits in mice and explored its potential mechanism. Our results showed that the oral administration of quercetin to DA-treated mice significantly improved their behavioural performance in a novel objective recognition task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of PPARγ coactivator 1α-mediated mitochondrial biogenesis signalling and an amelioration of mitochondrial dysfunction. Moreover, quercetin activated nuclear factorerythroid-2-related factor-2 (Nrf2)-mediated phase II enzymes and decreased reactive oxygen species and protein carbonylation. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated group. Taken together, these findings suggest that a reduction in mitochondrial dysfunction through the increase of AMPK activity, coupled with an increase in Nrf2 pathway mediated oxidative defence, may be one of the mechanisms by which quercetin improves cognitive impairment induced by DA in mice.

In the present study, we developed a highly sensitive and convenient biosensor consisting of gold nanoparticle (AuNP) probes and a gene chip to detect microRNAs (miRNAs). Specific oligonucleotides were attached to the glass surface as capture probes for the target miRNAs, which were then detected via hybridization to the AuNP probes. The signal was amplified via the reduction of HAuCl4by H2O2. The use of a single AuNP probe detected 10 pmol L-1of target miRNA. The recovery rate for miR-126 from fetal bovine serum was 81.5%–109.1%. The biosensor detection of miR-126 in total RNA extracted from lung cancer tissues was consistent with the quantitative PCR (qPCR) results. The use of two AuNP probes further improved the detection sensitivity such that even 1 fmol L-1of target miR-125a-5p was detectable. This assay takes less than 1 h to complete and the results can be observed by the naked eye. The platform simultaneously detected lung cancer related miR-126 and miR-125a-5p. Therefore, this low cost, rapid, and convenient technology could be used for ultrasensitive and robust visual miRNA detection.