Red ginseng extracts attenuate skin inflammation in atopic dermatitis through p70 ribosomal protein S6 kinase activation

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease with increased immunoglobulin E (IgE) levels. Activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling is known to occur in the inflammatory regions of AD skin. We previously demonstrated that red ginseng extract (RGE), as an anti-inflammatory agent, had potential for treating AD. However, it is still unclear whether RGE inhibits mTOR/p70S6K signaling. Thus, we examined the anti-inflammatory effects of RGE on IgE or interferon-γ (IFN-γ) induced signaling pathways. In KU812 human basophils, activation of Fcε receptor type Iα (FCεRI), also known as the high affinity IgE receptor, induced phosphorylation of both mTOR and p70S6K. Moreover, levels of phosphorylated p70S6K (p-p70S6K), but not p-mTOR, were decreased by RGE. RGE also decreased p-p70S6K levels in IFN-γ-stimulated human keratinocytes, suppressing the IFN-γ induced increase in levels of C-C chemokine ligand 2 mRNA. Interestingly, the increased p70S6K phosphorylation in skin lesions of AD model mice was attenuated by RGE treatment. In conclusion, RGE is a potential therapy against inflammatory responses involving the p70S6K signaling pathway.     

Changes in content of triterpenoids and polysaccharides in <Emphasis Type="Italic">Ganoderma lingzhi</Emphasis> at different growth stages

Ganoderma lingzhi is a traditional medicinal mushroom, and its extract contains many bioactive compounds. Triterpenoids and polysaccharides are the primary bioactive components that contribute to its medicinal properties. In this study, we quantified 18 triterpenoids, total triterpenoid content and total polysaccharide content in the ethanol and water extracts of G. lingzhi at different growth stages. Triterpenoids were quantified by liquid chromatograph–tandem mass spectrometry in the multiple-reaction-monitoring mode. Total triterpenoid and total polysaccharide content were determined by colorimetric analysis. The results indicated that the fruit bodies at an early growth stage had a higher content of ganoderic acid A, C2, I and LM2, as well as of ganoderenic acid C and D, than those at a later growth stage. In contrast, ganoderic acid K, TN and T–Q contents were higher in mature fruit bodies (maturation stage). The highest total triterpenoid and total polysaccharide contents were found in fruit bodies before maturity (stipe elongation stage or early stage of pileus formation). Our results provide information which will contribute to the establishment of an efficient cultivation system for G. lingzhi with a higher content of triterpenoids.     

The expression of the alpha1 subunit of Na+/K+-ATPase is related to tumor development and clinical outcomes in gastric cancer

Gastric Cancer - The Na+/K+-ATPase alpha1 subunit (ATP1A1) is a critical component of Na+/K+-ATPase (NKA), a membrane pump that maintains a low intracellular Na+/K+ ratio and retains cellular...     

ANO9 regulates PD-L2 expression and binding ability to PD-1 in gastric cancer

The function of ANO9 in gastrointestinal cancer remains unclear. We investigated the biological behaviors and clinical prognostic values of ANO9 in gastric cancer (GC). Knockdown experiments were performed on human GC cell lines using ANO9 siRNA. Eighty-four primary tissue samples from patients with advanced GC were examined immunohistochemically (IHC). Knockdown of ANO9 reduced the progression of cancer cells in MKN7 and MKN74 cells. A microarray analysis revealed that ANO9 regulated PD-L2 via interferon (IFN)-related genes. We confirmed using flow cytometry that the depletion of ANO9 reduced the binding ability to PD-1 by downregulating the expression of PD-L2 in MKN7 and MKN74 cells. IHC revealed a correlation between the expression of ANO9 and PD-L2 and also that the strong expression of ANO9 was an independent poor prognostic factor in patients with advanced GC. The present results indicate that ANO9 regulates PD-L2 and binding ability to PD-1 via IFN-related genes in GC. Therefore, ANO9 has potential as a biomarker and target of immune checkpoint blockage (ICB) for GC.     

Efficacy and safety of everolimus with reduced tacrolimus in living‐donor liver transplant recipients: 12‐month results of a randomized multicenter study

In a multicenter, open‐label, study, 284 living‐donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non‐inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference –0.7% (90% CI ?5.2%, 3.7%); P < .001 for non‐inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non‐inferiority (P < .001 for non‐inferiority), but not superiority and was similar between groups overall (mean ?8.0 vs. ?12.1 mL/min/1.73 m², P = .108), and in patients continuing randomized treatment (?8.0 vs. ?13.3 mL/min/1.73 m², P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria ≥1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC‐treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non‐inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432.     

Cep128 associates with Odf2 to form the subdistal appendage of the centriole

The mother centriole in a cell has two appendages, the distal appendage (DA) and subdistal appendage (SDA), which have roles in generating cilia and organizing the cellular microtubular network, respectively. In the knockout (KO) cells of Odf2, the component of the DA and SDA, both appendages simultaneously disappear. However, the molecular mechanisms by which the DA and SDA form independently but close to each other downstream of Odf2 are unknown. Here, using super‐resolution structured illumination microscopy (SR‐SIM), we found that the signal for GFP‐tagged Odf2 overlapped considerably with that of immunofluorescently labeled Cep128. We further found that Cep128 knockdown (KD) caused the dissociation of other SDA components from the centriole, including centriolin, Ndel1, ninein and Cep170, whereas Odf2 was still associated with the centriole. In contrast, the DA components remained associated with the centriole in Cep128 KD cells. Consistent with this observation, we identified Cep128 as an Odf2‐interacting protein by immunoprecipitation. Taken with the finding that Cep128 deletion decreased the stability of centriolar microtubules, our results indicate that Cep128 associates with Odf2 in the hierarchical assembly of SDA components to elicit the microtubule‐organizing function.     

Mutational patterns of hepatitis B virus genome and clinical outcomes after emergence of drug-resistant variants during lamivudine therapy: analyses of the polymerase gene and full-length sequences

It remains unclear whether mutational patterns of the hepatitis B virus (HBV) genome are associated with the development of severe hepatitis after the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) variants during lamivudine treatment. Thirty patients with chronic hepatitis B who had YMDD variants during lamivudine therapy and were followed up subsequently while receiving lamivudine alone for at least 6 months were examined retrospectively. The lamivudine resistant mutations in the HBV polymerase gene were detected by a line probe assay, and the full-length sequences of HBV DNA were determined in some patients. Between months 5 and 33 of therapy, mutations from methionine to isoleucine at rt204 (rtM204I) were detected in 18 patients, and mutations from methionine to valine at rt204 (rtM204V) were detected in 12. The rtM204V mutations were always accompanied by mutations from leucine to methionine at rt180 (rtL180M), while rtM204I mutations were not. Baseline characteristics, alanine aminotransferase (ALT) levels, and HBV DNA levels within 6 months after the emergence of YMDD variants did not differ significantly between patients with rtM204I alone and those with rtL180M/rtM204V. No specific mutation was identified on full-length sequence analysis in three patients with a hepatitis flare. During long term follow-up, the addition of rtL180M to rtM204I was found in four patients 7-31 months after detecting the change at rt204 and was linked to increased ALT levels. In conclusion, mutational patterns of HBV DNA at the time of emergence of YMDD variants were apparently unrelated to the clinical outcomes in Japanese patients with chronic hepatitis B during lamivudine therapy.