Photosensitizer-Polypeptide Conjugate with Synergistic Antibacterial Efficacy.

Recently, continuous emergence of resistant bacteria has appeared as one of the most serious threats to human health. Therefore, systematic exploration of new antibacterial materials is of guiding significance. In this study, a series of photosensitizer-polypeptide conjugate (PPa-cP) is readily synthesized through simple ring-opening reactions to realize the synergistic antibacterial effects on Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) under light irradiation. Compared with free PPa, the cationic PPa-cP shows enhanced binding ability with the negative surface of S. aureus through electrostatic interaction, exhibiting effective antibacterial activity against both S. aureus and MRSA in vitro under light irradiation. Among the synthesized PPa-cP, PPa-cP5 with the degree of polymerization of 37 and modified with a 1-methylimidazole side group exhibits the best antibacterial activity with a minimum inhibitory concentration value of 2 µm without light irradiation and 0.25 µm with light irradiation. Moreover, PPa-cP5 shows good hemocompatibility. The above-mentioned results elucidate that the positively charged PPa-cP5 can significantly increase the efficiency of photodynamic therapy and effectively eradicate S. aureus biofilm due to its potent penetration ability into S. aureus biofilms. Overall, the present study establishes an efficient strategy for the treatment of S. aureus and S. aureus biofilm infections.

Downregulation of miR­141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway.

The activation of hepatic stellate cells (HSCs) caused by stimulating factors or fibrogenic cytokines is the critical stage of liver fibrosis. Recent studies have demonstrated the influence of microRNAs (miRNAs or miRs) on HSC activation and transformation; however, the function and underlying mechanisms of miRNAs in HSC activation have not yet been completely clarified. In the present study, transforming growth factor ß1 (TGF­ß1) was used to treat human HSC lines (HSC­T6 and LX2 cells) to simulate the activation of HSCs in vivo and whether the expression of miRNAs in HSCs was affected by TGF­ß1 treatment was examined using a miRNA microarray. It was observed that miR­141 was one of the most upregulated miRNAs during HSC activation. Functional analyses revealed that miR­141 knockdown suppressed the viability of HSCs and inhibited the expression levels of pro­fibrotic markers. In addition, phosphatase and tensin homolog (PTEN), a well­known suppressor of the AKT/mammalian target of rapamycin (mTOR) pathway, was found to be directly targeted by miR­141 in HSCs. More importantly, the knockdown of PTEN markedly reversed the suppressive effects of miR­141 inhibition on the viability of and the expression levels of pro­fibrotic markers during HSC activation. Finally, it was observed that the downregulation of miR­141 blocked the TGF­ß1­induced activation of the AKT/mTOR pathway in HSCs. On the whole, the findings of the present study indicate that miR­141 inhibition suppresses HSC activation via the AKT/mTOR pathway by targeting PTEN, highlighting that miR­141 may serve as a novel therapeutic target for liver fibrosis.

Interleukin-35 Modulates the Imbalance Between Regulatory T Cells and T Helper 17 Cells in Enterovirus 71-Induced Hand, Foot, and Mouth Disease.

Interleukin (IL)-35 modulates the imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, which played vital roles in the pathogenesis of autoimmune and infectious diseases. However, the role of Tregs/Th17 cell imbalance and the regulatory functions of IL-35 have remained largely unknown in enterovirus 71 (EV71)-induced hand, foot, and mouth disease (HFMD). In this study, a total of 47 HFMD patients (30 with mild HFMD and 17 with severe HFMD) and 13 healthy individuals were enrolled. The frequencies of CD4+CD25+CD127dim/- Tregs and CD4+IL-17+ Th17 cells, as well as IL-35 expression levels, were measured. Cellular proliferation and cytokine production was also determined in purified Tregs following recombinant IL-35 stimulation. An imbalance between Tregs and Th17 cells was observed in children with severe HFMD, which manifested as a reduction in the Tregs population and an elevation in the Th17 population. Serum IL-35 concentrations were also decreased in case of severe HFMD, which correlated with the Tregs:Th17 cell ratios. Recombinant IL-35 stimulation increased the proportion of Tregs, but downregulated that of Th17 cells. Treatment with IL-35 enhanced Tregs suppressive function and IL-35 and IL-10 expression, but reduced IL-22 secretion in both healthy individuals and those with severe HFMD. The Tregs:Th17 cell ratio was increased in the convalescent patients, however, a significant reduction in serum IL-35 was not observed. Our findings indicated that EV71 infection shifted the Tregs:Th17 cell ratio through IL-35 by downregulating inhibitory cytokine production and reducing the cell-to-cell contact inhibition of effector T cells. Regulation of IL-35 as it relates to the Tregs/Th17 balance may play a critical role in the pathogenesis of EV71-associated HFMD.

Discovery and mechanism of action of Novel Baicalein modified derivatives as potent antihepatitis agent.

Anti-hepatitis B virus (HBV) activity was evaluated in HepG2 2.2.15 cells by novel Baicalein derivatives. The result showed that compounds 4k and 4h was found to be effective anti-HBV agent. Further, the effect of compounds 4k and 4h showed dose-dependent inhibition of HBV-DNA as compared to control together with significant inhibition of HbeAG and HbsAG expression in the tested dose. Both compounds showed considerable affinity against the HepG2.2.15 cells. Moreover, the docking study of compound 4k was carried out with HLA molecule showing excellent intermolecular interactions with the receptor via creation of numerous bonds with Ser5, Thr27, Asp29 and Phe8. The compound 4k showed significant effect on the HO-1 expression in HepG2.2.15 cells together with excellent anti-HBV activity in transgenic mouse confirmed by biochemical and histopathological parameters. Compound 4k also showed excellent pharmacokinetic profile in experimental animal and thus, provide a novel class of potent anti-HBV agents.

Expression of serum exosomal microRNA-21 in human hepatocellular carcinoma.

New strategies for the diagnosis of hepatocellular carcinoma (HCC) are urgently needed. There is an increasing interest in using microRNAs (miRNAs) as biomarkers in diseases. In this study, we examined the expression of miR-21 in serum exosomes from patients with HCC or chronic hepatitis B (CHB) and investigated the potential clinical significance of miR-21. Quantitative RT-PCR indicated that the concentration of miR-21 was significantly higher in exosomes than in exosome-depleted supernatants or the whole serum. Further, the expression level of serum exosomal miR-21 was significantly higher in patients with HCC than those with CHB or healthy volunteers (P < 0.0001, P < 0.0001, resp.). High level of miR-21 expression correlated with cirrhosis (P = 0.024) and advanced tumor stage (P = 0.001). Although serum level of miR-21 was higher in patients with HCC than in patients with CHB and healthy volunteers, the sensitivity of detection is much lower than using exosomal miR-21. These findings indicate that miR-21 is enriched in serum exosomes which provides increased sensitivity of detection than whole serum. Exosomal miR-21 may serve as a potential biomarker for HCC diagnosis.