Search

Because of their unique properties, antimicrobial peptides (AMPs) represent a potential reservoir of novel anticancer therapeutic agents. However, only a few AMPs can kill tumors with high efficiency, and obtaining inexpensive anticancer AMPs with strong activity is still a challenge. In our previous work, a series of original short amphiphilic triblock AMP (KnFmKn) analogues were developed which were demonstrated to exert excellent effects on bacterial infection, both in vitro and in vivo. Herein, the overall objectives were to assess the potent tumoricidal capacities of these analogues against human lung cancer cell line A549 and the underlying mechanism. The results of the CCK-8 assay revealed that the precise modification of the peptides' primary sequences could modulate their tumoricidal potency. In the tumoricidal progress, positive charge and hydrophobicity were the key driving forces. Among these peptides, K4F6K4 displayed the most remarkable tumoricidal activity. Furthermore, the excellent anticancer capacity of K4F6K4 was proven by the live/dead cell staining, colony formation assay, and tumor growth observations on xenografted mice, which indicated that K4F6K4 might be a promising drug candidate for lung cancer, with no significant adverse effects in vitro or in vivo. In addition, the cell apoptosis assay using flow cytometry, the morphology observations using the optical microscope, confocal microscopy using CellMask™ Deep Red staining, and scanning electron microscope suggested that membrane disruption was the primary mechanism of its antitumor action. Through analyzing the structure–activity relationship, it was found that the amount of positive charge required for KnFmKn to exert its optimal tumoricidal effect was more than that needed for the antimicrobial activity, while the optimal proportion of hydrophobicity was less. Our findings suggest that further analysis of the structure–activity relationship of AMPs' primary sequence variations will be beneficial. Hopefully, this work can provide guiding principles in designing peptide-based therapeutics for lung cancer. [ABSTRACT FROM AUTHOR]

Chiral recognition of DNA molecules is important because much evidence has indicated that transformations of chirality and diverse conformations of DNA are involved in a series of key biological events. Among these, enrichment of G-quadruplexes (GQs) in the genome, and the exploration of their multiple structures, has aroused great interest. Herein, we compared nearly 100 different sequences with 3′-tail sequences of variable length or different linkers or diverse loops and mutative ionic concentrations. All sequences were capable of forming stable GQs, with fluorescence signal enhancement upon binding with Δ- and Λ- [Ru(bpy)2(dppz-idzo)]2+ (Δ/Λ-1). Our results show that multiple factors, including the 3′-tail length, linkers, loop length and ionic concentration, regulate the enantioselectivity of GQs. Furthermore, molecular docking simulations revealed that chiral recognition of GQs depends on the binding site. To the best of our knowledge, this is the first systematic study regarding the regulation of multi-factors for GQ selectivity of chiral Ru-complexes. These results will serve as a useful reference for enantioselective recognition of genomic GQs and may facilitate the development of chiral anticancer agents for targeting GQs. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative joint disease involving cartilage. Exosomes derived from Mesenchymal stem cells (MSCs) therapy improves articular cartilage repair, but subcutaneous fat (SC) stromal cells derived exosomes (MSCsSC-Exos), especially engineering MSCsSC-Exos for drug delivery have been rarely reported in OA therapy. This objective of this study was to clarify the underlying mechanism of MSCsSC-Exos on cartilage repair and therapy of engineering MSCsSC-Exos for drug delivery in OA. MSCsSC-Exos could ameliorate the pathological severity degree of cartilage via miR-199a-3p, a novel molecular highly enriched in MSCsSC-Exos, which could mediate the mTOR-autophagy pathway in OA rat model. Intra-articular injection of antagomiR-199a-3p dramatically attenuated the protective effect of MSCsSC-Exos-mediated on articular cartilage in vivo. Furthermore, to achieve the superior therapeutic effects of MSCsSC-Exos on injured cartilage, engineering exosomes derived from MSCsSC as the chondrocyte-targeting miR-199a-3p delivery vehicles were investigated in vitro and in vivo. The chondrocyte-binding peptide (CAP) binding MSCsSC-Exos could particularly deliver miR-199a-3p into the chondrocytes in vitro and into deep articular tissues in vivo, then exert the excellent protective effect on injured cartilage in DMM-induced OA mice. As it is feasible to obtain human subcutaneous fat from healthy donors by liposuction operation in clinic, meanwhile engineering MSCsSC-Exos to realize targeted delivery of miR-199a-3p into chondrocytes exerted excellent therapeutic effects in OA animal model in vivo. Through combining MSCsSC-Exos therapy and miRNA therapy via an engineering approach, we develop an efficient MSCsSC-Exos-based strategy for OA therapy and promote the application of targeted-MSCsSC-Exos for drug delivery in the future. [ABSTRACT FROM AUTHOR]

Stem cells possess great potential for tissue regeneration due to their infrequent capability to differentiate into specialized some other cell lines. The progress of nanomaterials has been remarkable in recent years. Nanomaterials control cellular response by endocytosis, acting as scaffolding roles or nanocarriers and regulating extracellular matrix (ECM). Furthermore, some nanomaterials have outstanding optical and magnetic properties, so can be used for stem cells labeling and imaging which plays an essential role in defining the mechanisms governing stem-cells therapeutics. In this review, focus is put on recent developments in controlling the fate of stem cells and stem cells labeling and imaging by nanomaterials. The effect of nanomaterials based inorganic nanomaterials (e.g., carbon nanotubes, mesoporous silica nanoparticles, gold nanoparticles, etc.), organic materials (nanoscale topography), on the differentiation of mesenchymal stem cells, embryonic stem cells and cancer stem cells will be discussed. Optical imaging (fluorescence and up-conversion luminescence), magnetic resonance imaging and multimodal imaging by nanomaterials of stem cells will also be introduced. [ABSTRACT FROM AUTHOR]

Abstract: Microbe-assisted phytoremediation has been considered as a promising measure for the remediation of heavy metal-polluted soils. In this study, a metal-tolerance and plant growth-promoting endophytic bacterium JN6 was firstly isolated from roots of Mn-hyperaccumulator Polygonum pubescens grown in metal-contaminated soil and identified as Rahnella sp. based on 16S rDNA gene sequence analysis. Strain JN6 showed very high Cd, Pb and Zn tolerance and effectively solubilized CdCO3, PbCO3 and Zn3(PO4)2 in culture solution. The isolate produced plant growth-promoting substances such as indole-3-acetic acid, siderophore, 1-aminocyclopropane-1-carboxylic deaminase, and also solubilized inorganic phosphate. Based upon its ability in metal tolerance and solubilization, the isolate JN6 was further studied for its effects on the growth and accumulation of Cd, Pb and Zn in Brassica napus (rape) by pot experiments. Rape plants inoculated with the isolate JN6 had significantly higher dry weights, concentrations and uptake of Cd, Pb and Zn in both above-ground and root tissues than those without inoculation grown in soils amended with Cd (25mgkg−1), Pb (200mgkg−1) or Zn (200mgkg−1). The isolate also showed a high level of colonization in tissue interior of rapes. The present results demonstrated that Rahnella sp. JN6 is a valuable microorganism, which can cost-effectively improve the efficiency of phytoremediation in soils contaminated by Cd, Pb and Zn. [Copyright &y& Elsevier]

Background/Aims: Alternative splicing and DNA damage exhibit cross-regulation, with not only DNA damage inducing changes in alternative splicing, but alternative splicing itself possibly modulating the DNA damage response (DDR). Sirt1, a prominent anti-aging player, plays pivotal roles in the DDR. However, few studies have examined alternative splicing with DNA damage in neural stem cells (NSCs) and, in essence, nothing is known about whether SIRT1 regulates alternative splicing. Hence, we investigated the potential involvement of Sirt1-mediated alternative splicing in the NSC DDR. Methods: Genome-wide alternative splicing profiling was performed upon DNA damage induction and SIRT1 deletion. Results: DNA damage caused genome-wide changes in alternative splicing in adult NSCs and Sirt1 deficiency dramatically altered DDR-related alternative splicing. In particular, extensive alternative splicing changes in DDR-related processes such as cell cycle control and DNA damage repair were observed; these processes were dramatically influenced by Sirt1 deficiency. Phenotypically, Sirt1 deficiency altered the proliferation and DNA repair of adult NSCs, possibly by regulating alternative splicing. Conclusion: SIRT1 helps to regulate alternative splicing, which itself affects the DDR of NSCs. Our findings provide novel insight into the mechanisms underlying the DDR in stem cells. [ABSTRACT FROM AUTHOR]

• The ADSCs treatment repaired the articular cartilage and maintained chondrocytes ECM homeostasis through modulating chondrocytes autophagy in OA. • This is the first report that ADSCs promoted cartilage repair through inhibiting the expression of miR-7-5p in OA. • ATG4A was defined as a target gene of miR-7-5p. • The ADSCs treatment repaired the articular cartilage through the mTORC1 signaling pathways in OA. Osteoarthritis (OA) is a highly degenerative joint disease, mainly companying with progressive destruction of articular cartilage. Adipose-derived stromal cells (ADSCs) therapy enhances articular cartilage repair, extracellular matrix (ECM) synthesis and attenuates joints inflammation, but specific mechanisms of therapeutic benefit remain poorly understood. This study aimed to clarify the therapeutic effects and mechanisms of ADSCs on cartilage damage in the keen joint of OA rat model. Destabilization of the medial meniscus (DMM) and anterior cruciate ligament transection (ACLT) surgery-induced OA rats were treated with allogeneic ADSCs by intra-articular injections for 6 weeks. The protective effect of ADSCs in vivo was measured using Safranin O and fast green staining, immunofluorescence and western blot analysis. Meanwhile, the miRNA-7-5p (miR-7-5p) expression was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The mechanism of increased autophagy with ADSCs addition through decreasing miR-7-5p was revealed using oligonucleotides, and adenovirus in rat chondrocytes. The luciferase reporter assay revealed the molecular role of miR-7-5p and autophagy related 4A (ATG4A). The substrate of mTORC1 pathway: (p-)p70S6 and (p-)S6 in OA models with ADSCs addition were detected by western blotting. The ADSCs treatment repaired the articular cartilage and maintained chondrocytes ECM homeostasis through modulating chondrocytes autophagy in the OA model, indicators of the change of autophagic proteins expression and autophagic flux. Meanwhile, the increased autophagy induced by ADSCs treatment was closely related to the decreased expression of host-derived miR-7-5p, a negative modulator of OA progression. Functional genomics (overexpression of genes) in vitro studies demonstrate the inhibition of host-derived miR-7-5p in mediating the benefit of ADSCs administration in OA model. Then ATG4A was defined as a target gene of miR-7-5p, and the negative relation between miR-7-5p and ATG4A was investigated in the OA model treated with ADSCs. Furthermore, miR-7-5p mediated chondrocyte autophagy by targeting ATG4A in the OA model treated with ADSCs was confirmed with the rescue trial of ATG4A/miR-7-5p overexpression on rat chondrocyte. Finally, the mTORC1 signaling pathways mediated by host-derived miR-7-5p with ADSCs treatment were decreased in OA rats. ADSCs promote the chondrocytes autophagy by decreasing miR-7-5p in articular cartilage by targeting ATG4A and a potential role for ADSCs based therapeutics for preventing of articular cartilage destruction and extracellular matrix (ECM) degradation in OA. [ABSTRACT FROM AUTHOR]

Tau aggregation correlates rigorously with the progression and severity of Alzheimer's disease (AD). However, it is extremely challenging to develop tau-selective imaging probes due to similar β-sheet structures shared with Aβ fibrils. Herein, three new donor-π-acceptor fluorophores (T1 - T3) composed of 3,5-dimethoxy-N,N-dimethylaniline-4-yl and quinoxaline, bridged by 1–3 C C bond are rationally designed for selectively imaging tau aggregates. For the first time, we demonstrated the side substitution on D-π-A skeleton is significant for improving the selectivity of tau probes. Molecular docking results revealed that the lateral methoxy groups on molecular rotors could act as antennas to interact with surrounding tau hydrophilic residues via hydrogen-bond and other kinds of intermolecular interactions, improving selective recognition for tau aggregates. Compared with its non-side-substitution precursor T02 , T2 exhibited 4.7 times higher tau-over-Aβ selectivity after introducing methoxy substituents. Owing to the improved selectivity, T2 was successfully applied to detect tau aggregates in cells and pathologically relevant regions of AD mice model. This work verifies the pivotal role of side substitution on D-π-A skeleton in increasing the selectivity of tau probes, which provides a rational strategy to design novel tau probes with high selectivity in future. • An innovative strategy to improve selective imaging of tau aggregates was suggested. • Three new compounds T1-T3 synthesized and characterized accordingly. • Introducing lateral substituents improved tau-over-Aβ selectivity (4.7 times). • Probe T2 performed well in intracellular tau aggregates imaging and tissue staining. • The pivotal role of lateral substituents was revealed by molecular docking. [ABSTRACT FROM AUTHOR]

Aging of neural stem cell, which can affect brain homeostasis, may be caused by many cellular mechanisms. Autophagy dysfunction was found in aged and neurodegenerative brains. However, little is known about the relationship between autophagy and human neural stem cell (hNSC) aging. The present study used 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to treat neural precursor cells (NPCs) derived from human embryonic stem cell (hESC) line H9 and investigate related molecular mechanisms involved in this process. MPTP-treated NPCs were found to undergo premature senescence [determined by increased senescence-associated-β-galactosidase (SA-β-gal) activity, elevated intracellular reactive oxygen species level, and decreased proliferation] and were associated with impaired autophagy. Additionally, the cellular senescence phenotypes were manifested at the molecular level by a significant increase in p21 and p53 expression, a decrease in SOD2 expression, and a decrease in expression of some key autophagy-related genes such as Atg5, Atg7, Atg12, and Beclin 1. Furthermore, we found that the senescence-like phenotype of MPTP-treated hNPCs was rejuvenated through treatment with a well-known autophagy enhancer rapamycin, which was blocked by suppression of essential autophagy gene Beclin 1. Taken together, these findings reveal the critical role of autophagy in the process of hNSC aging, and this process can be reversed by activating autophagy. [ABSTRACT FROM AUTHOR]

Microbe-enhanced phytoremediation has been considered as a promising measure for the remediation of metal-contaminated soils. In this study, two bacterial strains JYX7 and JYX10 were isolated from rhizosphere soils ofPolygonum pubescensgrown in metal-polluted soil and identified as ofEnterobactersp. andKlebsiellasp. based on 16S rDNA sequences, respectively. JYX7 and JYX10 showed high Cd, Pb and Zn tolerance and increased water-soluble Cd, Pb and Zn concentrations in culture solution and metal-added soils. Two isolates produced plant growth-promoting substances such as indole acetic acid, siderophore, 1-aminocyclopropane-1-carboxylic deaminase, and solubilized inorganic phosphate. Based upon their ability in metal tolerance and solubilization, two isolates were further studied for their effects on growth and accumulation of Cd, Pb, and Zn inBrassica napus(rape) by pot experiments. Rapes inoculated with JYX7 and JYX10 had significantly higher dry weights, concentrations and uptakes of Cd, Pb, Zn in both above-ground and root tissues than those without inoculation grown in soils amended with Cd (25 mg kg−1), Pb (200 mg kg−1) or Zn (200 mg kg−1). The present results demonstrated that JYX7 and JYX10 are valuable microorganism, which can improve the efficiency of phytoremediation in soils polluted by Cd, Pb, and Zn. [ABSTRACT FROM PUBLISHER]

Abstract: Inspired by the enormous importance attributed to the structure and function of human telomeric DNA, we focus our attention on the interaction of [Ru(bpy)2(dppz)]2+ with the guanine-rich single-strand oligomer 5′-AGGGTTAGGGTTAGGGTTAGGG-3′ (22AG) and the complementary cytosine-rich strand (22CT). In Na+ buffer, 22AG may adopt an antiparallel basket quadruplex, whereas, it favours a mixed parallel/antiparallel structure in K+ buffer. 22CT may self-associate at acidic pH into an i-motif. In this paper, the interaction between [Ru(bpy)2(dppz)]2+ and each unusual DNA was evaluated. It was interesting that [Ru(bpy)2(dppz)]2+ could promote the human telomeric repeat 22AG to fold into intramolecular antiparallel G-quadruplex without any other cations. What''s more, [Ru(bpy)2(dppz)]2+ was found to have a strong preference for binding to G-quadruplexes that were induced through either Na+ or K+, while weak binding to i-motif was observed. The results also indicated that [Ru(bpy)2(dppz)]2+ could serve as a prominent molecular “light switch” for both G-quadruplexes, revealing a potential application of the title complex in luminescent signaling of G-quadruplex DNA. [Copyright &y& Elsevier]