Dietary cobalt oxide nanoparticles alleviate aging through activation of mitochondrial UPR in Caenorhabditis elegans.

Mitochondrial unfolded protein response (UPRmt), which is a mitochondrial proteostasis pathway, orchestrates an adaptive reprogramming for metabolism homeostasis and organismal longevity. Similar to other defense systems, compromised UPRmt is a feature of several age-related diseases. Here we report that dimercapto succinic acid (DMSA)-modified cobalt oxide nanoparticles (Co3O4 NPs), which have received wide-spread attention in biomedical fields, is a promising UPRmt activator and, more importantly, provides a gate for extending healthy lifespan. Methods: UPRmt activation by Co3O4 NPs was tested in transgenetic Caenorhabditis elegans (C. elegans) specifically expressing UPRmt reporter Phsp-6::GFP, and the underlying mechanism was further validated by mitochondrial morphology, mtDNA/nDNA, metabolism-related genes' expression, mitonuclear protein imbalance, oyxgen assumption and ATP level in C. elegans. Then therapeutic response aganist senescence was monitored by lifespan analysis, lipofusin contents, MDA contents, Fe accumulation, pharyngeal locomotion performance as well as athletic ability (head thrashes and body bends) at different developmental stages of C. elegans. RNAi towards ubl-5 or atfs-1 in UPRmt pathway was applied to clarify the role of UPRmt in Co3O4 NPs -mediated anti-aging effects. Finally, the effect of Co3O4 NPs on mitochondrial homeostasis and D-galactose-induced cell viability decline in mammalian cells were studied. Results: Co3O4 NPs was revealed as a bona fide activator of the UPRmt signaling pathway, through fine-tuning mitochondrial dynamics and inducing a stoichiometric imbalance between OXPHOS subunits encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) at early life stage of C. elegans. Phenotypically, Co3O4 NPs treatment protect C. elegans from external stresses. More importantly, dietary low level of Co3O4 NPs effectively extend lifespan and alleviate aging-related physiological and functional decline of worms, demonstrating its potential roles in delaying aging. While the protective effect exerted by Co3O4 NPs was compromised in line with atfs-1 or ubl-5 RNAi treatment. Further studies verified the conservation of Co3O4 NPs in activating UPRmt and exerting protective effects in mammalian cells. Conclusions: The results reveal beneficial effects of Co3O4 NPs on mitochondrial metabolic control, thus presenting their potential efficacy in anti-aging care.

Nanoparticulates reduce tumor cell migration through affinity interactions with extracellular migrasomes and retraction fibers.

Nano-tumor interactions are fundamental for cancer nanotherapy, and the cross-talk of nanomedicines with the extracellular matrix (ECM) is increasingly considered essential. Here, we specifically investigate the nano-ECM interactivity using drug-free nanoparticulates (NPs) and highly metastatic cancer cells as models. We discover with surprise that NPs closely bind to specific types of ECM components, namely, retraction fibers (RFs) and migrasomes, which are located at the rear of tumor cells during their migration. This interaction is observed to alter cell morphology, limit cell motion range and change cell adhesion. Importantly, NPs are demonstrated to inhibit tumor cell removal in vitro, and their anti-metastasis potential is preliminarily confirmed in vivo. Mechanically, the NPs are found to coat and form a rigid shell on the surface of migrasomes and retraction fibers via interaction with lipid raft/caveolae substructures. In this way, NPs block the recognition, endocytosis and elimination of migrasomes by their surrounding tumor cells. Thereby, NPs interfere with the cell-ECM interaction and reduce the promotion effect of migrasomes on cell movement. Additionally, NPs trigger alteration of the expression of proteins related to cell-cell adhesion and cytoskeleton organization, which also restricts cell migration. In summary, all the findings here provide a potential target for anti-tumor metastasis nanomedicines.

Selenium Nanoparticles as an Efficient Nanomedicine for the Therapy of Huntington's Disease.

Huntington's disease (HD) is an incurable disease with progressive loss of neural function, which is influenced by epigenetic, oxidative stress, metabolic, and nutritional factors. Targeting inhibition of huntingtin protein aggregation is a strategy for HD therapy, but the efficacy is unsatisfactory. Studies found that selenium (Se) levels in the brain are insufficient for HD disease individuals, while improvement in Se homeostasis in the brain may attenuate neuronal loss and dysfunction. In this study, we applied selenium nanoparticles (NPs) (Nano-Se) for the HD disease therapy by regulating HD-related neurodegeneration and cognitive decline based on transgenic HD models of Caenorhabditis elegans (C. elegans). At low dosages, Nano-Se NPs significantly reduced neuronal death, relieved behavioral dysfunction, and protected C. elegans from damages in stress conditions. The molecular mechanism further revealed that Nano-Se attenuated oxidative stress, inhibited the aggregation of huntingtin proteins, and downregulated the expression of histone deacetylase family members at mRNA levels. The results suggested that Nano-Se has great potential for Huntington's disease therapy. In conclusion, the mechanism about how Nano-Se NPs protect from damages in stress conditions and how they repair neural functions will benefit HD disease therapy. This study will also guide rational design of Nano-Se NPs or other selenium compounds to improve HD therapy in the future.

Small GTPases: Structure, biological function and its interaction with nanoparticles.

Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells. It plays an important role in cytoskeletal reorganization, cell polarity, cell cycle progression, gene expression and many other significant events in cells, such as the interaction with foreign particles. Therefore, it is of great scientific significance to understand the biological properties of small GTPases as well as the GTPase-nano interplay, since more and more nanomedicine are supposed to be used in biomedical field. However, there is no review in this aspect. This review summarizes the small GTPases in terms of the structure, biological function and its interaction with nanoparticles. We briefly introduced the various nanoparticles such as gold/silver nanoparticles, SWCNT, polymeric micelles and other nano delivery systems that interacted with different GTPases. These current nanoparticles exhibited different pharmacological effect modes and various target design concepts in the small GTPases study. This will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research direction. It is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines.

Simple, Selective and Sensitive Determination of CH3Hg⁺ Using Gold Nanocluster.

Mercury is a potent neurotoxin, which causes serious and permanent damage to biota including human beings. Nanomaterials like gold have been used to detect mercury, especially the mercuric ions in recent years, but few have been done on the determination of methylmercury (CH3Hg⁺). In this study, we present a simple, selective and sensitive method for the determination of CH3Hg⁺ co-existing with Hg²âº based on the fluorescence quenching of bovine serum albumin (BSA) stabilized gold nanoclusters (BSA-Au NCs). It was found that the fluorescence quenching of BSA-Au NCs by Hg²âº is stronger than CH3Hg⁺ at the same concentration. Hg²âº can be masked by EDTA while CH3Hg⁺ is less affected. Therefore, the determination of CH3Hg⁺ was achieved through EDTA masking. The detection limit for CH3Hg⁺ is 35 nmol/L after masking Hg²âº with EDTA. This method has been successfully applied to quantify CH3Hg⁺ in rice paddy water from Qingzhen, Guizhou and tap water from Beijing.

Evaluation of the influence of fullerenol on aging and stress resistance using Caenorhabditis elegans.

Fullerene derivatives have attracted extensive attention in biomedical fields and polyhydroxyl fullerene (fullerenol), a water-soluble fullerene derivative, is demonstrated as a powerful antioxidant. To further assess their anti-aging and anti-stress potential, we employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the effects of fullerenol on the growth, development, behavior and anti-stress ability in vivo. The data show that fullerenol has no obviously toxic effect on nematodes and can delay C. elegans aging progress under normal condition. Further studies demonstrate that fullerenol attenuates endogenous levels of reactive oxygen species and provides protection to C. elegans under stress conditions by up-regulating stress-related genes in a DAF-16 depend manner and improving lifespan. In summary, our data suggest that fullerenol might be a safe and reasonable anti-aging candidate with great potential in vivo.

Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity.

Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere(®)) and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, these results expound the antitumor efficacy and the potential working mechanisms of DSNs in its anticancer activity and toxicity, which provide a theoretical foundation to develop and apply a more efficient docetaxel formulation to treat cancer patients.

WS2 nanosheet as a new photosensitizer carrier for combined photodynamic and photothermal therapy of cancer cells.

We have developed a simple and efficient strategy to fabricate WS2 nanosheets with low toxicity and good water solubility via a liquid exfoliation method by using H2SO4 intercalation and ultrasonication. The as-prepared WS2 nanosheets were employed not only as an NIR absorbing agent for photothermal therapy (PTT) but also as a photosensitizer (PS) carrier for photodynamic therapy (PDT) due to their sheet like structure that offers large surface area to load PS molecules. Moreover, singlet-oxygen generation of the PSs-WS2 complex could be finely controlled by NIR irradiation that could manipulate the PSs release behavior from WS2 nanosheets. The synergistic anti-tumor effect of WS2 nanosheets mediated PDT-PTT was also evaluated carefully and the results clearly showed that the efficacy of combined PDT-PTT treatment of cancer cells is significantly higher than those of PDT-only and PTT-only treatment, indicating enhanced efficiency of the combined therapeutic system. In addition, the WS2 could be used as a computed tomography (CT) contrast agent for bio-imaging since W atoms have strong X-ray attenuation ability, making them a multifunctional theranostic platform for simultaneous imaging-guided diagnosis and therapy.

The influence on cell cycle and cell division by various cadmium-containing quantum dots.

Quantum dots (QDs) have attracted great attention because of their favorable optical properties and have been widely applied in biomedical fields. However, in recent years, there have been an increasing number of reports about the cytotoxicity of QDs, especially cadmium-containing QDs, which may release cadmium ions to induce cytotoxicity. Importantly, the chemical composition and surface modifications of cadmium-based QDs determine the amount of Cd(2+) released inside the cell. Thus, there is an urgent need for more systematic work to study the relationship between cytotoxicity and the surface properties of QDs. In this article, the cytotoxicity of seven cadmium-containing QDs with different constituent elements and surface chemistries are compared. The results show that the cytotoxicity of QDs is closely related to their constituent elements and surface properties: First, CdTe@ZnS core-shell QDs show much lower cytotoxicity than naked ones when they have similar surface modifications; second, the positively charged QDs are more toxic than the negatively charged ones. Moreover, both positively and negatively charged QDs without ZnS coatings lead to multipolar spindles, misaligned chromosomes, and G2/M checkpoint failures. Interestingly, although CdSe QDs with a PEG coating cause no apparent cytotoxicity in any of the cell lines studied, they can localize near the contractile ring during cytokinesis and then block contractile ring disassembly. The cellular effect of CdTe QDs comes not only from the release of cadmium ions but also the intracellular distribution of QD nanoparticles in cells and the associated nanoscale effects. It is also found that QD-caused cytokinesis failure is closely related to the decreased expression of Cyclin A and Cyclin B. Taken together, the above findings provide new insight into the dynamic fate of QDs during cell mitosis, and are important for understanding the intracellular effects of QDs on the mitotic spindle and chromosomes during cell division. Furthermore, this kind of cytotoxicity evaluation method should be applicable to studies of the biological effects and health impacts of other nanomaterials.