Golgi apparatus (GA) oxidative stress induced by in situ reactive oxygen species (ROS) could severely damage the morphology and function of GA, which may open up an avenue for effective photodynamic ...therapy (PDT). However, due to the lack of effective design strategy, photosensitizers (PSs) with specific GA targeting ability are in high demand and yet quite challenging. Herein, we report an aggregation-induced emission luminogen (AIEgen) based PS (TPE-PyT-CPS) that can effectively target the GA via caveolin/raft mediated endocytosis with a Pearson correlation coefficient up to 0.98. Additionally, the introduction of pyrene into TPE-PyT-CPS can reduce the energy gap between the lowest singlet state (S
) and the lowest triplet state (T
) (ΔE
) and exhibits enhanced singlet oxygen generation capability. GA fragmentation and cleavage of GA proteins (p115/GM130) are observed upon light irradiation. Meanwhile, the apoptotic pathway is activated through a crosstalk between GA oxidative stress and mitochondria in HeLa cells. More importantly, GA targeting TPE-T-CPS show better PDT effect than its non-GA-targeting counterpart TPE-PyT-PS, even though they possess very close ROS generation rate. This work provides a strategy for the development of PSs with specific GA targeting ability, which is of great importance for precise and effective PDT.
Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species to kill cancer cells. However, a high concentration of glutathione (GSH) is present in cancer ...cells and can consume reactive oxygen species. To address this problem, we report the development of a photosensitizer–MnO2 nanosystem for highly efficient PDT. In our design, MnO2 nanosheets adsorb photosensitizer chlorin e6 (Ce6), protect it from self‐destruction upon light irradiation, and efficiently deliver it into cells. The nanosystem also inhibits extracellular singlet oxygen generation by Ce6, leading to fewer side effects. Once endocytosed, the MnO2 nanosheets are reduced by intracellular GSH. As a result, the nanosystem is disintegrated, simultaneously releasing Ce6 and decreasing the level of GSH for highly efficient PDT. Moreover, fluorescence recovery, accompanied by the dissolution of MnO2 nanosheets, can provide a fluorescence signal for monitoring the efficacy of delivery.
A photosensitizer–MnO2 nanosystem has been designed for highly efficient photodynamic therapy. The nanosystem can react with intracellular glutathione (GSH), decreasing the level of GSH, releasing the photosensitizer completely, and thus improving the therapeutic efficiency.
DNAzymes hold promise for gene‐silencing therapy, but the lack of sufficient cofactors in the cell cytoplasm, poor membrane permeability, and poor biostability have limited the use of DNAzymes in ...therapeutics. We report a DNAzyme–MnO2 nanosystem for gene‐silencing therapy. MnO2 nanosheets adsorb chlorin e6‐labelled DNAzymes (Ce6), protect them from enzymatic digestion, and efficiently deliver them into cells. The nanosystem can also inhibit 1O2 generation by Ce6 in the circulatory system. In the presence of intracellular glutathione (GSH), MnO2 is reduced to Mn2+ ions, which serve as cofactors of 10–23 DNAzyme for gene silencing. The release of Ce6 generates 1O2 for more efficient photodynamic therapy. The Mn2+ ions also enhance magnetic resonance contrast, providing GSH‐activated magnetic resonance imaging (MRI) of tumor cells. The integration of fluorescence recovery and MRI activation provides fluorescence/MRI bimodality for monitoring the delivery of DNAzymes.
Multitasking: A smart carrier for DNAzymes has been developed in which MnO2 nanosheets are able to enhance cellular uptake of DNAzymes, protect them from endogenous nuclease digestion, and self‐generate in situ cofactors (Mn2+ ions) in the cell cytoplasm to maintain the catalytic activity of 10–23 DNAzyme for RNA cleavage and gene silencing. Ce6–DNAzyme=chlorin e6‐labelled DNAzyme.
DNAzymes, generated through in vitro selection processes, are single-stranded DNA catalysts that can catalyze a wide variety of reactions, such as RNA or DNA cleavage and ligation or DNA ...phosphorylation. Based on specific cofactor dependence and potent catalytic ability, DNAzymes have been extensively used to develop highly sensitive and specific sensing platforms for metal ions, small molecules, and biomacromolecules. However, in spite of their multiple strong enzymatic turnover properties, few reports have addressed the potential application of RNA-cleaving DNAzymes as therapeutic gene-silencing agents. The main challenges are being met with low efficiency of cellular uptake, instability and the lack of sufficient cofactors for cellular or in vivo study, which have limited the development of DNAzymes for clinical application. In recent years, substantial progress has been made to enhance the delivery efficiency and stability of DNAzymes by developing variety of methods. Smart metal oxide nanomaterials have also been used to meet the requirement of cofactors in situ. This review focuses on the gene silencing application of DNAzymes as well as their physicochemical properties. Methods of increasing the efficacy of DNAzymes in gene therapy are also discussed： delivery systems to enhance the cellular uptake, modifications to enhance the stability and smart systems to generate sufficient cofactors in situ. Finally, some future trends and perspectives in these research areas are outlined.
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•Spatio-temporal change of EHI and HAI was assessed by the VORS model and human land surface human activity intensity model.•A significant and increased spatial negative correlation ...between EHI and HAI was confirmed.•HAI dominated the variations of EHI in both the spatial pattern and the lower ecosystem health level.•The high-level healthy ecosystem is extremely sensitive to HAI change.
Human activities are the main factors threatening ecosystems, and ecological management should place a strong emphasis on guiding their positive development. More targeted and differentiated ecological preservation strategies can be proposed with research on the regional variability of the interaction between ecosystems and human activities. Utilizing the Vigor-Organization-Resilience-Services (VORS) model and the land surface human activity intensity model, the ecosystem health index (EHI) and human activity intensity (HAI) of the Poyang Lake Ecological Economic Zone (PLEEZ) were evaluated, respectively. Furthermore, their spatial association was investigated using spatial autocorrelation analysis, and the effect of HAI on EHI was analyzed using Geographic Detector and Geographic Weighted Regress. The results revealed that in the PLEEZ, (1) The zones of intensified human activity were highly consistent with the expansion of built-up land, and the EHI here has always been the lowest; (2) The HAI and EHI showed a significant and increasing spatial negative correlation, manifested as high HAI with low EHI clustering in the central plains and the adverse in the peripheral mountainous areas. (3) The HAI has the highest explanatory power on the spatial pattern of EHI, and its influence was greatest at the lower EHI. (4) Natural ecosystems with high EHI were highly sensitive to HAI, while areas with low EHI were less sensitive. The research can offer theoretical guidance for ecological construction in the future. The adverse effects of human activities in PLEEZ can be reduced through strict regulation of natural ecological sources, intensive utilization of human gathering areas, and promotion of green production and lifestyle.
The urokinase-type plasminogen activator(PLAU) and its receptor PLAUR participate in a series of cell physiological activities on the extracellular surface. Abnormal expression of
and
is associated ...with tumorigenesis. This study aims to evaluate the prognostic value of
transcription expression in glioma and to explore how they affect the generation and progression of glioma. In this study, online databases are applied, such as Oncomine, GEPIA, CGGA, cBioPortal, and LinkedOmics. Overexpression of PLAU/PLAUR was found to be significantly associated with clinical variables including age, tumor type, WHO grade, histology, IDH-1 mutation, and 1p19q status.
and
had a high correlation in transcriptional expression levels. High expression of
and
predicted a poor prognosis in primary glioma and recurrent glioma patients, especially in lower grade gliomas. Cox regression analysis indicated that high expression of
and
were independent prognostic factors for shorter overall survival in glioma patients. In gene co-expression network analysis
and
and their co-expression genes were found to be involved in inflammatory activities and tumor-related signaling pathways. In conclusion, PLAU and PLAUR could be promising prognostic biomarkers and potential therapeutic targets of glioma patients.
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disease in women of childbearing age and can cause metabolic disorder, infertility, and increased anxiety and depression; ...as a result, it can seriously affect the physical and mental health of fertile women. PCOS is a highly clinically heterogeneous disease with unclear etiology and pathogenesis, which increases the difficulty of treatment. The thyroid gland has complex regulatory effects on metabolism, reproduction, and emotion, and produces hormones that act on almost all cells of the human body. The clinical manifestations of PCOS are similar to some thyroid diseases. Furthermore, some thyroid diseases, such as subclinical hypothyroidism (SCH), not only increase the incidence rate of PCOS, but also exacerbate its associated metabolic abnormalities and reproductive disorders. Interestingly, PCOS also increases the incidence of some thyroid diseases. However, the role of the thyroid in PCOS remains unclear. This review is intended to thoroughly explore the critical role of the thyroid in PCOS by summarizing the comorbidity of PCOS and thyroid diseases and their combined role in metabolic disorders, related metabolic diseases, and reproductive disorders; and by analyzing the potential mechanism through which the thyroid influences the development and progression of PCOS and its symptoms. We hope this review will provide a valuable reference for the role of the thyroid in PCOS.
•Tumor microenvironment serves as an effective target for cancer treatment.•Manganese-based nanomaterials have high potential to target and modulate TME.•Manganese-based nanomaterials have been ...widely used for TME-responsive cancer treatment.
Tumor microenvironment (TME), which characteristically displays hypoxia, immunosuppression, reprogramming metabolism and mild acidity, has been considered as an ideal target for cancer treatment. In the past few decades, an increasing number of TME-responsive nanomaterials have been developed. Among them, manganese-based nanomaterials (Mn-based NMs) have stimulated growing attentions owing to their unique characteristics such as tunable structures/morphologies, novel magnetic/optical properties, strong catalytic activities and good biodegradability. More importantly, they have excellent TME targetability and significant potential to modulate TME. In this review, we introduce different types of Mn-based NMs and discuss their strategies to modulate the TME, such as oxygen generation, pH value increase, reactive oxygen species production, glutathione/hydrogen peroxide depletion, glucose exhaustion, and innate or adaptive immunity activation, which are always accompanied by increased imaging signals for response monitoring. Such great advantages endow Mn-based NMs a broad range of applications in TME-responsive cancer therapies, including photodynamic therapy (PDT), sonodynamic therapy (SDT), radiotherapy, starvation therapy, chemodynamic therapy (CDT), ferroptosis-mediated therapy, chemotherapy, gene therapy, gas therapy and immunotherapy. Besides, cancer therapies through generating heat in TME are also outlined, including magnetic hyperthermia, microwave thermal therapy (MTT), microwave dynamic therapy (MDT) and photothermal therapy (PTT). Representative examples of each treatment modality and combination therapy are presented. Finally, future opportunities and challenges of TME-responsive Mn-based NMs for cancer treatment are tentatively proposed.
Gel polymer electrolytes (GPE) composed of triethylene glycol diacetate (TEGDA)-2-propenoic acid butyl ester (BA) copolymer and commercial used liquid organic electrolyte are prepared via in situ ...polymerization. The ionic conductivity of the as-prepared GPE can reach 5.5 10-3 S cm-1 with 6 wt% monomers and 94 wt% liquid electrolyte at 25 degree C. Additionally, the temperature dependence of the ionic conductivity is consistent with an Arrhenius temperature behavior in a temperature range of 20-90 degree C. Furthermore, the electrochemical stability window of the GPE is 5 V at 25 degree C. A Li|GPE|(LiLi1/6Ni1/4Mn7/12O2) cell has been fabricated, which shows good charge-discharge properties and stable cycle performance compared to liquid electrolyte under the same test conditions.
Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH （low） insertion peptide （pHLIP） with a disulfide bond which imparts extracellular pH （pHe）-driven tumor targeting ...ability, has been successfully developed for bimodal photodynamic and photothermal therapy. In this bimodal therapy, chlorin e6 （Ce6）, a second-generation photosensitizer （PS）, is used for photodynamic therapy （PDT）. Gold nanorods （AuNRs） are used as a hyperthermia agent for photothermal therapy （PTT） and also as a nanocarrier and quencher of Ce6. pHLIPss is designed as a pile-driven targeting probe to enhance accumulation of Ce6 and AuNRs in cancer cells at low pH. In Ce6- pHLIPss-AuNRs, Ce6 is close to and quenched by AuNRs, causing little PDT effect. When exposed to normal physiological pH 7.4, Ce6-pHLIPs~-AuNRs loosely associate with the cell membrane. However, once exposed to acidic pH 6.2, pHLIP actively inserts into the cell membrane, and the conjugates are translocated into cells. When this occurs, Ce6 separates from the AuNRs as a result of disulfide bond cleavage caused by intracellular glutathione （GSH）, and singlet oxygen is produced for PDT upon light irradiation. In addition, as individual PTT agent, AuNRs can enhance the accumulation of PSs in the tumor by the enhanced permeation and retention （EPR） effect. Therefore, as indicated by our data, when exposed to acidic pH, Ce6-pHLIPss-AuNRs can achieve synergistic PTT/PDT bimodality for cancer treatment.
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