Tumor cells metabolize in distinct pathways compared with most normal tissue cells. The resulting tumor microenvironment would provide characteristic physiochemical conditions for selective tumor ...modalities. Here we introduce a concept of sequential catalytic nanomedicine for efficient tumor therapy by designing and delivering biocompatible nanocatalysts into tumor sites. Natural glucose oxidase (GOD, enzyme catalyst) and ultrasmall Fe
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nanoparticles (inorganic nanozyme, Fenton reaction catalyst) have been integrated into the large pore-sized and biodegradable dendritic silica nanoparticles to fabricate the sequential nanocatalyst. GOD in sequential nanocatalyst could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H
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for subsequent Fenton-like reaction catalyzed by Fe
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nanoparticles in response to mild acidic tumor microenvironment. Highly toxic hydroxyl radicals are generated through these sequential catalytic reactions to trigger the apoptosis and death of tumor cells. The current work manifests a proof of concept of catalytic nanomedicine by approaching selectivity and efficiency concurrently for tumor therapeutics.The specific metabolism of cancer cells may allow for selective tumor therapeutics. Here, the authors show that a suitable combination of an enzyme and iron nanoparticles loaded on dendritic silica induces apoptosis of cancer cells in response to the glucose-reliant and mild acidic microenvironment.
Pure organic room temperature phosphorescence (RTP) has unique advantages and various potential applications. However, it is challengeable to achieve organic RTP under visible and near-infrared ...(NIR)-light excitation, especially in aqueous solution. Herein we assemble difluoroboron β-diketonate compounds to form organic nanoparticles (NPs) in water. The resulting NPs are able to show efficient RTP, effective uptake, and bright imaging of HeLa cells under both visible- and NIR-light excitation. More strikingly, spectroscopic study, single-crystal X-ray diffraction, and DFT calculation reveal that the efficient RTP in organic NPs is originated from dimers in their excited states. The multiple interactions and intermolecular charge transfer in the dimer structures are of significance in promoting the production of dimer triplet excited states and suppressing the nonradiative decays to boost the RTP under visible- and NIR-light irradiation in water.
Pathological angiogenesis is a critical component of diseases, such as ocular disorders, cancers, and atherosclerosis. It is usually caused by the abnormal activity of biological processes, such as ...cell proliferation, cell motility, immune, or inflammation response. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of these biological processes. However, the role of lncRNA in diabetes mellitus-induced microvascular dysfunction is largely unknown.
To elucidate whether lncRNA-myocardial infarction-associated transcript (MIAT) is involved in diabetes mellitus-induced microvascular dysfunction.
Using quantitative polymerase chain reaction, we demonstrated increased expression of lncRNA-MIAT in diabetic retinas and endothelial cells cultured in high glucose medium. Visual electrophysiology examination, TUNEL staining, retinal trypsin digestion, vascular permeability assay, and in vitro studies revealed that MIAT knockdown obviously ameliorated diabetes mellitus-induced retinal microvascular dysfunction in vivo, and inhibited endothelial cell proliferation, migration, and tube formation in vitro. Bioinformatics analysis, luciferase assay, RNA immunoprecipitation, and in vitro studies revealed that MIAT functioned as a competing endogenous RNA, and formed a feedback loop with vascular endothelial growth factor and miR-150-5p to regulate endothelial cell function.
This study highlights the involvement of lncRNA-MIAT in pathological angiogenesis and facilitates the development of lncRNA-directed diagnostics and therapeutics against neovascular diseases.
Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have ...facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake.
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phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation impedes its association with chaperone HSP90. Thus, PP2C and PKA may orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.
Chalcogen bonding (ChB) has emerged as a promising tool in organic synthesis. However, compared with the well‐developed selenium‐ and tellurium‐based salt catalysts, the ChB catalysis of sulfonium ...salts is still unknown. Here, we report a new type of alkynyl‐sulfonium salt ChB catalysis for various ionic transformations, including transfer hydrogenation, bromination, bromolactonization, dimerization of 1,1‐diphenylethylene, nitro‐Michael addition reaction and Ritter reaction. More importantly, the photocapability of ChB was first demonstrated to generate alkynyl radicals for the synthesis of a variety of chalcogenoacetylenes. Mechanistic studies shed light on the mechanism of the photoinduced reactions and confirmed the involvement of alkynyl radicals which are difficult to generate otherwise.
Alkynyl sulfonium salts were employed as chalcogen bonding (ChB) catalysts for the first time. They display superior capability in the generation of alkynyl radicals under blue‐light irradiation.
Aims
This study aimed to detect alterations of brain functional connectivity (FC) in acute mild traumatic brain injury (mTBI) and to estimate the extent to which these FC differences predicted the ...characteristics of posttraumatic cognitive impairment.
Methods
Resting‐state fMRI data were acquired from acute mTBI patients (n = 50) and healthy controls (HCs) (n = 43). Resting‐state networks (RSNs) were established based on independent component analysis (ICA), and functional network connectivity (FNC) analysis was performed. Subsequently, we analyzed the correlations between FNC abnormalities and cognitive impairment outcomes.
Results
Altered FC within the salience network (SN), sensorimotor network (SMN), default mode network (DMN), executive control network (ECN), visual network (VN), and cerebellum network (CN) was found in the mTBI group relative to the HC group. Moreover, different patterns of altered network interactions were found between the mTBI patients and HCs, including the SN‐CN, VN‐SMN, and ECN‐DMN connections. Correlations between functional disconnection and cognitive impairment measurements in acute mTBI patients were also found.
Conclusion
This study indicated that widespread FNC impairment and altered integration existed in mTBI patients at acute stage, suggesting that FNC disruption as a biomarker may be applied for the early diagnosis and prediction of cognitive impairment in mTBI.
Widespread functional network connectivity (FNC) impairment and altered integration existed in acute mTBI, suggesting that FNC disruption as a biomarker may be applied for the early diagnosis and prediction of cognitive impairment in mTBI.
Chromodomain-helicase-DNA-binding protein 1 (CHD1) deletion is among the most common mutations in prostate cancer (PCa), but its role remains unclear. In this study, RNA sequencing was conducted in ...PCa cells after clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-based CHD1 knockout. Gene set enrichment analysis (GSEA) indicated upregulation of hypoxia-related pathways. A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1α (HIF1α) expression. Mechanistic investigation revealed that CHD1 deletion upregulated HIF1α by transcriptionally downregulating prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase catalyzing the hydroxylation of HIF1α and thus promoting its degradation by the E3 ligase von Hippel-Lindau tumor suppressor (VHL). Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis, possibly through HIF1α target genes. Taken together, these findings indicate that CHD1 deletion enhances HIF1α expression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.
Ceramic biomaterials have been investigated for several decades, but their potential biomedical applications in cancer therapy have been paid much less attentions, mainly due to their lack of related ...material functionality for combating the cancer. In this work, we report, for the first time, that MAX ceramic biomaterials exhibit the unique functionality for the photothermal ablation of cancer upon being exfoliated into ultrathin nanosheets within atomic thickness (MXene). As a paradigm, biocompatible Ti3C2 nanosheets (MXenes) were successfully synthesized based on a two-step exfoliation strategy of MAX phase Ti3AlC2 by the combined HF etching and TPAOH intercalation. Especially, the high photothermal-conversion efficiency and in vitro/in vivo photothermal ablation of tumor of Ti3C2 nanosheets (MXenes) were revealed and demonstrated, not only in the intravenous administration of soybean phospholipid modified Ti3C2 nanosheets but also in the localized intratumoral implantation of a phase-changeable PLGA/Ti3C2 organic–inorganic hybrid. This work promises the great potential of Ti3C2 nanosheets (MXenes) as a novel ceramic photothermal agent used for cancer therapy and may arouse much interest in exploring MXene-based ceramic biomaterials to benefit the biomedical applications.
Abstract Background Epidemiological studies have shown that ambient air pollution is closely associated with increased respiratory inflammation and decreased lung function. Particulate matters (PMs) ...are major components of air pollution that damages lung cells. However, the mechanisms remain to be elucidated. This study examines the effects of PMs on intercellular adhesion molecule-1 (ICAM-1) expression and the related mechanisms in vitro and in vivo. Result The cytotoxicity, reactive oxygen species (ROS) generation, and monocyte adherence to A549 cells were more severely affected by treatment with O-PMs (organic solvent-extractable fraction of SRM1649b) than with W-PMs (water-soluble fraction of SRM1649b). We observed a significant increase in ICAM-1 expression by O-PMs, but not W-PMs. O-PMs also induced the phosphorylation of AKT, p65, and STAT3. Pretreating A549 cells with N-acetyl cysteine (NAC), an antioxidant, attenuated O-PMs-induced ROS generation, the phosphorylation of the mentioned kinases, and the expression of ICAM-1. Furthermore, an AKT inhibitor (LY294002), NF-κB inhibitor (BAY11–7082), and STAT3 inhibitor (Stattic) significantly down-regulated O-PMs-induced ICAM-1 expression as well as the adhesion of U937 cells to epithelial cells. Interleukin-6 (IL-6) was the most significantly changed cytokine in O-PMs-treated A549 cells according to the analysis of the cytokine antibody array. The IL-6 receptor inhibitor tocilizumab (TCZ) and small interfering RNA for IL-6 significantly reduced ICAM-1 secretion and expression as well as the reduction of the AKT, p65, and STAT3 phosphorylation in O-PMs-treated A549 cells. In addition, the intratracheal instillation of PMs significantly increased the levels of the ICAM-1 and IL-6 in lung tissues and plasma in WT mice, but not in IL-6 knockout mice. Pre-administration of NAC attenuated those PMs-induced adverse effects in WT mice. Furthermore, patients with chronic obstructive pulmonary disease (COPD) had higher plasma levels of ICAM-1 and IL-6 compared to healthy subjects. Conclusion These results suggest that PMs increase ICAM-1 expression in pulmonary epithelial cells in vitro and in vivo through the IL-6/AKT/STAT3/NF-κB signaling pathway.
A clerodane diterpene compound 16-hydroxycleroda-3,13-dien-15,16-olide (CD) is considered a therapeutic agent with pharmacological activities. The present study investigated the mechanisms of ...CD-induced apoptosis in T24 human bladder cancer cells. CD inhibited cell proliferation in a concentration and time-dependent manner. CD-induced overproduction of reactive oxygen species and reduced mitochondrial membrane potential, associated with reduced expression of Bcl-2 and increased levels of cytosolic cytochrome c, cleaved PARP-1 and caspase-3. In addition, CD treatment led to cell cycle arrest at the G0/G1 phase and inhibited expression of cyclin D1 and cyclin-dependent kinases 2 and 4 and led to increased levels of p21, p27Kip1 and p53. All of these events were accompanied with a reduction of pEGFR, pMEK1/2, pERK1/2, pAkt, pmTOR, pP70S6K1, HIF-1α, c-Myc and VEGF. RNAseq-based analysis revealed that CD-induced cell death was characterised by an increased expression of stress and apoptotic-related genes as well as inhibition of the cell cycle-related genes. In summary, CD induces apoptosis in T24 bladder cancer cells through targeting multiple intracellular signaling pathways as a result of oxidative stress and cell cycle arrest.
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