Excessive Intracellular Reactive Oxygen Species Research Articles

Multifunctional cerium oxide nanozymes with high ocular surface retention for dry eye disease treatment achieved by restoring redox balance

Dry eye disease (DED) is a kind of multifactorial ocular surface disease that displays ocular discomfort, visual disturbance, and tear film instability. Oxidative stress is a fundamental pathogenesis in DED. An imbalance between the reactive oxygen species (ROS) level and protective enzyme action will lead to oxidative stress, cell dysfunction, tear hyperosmolarity, and inflammation. Herein, a multifunctional cerium oxide nanozyme with high ocular surface retention property was designed to neutralize over-accumulated ROS and restore redox balance. Cerium oxide nanozymes were fabricated via branched polyethylenimine-graft-poly (ethylene glycol) nucleation and dispersion, followed by phenylboronic acid (PBA) functionalization (defined as Ce@PB). Due to the dynamic chemical bonding formation between the PBA segment and the cis-diol groups in the mucin layer of the tear film, Ce@PB nanozymes possess good adhesive capability to the ocular surface, thus extending the drug's retention time. On the other hand, Ce@PB nanozymes could mimic the cascade processes of superoxide dismutase and catalase to maintain intracellular redox balance. In vitro and in vivo studies suggest that such multifunctional nanozymes possess good biocompatibility and hemocompatibility. More importantly, Ce@PB nanozymes treatment in the animal model could repair corneal epithelial defect, increase the number of goblet cells and promote tear secretion, thus achieving an effective treatment for DED. Statement of Significance• PBA-functionalized bPEI-g-PEG-based cerium oxide (Ce@PB) nanozymes were designed and fabricated.• The Ce@PB nanozymes have superoxide dismutase (SOD) and catalase (CAT) enzyme-like activity scavenging excessive intracellular reactive oxygen species (ROS).• The Ce@PB nanozymes demonstrate extended retention on the ocular surface and can effectively treat dry eye disease.

Flow-through inactivation of pathogenic Escherichia coli by titanium suboxide reactive electrochemical membranes: Unlocking the coupled mechanics of electrochemical and subcellular alterations

Limited mass transfer controlled by diffusion and unexplored disinfection mechanisms at the subcellular alternation respond to different electrochemical reactions always obstacles the electrochemical disinfection decentralized water treatment. Here, a large-scale reactive electrode membrane composed of titanium suboxide (TiSO-REM) was pioneered for pathogen inactivation and mechanism exploration. Complete bacteria inactivation (>7.1 log reduction) was achieved after 20 min of electrolysis at 1440 L m−2 h−1 (LMH) and 15 mA cm−2. Electrostatic adsorption facilitated the interaction of pathogens with oxidants in the electrode boundary layer by enhancing the adhesion of Escherichia coli at anode surface, resulting in 25 % improvement in removal. Subcellular alternation of waterborne pathogens depended on specific electrochemical mechanisms. Direct electron transfer (DET) unbalanced intracellular metabolism by excessive intracellular reactive oxygen species accumulation. While more violent electro-generated •OH annihilated the whole cells with disorderly alternation which also effectively reduced the risk of bacterial regeneration with no bacterial resuscitation. The study also provides a universal model to develop sustainable technologies for pathogen inactivation and precise regulation of inactivation efficiency from a mechanistic perspective for a wide range of engineering applications like water disinfection and bio-safety control.

Gallium-based metal–organic frameworks with antibacterial and anti-inflammatory properties for oral health protection

The fascial space of the oral and maxillofacial region contains loose connective tissues, which possess weak anti-infection ability and are often prone to infection, leading to acute suppurative inflammation and sepsis through blood. Although antibiotic use can reduce the probability of bacterial infections, owing to the emergence of antibiotic-resistant bacteria, the search for new antimicrobial drugs is imminent. Herein, we report a metal–organic framework (MOF) antibacterial material designed and synthesized with gallium (Ga) as the central atom, which possesses significant antibacterial, anti-inflammatory, and antioxidant effects. Our data suggested that GA-based MOFs (Ga–MOFs; 1 μg/mL) could sufficiently kill Porphyromonas gingivalis, Streptococcus pyogenes, and Staphylococcus aureus. Ga–MOFs exhibited a bactericidal effect against these three pathogens by disrupting biofilm formation, exopolysaccharide production, and bacterial membrane integrity. In addition, we found that 1 μg/mL of Ga–MOFs was not cytotoxic to human oral epithelial cell (HOEC) lines and it significantly reduced the adhesion of the three pathogens to HOEC. Ga–MOFs protect macrophages from excessive oxidative stress by scavenging excess intracellular reactive oxygen species and upregulating antioxidant gene levels, thereby enhancing cellular antioxidant defense. In addition, Ga–MOFs can promote the transformation of macrophages from the proinflammatory phenotype to the anti-inflammatory phenotype, thereby protecting oral health. Herein, novel Ga–MOF materials were chemically synthesized for therapeutic applications in oral infections, which provides new ideas for the development of novel nonantibiotic drugs to accelerate patient recovery.

Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes

The clinical treatment of human acute myeloid leukemia (AML) is rapidly progressing from chemotherapy to targeted therapies led by the BCL-2 inhibitor venetoclax (VEN). Despite its unprecedented success, VEN still encounters clinical resistance. Thus, uncovering the biological vulnerability of VEN-resistant AML disease and identifying effective therapies to treat them are urgently needed. We have previously demonstrated that iron oxide nanozymes (IONE) are capable of overcoming chemoresistance in AML. The current study reports a new activity of IONE in overcoming VEN resistance. Specifically, we revealed an aberrant redox balance with excessive intracellular reactive oxygen species (ROS) in VEN-resistant monocytic AML. Treatment with IONE potently induced ROS-dependent cell death in monocytic AML in both cell lines and primary AML models. In primary AML with developmental heterogeneity containing primitive and monocytic subpopulations, IONE selectively eradicated the VEN-resistant ROS-high monocytic subpopulation, successfully resolving the challenge of developmental heterogeneity faced by VEN. Overall, our study revealed an aberrant redox balance as a therapeutic target for monocytic AML and identified a candidate IONE that could selectively and potently eradicate VEN-resistant monocytic disease.

Inactivation of fungal spores using household BDD device as a POU purification device: Application evaluation, influencing factors, and mechanisms

Fungal contamination is commonly found in water supply systems, with filamentous fungi posing a particular threat through secondary pollution and potential risks to drinking water safety. In this study, an electrolytic device, with boron-doped diamond (BDD) as the anode material, was proposed for use as a point-of-use (POU) water treatment device to address the fungal contamination in tap water. The BDD device was found to effectively inactivate Aspergillus terrestris spores under different processing current intensities, water hardness, and alkalinity conditions. Moreover, in practical tap water applications, it also exhibited effective inactivation of Aspergillus terrestris spores and good efficiency in removing antibiotic-resistant genes (ARGs). During the electrolysis, various active species are produced, including ozone, reactive chlorine, and extracellular reactive oxygen species (eROS) such as •OH, •O2− and •1O2. Addtionally, spores produce excessive intracellular reactive oxygen species (iROS) under stimulus. These species could damage the cell membrane, resulting in DNA and TN leakage, a decrease in cellular ATP content, and destruction of surface morphology. This study provides a novel solution for eliminating fungal contamination in water endpoints.

Electron Redistribution in Iridium-Iron Dual-Metal-Atom Active Sites Enables Synergistic Enhancement for H2O2 Decomposition.

Developing efficient heterogeneous H2O2 decomposition catalysts under neutral conditions is of great importance in many fields such as clinical therapy, sewage treatment, and semiconductor manufacturing but still suffers from low intrinsic activity and ambiguous mechanism understanding. Herein, we constructed activated carbon supported with an Ir-Fe dual-metal-atom active sites catalyst (IrFe-AC) by using a facile method based on a pulsed laser. The electron redistribution in Ir-Fe dual-metal-atom active sites leads to the formation of double reductive metal active sites, which can strengthen the metal-H2O2 interaction and boost the H2O2 decomposition performance of Ir-Fe dual-metal-atom active sites. Ir-Fe dual-metal-atom active sites show a high second-order reaction rate constant of 3.53 × 106 M-1·min-1, which is ∼106 times higher than that of Fe3O4. IrFe-AC is effective in removing excess intracellular reactive oxygen species, protecting DNA, and reducing inflammation under oxidative stress, indicating its therapeutic potential against oxidative stress-related diseases. This study could advance the mechanism understanding of H2O2 decomposition by heterogeneous catalysts and provide guidance for the rational design of high-performance catalysts for H2O2 decomposition.

Protective Effects of Hinokitiol on Neuronal Ferroptosis by Activating the Keap1/Nrf2/HO-1 Pathway in Traumatic Brain Injury.

In this study, we investigated the effects of hinokitiol, a small-molecule natural compound, against neuronal ferroptosis after traumatic brain injury (TBI). A controlled cortical impact (CCI) mouse model and excess glutamate-treated HT-22 cells were used to study the effects of hinokitiol on TBI. Hinokitiol mitigated TBI brain tissue lesions and significantly improved neurological function. Neuron loss and iron deposition were ameliorated after hinokitiol administration. Hinokitiol alleviated excessive glutamate-induced intracellular reactive oxygen species (ROS), lipid peroxidation, and Fe2+ accumulation in HT-22. Mechanistically, hinokitiol upregulated heme oxygenase-1 (HO-1) expression, promoted nuclear factor-erythroid factor 2-related factor 2 (Nrf2) nuclear translocation, and inhibited the activation of microglia and astrocyte after TBI. These results suggest that hinokitiol has neuroprotective effects on rescuing cells from TBI-induced neuronal ferroptosis. In summary, hinokitiol is a potential therapeutic candidate for TBI by activating the Nrf2/Keap1/HO-1 signaling pathway.

Sensitive and Selective Dual-Mode Responses to Reactive Oxygen Species by Chiral Manganese Dioxide Nanoparticles for Antiaging Skin.

Excessive accumulation of reactive oxygen species (ROS) can lead to oxidative stress and oxidative damage, which is one of the important factors for aging and age-related diseases. Therefore, real-time monitoring and the moderate elimination of ROS is extremely important. In this study, a ROS-responsive circular dichroic (CD) at 553nm and magnetic resonance imaging (MRI) dual-signals chiral manganese oxide (MnO2 ) nanoparticles (NPs) are designed and synthesized. Both the CD and MRI signals show excellent linear ranges for intracellular hydrogen peroxide (H2 O2 ) concentrations, with limits of detection (LOD) of 0.0027nmol/106 cells and 0.016nmol/106 cells, respectively. The lower LOD achieved with CD detection may be attributable to its higher anti-interference capability from the intracellular matrix. Importantly, ROS-induced cell aging is intervened by chiral MnO2 NPs via redox reactions with excessive intracellular ROS. In vivo experiments confirm that chiral MnO2 NPs effectively eliminate ROS in skin tissue, reduce oxidative stress levels, and alleviate skin aging. This approach provides a new strategy for the diagnosis and treatment of age-related diseases.

Efficacy Evaluation of a Tetracyclic Triterpene Compound Targeting Multiple Apoptosis Proteins for the Development of a Multiple Myeloma Treatment

Introduction:Multiple myeloma (MM) is an incurable hematologic cancer that originates in plasma cells and occurs primarily in older patients over 60. This study screened for hit compounds for MM treatments targeting mitochondria and apoptosis proteins. Further, non-clinical testing, including molecular docking analysis, was performed. Methods: Based on our previous studies, candidate compounds targeting mitochondria were screened (www.medchemexpress.com). The killing effect of the compounds on MM cell lines (RPMI8226, IM9, and U266) was examined using a sulforhodamine B assay. Apoptosis mechanisms were investigated in vitro. Complex immunocompromised mice were established by injecting RPMI8226-RFP-FLuc cells through the tail vein. Efficacy of the KBB-N2 activity was assessed following intraperitoneal (15 or 30 mg/kg/day) and tail vein (7 mg/kg/day) infusions for three days a week at daily intervals. Toxicity, pharmacokinetics, and molecular docking analyses were performed according to the established protocols. Results: The hit compound, KBB-N2, a tetracyclic triterpene, was identified as an MM-targeted compound with cytotoxic effects. The primary mechanism of action of KBB-N2 in MM cells was inhibiting the activity of the mitochondrial electron transport (ETC) complex, resulting in the generation of excess intracellular reactive oxygen species (ROS), which led to tumor cell death by ROS-mediated apoptosis. In addition, exposure to KBB-N2 inhibited the activity of catalase, a powerful antioxidant enzyme in MM cells. Severe suppression of normal hematopoietic stem cell function was observed with lenalidomide administration at a concentration of 25 μM. However, this toxicity was not observed when KBB-N2 was administered at doses up to 60 μM. KBB-N2 activity involves PARP cleavage and caspase activation in the apoptotic pathway. Furthermore, KBB-N2 inhibited cell growth and exerted cytotoxicity. KBB-N2 induced apoptosis by activating the P53 apoptosis pathway in MM cells. In vivo, all untreated tumor-bearing mice showed rapid tumor growth and severe plasmacytomas, which led to death within seven weeks. Mice treated with KBB-N2 had significantly inhibited tumor growth and longer survival times. The molecular docking assay revealed the optimal docking conformation binding energy of KBB-N2 with docking scores (kcal/M) of -7.3 and -9.8 for ETC complexes I and III, respectively. Conclusions: The triterpene compound, KBB-N2, was identified as a hit compound and may act as a targeted agent for MM treatment. The antimyeloma activity of KBB-N2 involves interference with the ETC complex and leads to MM cell death.

MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function

Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.

Liposomal Resveratrol Alleviates Platelet Storage Lesion via Antioxidation and the Physical Buffering Effect.

Platelet transfusion is essential in the treatment of platelet-related diseases and the prevention of bleeding in patients with surgical procedures. Platelet transfusion efficacy and shelf life are limited mainly by the development of platelet storage lesion (PSL). Mitigating PSL is the key to prolonging the platelet shelf life and reducing wastage. Excess intracellular reactive oxygen species (ROS) are one of the main factors causing PSL. In this study, we explored a nanomedicine strategy to improve the quality and functions of platelets in storage. Resveratrol (Res), a natural plant product, is known for its antioxidative effect. However, medical applications of Res are limited due to its low water solubility and stability. Therefore, we used a resveratrol-loaded liposomal system (Res-Lipo) to better utilize the antioxidant effect of the drug. This study aimed to evaluate the effect of Res-Lipo on platelet oxidative stress and alleviation of PSL during the storage time. Res-Lipo scavenged intracellular ROS and inhibited platelet apoptosis and activation during storage. Res-Lipo not only maintained mitochondrial function but also improved platelet aggregation in response to adenosine 5'-diphosphate. These results revealed that Res-Lipo ameliorated PSL and prolonged the platelet survival time in vivo. The strategy provides a potential method for extending the platelet storage time and might be considered a potential and safe additive to alleviate PSL.

Microenvironment responsive pod-structured astaxanthin nanocarrier for ameliorating inflammatory bowel disease

Anti-inflammatory drugs targeting inflammatory bowel disease (IBD) have attracted considerable attention but still face low therapeutic outcomes and frequent side effects. Astaxanthin (ATX), a natural ketone, possesses potent antioxidant and anti-inflammatory properties. However, it faces problems such as poor water solubility, photothermal instability, and low bioavailability. Here, we employed a supramolecular encapsulation strategy to create a nanoscale oral delivery system for ATX (referred to as FC-ATX NPs) by coupling fucoidan (FUC) with chitosan oligosaccharides (COS). The obtained FC-ATX NPs exhibited a particular “bean pod” structure with uniform size, good encapsulation efficiency, excellent physical and chemical stability, pH-triggered intestinal targeted slow-release properties, and potent antioxidant capacity. In vitro cell culture experiments showed that FC-ATX NPs promoted cellular uptake and scavenged excessive intracellular reactive oxygen species (ROS). In mouse models of colitis, FC-ATX NPs enhanced the drug absorption of intestinal epithelial cells and effectively accumulated at the site of inflammation. This work provides an efficient approach to enhance the bioavailability of ATX and has excellent application potential as an oral targeted delivery system for colitis therapy.

Enzyme-triggered deep tumor penetration of a dual-drug nanomedicine enables an enhanced cancer combination therapy.

Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species (ROS) via emerging nanomedicines. However, tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site, and ROS at a low level promote tumor cell growth, thus diminishing the therapeutic effect of these nanomedicines. Herein, we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine (Lap@pOEGMA-b-p(GFLG-Dendron-Ppa), GFLG-DP/Lap NPs) that incorporates a photosensitizer, Pyropheophorbide a (Ppa), for ROS therapy and Lapatinib (Lap) for molecular targeted therapy. Lap, an epidermal growth factor receptor (EGFR) inhibitor that plays a role in inhibiting cell growth and proliferation, is hypothesized to synergize with ROS therapy for effectively killing cancer cells. Our results suggest that the enzyme-sensitive polymeric conjugate, pOEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), releases in response to cathepsin B (CTSB) after entering the tumor tissue. Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes, which promotes efficient penetration and long-term retention. Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity. Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis. Meanwhile, Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions, thus generating a significant synergistic anti-tumor therapeutic effect. This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.

Selenium-Doped Mesoporous Bioactive Glass Regulates Macrophage Metabolism and Polarization by Scavenging ROS and Promotes Bone Regeneration In Vivo.

Bone regeneration is complex and involves multiple cells and systems, with macrophage-mediated immune regulation being critical for the development and regulation of inflammation, angiogenesis, and osteogenesis. Biomaterials with modified physical and chemical properties (e.g., modified wettability and morphology) effectively regulate macrophage polarization. This study proposes a novel approach to macrophage-polarization induction and -metabolism regulation through selenium (Se) doping. We synthesized Se-doped mesoporous bioactive glass (Se-MBG) and demonstrated its macrophage-polarization regulation toward M2 and its enhancement of the macrophage oxidative phosphorylation metabolism. The underlying mechanism is the effective scavenging of excessive intracellular reactive oxygen species (ROS) by the Se-MBG extracts through the promotion of peroxide-scavenging enzyme glutathione peroxidase 4 expression in the macrophages; this, in turn, improves the mitochondrial function. Printed Se-MBG scaffolds were implanted into rats with critical-sized skull defects to evaluate their immunomodulatory and bone regeneration capacity in vivo. The Se-MBG scaffolds demonstrated excellent immunomodulatory function and robust bone regeneration capacity. Macrophage depletion with clodronate liposomes impaired the Se-MBG-scaffold bone regeneration effect. Se-mediated immunomodulation, which targets ROS scavenging to regulate macrophage metabolic profiles and mitochondrial function, is a promising concept for future effective biomaterials for bone regeneration and immunomodulation.

Encapsulation of tea polyphenols into high amylose corn starch composite nanofibrous film for active antimicrobial packaging

Starch-based composite nanofibrous films loaded with tea polyphenols (TP) were successfully fabricated through electrospinning high amylose corn starch (HACS) with aid of polyvinyl alcohol (PVA), referred as HACS/PVA@TP. With the addition of 15 % TP, HACS/PVA@TP nanofibrous films exhibited enhanced mechanical properties and water vapor barrier capability, and their hydrogen bonding interactions were further evidenced. TP was slowly released from the nanofibrous film and followed Fickian diffusion mechanism, which achieved the controlled sustained release of TP. Interesting, HACS/PVA@TP nanofibrous films effectively improved antimicrobial activities against Staphylococcus aureus (S. aureus) and prolonged the shelf life of strawberry. HACS/PVA@TP nanofibrous films showed superior antibacterial function by by destroying cell wall and cytomembrane, and degrading existing DNA fragments, stimulating excessive intracellular reactive oxygen species (ROS) generation. Our study demonstrated that the functional electrospun Starch-based nanofibrous films with enhanced mechanical properties and superior antimicrobial activities were potential for the application in active food packaging and relative areas.

Protective Effects of Piceatannol on DNA Damage in Benzo[a]pyrene-Induced Human Colon Epithelial Cells

Evidence shows that the dietary intake of polycyclic aromatic hydrocarbons (PAHs) from food processing induces the cellular DNA damage response and leads to the development of colorectal cancer (CRC). Therefore, protecting from cellular DNA damage might be an effective strategy in preventing CRC. Benzo[a]pyrene (B[a]P) was used as a CRC initiator in the present study. Compared with other stilbenoids, piceatannol (PIC) showed the most effective inhibition of B[a]P-induced cytochrome P450 1B1 (CYP1B1) protein expression in NCM460 normal human colon epithelial cells. PIC treatment alleviated DNA migration and enhanced the expression of DNA-repair-related proteins, including histone 2AX (H2AX), checkpoint kinase 1 (Chk1), and p53, in B[a]P-induced NCM460 cells. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) revealed that PIC exerted antioxidative effects on NCM460 cells by increasing the glutathione (GSH) content and scavenging the excess intracellular reactive oxygen species (ROS) induced by B[a]P. Furthermore, PIC suppressed B[a]P-induced CYP1B1 protein expression and stimulated miR-27b-3p expression. The upregulation of phase II detoxification enzymes, such as nicotinamide adenine dinucleotide phosphate (NADPH) and quinone oxidoreductase 1 (NQO1), and the antioxidative enzyme, heme oxygenase 1 (HO-1), via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was observed in the PIC-treated group. Our results suggest that PIC is a potential CRC-blocking agent due to its ability to alleviate DNA damage, decrease intracellular ROS production, modulate the metabolism and detoxification of B[a]P, and activate the Nrf2 signaling pathway in B[a]P-induced NCM460 cells.

Jasmine tea extract enhances human retinal pigment epithelial cells survival after UVB irradiation

To examine the protecting effect of jasmine tea extract (JTE) against ultraviolet B (UVB) induced damage on human retinal pigment epithelial (RPE) cells, the RPE cells were subjected to UVB exposure and sequential JTE administration. The cell viability, intracellular reactive oxygen species (ROS), and apoptosis were determined by MTT, 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate and flow cytometer assays, respectively. Further, the cells treated with UVB irradiation and sequential JTE administration were subjected to RNA-sequencing analysis in order to identify genes and pathways involved in the UVB-induced damage and JTE protecting mechanisms. The results showed that JTE effectively attenuated the UVB-induced cell injury by reducing the excessive intracellular ROS generation, and inhibiting the expression of apoptotic genes such as Bax, Caspase-3/9. This finding may offer a promising candidate for the prevention of UVB exposure related eye diseases.

Antisenescence ZIF-8/Resveratrol Nanoformulation with Potential for Enhancement of Bone Fracture Healing in the Elderly.

Accumulation of senescent cells in the elderly impairs bone homeostasis. It is important to alleviate cell senescence and scavenge excessive oxidative stress for enhanced bone fracture healing in elderly patients. In this study, resveratrol (RSV), an antioxidant drug, was encapsulated in a biocompatible zeolitic imidazolate framework-8 (ZIF-8) nanoparticle to protect it from oxidation and improve its bioavailability. Cells responsible for bone healing, including osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs), macrophages, and endothelial cells, were used to evaluate the regulatory role of the nanoformulation in the alleviation of cellular senescence and promotion of cell functions. It was proved that the nanoformulation sustainably released RSV with well-preserved bioactivity and improved bioavailability. Cell experiments confirmed that ZIF-8/RSV was capable of alleviating the senescence of cells [human osteoblasts (HOBs), BMSCs, H2O2-induced senescent vascular endothelial cells (HUVECs)] and scavenging excessive intracellular reactive oxygen species (ROS). Excitingly, the ZIF-8/RSV improved the osteogenic ability of senescent osteoblasts and promoted macrophage M2 polarization. In addition, the ZIF-8/RSV also enhanced the angiogenic function of senescent HUVECs. More importantly, the ZIF-8/RSV nanoformulation outperformed the REV alone, indicating the critical role of encapsulation using ZIF-8. These findings suggest that the ZIF-8/RSV nanoformulation exhibits potential for bone fracture treatment in elderly patients.

Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD-L1 for Enhanced Cancer Immunotherapy.

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existing Cu ionophores are small molecules with a short blood half-life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)-sensitive polymer (PHPM) is designed, which is used to co-encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA-Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti-programmed cell death protein ligand-1antibody (αPD-L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD-L1for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.

Electrophysiological microenvironment and site-specific cell behaviors regulated by fibrous aniline trimer-based polyurethanes in bone progressive regeneration

Inspired by the endogenous electric field of natural bone tissue, fibrous aniline trimer (AT)-based polyurethane (FPAT) membranes have been fabricated with good electroactivity through electrospinning, which may serve to restore electrophysiological microenvironment and regulate site-specific cell behaviors to promote osteogenesis. By virtue of the redox activity, the electroactive FPAT membranes exhibited the progressive scavenging ability of reactive oxygen species (ROS) with increasing AT content. Furthermore, a systematic study of specific biomarkers was practiced to draw a comprehensive understanding of the bioelectrical stimulation, including in vitro cell experiments, in vivo RNA-sequencing, subcutaneous implantation, and bone defect repair. Focused on site-specific cell behaviors, both macrophages and mesenchymal stem cells (MSCs)were significantly regulated by the AT-based membranes on electrophysiological microenvironment. For macrophages, the AT-based membranes polarized macrophages to M2 phenotype by efficiently clearing excessive ROS to manipulate the osteoimmune microenvironment in vitro and in vivo. For MSCs, the FPAT membranes scavenged excessive intracellular ROS and elevated intracellular Ca2+ concentration, thereby promoting cell proliferation and driving osteogenesis differentiation. Histology results and gene expression profiles on a rat calvarial bone defect model discovered the efficacy of the AT-based membranes in immunomodulation and osteogenesis. Moreover, the upregulated genes at the RNA level and signaling pathways testified that the electroactive FPAT membranes were strongly involved in regulating macrophage polarization and bone repairing process. This work demonstrated an efficacious therapy of electroactive FPAT membranes from the regulatory mechanism, cellular to tissue levels in bone progressive regeneration, which could provide a legible evaluation system for conductive materials.