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The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is needed for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, achieving Olig2 overexpression in vivo remains a formidable technological challenge. To address this challenge, we employed lipid nanoparticle (LNP)-mediated delivery of Olig2 synthetically modified messenger RNA (mRNA) as a viable method for in vivo Olih2 protein overexpression. Specifically, we developed CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) to achieve targeted Olig2 protein expression within PDGFRα+ OPCs, with the goal of promoting remyelination for ischemic stroke therapy. We show that C-Olig2 promotes the differentiation of PDGFRα+ OPCs derived from mouse neural stem cells into mature oligodendrocytes in vitro, suggesting that mRNA-mediated Olig2 overexpression is a rational approach to promote oligodendrocyte differentiation and remyelination. Furthermore, when C-Olig2 was administered to a murine model of ischemic stroke, it led to improvements in blood‒brain barrier (BBB) integrity, enhanced remyelination, and rescued learning and cognitive deficits. Our comprehensive analysis, which included bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq), revealed upregulated biological processes related to learning and memory in the brains of mice treated with C-Olig2 compared to those receiving empty LNPs (Mock). Collectively, our findings highlight the therapeutic potential of multifunctional nanomedicine targeting mRNA expression for ischemic stroke and suggest that this approach holds promise for addressing various brain diseases. While Olig2 overexpression in OPCs represents a promising therapeutic avenue for enhancing remyelination in ischemic stroke, in vivo strategies for achieving Olig2 expression pose considerable technological challenges. The delivery of mRNA via lipid nanoparticles is considered aa viable approach for in vivo protein expression. In this study, we engineered CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) with the aim of achieving specific Olig2 overexpression in mouse OPCs. Our findings demonstrate that C-Olig2 promotes the differentiation of OPCs into oligodendrocytes in vitro, providing evidence that mRNA-mediated Olig2 overexpression is a rational strategy to foster remyelination. Furthermore, the intravenous administration of C-Olig2 into a murine model of ischemic stroke not only improved blood-brain barrier integrity but also enhanced remyelination and mitigated learning and cognitive deficits. These results underscore the promising therapeutic potential of multifunctional nanomedicine targeting mRNA expression in the context of ischemic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]

This study reports an ultrasound-mediated and two-dimensional (2D) porous vermiculite nanosheets (VMT NSs)-based nanocatalyst platform (Arg@VMT@PDA-PEG) that synergistically harnessed the Fenton reaction-based chemodynamic therapy (CDT), 2D semiconductor-based sonodynamic therapy (SDT) and nitric oxide (NO)-based gas therapy for combination cancer therapy. The tumor microenvironment responsive degradation of polydopamine (PDA) shell could not only prevent L-Arg, a NO donor, leakage during blood circulation, but also selectively release the active sites of VMT NSs for catalytic reactions in tumor cells. Additionally, the Fenton reactions mediated by the abundant Fe2+/Fe3+ in VMT NSs could efficiently produce ·OH and consume glutathione (GSH) for CDT. Moreover, the reactive oxygen species (ROS, ·OH and ·O 2 −) produced by ultrasound-triggered Arg@VMT@PDA-PEG could not only execute SDT but also oxidize L-Arg to NO for synergetic gas therapy. The results show that the transformation of ROS to NO can enhance curative efficacy owing to the ability of NO with much longer life-time in freely diffusing into cells from intercellular space. This biodegradable Arg@VMT@PDA-PEG nanocatalytic platform integrating three different catalytic reactions provides a new therapeutic paradigm for combination cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

We previously found that transient receptor potential ankyrin 1 (TRPA1) in guinea pig tracheal epithelial cells was elevated after 14 days of cigarette smoke (CS) exposure. However, the mechanism underlying CS-induced TRPA1 expression remains unknown. Here, we explored whether cigarette smoke extract (CSE)-induced TRPA1 expression is related with modulation of HIF1α in A549 cells. Our results showed that CSE increased TRPA1 expression in A549 cells, decreased Iκ B, PHD2, and HDAC2, and increased ROS release and nuclear translocation of NF-κ B and HIF1α. Moreover, HIF1α siRNA and/or MG132 (a proteasome inhibitor) pretreatment significantly inhibited CSE-induced TRPA1 expression and HIF1α nuclear translocation in A549 cells. However, HIF1α siRNA pretreatment did not affect CSE-induced NF-κ B nuclear translocation, suggesting that CSE-induced TRPA1 expression in A549 cells is directly mediated by HIF1α, but not by NF-κ B. Similar to CSE treatment, treatment of A549 cells with LPS caused significant increases in nuclear translocation of NF-κ B and HIF1α mRNA expression, but did not alter TRPA1 mRNA expression. However, pretreatment with PHD2 siRNA did result in increased TRPA1 mRNA expression in LPS-treated A549 cells; an effect that was inhibited by SN50 (a NF-κ B inhibitor). It suggests a role for NF-κ B to indirectly regulate TRPA1 mRNA expression via modulating HIF1α mRNA transcription. In addition, treatment cells with HDAC2 siRNA plus 2%CSE resulted in increased HIF1α nuclear translocation and TRPA1 expression, which was significantly inhibited by MG132 and HIF1α siRNA. These results suggest that HDAC2 indirectly modulates TRPA1 expression by promoting the DNA-binding activity of HIF1α. These findings show that CSE increases TRPA1 expression in airway epithelial cells by directly activating HIF1α, and that this increase in TRPA1 expression is indirectly regulated via NF-κ B, PHD2 and HDAC2 modulation of HIF1α activity. [ABSTRACT FROM AUTHOR]

Fenton reaction-based chemodynamic therapy is hardly a self-sufficient cancer treatment, due to its stringent reaction conditions, limited substrate concentration, and negative feedback from the tumor microenvironment. Herein, we synthesized a novel two-dimensional (2D) vanadium-based nanosheets (Vanadene, V NSs) with polyvalent surfaces (VIV/VV), a very narrow band gap of 0.8 eV, and high biodegradability by a liquid-phase exfoliation strategy. The polyvalent surface endowed its multiple capabilities to modulate TME through GSH consumption and O 2 production via VV and to catalyze a Fenton-like reaction to produce ·OH under a mild condition via VIV. In addition, efficient energy conversions including near-infrared (NIR)-thermal conversion (photothermal therapy, PTT) and NIR-electron conversion (photodynamic therapy, PDT) were ensured by the narrow band gap, in which NIR-thermal conversion enhanced the Fenton-like reaction activity through accelerating ionization while NIR-electron conversion catalyzed the conversion of O 2 to ·O 2 − for further breaking redox homeostasis. Moreover, V NSs-based nanocatalyst can be slowly degraded into non-toxic species, enabling it to be innocuously eliminated from the body after completing tumor eradication by single drug injection and single NIR irradiation. Therefore, this study provides new insights into a universal nanoplatform for NIR-enhanced combination cancer therapy, highlighting the utility of 2D V NSs in the field of biomedicine. [ABSTRACT FROM AUTHOR]

Background: Rhizoma smilacis glabrae (RSG, tufuling) has been widely used in traditional Chinese medicine for deoxidation, dampness relief, and easing joint movement. The chemical composition of RSG has been systematically confirmed, and some of its compounds have been revealed to possess antioxidant, anti-inflammatory, immunomodulatory, hypouricemic, and hepatoprotective effects.Purpose: We aimed to clarify whether a RSG extract attenuates hyperuricemia, paw edema, and renal injury in mice with potassium oxonate (PO)- and monosodium urate (MSU)-induced chronic hyperuricemia and gout.Methods: RSG water extract was obtained and analyzed by HPLC-DAD-MS/MS. To establish a murine model with chronic hyperuricemia and gout, PO was orally administered daily from day 0 to day 24, whereas MSU was injected into the tibiotarsal joint on day 21. The mice in the drug intervention groups were treated once daily with doses of allopurinol or RSG extract from day 21 to day 24. The diameter of the ankle joints was measured with calipers. Serum TNF-α and IL-1β concentrations, hepatic XOD activity, and uric acid, creatinine, and blood urea nitrogen (BUN) levels were also determined. The right kidney and articular cavities were fixed, cut into sections, and stained with hematoxylin and eosin.Results: Nine compounds in the RSG water extract were unambiguously identified as 5-O-caffeoylshikimic acid, neoastilbin, astilbin, taxifolin, neoisoastilbin, isoastilbin, engeletin, isoengeletin, and trans-resveratrol. The RSGE treatment dose-dependently reduced PO- and MSU-induced paw edema, serum TNF-α, IL-1β, IL-6, IL-12, uric acid, and BUN, while significantly elevated serum IL-10, urinary uric acid and creatinine levels as compared with the respective values in the hyperuricemic and gouty mice group (vehicle group). Moreover, the hepatic XOD activity was dose-dependently reduced by the RSGE treatment. In addition, RSGE treatment not only ameliorated the infiltration of inflammatory cells, tubular dilation and vacuole formation in renal tubular, but also improved the synovial hyperplasia, reduced inflammatory cells infiltration into the synovium, and diminished the erosive damage in the cartilage.Conclusion: The murine model with chronic hyperuricemia and gout be built in present study is consistent with the clinical symptoms of patients with long-standing hyperuricemia and acute gouty arthritis. RSG water extract has potent efficacy in ameliorating murine hyperuricemia and gout induced by PO and MSU. [ABSTRACT FROM AUTHOR]

Tumor cells reprogram the metabolic pathways to acquire abundant nutrients and sustain malignant proliferation. This fierce metabolic competition in tumor ecosystem has been uncovered to be associated with tumor microenvironmental immunosuppression. Here we develop an adenosine triphosphate (ATP)-exhausted nanocomplex (IR@ZIF-RGD) to intervene in tumor energy metabolism and regulate tumor immune microenvironment. IR@ZIF-RGD could effectively deplete intracellular ATP and inhibit ATP synthesis by ATP-responsive ZIF-90 and siRNA targeting thioredoxin reductase-2, respectively, thus leading to tumor metabolism disorders and immunosuppressive reversion. Meanwhile, IR@ZIF-RGD induced oxidative stress and ICG triggered photothermal therapy could provoke potent immunogenic cell death to enhance antitumor immunogenicity. Such a photo-immunometabolic nanocomplex has been demonstrated to be an efficient vaccine to elicit protective anticancer immune response in vivo, achieving suppressed growth of both primary and abscopal tumors, as well as inhibited tumor metastasis. [ABSTRACT FROM AUTHOR]

In this study, we investigate the effect and underlying mechanism of hyperbaric oxygen (HBO) treatment on a model of repeated cerebral ischemia-reperfusion injury (IR). Eighty rats were randomly separated into sham, vehicle, hyperbaric air (HBA; 0.25 MPa, 60 min), and HBO (0.25 MPa, 60 min) groups. Repeated cerebral IR was induced by ligating the right and left bilateral common carotid arteries for 10 min and then allowing reperfusion for 10 min. This pattern was repeated three times. The neuroprotective effects of HBO were assessed by animal behavior, neuron morphology, inflammatory markers, intracellular calcium ion content, and autophagy-related protein and gene expression. Our result showed that HBO improved learning and memory in the navigation trail and probe trail of the Morris water maze, and these findings were supported by the observation data from 2,3,5-Triphenyltet-razolium chloride staining, Nissl staining, and electron microscopic. Importantly, we found that HBO reduced excessive autophagy in the prefrontal cortex, which was evidenced by activating of the mammalian target of the rapamycin (mTOR) and 4E-BP1, as well as suppression of LC3II and ATG5. Moreover, HBO significantly inhibited the cerebral IR-induced inflammatory reaction. Furthermore, HBO treatment modulated autophagy pathway-related factors, including producing a decrease in the intracellular calcium ion concentration and p53 level; meanwhile, the levels of BDNF and p-Akt were increased. Our results indicated that HBO protected against IR-induced neuron injury by attenuating autophagy, inflammation, and calcium overload. These results provide a new mechanism and laboratory evidence for clinical treatment of VD. [ABSTRACT FROM AUTHOR]