Metal natural product complex Ru-procyanidins with quadruple enzymatic activity combat infections from drug-resistant bacteria.

Bacterial infection hampers wound repair by impeding the healing process. Concurrently, inflammation at the wound site triggers the production of reactive oxygen species (ROS), causing oxidative stress and damage to proteins and cells. This can lead to chronic wounds, posing severe risks. Therefore, eliminating bacterial infection and reducing ROS levels are crucial for effective wound healing. Nanozymes, possessing enzyme-like catalytic activity, can convert endogenous substances into highly toxic substances, such as ROS, to combat bacteria and biofilms without inducing drug resistance. However, the current nanozyme model with single enzyme activity falls short of meeting the complex requirements of antimicrobial therapy. Thus, developing nanozymes with multiple enzymatic activities is essential. Herein, we engineered a novel metalloenzyme called Ru-procyanidin nanoparticles (Ru-PC NPs) with diverse enzymatic activities to aid wound healing and combat bacterial infections. Under acidic conditions, due to their glutathione (GSH) depletion and peroxidase (POD)-like activity, Ru-PC NPs combined with H2O2 exhibit excellent antibacterial effects. However, in a neutral environment, the Ru-PC NPs, with catalase (CAT) activity, decompose H2O2 to O2, alleviating hypoxia and ensuring a sufficient oxygen supply. Furthermore, Ru-PC NPs possess exceptional antioxidant capacity through their superior superoxide dismutase (SOD) enzyme activity, effectively scavenging excess ROS and reactive nitrogen species (RNS) in a neutral environment. This maintains the balance of the antioxidant system and prevents inflammation. Ru-PC NPs also promote the polarization of macrophages from M1 to M2, facilitating wound healing. More importantly, Ru-PC NPs show good biosafety with negligible toxicity. In vivo wound infection models have confirmed the efficacy of Ru-PC NPs in inhibiting bacterial infection and promoting wound healing. The focus of this work highlights the quadruple enzymatic activity of Ru-PC NPs and its potential to reduce inflammation and promote bacteria-infected wound healing.

Engineering a hyaluronic acid-encapsulated tumor-targeted nanoplatform with sensitized chemotherapy and a photothermal effect for enhancing tumor therapy.

Chemotherapy remains one of the most widely used cancer treatment modalities in clinical practice. However, the characteristic microenvironment of solid tumors severely limits the anticancer efficacy of chemotherapy. In addition, a single treatment modality or one death pathway reduces the antitumor outcome. Herein, tumor-targeting O2 self-supplied nanomodules (CuS@DOX/CaO2-HA) are proposed that not only alleviate tumor microenvironmental hypoxia to promote the accumulation of chemotherapeutic drugs in tumors but also exert photothermal effects to boost drug release, penetration and combination therapy. CuS@DOX/CaO2-HA consists of copper sulfide (CuS)-loaded calcium peroxide (CaO2) and doxorubicin (DOX), and its surface is further modified with HA. CuS@DOX/CaO2-HA underwent photothermal treatment to release DOX and CaO2. Hyperthermia accelerates drug penetration to enhance chemotherapeutic efficacy. The exposed CaO2 reacts with water to produce Ca2+, H2O2 and O2, which sensitizes cells to chemotherapy through mitochondrial damage caused by calcium overload and a reduction in drug efflux via the alleviation of hypoxia. Moreover, under near infrared (NIR) irradiation, CuS@DOX/CaO2-HA initiates a pyroptosis-like cell death process in addition to apoptosis. In vivo, CuS@DOX/CaO2-HA demonstrated high-performance antitumor effects. This study provides a new strategy for synergistic enhancement of chemotherapy in hypoxic tumor therapy via combination therapy and multiple death pathways.

Tannic acid and zinc ion coordination of nanase for the treatment of inflammatory bowel disease by promoting mucosal repair and removing reactive oxygen and nitrogen species.

Colon mucosal overexpression of reactive oxygen and nitrogen species (RONS) accelerates the development of inflammatory bowel disease (IBD) and destroys the mucosa and its barrier. IBD can be alleviated by removing RONS from the inflamed colon. The preparation of strong and efficient nanoantioxidants remains a challenge despite the development of numerous nanoantioxidants. In this paper, Zn-TA nanoparticles with fine hollow microstructure (HZn-TA) were successfully prepared and could be effectively used to treat IBD. In the first step, ZIF-8 nanoparticles were synthesized by a one-pot method. On this basis, HZn-TA nanoparticles were etched by TA, and a multifunctional nanase was developed for the treatment of IBD. RONS, including reactive oxygen species (ROS) and nitric oxide (NO), can be eliminated to increase cell survival following Hydrogen peroxide (H2O2) stimulation, including reactive oxygen species (ROS) and nitric oxide (NO with hydrogen peroxide (H2O2). In a model for preventing and delaying acute colitis, clearance of RONS has been shown to reduce intestinal inflammation in mice by reducing colon damage, proinflammatory cytokine levels, the spleen index, and body weight. Intestinal mucosal healing can be promoted by HZn-TA nanoparticles, which can upregulate zonula occludens protein 1 (ZO-1) and claudin-1 expression. Based on the results of this study, HZn-TA nanoparticles were able to effectively treat IBD with minimal adverse effects by being biocompatible, multienzyme active, and capable of scavenging RONS. Therefore, we pioneered the application of HZn-TA nanoparticles for the treatment of IBD, which are capable of clearing RONS without significant adverse effects. STATEMENT OF SIGNIFICANCE: ➢ HZn-TA nanoparticles were successfully prepared and could be effectively used to treat IBD. ➢ Intestinal mucosal healing can be promoted by HZn-TA nanoparticles, which can upregulate ZO-1 and claudin-1 expression. ➢ HZn-TA nanoparticles were able to effectively treat IBD with minimal adverse effects by being biocompatible, multienzyme active, and capable of scavenging RONS.

Two-dimensional TiO nanosheets with photothermal effects for wound sterilization.

To combat multidrug-resistant bacteria, researchers have poured into the development and design of antimicrobial agents. Here, low-cost two-dimensional (2D) antibacterial material titanium monoxide nanosheets (TiO NSs) were prepared by an ultrasonic-assisted liquid-phase exfoliation method. When cultured with bacteria, TiO NSs showed intrinsic antimicrobial capacity, possibly due to membrane damage caused by the sharp edges of TiO NSs. Under near-infrared (NIR) laser irradiation, TiO NSs showed high photothermal conversion efficiency (PTCE) and sterilization efficiency. By combining these two antibacterial mechanisms, TiO NSs exhibited a strong killing effect on Gram-negative Escherichia coli (E. coli) and Gram-positive methicillin-resistant Staphylococcus aureus (MRSA). Especially after treatment with TiO NSs (150 µg mL-1) +near-infrared (NIR) light irradiation, both bacteria were completely killed. In vivo experiments on wound repair of bacterial infection further confirmed its antibacterial effect. In addition, TiO NSs had no obvious toxicity or side effects, so as a kind of broad-spectrum 2D antibacterial nanoagent, TiO NSs have broad application prospects in the field of pathogen infection.

Injectable Hydrogel Containing TiO Nanosheets for Synergistic Photothermal/Thermodynamic Therapy.

Tumors have become the biggest obstacle to human health, and there are various treatment methods at present. Photothermal therapy (PTT) is usually ineffective and does not inhibit tumor progression due to the inability of the lasers to penetrate deeply. Therefore, most existing studies chose a 1064 nm laser with stronger penetrating power; meanwhile, studies have shown that the inclusion of harmful free radicals can significantly improve the antitumor efficacy. Herein, TiO nanosheets (NSs) were creatively prepared and encapsulated with an alkyl radical generator {2,2'-azobis[2-(2-imidazoline-2-yl)propane] dihydrochloride, [AIPH]} in sodium alginate (ALG) hydrogel for effective tumor killing by PTT and pairing with dangerous free radicals. TiO NSs were obtained by the liquid-phase exfoliation method, together with AIPH, which were in situ coencapsulated multifunctional hydrogels formed by the combination of Ca2+ and ALG. This ALG hydrogel could enrich TiO NSs and AIPH at the tumor site for a long time, and through the excellent photothermal properties of TiO NSs, AIPH could slowly and effectively generate alkyl radicals at the tumor site, which, in turn, gave it a better antitumor effect compared with that of TiO NSs in the deep hypoxic environment of the tumor. The AIPH + TiO + ALG hydrogel has distinctive anticancer capabilities based on the results of both in vivo and in vitro experiments. This material also has good biosafety. By combining PTT and free radical treatment, this work provides a novel therapeutic method to achieve oxygen-independent free radical production and enhance therapeutic efficacy.

Multifunctional two-dimensional Bi2Se3 nanodiscs for anti-inflammatory therapy of inflammatory bowel diseases.

The overexpression of reactive oxygen and nitrogen species (RONS) in the colonic mucosa destroys the mucosa and its barrier, accelerating the occurrence of inflammatory bowel disease (IBD). The elimination of RONS from the inflammatory colon has proven effective in alleviating IBD. Although many nanoantioxidants have been developed, preparing robust and efficient nano-antioxidants remains challenging. Herein, by modifying bismuth selenide (Bi2Se3) nanodiscs with polyvinylpyrrolidone (PVP), a multifunctional nanozyme based on 2D nanomaterials was developed for the treatment of IBD. By eliminating multiple RONS, such as hydroxyl radicals (•OH), superoxide anions (O2-•), nitric oxide (NO), and Bi2Se3 nanodiscs enhanced cellular survival after H2O2 stimulation. As evidenced by colonic injury, reduced body weight, spleen index, and proinflammatory cytokine levels in mice, RONS clearance alleviated intestinal inflammation in a prevention and delay model of acute colitis. 16S rDNA amplicon sequencing reveals that Bi2Se3 nanodiscs had the potential to regulate intestinal flora, increase the proportion of Firmicutes to Bacteroidetes, inhibit Proteobacteria bacteria, and restore intestinal homeostasis. This study highlights the use of Bi2Se3 nanodiscs with excellent biocompatibility, multienzyme functionality, and RONS scavenging ability as treatments for IBD without apparent adverse effects. STATEMENT OF SIGNIFICANCE: RONS were efficiently scavenged by Bi2Se3 nanodiscs. Bi2Se3 nanodiscs could be as a promising and potentially safe theraeputic agent for IBD. The gut microbiota could be modulated by Bi2Se3 nanodiscs.

Membrane multiple quantum well electro-optical modulator employing low loss high-k radio-frequency slot waveguides.

A membrane multiple quantum well (MQW) electro-optical (EO) modulator exploiting low loss high-k radio-frequency (RF) slot waveguides is proposed for sub-terahertz bandwidth. By employing high-k barium titanate (BTO) claddings in place of doped InP cladding layers in traditional InP-based MQW modulators, the proposed modulator exhibits enhanced modulation efficiency and bandwidth as well as reduced insertion loss. A low half-wave voltage-length product of 0.24 V·cm is estimated, together with over 240 GHz bandwidth for a 2-mm-long modulation region, thus allowing sub-terahertz operation.

The Efficacy of the Systemic Immune-Inflammation Index and Prognosis Nutritional Index for the Diagnosis of Venous Thromboembolism in Gastrointestinal Cancers.

Purpose: This study aimed to analyze the association between venous thromboembolism (VTE) and inflammatory markers like systemic immune-inflammation index (SII) and prognosis nutritional index (PNI), and to evaluate their efficacy for the diagnosis of VTE in patients with gastrointestinal malignancies. Patients and Methods: A total of 1326 patients with the initial diagnosis of gastrointestinal cancer in the First Affiliated Hospital of Anhui Medical University (AHMU) were enrolled in the training cohort. Univariate and multivariate analysis was used to pinpoint independent predictors of VTE, which were eventually visualized as the nomogram models. The Akaike Information Criterion (AIC) was used to screen the best model. The receiver operating characteristic curve (ROC) and the clinical decision curve analysis (DCA) were utilized to evaluate the models' predictive performance in the training queue and another external sample of 250 patients at the Second Affiliated Hospital of AHMU. Results: A total of 476 patients were complicated with VTE in the training cohort. Multifactorial analysis of clinical characteristics and inflammatory markers showed that PNI, SII, age, tumor location, and therapy were independent risk factors of VTE, visualized as model A. Another model B was constructed by adding coagulation markers to the previous analysis. Model B was the best prediction model with the minimum AIC value, followed by model A with an AUC of 0.806 (95% CI 0.782~0.830) which was similar to model B's 0.832 (95% CI 0.810~0.855) but significantly higher than the currently widely used Khorana score's 0.592 (95% CI 0.562~0.621) and the CATS score's 0.682 (95% CI 0.653~0.712). The external verification yielded similar findings, with the AUC being 0.792 (95% CI 0.734~0.851), 0.834 (95% CI 0.778~0.890), 0.655 (95% CI 0.582~0.729), and 0.774 (95% CI 0.699~0.849) respectively. The DCA curves demonstrated that new models had excellent usefulness in screening patients with a high VTE risk. Conclusion: The SII and PNI were simple and viable inflammatory markers associated with VTE, and the nomogram based on them and clinical features had a meaningful clinical utility for VTE in patients with gastrointestinal malignancies.

Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis.

BACKGROUND: This study aimed to investigate the effect of bone marrow mesenchymal stem cell (BMSC)-derived exosome injection on cartilage damage and pain relief in both in vitro and in vivo models of osteoarthritis (OA). METHODS: The BMSCs were extracted from rat bone marrow of the femur and tibia. Chondrocytes were treated with IL-1ß to establish the in vitro model of OA. Chondrocyte proliferation and migration were assessed by CCK-8 and transwell assay, respectively. A rat model of OA was established by injection of sodium iodoacetate. At 6 weeks after the model was established, the knee joint specimens and dorsal root ganglion (DRG) of rats were collected for histologic analyses. For pain assessment, paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were evaluated before model establishment and at 1, 2, 4, and 6 weeks after model establishment. RESULTS: Exosomes can be endocytosed with the chondrocytes in vitro. Exosome treatment significantly attenuated the inhibitory effect of IL-1ß on the proliferation and migration of chondrocytes. Exosome pre-treatment significantly attenuated IL-1ß-induced downregulation of COL2A1 and ACAN and upregulation of MMP13 and ADAMTS5. In the animal study, exosome treatment significantly upregulated COL2A1 protein and downregulated MMP13 protein in the cartilage tissue of the OA rat. At weeks 2, 4, and 6, the PWL value was significantly improved in the exosome-treated OA rats as compared with the untreated OA animals. Moreover, exosome treatment significantly alleviated the upregulation of CGRP and iNOS in the DRG tissue of OA rats. CONCLUSION: BMSC-derived exosomes can effectively promote cartilage repair and extracellular matrix synthesis, as well as alleviate knee pain in the OA rats.

Inhibition of astrocytic differentiation of transplanted neural stem cells by chondroitin sulfate methacrylate hydrogels for the repair of injured spinal cord.

Neural stem cell (NSC) transplantation exerts a therapeutic effect on spinal cord injury (SCI) but is limited to an unregulated differentiation pattern by which NSCs preferentially differentiate into astrocytes, with relatively few neurons. It is well established that the increased NSC-derived astrocytes exhibit aberrant axonal sprouting associated with allodynia-like symptoms of the forepaws. Some strategies have been used to overcome this issue, such as regulation of major pathways, ex vivo gene transfer, and genetic overexpression. However, lack of efficiency, viral vector safety issues and the risk of tumorigenesis have hindered the clinical application of these treatments. Here, we show that astrocytic differentiation of NSCs in vitro and in vivo can be inhibited by encapsulation of cells in a three-dimensional chondroitin sulfate methacrylate (CSMA) hydrogel. When CSMA hydrogels were used to transplant NSCs, the combinatory implant promoted functional recovery and attenuated the hypersensitivity responses of the forepaws. Further analysis showed that transplantation of NSCs within CSMA hydrogels reduced injured cavity areas and promoted neurogenesis rather than fibroglial formation after graft implantation. Furthermore, the treatment prevented allodynia-related CGRP/GAP43-positive nociception due to fibers sprouting into inappropriate lamina regions. Taken together, these findings show that CSMA/NSCs combined transplantation helps prevent adverse side effects of NSCs treatment and promotes recovery of SCI.

A new chiral pyrrolyl α-nitronyl nitroxide radical attenuates ß-amyloid deposition and rescues memory deficits in a mouse model of Alzheimer disease.

The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer's disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on ß-amyloid (Aß) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aß exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aß deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.

Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired in Fmr1 knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied. RESULTS: Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice. CONCLUSION: The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.

Neuroprotective effects of Salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro.

Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L. that elicits neuroprotective effects in vivo and in vitro. Tyrosol galactoside (Tyr), an analog of Sal, was recently synthesized in our laboratory. The purpose of the current study was to investigate and compare the neuroprotective effects of Sal and Tyr against focal cerebral ischemia in vivo and H(2)O(2)-induced neurotoxicity in vitro. Sal and Tyr significantly prevented a cerebral ischemic injury induced by a 2 h middle cerebral artery occlusion and a 24 h reperfusion in rats in vivo. Furthermore, the oxidative insult was markedly attenuated by treatments of Sal and Tyr in the cultured rat cortical neurons after a 30 min exposure to 50 µM of H(2)O(2). Western blot analysis revealed that Sal and Tyr decreased the expression of Bax and restored the balance of pro- and anti-apoptotic proteins. The neuroprotective effects of these two analogues show that Tyr has a better antioxidative action compared with Sal both in vivo and in vitro, and suggest that the antioxidant activity of Sal and Tyr may be partly due to their different substituents in their glycosyl groups. This gives a new insight into the development of therapeutic natural antioxidants against oxidative stress.

Acute stress induces down-regulation of large-conductance Ca2+-activated potassium channels in the lateral amygdala.

Large-conductance Ca2+-activated potassium channels (BKCa) are highly expressed in the lateral amygdala (LA), which is closely involved in assigning stress disorders, but data on their role in the neuronal circuits of stress disorders are limited. In the present study, a significant reduction in BKCa channel expression in the amygdala of mice accompanied anxiety-like behaviour induced by acute stress. Whole-cell patch-clamp recordings from LA neurons of the anxious animals revealed a pronounced reduction in the fast after-hyperpolarization (fAHP) of action potentials mediated by BKCa channels that led to hyperexcitability of the LA neurons. Activation of BKCa channels in the LA reversed stress-induced anxiety-like behaviour after stress. Furthermore, down-regulated BKCa channels notably increased the evoked NMDA receptor-mediated excitatory postsynaptic potentials at the thalamo-LA synapses. These data demonstrate, for the first time, that restraint stress-induced anxiety-like behaviour could at least partly be explained by alterations in the functional BKCa channels in the LA.

Blocking α4ß2 and α7 nicotinic acetylcholine receptors inhibits the reinstatement of morphine-induced CPP by drug priming in mice.

Investigating the interaction between nicotinic and opioid receptors is of great interest for both basic mechanistic and clinical reasons. Morphine and nicotine, two common drugs of abuse, share several behavioral and rewarding properties. However, little is known about the subtypes of nicotinic acetylcholine receptors (nAChR) in the reinstatement of morphine-induced conditioned place preference (CPP). In this study, we found that a non-specific nAChR agonist, nicotine (0.5mg/kg), had no effects on the reinstatement of morphine-induced CPP. However, we found that pretreatment with specific α(4)ß(2) and α(7) nAChR subtype antagonists, dihydroxy-ß-erithroidine (DHßE, 5mg/kg) and methyllycaconitine (MLA, 4 mg/kg), 20 min prior to administration of morphine, inhibited the reinstatement of morphine-induced CPP by drug priming in mice. Furthermore, depression of the reinstatement of morphine-induced CPP by a single DHßE or MLA treatment lasted at least three days later when the reinstatement was induced by morphine priming. The data suggest that specific nAChR subtypes, i.e., α(4)ß(2) and α(7), may contribute to the reinstatement of morphine-induced CPP by drug priming in mice.