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Osteoarthritis (OA), a widespread degenerative disease characterized by cartilage destruction, has emerged as a public health challenge in the current aging society. In addition to applied steroids and surgery, near-infrared (NIR) sensitive nano-enzyme for the treatment of osteoarthritis through mitochondrial repair and cartilage protection is attractive and promising. In this study, a NIR sensitive multifunctional heterostructure (EGCG (Epigallocatechin gallate) decorated Au-Ag nano-jars (E@Au-Ag)) was introduced as an enzyme-sensitive active nanoplatform for the treatment of osteoarthritis. Molecular biology results indicated that E@Au-Ag possesses intrinsic properties of anti-oxidative stress and was able to reduce the apoptosis rate of chondrocytes by 83.3%. The area of the intra-articular joint cavity injected with E@Au-Ag can be elevated to 46.6 °C under NIR to promote the release of EGCG further to induce cartilage regeneration. X-ray radiography and section staining showed that E@Au-Ag reduced cartilage damage and decreased OARSI scores by approximately 52% after 8 weeks of treatment in a surgically induced OA model. The results demonstrated that this multifunctional enzyme-like nanoplatform with a synergistic NIR sensitive property to facilitate cartilage migration and regeneration repair provides a promising OA treatment strategy. 1. NIR-sensitive nano-enzyme is gaining much attention in the field of biomedical materials. 2. EGCG decorated Au-Ag nano-heterostructures were utilized as NIR-sensitive nano-enzymes for the treatment of osteoarthritis through mitochondrial repair and cartilage protection. 3. The obtained multifunctional Au-Ag nano-heterostructures are promising for osteoarthritis treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Multidrug-resistant (MDR) bacteria-induced infection is becoming a huge challenge for clinical treatment, especially for non-healing diabetic wound infections, which increase patient mortality. MRSA infections and delayed wound healing (methicillin-resistant Staphylococcus aureus) accounted for a higher proportion. Although surgical debridement and continuous use of antibiotics are still the main clinical treatments, new multifunctional therapeutic nanoplatform are attractive for MIDW. Thus, in the present study, black phosphorus quantum dots (BPQDs) encapsulated in hydrogel (BPQDs@NH) were utilized as nanoplatforms for MIDW treatment to achieve the multifunctional properties of NIR (near infrared) responsiveness, ROS (reactive oxygen species) generation and antibacterial activity. Upon NIR irradiation, the temperature of the BPQDs@NH-treated MIDW area rapidly increased up to 55 °C for sterilization. In vitro experiments showed that BPQDs@NH exerted a synergistic effect on inhibiting MRSA by producing of ROS, lipid peroxidation, glutathione, adenosine triphosphate accumulation and bacterial membrane destruction upon NIR irradiation. The resulting BPQDs@NH achieved an effective sterilization rate of approximately 90% for MRSA. Furthermore, animal experiments revealed that BPQDs@NH achieved an effective closure rate of 95% for MIDW after 12 days by reducing the inflammatory response and regulating the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Meanwhile, intravenous circulation experiments showed good biocompatibility of BPQDs, and no obvious damage to rat major organs was observed. The obtained results indicated that BPQDs@NH achieved the synergistic functions of NIR-responsiveness, ROS generation, and antibacterial activity and promoted wound healing, suggesting that they are promising multifunctional nanoplatforms for MIDW healing. 1. NIR-triggered ROS-generating and antibacterial nanoplatforms are attractive in the wound healing field. 2. In this work, black phosphorus quantum dots encapsulated in a hydrogel were used as a nanoplatform for treating MRSA infected wounds. 3. The obtained materials have achieved an effective sterilization rate for MRSA and effective wound closure rate. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights • RAGE blockade reduced CNPase and MBP positive Oligodendrocytes after SCI. • RAGE was involved in regulating Oligodendrocyte autophagy after injury. • RAGE blockade attenuated survived neurons at ventral horn after SCI. Abstract Receptor for advanced glycation end product (RAGE) is involved in neuronal inflammation, cell cycle and differentiation. However, the role of RAGE in autophagy in the process of spinal cord injury (SCI) is yet unknown. The present study investigated the effect of RAGE blockade on autophagy in SCI. A rat Allen SCI model was established and the animals were micro-injected with rabbit RAGE neutralizing antibody or rabbit polyclonal Ig G immediately after the injury. The oligodendrocytes(OLs) marker, 2′, 3′-cyclic nucleotide 3′-phosphodiesterase(CNPase) and autophagy-related marker microtubule associated protein light chain 3B(LC3B) were evaluated by Western blot. Furthermore, myelin basic protein (MBP) and LC3B double staining were observed in the SCI via immunofluorescence. The results showed that RAGE blockade reduced the expression of CNPase, promoted LC3B-II/I and p62 expression after SCI. In addition, the MBP/LC3B double positive oligodendrocytes-expressing LC3B was up-regulated by RAGE blockade. Moreover, RAGE blockade attenuated the neuronal survival at ventral horn after SCI. The present study revealed the role of RAGE in maintaining oligodendrocyte autophagy to promote neuronal regeneration post-SCI. [ABSTRACT FROM AUTHOR]

We have previously reported that intra-articular injection of xanthan gum (XG) could significantly ameliorate the degree of joint cartilage degradation and pain in experimental osteoarthritis (OA) model in vivo . In this present study, we evaluated the protective effect of XG against Sodium nitroprusside (SNP)-induced rabbit articular chondrocytes apoptosis in vitro . Rabbit articular chondrocytes were incubated with various concentrations of XG for 24 h prior to 0.5 mmol/L SNP co-treatment for 24 h. The proliferation of chondrocytes was analyzed using MTT assay. The chondrocytes early apoptosis rates were evaluated using Annexin V-FITC/PI flow cytometry. The morphology of apoptosis chondrocytes were observed by scanning electron microscopy (SEM). The loss/disruption of mitochondrial membrane potential was detected using rhodamin 123 by confocal microscope. The concentration of prostaglandin E 2 (PGE 2 ) in cell culture supernatants was evaluated using ELISA assay. The results showed that XG could significantly reverse SNP-reduced cell proliferation and inhibited cell early apoptosis rate in a dose-dependent manner. XG alleviated loss/disruption of mitochondrial membrane potential and decreased the PGE 2 level of chondrocytes cell culture supernatants in SNP-induced chondrocytes. These results of the present research strongly suggest that XG can protect rabbit articular chondrocytes against SNP-induced apoptosis in vitro . [ABSTRACT FROM AUTHOR]

• Resveratrol therapy improved the motor function of post-SCI rats. • Resveratrol therapy improved the the survival of motor neurons and reduced lesion sizein the rats after SCI. • SIRT-1/NF-κB signaling pathway was activated by resveratrol in the rats after SCI. • Resveratrol treatment reduced inflammatory response and increased the expression of BDNF after SCI. • Resveratrol upregulates SIRT-1 and inhibits inflammation after SCI in rats. Spinal cord injury (SCI) can cause severe trauma to the central nervous system. Resveratrol has been widely studied for several of its medicinal properties, including anti-inflammatory, anti-aging and anti-oxidative effects. The regulation of SIRT-1 is thought to be related to the effects of resveratrol. As a downstream component of SIRT-1, NF-κB is one of the important signaling pathways that regulate the inflammatory response. Herein, we explored how treatment with resveratrol promoted recovery of motor function after SCI by activating the SIRT-1/NF-κB signaling pathway and inhibiting inflammation in rat models. Recovery of hind limb function was observed using the Basso, Beattie, and Bresnahan locomotor rating scale at different time points after SCI. Western blot analysis, immunofluorescence, Nissl staining and HE staining were utilized to observe the morphological characteristics of spinal cord tissue, as well as the expression of SIRT-1, NF-κB, TNF-α, IL-1β, IL-6 and brain-derived neurotrophic factor. Resveratrol treatment promoted motor function recovery, increased the expression of brain-derived neurotrophic factor, and reduced loss of motor neurons and lesion size among rats after SCI. Meanwhile, inflammatory response was inhibited as the SIRT-1/NF-κB signaling pathway was modulated. These results suggest that resveratrol can help achieve neuroprotective effect by inhibiting inflammation, regulated by the SIRT-1/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Spinal cord injury is a serious traumatic nervous system disorder characterized by extensive neuronal apoptosis. Oxidative stress, a key factor in neuronal apoptosis, leads to the accumulation of reactive oxygen species, making mitochondrial quality control within cells crucial. Previous studies have demonstrated zinc's anti-inflammatory and anti-apoptotic properties in protecting mitochondria during spinal cord injury treatment, yet the precise mechanisms remain elusive. Single-cell sequencing analysis has identified Lgals3 and Bax as core genes in apoptosis. This study aimed to investigate whether zinc ions protect intracellular mitochondria by inhibiting the apoptotic proteins Lgals3 and Bax. We elucidated zinc ions' key role in mitigating mitochondrial quality control dysfunction triggered by oxidative stress and confirmed this was achieved by targeting the Lgals3-Bax pathway. Zinc's inhibitory effect on this pathway not only preserved mitochondrial integrity but also significantly reduced PANoptosis after spinal cord injury. Under oxidative stress, zinc ion regulation of mitochondrial quality control reveals an organelle-targeted therapeutic strategy, offering a novel approach for more precise treatment of spinal cord injury. [Display omitted] • Zinc ions modulate mitochondrial quality control through Lgals3. • Lgals3 regulates mitochondrial quality control within cells by modulating Bax. • Zinc ions alleviate PANoptosisby regulating mitochondrial quality through the Lgals3-Bax pathway. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is very complex and causes complicated neurological disorders with serious socioeconomic implications. After SCI, some cells are seriously damaged and the lesion face physiological, anatomical, chemical, and immune system changes that hinder their attempts for recovering. Near-Infrared (NIR) light-assisted therapy for SCI treatment is quite limited, but the reported work has shown great promise to combat SCI, which particularly has more efficient anti-inflammation and tissue regeneration effects. To advance research on NIR adjuvant therapy for SCI, we summarized the reported strategies including the NIR light-assisted control-release system and NIR light-assisted photothermal therapy (NIR-PTT) to assist therapy of SCI. In addition, the prospect and challenges for widespread clinical implementation of NIR-assisted therapeutics are discussed. • Inhibition of secondary injury is an effective treatment for spinal cord injury. • At present, the commonly used clinical methods have great side effects. • NIR light-assisted therapy deserves deeper investigation for the therapy of spinal cord injury. • Using search tools with spinal cord injury NIR as the keyword to found some reports. • Facilitating the future advancement of NIR light-assisted therapy for spinal cord injury. [ABSTRACT FROM AUTHOR]

The signal transducer and activator of transcription 1 (STAT1) is associated with neuronal cell death after cerebral ischemia. However, the role of STAT1 in the spinal cord injury (SCI) remains unclear. Here, we examined whether STAT1 blockade reduces neural tissue damage and locomotor impairment after SCI in mice. The small interfering RNA against STAT1 (STAT1 siRNA) or control non-targeting siRNA was injected intraperitoneally into SCI mice. Histological damage and locomotor function were evaluated. Inflammatory markers and apoptosis were determined. STAT1 siRNA treatment significantly decreased the histological damage following SCI. STAT1 siRNA-treated mice showed significantly improved locomotor function compared with the controls. Furthermore, TNF-α, IL-1β, and IL-6 levels at the injured site from the STAT1 siRNA-treated group were significantly reduced and IL-10 increased, in comparison with controls. The NF-κB activation and apoptosis in SCI were also inhibited. These results reveal that selective STAT1 inhibition reduced neural tissue damage and locomotor impairment by regulating inflammatory response and possibly apoptosis. STAT1 represents a novel therapeutic target after SCI. [ABSTRACT FROM AUTHOR]

Macrophages and microglia (M/Ms) in the injured spinal cord maintain a predominantly neurotoxic M1 phenotype that is disadvantageous to repair in the development of spinal cord injury (SCI). It has been reported that tumor necrosis factor (TNF) that polarize M/Ms toward M1 state in various disorders. In this study, we found that ablation of TNF endorsed the beneficial conversion from M1 to M2 phenotype and improved the mitochondrial metabolism in vivo and in vitro. In addition, PGC-1α that accumulates in TNF null mice, a major participant of mitochondrial metabolism, downregulated ROS activity and the expressions of M1-specific mRNA. Moreover, the absence of TNF upgraded the morphology and quantity of damaged mitochondria and rapidly switched to M2 phenotype as compare to administration of N-Acetyl- l -cysteine (NAC). Furthermore, systemic application of TPEN showed that increased ratio of M1 M/Ms. These combined results supporting predominant and prolonged TNF expression that is destructive to recovery after SCI. These results indicated that TNF would have great potential immunomodulatory for the treatment of SCI. Scheme 1. The ablation of TNF upregulates M2 M/Ms, inhibits M1 M/Ms and continuously promotes neurons survival. [Display omitted] • TNF promotes M1 Polarization in the Injured Spinal Cord. • TNF Drives ROS-Induced mitochondrial activity after SCI. • Decreased Intracellular Zinc Influences TNF Expression and M/Ms Polarization. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel anti-inflammatory nanoplatform targeting CD44. • Invisibility in the blood circulation. • Good stability and conversion potential. • Suitable for various inflammatory diseases. Uncontrolled inflammatory response is both an intervention target for various diseases, and the design basis for drug delivery strategies. In this work, based on the highly enriched characteristics of M1 type macrophages in local inflammation, we used exosomes derived from bone marrow mesenchymal stem cells (BMSC) as drug carriers, modified with hyaluronic acid (HA) and polyethylene glycol (PEG) to prepare an inflammation targeted and anti-inflammatory treatment nanoplatform (EXs-PH). By targeting M1 macrophages, HA endows EXs-PH with the ability to target inflammation, while PEG reduces the interaction between plasma proteins and exosome membrane proteins, giving the exosomes the ability to circulate within the body for a long time. The results indicate that after HA and PEG (PH) modification, exosomes derived from BMSC (EXs) can effectively enrich in the inflammatory site, achieving precise administration of curcumin (Cur) with anti-inflammatory and repair promoting functions. In vivo experiments on acute and chronic inflammatory models of spinal cord injury (SCI) and rheumatoid arthritis (RA) also showed that PH modified Exs loaded with Cur (Cur@EXs-PH) were more effective in improving the recovery of motor function after lesions. In conclusion, the engineered Cur@EXs-PH we designed, provides a new drug delivery carrier for treating inflammatory diseases. [ABSTRACT FROM AUTHOR]

• Liraglutide promotes motor function recovery, reduces necrotic cavity and the loss of neurons after spinal contusion. • Liraglutide treatment promotes autophagy and autophagic flux in neurons after spinal contusion injury. • Liraglutide stimulates the autophagic responses via the AMPK-FOXO3 signaling pathway after spinal contusion injury. Spinal cord injury (SCI) induced by trauma is a devasting neurological consequences. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, has be shown to have neuroprotective effects in several neurodegenerative diseases. However, the potential benefits of liraglutide as well as the underlying mechanisms for its therapeutic benefit for SCI are unclear. We aimed to investigate the therapeutic benefits and decipher the potential signaling pathways of liraglutide in spinal contusion injury. A SD rat model with controlled spinal contusion was established for this study. Behavioral tests and histological examinations were performed to assess the neuroprotective benefits. Several autophagy markers were measured by western blot analysis and immunofluorescence staining, including LC3B, Beclin-1 and p62. In addition, the AMPK-FOXO3 signaling pathway was investigated. Our results demonstrated that liraglutide treatment strongly enhanced motor function recovery and alleviated the degree of necrosis and loss of motor neurons in the spinal cord tissue after contusion. Autophagic responses were activated by liraglutide. LC3B-II/LC3B-I and Beclin-1 expression was enhanced while p62 expression was reduced. In addition, the levels of p-AMPK/AMPK, FOXO3 and p-FOXO3 (phospho S253) were notably up-regulated by liraglutide. These effects were partly reversed by Compound C, an AMPK inhibitor. In summary, our results demonstrated that liraglutide was therapeutically beneficial in treating spinal contusion injury and its underlying mechanism was through the activation of autophagic responses through the AMPK-FOXO3 signaling pathway. [ABSTRACT FROM AUTHOR]

• Monodispersed chitosan nanospheres functionalized by mesoporous SiO 2 and folic acid were prepared. • The products have high drug loading efficiency, excellent circulation stability and sustained release property. • The products were pH-responsive, folic acid-triggered uptake and nuclear targeting. Ideal nanoscale drug delivery system (DDS) should be biocompatible, having targeted recognition and controlled release properties. In this work, monodispersed, doxorubicin (Dox) loaded chitosan (Cts) nanospheres functionalized by mesoporous SiO 2 and folic acid (FA) were prepared, briefly named as DCSF NSs. The prepared raspberry-like DCSF NSs had an average size of 440 nm and drug loading efficiency (DLE) of 42.61%. The drug release results confirmed that the release of Dox could be controlled by pH change. Cell apoptosis results indicated that the obtained DCSF NSs could kill 90% of MCF-7 cells in 48 h. Confocal laser scanning microscopy (CLSM) results further revealed that folic acid could mediate the cellular uptake of DCSF NSs. These results demonstrated that the obtained DCSF NSs were pH-responsive, folic acid-triggered nuclear targeted, which can be used as ideal DDS for tumor chemotherapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Safe and effective stimuli-responsive nanocarriers are very important for tumor chemotherapy. • GSH and enzyme responsive nanocarriers from self-assembly of green tea polyphenols and BSA were successfully prepared. • The products are folic acid-triggered uptake and nuclear targeting. Abstract Developing safe and effective stimuli-responsive nanocarriers is very important for tumor chemotherapy. In this work, bovine serum albumin (BSA) and green tea polyphenol (TP) were used to prepare glutathione (GSH) and enzyme (trypsin) responsive nanocarriers for doxorubicin (DOX). These nanocarriers were further modified with folate, briefly named as DOX@BSA-TP-FA NSs. The diameter of nanocarriers was about 220 nm. The DOX loading efficiency and loading amount were 86.4% and 23.5 wt%, respectively. The cellular uptake, apoptosis, and GSH and trypsin responsive release properties of these nanocarriers were investigated. [ABSTRACT FROM AUTHOR]

[Display omitted] • GSH-AuNCs were found to accumulate endogenous zinc in the injured spinal cord. • A new mechanism based on the accumulation of endogenous zinc in the treatment of SCI was proposed. • Endogenous zinc accumulation stimulates immunotherapy. • R. The proposed treatment has memory therapeutic effects. Spinal cord injury (SCI) can cause very serious bodily harm or even paralysis. However, all clinical drugs require long-term use to relieve the disease, causing toxicity and side effects. Zinc tends to activate the self-defense system to repair SCI, but the currently reported zinc supplementation is not efficient to cure SCI due to the poor targeting effects. The zinc delivery system has been employed to improve the targeting efficiency, which also increases the complexity and toxicity of drugs. On the other hand, we envisage that if there is a drug that can accumulate and activate endogenous zinc in the lesions of the spinal cord and stimulate immunotherapy, it can not only reduce long-term drug dependence but also significantly improve the therapeutic effect on SCI. Herein, we found zinc deficiency for SCI mice, but more zinc accumulated in the lesions of the spinal cord after the administration of GSH-AuNCs in SCI mice. Meanwhile, more microglia/macrophages polarize toward M2 from M1 phenotypes after zinc accumulation which enhances immunotherapy effects. Thereafter, the inflammatory response was inhibited, which exerts a neuroprotective effect. As well as this, the current treatment showed memory effects for zinc accumulation even after stopping the drug administration, allowing endogenous zinc to continue its induction of multiple therapeutic effects. Due to the direct and memory curative function, the lesions of SCI mice were well recovered and the motor functions were also significantly improved. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • pH responsive, antibacterial, multistage structured microspheres were designed. • These microspheres can effectively kill S. aureus and promote proliferation of osteoblasts. • These microspheres can package abundant tea polyphenols and protect their antioxidant activity. Abstract The treatment of bone infection requires drug carriers take large number of cargo, be antibacterial, promote proliferation and differentiation of osteoblasts. Herein, we proposed a strategy of preparing pH responsive, antibacterial, multistage structured microspheres encapsulated with green tea polyphenol used for minimally invasive treatment of bone infection. Tea polyphenol (TP) were encapsulated by porous silica nanospheres (SiO 2 NSs). Then, sodium alginate (SA) microgel spheres (MSs) were prepared to encapsulate a lot of TP loaded SiO 2 NSs. The outer layer of obtained TP@SiO 2 @SA microgel spheres were further wrapped by pH sensitive CaCO 3. Mineral out-layer of the composite microspheres is used to neutralize the acidic environment caused by bacterial infection. At the same time, encapsulated TP is released pH sensitively to resist oxidative stress. Our results exhibited excellent drug delivery properties including drug loading efficiency (DLE) of 92.96% and drug loading content (DLC) of 19.62%. Besides, results demonstrated that TP@SiO 2 @SA@CaCO 3 MSs can effectively kill Staphylococcus aureus and promote proliferation and differentiation of osteoblasts under stimulation of H 2 O 2 at pH = 5.5. [ABSTRACT FROM AUTHOR]

Abstract Aim Spinal cord injury (SCI) causes increased apoptosis of neurons, leading to irreversible dysfunction of the spinal cord. In this study, we investigated the effects of the progression of SCI and potential regulation of apoptosis after the Pleckstrin homology (PH) domain and leucine rich repeat protein phosphatase 1 ( PHLPP1 ) gene was silenced. Main methods Spinal cord injection, and neuronal transfection with a recombinant adenovirus vector encoding small interfering RNA (siRNA) against PHLPP1 (AdsiPHLPP1) successfully silenced PHLPP1. These created in vivo and in vitro PHLPP1-silenced models, respectively, resulting in stable expression of the transgene in neurons. Key findings The results showed that silencing of PHLPP1 evidently reduced levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) after SCI. Western blot analysis revealed that the mice injected with AdsiPHLPP1 showed increased the expression of pro-apoptotic factors (Bax and cleaved-caspase 3), and reduced levels of neurotrophic (BDNF) and anti-apoptotic (Bcl-2) factors, both in vivo and in vitro. The motor function of AdsiPHLPP1-injected mice was restored more slowly than that of wild type (WT) mice. In addition, the number of motor neurons surviving in the anterior horn of the spinal cord was also reduced after SCI. Significance Our results confirm that silencing of PHLPP1 promotes neuronal apoptosis and inhibits functional recovery after injury in vivo and in vitro. Consequently, PHLPP1 represents a potential therapeutic target gene for the clinical treatment of SCI. [ABSTRACT FROM AUTHOR]

N -(2-(3-fluorobenzyl)-2 H -indazol-5-yl)-2-phenyl-2 H -pyrazolo[4,3 -c ]qui- nolin-4-amine (LZC-2b) with a quinoline structure was synthesized as an anticancer prodrug. The pH sensitive anticancer drugs obtained by a simple hydrothermal method. The interaction of chitosan (Cts) and LZC-2b is used to complete the encapsulation without any cross-linking. The obtained micromedicine (LZC-2b@Cts-MSs) has an average size of ∼980 nm. The drug loading efficiency (DLE) of LZC-2b@Cts-MSs was about 79%. In addition, drug release from LZC-2b@Cts-MSs was pH depended. At pH = 7.4, only 5.1% of loaded LZC-2b was released, while 90.3% of loaded LZC-2b was released at pH = 5.0. Cell culture results indicate that LZC-2b@Cts-MSs can be easily uptaken by KB cells. Cell viability results show that KB cells can be effectively killed by LZC-2b@Cts-MSs. Our strategy of synthesis and preparation of pH responsive LZC-2b@Cts-MSs has promising prospect in chemotherapy of oral cancer. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is one of the most common chronic diseases and characterized by degradation of articular cartilage. We have previously reported xanthan gum (XG) injection preparation with high molecular weights ( Mw ) in ranging from 3 × 10 6 Da to 5 × 10 6 Da (HM-XG) could enhance the viscosity of synovial fluid, protect joint cartilage in rabbit, and the therapeutical effect has no significance difference with an existing clinical medication (sodium hyaluronate, SH) at the same injection frequency (once weekly for 5 weeks). Herein, we prepared a XG injection preparation with a low M w (LM-XG) in ranging from 1 × 10 6 Da to 1.5 × 10 6 Da, and evaluated the therapeutical effect for OA therapy at once every 2 weeks for 5 weeks with an SH at once weekly for 5 weeks as reference. The model of OA was induced using anterior cruciate ligament transection (ACLT) in a rabbit in vivo and also using sodium nitroprusside (SNP) in cell culture in vitro . The results showed that LW-XG could also protect cartilage from damage, decrease the concentration of nitric oxide (NO) in synovial fluid and reverse the amplification of the knee joint width similar to HM-XG as our previously reported. At the cellular level, LW-XG promotes proliferation while decreases apoptosis of chondrocytes. Mechanistically at the molecular level, these effects are elicited via down-regulation of the protein levels of caspase-3 and bax and up-regulation of the protein levels of bcl-2 in cartilage in both in vivo and in vitro. These results showed that LW-XG maybe become an excellent candidate long-acting drug for treating OA. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating condition with few effective treatments. Resveratrol, a polyphenolic compound, has exhibited neuroprotective effects in many neurodegenerative diseases. However, the explicit effect and mechanism of resveratrol on SCI is still unclear. Adenosine 5′ monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1), the downstream protein, play key roles in metabolizing of energy, resisting of resistance, and cellular protein homeostasis. In this study, we determined the effects of resveratrol on SCI and their potential relationship with SIRT1/AMPK signaling pathway, autophagy and apoptosis. To determine the effect of resveratrol on SCI recovery, a spinal cord contusion model was employed. Rats received treatment with resveratrol or DMSO immediately following contusion. We determined that Basso, Beattie, and Bresnahan (BBB) scores were significantly higher for injured rats treated with resveratrol. Nissl and HE staining revealed that resveratrol treatment significantly reduced the loss of motor neurons and lesion size in the spinal cord of injured rats when compared to vehicle-treated animals. Spinal cord tissue was assessed by Western blot, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analyses 7 days after injury for changes in expression of SIRT1/AMPK signaling pathway, autophagy and apoptosis proteins. Expression of SIRT1, p-AMPK, Beclin-1, LC3-B, and Bcl-2 was elevated in resveratrol-treated animals, whereas expression of p62, Cleaved Caspase-3, Caspase-9, and Bcl-2 associated X protein (Bax) was inhibited. Immunofluorescence analysis of primary neurons treated with resveratrol alone or in combination with Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) revealed that treatment with the inhibitors blocks the increased LC3-B expression in cells and increases the portion of TUNEL-positive cells. Taken together, these results suggest that resveratrol exerts neuroprotective effects on SCI by regulating autophagy and apoptosis mediated by the SIRT1-AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Bacterial infection has been a huge obstacle for diabetic wound healing. • NIR-sensitive peroxidase-like catalytic nanozyme is very attracting for bacterial infected diabetic wound healing. • Au nanoclusters modified MOFs were constructed by in-situ growth method used for infected diabetic wound healing. Bacterial biofilms often hinder the healing of infected chronic wounds. Hence, it is significant to explore ways to destroy bacterial biofilms. In this work, a photothermal therapy strategy of designing Au clusters modified ZIF-8 MOFs (Au@ZIF-8) as peroxidase-like catalytic nanozyme was proposed for bacterial infected wound healing. Under near-infrared laser (NIR), the prepared Au@ZIF-8 present enhanced peroxidase-like activity and excellent photothermal response properties. Au@ZIF-8 achieved bacterial membrane disruption rate of 66.3% and MRSA clearance rate up to 97%. Au@ZIF-8 also catalyzed endogenous H 2 O 2 to OH and achieved almost 97.4% healing rate in animal experiments. The prepared Au@ZIF-8 with peroxidase-like catalytic nanozyme properties has great potential in the treatment of infected diabetic wounds through bacterial membranes disruption and protein leakage promotion. [ABSTRACT FROM AUTHOR]

[Display omitted] • The photothermal combination strategy based on EGCG and gold nanoparticles is a new attempt at periodontal bone repair. • EGCG combined with gold nanoparticles as a nanoplatform for periodontal disease bone repair and inhibition of oral bacterial infection. • The obtained hydrogel nanoplatform achieved an effective sterilization rate and promoted osteogenesis by promoting angiogenesis. Periodontitis caused by bacteria is the most common oral disease. In the face of plaque formation, traditional scaling and antibiotic treatment can lead to gum recession, drug resistance and other side effects. The nanoplatform of multifunctional complex treatment is attractive for the treatment of periodontitis. In this study, epigallocatechin gallate (EGCG) was loaded into gold nanoparticle-modified hydrogels (E-Au@H) to achieve the synergistic functions of near-infrared (NIR) photosensitization, bactericidal and periodontal tissue regeneration. E-Au@H rapidly heats up to 50.7 °C within 5 min under NIR light irradiation, exerting a good photothermal effect, while the NIR spectrum can effectively control the release of tea polyphenols, enhance the antibacterial effect, promote angiogenesis and improve bone regeneration. In vitro studies showed that NIR-irradiated composites inhibited S. aureus , E. coli and S. aureus biofilms by 94 %, 92 % and 74 %, increased alkaline phosphatase activity 5-fold after 7 days and increased extracellular matrix mineralization rate 3-fold after 21 days. The rat periodontitis model successfully demonstrated that E-Au@H with NIR light irradiation inhibited dental plaque biofilm by 87 % and promoted alveolar bone regeneration by 38 %. The experimental results suggest that this hydrogel with a NIR-sensitive composite nanoplatform offers new possibilities for the treatment of periodontal disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sul-MPBs showed sustained and H 2 O 2 -induced accelerated release of sulfasalazine. • Sul-MPBs exhibited ROS-scavenging properties against mitochondrial dysfunction. • Sul-MPBs showed remarkable improvement of IBD. Inflammatory bowel disease (IBD) is a life-threatening organ dysfunction amplified by complex interactions between genetic, environmental, and immune factors. Sulfasalazine (Sul), an immunosuppressant, can potentially treat autoinflammation-induced disorders; however, clinical application of Sul is hindered by its inability to be directly taken up by cells. To address this challenge, we developed Mn doped prussian blue nanozymes (MPBs) to directly deliver Sul for targeting reactive oxygen species (ROS)-enriched microenvironment. The artificial nanozyme (Sul-MPBs) exhibits reactive oxygen species (ROS)-scavenging properties against hydrogen peroxide (H 2 O 2)-mediated mitochondrial dysfunction and possesses both catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)-like properties in vitro. Furthermore, it significantly enhances therapeutic effects in treating dextran sulfate sodium salt (DSS)-induced IBD via alleviating ROS-mediated inflammatory responses. This study demonstrates good biocompatibility and protective properties of this artificial nanozyme, thus potentially leading to a highly innovative and translational approach to treat IBD efficiently and safely. [ABSTRACT FROM AUTHOR]

[Display omitted] • We proposed that ROS and proinflammatory cytokines are important for the development of RA to an advanced stage. • Effective ROS-responsive celastrol-loaded nanomedicines were developed and show a curative effect on RA. • This work opens a new direction for the classification and treatment of autoimmune diseases. Inflammatory cascade is a prevalent and lethal adverse event that severely affects rheumatoid arthritis (RA) patients receiving clinic therapeutics. It is correlated with the response to macrophages caused by reactive oxygen species (ROS). Currently, ROS-targeted treatment is a potential strategy that can reduce the risk of RA-related obvious adverse effects, but at the cost of therapeutic efficacy. Herein, we reported folic acid (FA) modified ROS-responsive celastrol (Cel)-loaded (Cel/FA-Oxi-βCD NPs) that can release RA symptoms without chemotherapeutic agents and validated anti-inflammatory effect. In vitro study, NPs can be effectively internalized by activated macrophages and the released Cel from NPs significantly induced apoptosis in activated RAW264.7, indicating that Cel/FA-Oxi-βCD NPs remodeled the macrophages polarization homeostasis for the protection of inflamed joint microenvironment. Moreover, Cel/FA-Oxi-βCD NPs significantly decreased proinflammatory cytokines levels in serum, synovial and cartilage in collagen-induced arthritis (CIA) rats, and alleviated synovitis and cartilage destruction with excellent biocompatibility. Collectively, Cel/FA-Oxi-βCD NPs incorporated with ROS-responsive pro-apoptotic activity in macrophages, hold a great potential for clinical treatment of RA. [ABSTRACT FROM AUTHOR]

Autophagy plays an essential role in neurodevelopment, axonal guidance, neuropathic pain remission, and neuronal survival. Inhibiting the mammalian target of rapamycin (mTOR) signaling pathway can induce the occurrence of autophagy. In this study, we initially detected the effect of probucol on autophagy after spinal cord injury (SCI) by intraperitoneally injecting spinal cord-injured rats with probucol for 7 days. The levels of Beclin1 and LC3B were evidently enhanced at 7 days post-operation. However, the increase in the phosphorylated AMP-activated protein kinase (AMPK) protein and the decrease in ribosomal protein S6 kinase p70 subtype (p70S6K) phosphorylation level simultaneously occurred after SCI. Moreover, the expression levels of apoptosis-related proteins of Caspase-3, Caspase-9, and Bax were significantly reduced. Immunofluorescence results indicated that the expression of Caspase-3 protein was evidently decreased and that of Beclin-1 protein was increased by probucol. Nissl staining and Basso, Beattie, and Bresnahan scores showed that the quantity and function of motor neurons were visibly preserved by probucol after SCI. This study showed that probucol inhibited the mTOR signaling pathway to induce autophagy, reduce neural cell apoptosis and promote recovery of neurological function after SCI. [ABSTRACT FROM AUTHOR]

In this paper, we facilitated the preparation of uniform calcium carbonate nanospheres and the encapsulation of anticancer drug (Doxorubicin, Dox) in one step by a facile bio-inspired mineralization method at room temperature. Hesperidin (Hesp), a natural originated flavanone glycoside, was introduced as crystallization modifier. The obtained Dox encapsulated CaCO 3 nanospheres (Dox@CaCO 3 -Hesp NSs) having a narrow size range of ~ 200 nm. The drug loading/release studies reveal that these Dox@CaCO 3 -Hesp NSs have a drug loading efficiency (DLE) of 83% and drug loading content (DLC) of 14 wt%. Besides, the release of Dox from Dox@CaCO 3 -Hesp NSs was pH depended. At pH = 7.4, only a small amount (~ 28%) of Dox was released. While at pH = 5.0, all amount of incorporated Dox was released. Confocal laser scanning microscopy (CLSM) image reveals the Dox@CaCO 3 -Hesp NSs can internalize the cells. These results suggest the Dox@CaCO 3 -Hesp NSs can be potentially used to utilize pH-responsive delivery of anticancer drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • NIR-sensitive, ROS generating, targeting capable nanoplatforms are attractive in cancer therapy. • IR780-modified Ti 3 C 2 nanosheets were prepared as NIR-triggered nanoplatforms to treat laryngeal cancer through the mitochondrial-dependent apoptosis pathway. • The obtained multifunctional materials hold promising potential for laryngeal cancer treatment. Laryngeal cancer is the most common malignant tumor for which there is still a lack of effective treatment. Traditional radiotherapy, chemotherapy, and surgery all have significant side effects. Therefore, multifunctional collaborative therapeutic nanoplatforms are attractive to patients with laryngeal cancer. In this study, a near-infrared responsive IR780-modified MXene (Ti 3 C 2) nanosheet was proposed as a strategy for targeted therapy to achieve the synergistic functions of photothermal (PTT) therapy, photodynamic (PDT) therapy and mitochondrial pathway apoptosis. Electron spin resonance results showed that Ti 3 C 2 @IR780 could produce singlet linear oxygen for PDT. Molecular biology studies showed that Ti 3 C 2 @IR780 had the outstanding ability to generate ROS to disrupt mitochondrial function, resulting in apoptosis of cancer cells up to 60.51%. In vivo experiments showed that Ti 3 C 2 @IR780 could effectively aggregate at tumor sites. The temperature of the tumor region could reach 63.7 °C in the presence of near-infrared light. Tumor growth was inhibited by 92% during the treatment, and there was no recurrence. Results of the sections showed an 88.1% reduction in microtumor vascularity with Ti 3 C 2 @IR780 treatment for 21 days compared to the control group. These findings suggest that this multifunctional nanoplatform with synergistic NIR-sensitive properties can effectively inhibit tumor growth, providing an ideal strategy for cancer treatment. [ABSTRACT FROM AUTHOR]