ß-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway.

Osteoarthritis (OA) is widely recognized as the prevailing joint disease associated with aging. The ketogenic diet (KD) has been postulated to impede the advancement of various inflammatory ailments. ß-Hydroxybutyrate (ßOHB), a prominent constituent of ketone bodies, has recently been proposed to possess crucial signaling capabilities. In this study, we propose to explore the role and mechanism of ßOHB in OA. Tissue staining and inflammatory factor assay were employed to evaluate the impacts of KD and ßOHB on OA rats. The oxidative stress conditions in chondrocytes were induced using tert-butyl hydroperoxide (TBHP). The mechanisms were determined using the siRNA of hydroxycarboxylic acid receptor 2 (HCAR2), the antagonist of adenosine monophosphate-activated protein kinase (AMPK), and the inhibitor of mitophagy. The administration of KD demonstrated a reduction in pathological damage to cartilage, as well as a decrease in plasma levels of inflammatory factors. Furthermore, it resulted in an increase in the concentration of ßOHB in the blood and synovial fluid. In vitro experiments showed that ßOHB facilitated mitophagy and adenosine triphosphate production. Besides, ßOHB mitigated chondrocyte senescence, inflammatory factors secretion, extracellular matrix degradation, and apoptosis induced by TBHP. Subsequent investigations indicated that the protective effects of ßOHB were no longer observed following the knockdown of HCAR2, the antagonist of AMPK, or the inhibitor of mitophagy. Moreover, in vivo studies suggested that ßOHB played a protective role by targeting the HCAR2-AMPK-PINK1 axis. In conclusion, ßOHB enhanced chondrocyte mitophagy through the HCAR2/AMPK/PINK1/Parkin pathway, offering a potential therapeutic approach for the treatment of OA.

The metabolic characteristics and changes of chondrocytes in vivo and in vitro in osteoarthritis.

Osteoarthritis (OA) is an intricate pathological condition that primarily affects the entire synovial joint, especially the hip, hand, and knee joints. This results in inflammation in the synovium and osteochondral injuries, ultimately causing functional limitations and joint dysfunction. The key mechanism responsible for maintaining articular cartilage function is chondrocyte metabolism, which involves energy generation through glycolysis, oxidative phosphorylation, and other metabolic pathways. Some studies have shown that chondrocytes in OA exhibit increased glycolytic activity, leading to elevated lactate production and decreased cartilage matrix synthesis. In OA cartilage, chondrocytes display alterations in mitochondrial activity, such as decreased ATP generation and increased oxidative stress, which can contribute to cartilage deterioration. Chondrocyte metabolism also involves anabolic processes for extracellular matrix substrate production and energy generation. During OA, chondrocytes undergo considerable metabolic changes in different aspects, leading to articular cartilage homeostasis deterioration. Numerous studies have been carried out to provide tangible therapies for OA by using various models in vivo and in vitro targeting chondrocyte metabolism, although there are still certain limitations. With growing evidence indicating the essential role of chondrocyte metabolism in disease etiology, this literature review explores the metabolic characteristics and changes of chondrocytes in the presence of OA, both in vivo and in vitro. To provide insight into the complex metabolic reprogramming crucial in chondrocytes during OA progression, we investigate the dynamic interaction between metabolic pathways, such as glycolysis, lipid metabolism, and mitochondrial function. In addition, this review highlights prospective future research directions for novel approaches to diagnosis and treatment. Adopting a multifaceted strategy, our review aims to offer a comprehensive understanding of the metabolic intricacies within chondrocytes in OA, with the ultimate goal of identifying therapeutic targets capable of modulating chondrocyte metabolism for the treatment of OA.

Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.

Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid ß-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.

Cerium oxide nanoparticles-carrying human umbilical cord mesenchymal stem cells counteract oxidative damage and facilitate tendon regeneration.

BACKGROUND: Tendon injuries have a high incidence and limited treatment options. Stem cell transplantation is essential for several medical conditions like tendon injuries. However, high local concentrations of reactive oxygen species (ROS) inhibit the activity of transplanted stem cells and hinder tendon repair. Cerium oxide nanoparticles (CeONPs) have emerged as antioxidant agents with reproducible reducibility. RESULTS: In this study, we synthesized polyethylene glycol-packed CeONPs (PEG-CeONPs), which were loaded into the human umbilical cord mesenchymal stem cells (hUCMSCs) to counteract oxidative damage. H2O2 treatment was performed to evaluate the ROS scavenging ability of PEG-CeONPs in hUCMSCs. A rat model of patellar tendon defect was established to assess the effect of PEG-CeONPs-carrying hUCMSCs in vivo. The results showed that PEG-CeONPs exhibited excellent antioxidant activity both inside and outside the hUCMSCs. PEG-CeONPs protect hUCMSCs from senescence and apoptosis under excessive oxidative stress. Transplantation of hUCMSCs loaded with PEG-CeONPs reduced ROS levels in the tendon injury area and facilitated tendon healing. Mechanistically, NFκB activator tumor necrosis factor α and MAPK activator dehydrocrenatine, reversed the therapeutic effect of PEG-CeONPs in hUCMSCs, indicating that PEG-CeONPs act by inhibiting the NFκB and MAPK signaling pathways. CONCLUSIONS: The carriage of the metal antioxidant oxidase PEG-CeONPs maintained the ability of hUCMSCs in the injured area, reduced the ROS levels in the microenvironment, and facilitated tendon regeneration. The data presented herein provide a novel therapeutic strategy for tendon healing and new insights into the use of stem cells for disease treatment.

The molecular link between obstructive sleep apnea and osteoarthritis: based on bioinformatics analysis and experimental validation.

BACKGROUND: Obstructive sleep apnea (OSA) and osteoarthritis (OA) are highly prevalent and seriously affect the patient's quality of life. Patients with OSA have a high incidence of OA, however, the underlying mechanism remains unclear. Here, we investigated the molecular link between OSA and OA via bioinformatics analysis and experimental validation. METHODS: We downloaded a peripheral blood monocyte microarray profile (GSE75097) for patients with OSA and two synovial microarray profiles (GSE55235 and GSE55457) for patients with OA from the Gene Expression Omnibus database. We identified OSA-associated differentially expressed genes (OSA-DEGs) in patients with OA. Additionally, we constructed protein-protein interaction networks to identify the key genes involved in OA. Immunohistochemistry was performed to verify the expression of key genes in OA rat models. RNA interference assay was performed to validate the effects of key genes on synovial cells. Gene-miRNA, gene-transcription factor, and gene-drug networks were constructed to predict the regulatory molecules and drugs for OA. RESULTS: Fifteen OSA-DEGs screened using the threshold criteria were enriched in the tumor necrosis factor (TNF) pathway. Combining the 12 algorithms of CytoHubba, we identified JUNB, JUN, dual specificity phosphatase 1 (DUSP1), and TNF-alpha-induced protein 3 (TNFAIP3) as the key OSA-DEGs involved in OA development. Immunohistochemistry and quantitative polymerase chain reaction revealed that these key genes were downregulated in the OA synovium, promoting TNF-α expression. Therefore, OSA-DEGs, JUN, JUNB, DUSP1, and TNFAIP3 function in OA by increasing TNF-α expression. Our findings provide insights on the mechanisms underlying the effects of OSA on OA.

Down-regulation of Jun induces senescence through destabilizing chromatin in osteoarthritis chondrocytes.

OBJECTIVE: Osteoarthritis (OA) is the most common degenerative joint disease leading to disability worldwide. Cellular senescence is considered to be a fundamental pathogenic mechanism in the development of OA and has attracted increasing attention. However, regulatory mechanisms underlying chondrocyte senescence in OA remain unclear. METHODS: Bioinformatic methods were used to screen key genes. Immunohistochemistry and the quantitative reverse transcription polymerase chain reaction were used to evaluate gene expression. RNA intervention experiments were performed to explore the functions of key genes. RESULTS: We used 494 aging-associated genes provided by the Aging Atlas to identify the co-expression modules associated with age and OA. Thirty age-associated differentially expressed genes (ASDEGs) were identified. Using cytoHubba in Cytoscape, we identified Jun as the hub-ASDEG for OA chondrocytes. We confirmed the downregulation of Jun in OA rats and senescent chondrocytes by immunohistochemistry and quantitative reverse transcription polymerase chain reaction, respectively. Inhibition of proliferation and accelerated senescence were observed in chondrocytes treated with siRNA against Jun. Mechanistically, we observed micronuclei formation and reduced expression of H3K9me3 and heterochromatin protein 1gamma in siRNA-Jun-treated chondrocytes, indicating that destabilization of chromatin occurred during this treatment. CONCLUSION: Jun plays a crucial role in OA development and causes senescence by destabilizing chromatin in chondrocytes. These findings provide new insights into OA progression and suggest promising therapeutic targets.

Therapeutic effects of different intervention forms of human umbilical cord mesenchymal stem cells in the treatment of osteoarthritis.

Osteoarthritis (OA) is a common and disabling disease. For advanced OA, surgical treatment is still the main treatment. Human umbilical cord mesenchymal stem cells (hUC-MSCs) are self-regenerative pluripotent cells, that coordinate cartilage regeneration by secreting various trophic factors, which adjust the injured tissue environment. hUC-MSCs secret extracellular vesicles and participates in OA treatment by transmitting bioactive molecules related to migration, proliferation, apoptosis, inflammatory reaction, extracellular matrix synthesis and cartilage repair. In addition, the combination of multiple substances represented by cartilage matrix and hUC-MSCs also have a significant synergistic effect on OA treatment. Because hUC-MSCs have shown considerable promise in cartilage repair, some scholars have proposed transplanting mesenchymal stem cells into damaged cartilage to delay OA progression. This article reviews the application of hUC-MSCs as a treatment for OA. With the continuous development of routine clinical applications, more reliable intervention modalities for hUC-MSCs in OA treatment will be discovered for the time to come.

Barasertib impedes chondrocyte senescence and alleviates osteoarthritis by mitigating the destabilization of heterochromatin induced by AURKB.

Osteoarthritis (OA) is a common joint disease characterized by progressive cartilage loss that causes disability worldwide. The accumulation of senescent chondrocytes in aging human cartilage contributes to the high incidence of OA. Heterochromatin instability, the hallmark and driving factor of senescence, regulates the expression of the senescence-associated secretory phenotype that induces inflammation and cartilage destruction. However, the role of heterochromatin instability in OA progression remains unclear. In this work, we identified AURKB as a key senescence-associated chromatin regulator using bioinformatics methods. We found that AURKB was upregulated in OA cartilage and chondrocytes exposed to abnormal mechanical strain. Overexpression of AURKB could cause senescence and heterochromatin instability. Furthermore, the AURKB inhibitor Barasertib reversed senescence and heterochromatin instability in chondrocytes and alleviated OA in a rat model. Mechanistically, abnormal mechanical strain increased AURKB levels through the Piezo1/Ca2+ signaling axis. Blocking Piezo1/Ca2+ signaling by short interfering RNA against Piezo1 and Ca2+ chelator BAPTA could reduce the expression of AURKB and alleviate senescence in chondrocytes exposed to abnormal mechanical strain. In conclusion, our data confirmed that abnormal mechanical strain increases the expression of AURKB by activating the Piezo1/Ca2+ signaling axis, leading to destabilized heterochromatin and senescence in chondrocytes, whereas Barasertib consolidates heterochromatin, counteracts senescence and alleviates OA.

Trimethylamine-N-oxide sensitizes chondrocytes to mechanical loading through the upregulation of Piezo1.

BACKGROUND: Mechanical strain plays a crucial role in chondrocyte apoptosis and osteoarthritis (OA) disease progression through Piezo1. Trimethylamine-N-oxide (TMAO) is a diet-derived metabolite that correlates positively with multiple chronic diseases. Herein, we explored the potential role of TMAO in sensitizing chondrocytes to Piezo1-mediated mechanotransduction. METHODS: The cytotoxicity of TMAO on chondrocytes was assayed. Piezo1 expression was measured after TMAO intervention. Pathological mechanical loading or Yoda1 (a specific Piezo1 channel activator) was administered in chondrocytes. The calcium levels and cytoskeleton in chondrocytes were observed by fluorescence microscopy. Flow cytometry, western blotting, and mitochondrial membrane potential assays were utilized to evaluate apoptosis. A rat OA model was constructed by anterior cruciate ligament transection. Hematoxylin-eosin staining, Safranin-O/Fast Green staining, immunochemistry, and TUNEL were applied to estimate OA severity. RESULTS: TMAO intervention alone did not affect chondrocyte viability up to 600 µM. TMAO significantly increased Piezo1 expression and up-regulated intracellular calcium levels, further leading to cytoskeletal damage. Mechanical strain or Yoda1 treatment significantly induced chondrocyte apoptosis. Notably, TMAO intervention further aggravated chondrocyte apoptosis and cartilage destruction under pathological mechanical loading. CONCLUSION: TMAO significantly up-regulated Piezo1 expression and sensitized chondrocytes to mechanical loading, which may be closely related to the pathogenesis of OA.

Ceria Nanoparticles Alleviated Osteoarthritis through Attenuating Senescence and Senescence-Associated Secretory Phenotype in Synoviocytes.

Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles (CeNP) have exhibited therapeutic effects in multiple age-related diseases due to their unique capability of ROS scavenging. However, the role of CeNP in OA remains unknown. Our results revealed that CeNP could inhibit the expression of senescence and SASP biomarkers in multiple passaged and hydrogen-peroxide-treated synoviocytes by removing ROS. In vivo, the concentration of ROS in the synovial tissue was remarkably suppressed after the intra-articular injection of CeNP. Likewise, CeNP reduced the expression of senescence and SASP biomarkers as determined by immunohistochemistry analysis. The mechanistic study showed that CeNP inactivated the NFκB pathway in senescent synoviocytes. Finally, safranin O-fast green staining showed milder destruction of articular cartilage in the CeNP-treated group compared with the OA group. Overall, our study suggested that CeNP attenuated senescence and protected cartilage from degeneration via scavenging ROS and inactivating the NFκB signaling pathway. This study has potentially significant implications in the field of OA as it provides a novel strategy for OA treatment.

Indole-3-propionic acid alleviates chondrocytes inflammation and osteoarthritis via the AhR/NF-κB axis.

BACKGROUND: Osteoarthritis (OA) is a common chronic disease characterized by chronic inflammation and extracellular matrix degradation. Indole-3-propionic acid (IPA) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in a variety of diseases. In this study, we further investigated the potential therapeutic role of IPA in OA and the underlying mechanism. METHODS: IL-1ß was utilized to induce chondrocyte inflammation. Then, the cytotoxicity of IPA on rat chondrocytes was assessed. Meanwhile, RT-qPCR, Griess reaction, ELISA, Western blot and immunofluorescence were performed to evaluate the expression of inflammatory factors and stromal proteins, and the NF-κB pathway in chondrocytes treated with IL-1ß alone, with IPA or with aryl hydrocarbon receptor (AhR) knockdown. An OA rat model was established by anterior cruciate ligament transection, and hematoxylin-eosin staining, Safranin-O/Fast Green staining and immunochemistry were applied to estimate OA severity. RESULTS: IPA did not affect cellular viability at concentrations up to 80 µM. IPA significantly inhibited the IL-1ß-induced expression of inflammatory factors (Nitric oxide, PGE2, TNF-α, IL-6, iNOS and COX-2) and matrix-degrading enzymes (MMP-3, MMP-13 and ADAMTS-5), upregulated the expression of anabolic markers (aggrecan and collagen-II) and inactivated the NF-κB pathway. However, AhR knockdown could abolish the above protection capabilities and the suppression of the NF-κB pathway induced by IPA. Furthermore, IPA significantly reduced serum inflammatory cytokines expression, cartilage destruction and synovitis in vivo, demonstrating its protective role in OA progression. CONCLUSION: IPA improved IL-1ß-induced chondrocyte inflammation and extracellular matrix degradation through the AhR/NF-κB axis, which provides an innovative therapeutic strategy for OA.

Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain.

Excessive mechanical strain is the prominent risk factor for osteoarthritis (OA), causing cartilage destruction and degeneration. However, the underlying molecular mechanism contributing to mechanical signaling transduction remains unclear in OA. Piezo type mechanosensitive ion channel component 1 (Piezo1) is a calcium-permeable mechanosensitive ion channel and provides mechanosensitivity to cells, but its role in OA development has not been determined. Herein, we found up-regulated expression of Piezo1 in OA cartilage, and that its activation contributes to chondrocyte apoptosis. The knockdown of Piezo1 could protect chondrocytes from apoptosis and maintain the catabolic and anabolic balance under mechanical strain. In vivo, Gsmtx4, a Piezo1 inhibitor, markedly ameliorated the progression of OA, inhibited the chondrocyte apoptosis, and accelerated the production of the cartilage matrix. Mechanistically, we observed the elevated activity of calcineurin (CaN) and the nuclear transfection of nuclear factor of activated T cells 1 (NFAT1) under mechanical strain in chondrocytes. Inhibitors of CaN or NFAT1 rescued the pathologic changes induced by mechanical strain in chondrocytes. Overall, our findings revealed that Piezo1 was the essential molecule response to mechanical signals and regulated apoptosis and cartilage matrix metabolism via the CaN/NFAT1 signaling axis in chondrocytes, and that Gsmtx4 could be an attractive therapeutic drug for OA treatment.

Indole-3-aldehyde alleviates chondrocytes inflammation through the AhR-NF-κB signalling pathway.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease characterized by chronic inflammation. Indole-3-aldehyde (3-IAld) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in multiple inflammatory diseases. However, the potential therapeutic role of 3-IAld in OA and the underlying mechanism remain to be explored. METHODS: IL-1ß was utilized to induce chondrocytes inflammation. Then, cell counting kit-8 was carried out to assess the cytotoxicity of 3-IAld on rat chondrocytes viability. Meanwhile, RT-qPCR, Western blot, and immunofluorescence were performed to evaluate the expression of inflammatory factors, matrix-degrading enzymes and matrix synthesis protein, and the NF-κB pathway in chondrocytes treated with IL-1ß alone, with 3-IAld or with siRNA-AhR. RESULTS: Our results showed that 3-IAld did not affect cellular viability at concentrations up to 50 µM. 3-IAld significantly inhibited the expression of pro-inflammatory cytokines (IL-6, iNOS and COX-2), and matrix-degrading enzymes (MMP3, MMP13 and ADAMTS5), upregulated the expression of matrix synthesis protein (aggrecan and collagen-II), and inactivated the NF-κB pathway in IL-1ß-treated chondrocytes. However, AhR knockdown could totally abolish the aforementioned therapeutic capabilities and the inactivation of the NF-κB pathway induced by 3-IAld. CONCLUSIONS: 3-IAld reduced inflammation through the AhR-NF-κB signalling pathway in IL-1ß-induced chondrocytes, which is expected to provide a new therapeutic strategy for OA.

High expression of Piezo1 induces senescence in chondrocytes through calcium ions accumulation.

BACKGROUND: Chondrocytes senescence is closely related to orthopedic degenerative diseases such as osteoarthritis (OA). Calcium ions (Ca2+) accumulation is a common phenomenon in senescent cells, which causes mitochondrial dysfunction and ROS generation to promote the process of senescence. Piezo1 is a mechanosensitive ion channel with a unique affinity for Ca2+. However, the role of Piezo1-mediated Ca2+ accumulation in senescent chondrocytes remains unclear. METHODS: First, the senescent chondrocytes model was constructed by subcultring primary chondrocytes (P0) to 5th passages (P5). CCK8 and clone formation assay was utilized to assess the proliferation capacity of the chondrocytes. The intracellular Ca2+ and ROS concentrations were evaluated by the Fluo-4-AM Ca2+ probe and DCFH-DA fluorescent probe. ß-Galactosidase staining was used to assess the percentage of senescent cells. The expression of Piezo1, senescence-related and senescence-associated secretory phenotype (SASP)-related genes were detected by real-time quantitative PCR (RT-qPCR) and immunofluorescence. Then, knockdown of Piezo1 in P5 chondrocytes was performed and the above indexes were evaluated. Lastly, P0 chondrocytes were treated with Yoda1 (Piezo1 activator) and BAPTA-AM (Ca2+ chelator) and the above indexes were evaluated. RESULTS: Senescent chondrocytes exhibited intracellular Ca2+ and ROS accumulation. Piezo1 expression levels were increased in senescent chondrocytes and aged mouse cartilage tissue. Knockdown of Piezo1 in P5 chondrocytes reduced Ca2+ and ROS concentrations, promoted the proliferation and reduced the proportion of senescent cells and the expression of SASP-related genes. Activation of Piezo1 in chondrocytes by Yoda1 inhibited the proliferation, promoted senescence and SASP, and increased the concentration of cellular Ca2+ and ROS, but BAPTA-AM intervention reversed these phenomena. CONCLUSION: This study confirmed for the first time that the high expression of Piezo1 mediated senescence in chondrocytes through Ca2+ accumulation. Piezo1 may be a new target for treating senescence-related OA.

Construction of chitosan/Ag nanocomposite sponges and their properties.

Chitosan/Ag nanocomposite sponges were prepared by soaking the chitosan hydrogels in AgNO3 aqueous solution, which was heated at 80 °C to synthesize Ag nanoparticles (AgNPs) in the porous chitosan matrix and freeze-dried. The structure and properties of the nanocomposite sponges were characterized by FT-IR, X-ray diffraction (XRD), scanning electron microscopy (SEM), and compressive testing. In our findings, the pores of the chitosan hydrogel were used as a microreactor to synthesize AgNPs, which could distribute evenly on the chitosan matrix. The chitosan/Ag nanocomposite sponges exhibited good mechanical properties, suitable water vapor transmission and noncytotoxicity. Antibacterial test revealed their excellent antibacterial activity against Staphylococcus aureus and E. coli. The chitosan/Ag nanocomposite sponges would have great potential as wound dressings due to their good properties and facile industrialization.

Nanocarrier-based activation of necroptotic cell death potentiates cancer immunotherapy.

Even though immunological checkpoint inhibitors have demonstrated a potent anti-tumor effect in clinical practice, the low immunogenicity of the majority of tumors still results in a lower response rate and a higher resistance to mono-immunotherapy. Recent studies revealed that immunogenic cell death (ICD) augments T cell responses against some cancers, thus indicating that this combination therapy may further improve the anti-tumor immunity produced by anti-PD-1/PD-L1. Herein a robust synergetic strategy is reported to integrate the activation of necroptotic cell death and the subsequent using of immune checkpoint inhibitors. Liposomes have good biocompatibility and are widely used as drug carriers. Using liposomes as TNF-α-loaded nanoplatforms achieves in vivo tumor targeting and long-term retention in the tumor microenvironment. Tumor cells treated with TNF-α-loaded liposomes exhibited the hallmarks of ICD including the release of high mobility group box 1 (HMGB1) and lactate dehydrogenase (LDH). Additionally, the tumor cell necrosis caused by TNF-α induces the in situ release of tumor-specific antigens, thus increasing the dendritic cell (DC) activation and T cell infiltration when combined with the checkpoint blockade therapy. Collectively, significant tumor reduction is accomplishable by this synergetic strategy, in which TNF-α-loaded liposomes convert the tumor cell into an endogenous vaccine and improve the anti-tumor immunity of anti-PD-1/PD-L1.

Corrigendum to "Controlled Release of Interleukin-1 Receptor Antagonist from Hyaluronic Acid-Chitosan Microspheres Attenuates Interleukin-1ß-Induced Inflammation and Apoptosis in Chondrocytes".

[This corrects the article DOI: 10.1155/2016/6290957.].

Biocompatible and biodegradable chitosan/sodium polyacrylate polyelectrolyte complex hydrogels with smart responsiveness.

Bulk homogeneous polyelectrolyte complex hydrogels (PCH) are difficult to prepare due to the flocculation effect between polyelectrolytes with opposite charges. Herein, novel chitosan/sodium polyacrylate (PAAS) polyelectrolyte complex hydrogels (CPG) were fabricated successfully by cross-linking chitosan and PAAS with epichlorohydrin (ECH) through inhibiting protonation effect of chitosan in alkali/urea aqueous solution. The swelling behaviors of CPG were studied systematically in different solutions. The equilibrium swelling ratio of chitosan hydrogel in water increased dramatically from 46.3 to 404.8 g/g by the introduction of PAAS. CPG exhibited different swelling ratios towards different pH solutions, physiological solutions and salt solutions with different concentrations, showing obvious smart responsive properties. Moreover, CPG hydrogels exhibited relatively high compressive strength, good biocompatibility and in vitro biodegradability. Therefore, this work provided a novel PCH and shed light on the fabrication of other PCH, showing potential applications in the fields of agriculture, foods, tissue engineering and drug delivery.

Epigenetics-Based Tumor Cells Pyroptosis for Enhancing the Immunological Effect of Chemotherapeutic Nanocarriers.

Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.

Nanoparticles from Cuttlefish Ink Inhibit Tumor Growth by Synergizing Immunotherapy and Photothermal Therapy.

Natural nanoparticles have been extensively studied due to their diverse properties and easy accessibility. Here, the nanoparticles extracted from cuttlefish ink (CINPs) with significant antitumor efficacy are explored. These CINPs, with spherical morphology, good dispersibility, and biocompatibility, are rich in melanin and contain a variety of amino acids and monosaccharides. Through the activation of mitogen-activated protein kinase (MAPK) signaling pathway, CINPs can efficiently reprogram tumor-associated macrophages (TAMs) from immune-suppressive M2-like phenotype to antitumor M1-like phenotype. Besides, under near-infrared (NIR) irradiation, CINPs exhibit high photothermal effect and tumor cell killing ability, which make them a potential candidate in photothermal therapy (PTT) of tumor. In vivo, CINPs can increase the proportion of M1 macrophages and foster the recruitment of cytotoxic T lymphocytes (CTLs) to tumors, leading to reduced primary tumor growth and lung metastasis. In combination with their photothermal effect, which can induce tumor-specific antigens release, CINPs could almost completely inhibit tumor growth accompanied by more active immune responses. Collectively, these CINPs described here can provide both tumor immunotherapy and PTT, implying that CINPs are promising for tumor treatment.