Glucose-modified BSA/procyanidin C1 NPs penetrate the blood-brain barrier and alleviate neuroinflammation in Alzheimer's disease models.

Alzheimer's disease (AD) is a chronic neurodegenerative disease with high prevalence, long duration and poor prognosis. The blood-brain barrier (BBB) is a physiologic barrier in the central nervous system, which hinders the entry of most drugs into the brain from the blood, thus affecting the efficacy of drugs for AD. Natural products are recognized as one of the promising and unique therapeutic approaches to treat AD. To improve the efficiency and therapeutic effect of the drug across the BBB, a natural polyphenolic compound, procyanidin C-1 (C1) was encapsulated in glucose-functionalized bovine serum albumin (BSA) nanoparticles to construct Glu-BSA/C1 NPs in our study. Glu-BSA/C1 NPs exhibited good stability, slow release, biocompatibility and antioxidant properties. In addition, Glu-BSA/C1 NPs penetrated the BBB, accumulated in the brain by targeting Glut1, and maintained the BBB integrity both in vitro and in vivo. Moreover, Glu-BSA/C1 NPs alleviated memory impairment of 5 × FAD mice by reducing Aß deposition and Tau phosphorylation and promoting neurogenesis. Mechanistically, Glu-BSA/C1 NPs significantly activated the PI3K/AKT pathway and inhibited the NLRP3/Caspase-1/IL-1ß pathway thereby suppressing neuroinflammation. Taken together, Glu-BSA/C1 NPs could penetrate the BBB and mitigate neuroinflammation in AD, which provides a new therapeutic approach targeting AD.

MG53/GMs/HA-Dex neural scaffold promotes the functional recovery of spinal cord injury by alleviating neuroinflammation.

The adverse microenvironment, including neuroinflammation, hinders the recovery of spinal cord injury (SCI). Regulating microglial polarization to alleviate neuroinflammation at the injury site is an effective strategy for SCI recovery. MG53 protein exerts obvious repair ability on multiple tissues damage, but with short half-life. In this study, we composited an innovative MG53/GMs/HA-Dex neural scaffold using gelatin microspheres (GMs), hyaluronic acid (HA), and dextran (Dex) loaded with MG53 protein. This novel neural scaffold could respond to MMP-2/9 protein and stably release MG53 protein with good physicochemical properties and biocompatibility. In addition, it significantly improved the motor function of SCI mice, suppressed M1 polarization of microglia and neuroinflammation, and promoted neurogenesis and axon regeneration. Further mechanistic experiments demonstrated that MG53/GMs/HA-Dex hydrogel inhibited the JAK2/STAT3 signaling pathway. Thus, this MG53/GMs/HA-Dex neural scaffold promotes the functional recovery of SCI mice by alleviating neuroinflammation, which provides a new intervention strategy for the neural regeneration and functional repair of SCI.

Neuronal Panx1 drives peripheral sensitization in experimental plantar inflammatory pain.

BACKGROUND: The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood. METHODS: Wild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund's adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and ß-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. ß-galactosidase (ß-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice. RESULTS: Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/ß-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca2+ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/ß-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of ß-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG. CONCLUSIONS: The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.

SIRT2-mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma.

ATP citrate lyase (ACLY), as a key enzyme in lipid metabolism, plays an important role in energy metabolism and lipid biosynthesis of a variety of tumours. Many studies have shown that ACLY is highly expressed in various tumours, and its pharmacological or gene inhibition significantly inhibits tumour growth and progression. However, the roles of ACLY in oesophageal squamous cell carcinoma (ESCC) remain unclear. Here, our data showed that ACLY inhibitor significantly attenuated cell proliferation, migration, invasion and lipid synthesis in different ESCC cell lines, whereas the proliferation, migration, invasion and lipid synthesis of ESCC cells were enhanced after ACLY overexpression. Furthermore, ACLY inhibitor dramatically suppressed tumour growth and lipid metabolism in ESCC cells xenografted tumour model, whereas ACLY overexpression displayed the opposite effect. Mechanistically, ACLY protein harboured acetylated modification and interacted with SIRT2 protein in ESCC cells. The SIRT2 inhibitor AGK2 significantly increased the acetylation level of ACLY protein and inhibited the proliferation and migration of ESCC cells, while overexpression of ACLY partially reversed the inhibitory effect of AGK2 on ESCC cells. Overall, these results suggest that targeting the SIRT2/ACLY signalling axis may be a potential therapeutic strategy for ESCC patients.

REGγ Mitigates Radiation-Induced Enteritis by Preserving Mucin Secretion and Sustaining Microbiome Homeostasis.

Radiation-induced enteritis, a significant concern in abdominal radiation therapy, is associated closely with gut microbiota dysbiosis. The mucus layer plays a pivotal role in preventing the translocation of commensal and pathogenic microbes. Although significant expression of REGγ in intestinal epithelial cells is well established, its role in modulating the mucus layer and gut microbiota remains unknown. The current study revealed notable changes in gut microorganisms and metabolites in irradiated mice lacking REGγ, as compared to wild-type mice. Concomitant with gut microbiota dysbiosis, REGγ deficiency facilitated the infiltration of neutrophils and macrophages, thereby exacerbating intestinal inflammation after irradiation. Furthermore, fluorescence in situ hybridization assays unveiled an augmented proximity of bacteria to intestinal epithelial cells in REGγ knockout mice after irradiation. Mechanistically, deficiency of REGγ led to diminished goblet cell populations and reduced expression of key goblet cell markers, Muc2 and Tff3, observed in both murine models, minigut organoid systems and human intestinal goblet cells, indicating the intrinsic role of REGγ within goblet cells. Interestingly, although administration of broad-spectrum antibiotics did not alter the goblet cell numbers or mucin 2 (MUC2) secretion, it effectively attenuated inflammation levels in the ileum of irradiated REGγ absent mice, bringing them down to the wild-type levels. Collectively, these findings highlight the contribution of REGγ in counteracting radiation-triggered microbial imbalances and cell-autonomous regulation of mucin secretion.

Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1.

Increasing evidence has demonstrated that glutaminase (GLS) as a key mitochondrial enzyme plays a pivotal role in glutaminolysis, which widely participates in glutamine metabolism serving as main energy sources and building blocks for tumor growth. However, the roles and molecular mechanisms of GLS in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we found that GLS was highly expressed in ESCC tissues and cells. GLS inhibitor CB-839 significantly suppressed cell proliferation, colony formation, migration and invasion of ESCC cells, whereas GLS overexpression displayed the opposite effects. In addition, CB-839 markedly suppressed glucose consumption and lactate production, coupled with the downregulation of glycolysis-related proteins HK2, PFKM, PKM2 and LDHA, whereas GLS overexpression exhibited the adverse results. In vivo animal experiment revealed that CB-839 dramatically suppressed tumor growth, whereas GLS overexpression promoted tumor growth in ESCC cells xenografted nude mice. Mechanistically, GLS was localized in mitochondria of ESCC cells, which interacted with PDK1 protein. CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.

Cowberry extract loaded chitosan hydrogel with photothermal and antioxidant properties promotes infected wound healing.

Bacterial infection and oxidative stress impede clinical wound healing. Herein, the plant-derived cowberry extract (CE) was first explored as a natural photothermal agent and antioxidant to deal with bacterial infection and oxidative stress. After loading in the carboxymethyl chitosan (CMCs)/oxidized dextran (Odex) hydrogel, the photothermal effect of CE was highly enhanced by CMCs. The controlled temperature induced by CE-containing hydrogel under NIR laser irradiation could rapidly (10 min) and effectively kill Staphylococcus aureus (S. aureus, 99.3 %) and Escherichia coli (E. coli, 94.6 %). Besides, this hydrogel exhibited a fast gelation and hemostasis abilities, high stability, adhesion and ROS scavenging capabilities, as well as good injectability and biocompatibility. Above superior properties make this hydrogel to accelerate the wound healing in S. aureus-infected mice, and it is expected to be a potential clinical wound dressing.

Mild hyperthermia-assisted chitosan hydrogel with photothermal antibacterial property and CAT-like activity for infected wound healing.

Infected wounds pose a serious threat to public health and pose a significant challenge and financial burden worldwide. The treatment of infected wounds is now an urgent problem to be solved. Herein, mild hyperthermia-assisted hydrogels composed of carboxymethyl chitosan (CMCs), oxidized dextran (Odex), epigallocatechin gallate (EGCG) and PtNPs@PVP (CAT-like nanoenzymes) were proposed for the repair of infected wounds. The incorporation of PtNPs@PVP nanoenzymes give the hydrogels excellent photothermal property and CAT-like activity. When the temperature is maintained at 42-45 °C under 808 nm near infrared (NIR) exposure, the CMCs/Odex/EGCG/Nanoenzymes (COEN2) hydrogel demonstrated highly enhanced antibacterial ability (95.9 % in vivo), hydrogen peroxide (H2O2) scavenging ratio (85.1 % in vitro) and oxygen supply (20.7 mg/L in vitro). Furthermore, this mild-heat stimulation also promoted angiogenesis in the damaged skin area. Overall, this multifunctional hydrogel with antibacterial, antioxidant, oxygen supply, hemostasis, and angiogenesis capabilities has shown great promise in the repair of infected wounds. This study establishes the paradigm of enhanced infected wound healing by mild hyperthermia-assisted H2O2 scavenging, oxygen supplemental, and photothermal antibacterial hydrogels.

ROS/pH dual responsive PRP-loaded multifunctional chitosan hydrogels with controlled release of growth factors for skin wound healing.

Platelet-rich plasma (PRP) contains a variety of growth factors (GFs) and has been used in the treatment of a variety of diseases, including skin lesions. In particular, PRP with low immunogenicity will be more widely used. However, the explosive release of GFs limits its further application. In order to achieve controlled release of GFs, a multifunctional and reactive oxygen species (ROS)/pH dual responsive hydrogel was developed to load PRP derived from human cord blood for the treatment of skin wound healing. Based on the hydrogen bond and Schiff base interaction, carboxymethyl chitosan (CMCS), oxidized dextran (Odex) and oligomeric procyanidins (OPC) were crosslinked to form CMCS/Odex/OPC/PRP hydrogel with good injectability, self-healing, adhesion, ROS scavenging, antibacterial activity, controlled and sustained release of GFs. In vitro cell experiments suggested that this hydrogel possessed excellent biocompatibility and could promote the proliferation and migration of L929. In vivo healing of full-layer skin wounds further indicated that the prepared hydrogel could regulate inflammation and promote epithelialization, collagen deposition, and angiogenesis. In summary, this present study demonstrates that CMCS/Odex/OPC/PRP hydrogel may serve as a promising multifunctional dressing for skin wound healing.

A multifunctional hydrogel dressing with high tensile and adhesive strength for infected skin wound healing in joint regions.

Most hydrogel dressings are designed for skin wounds in flat areas, and few are focused on the joint skin regions which undergo frequent movement. The mismatch of mechanical properties and poor fit between a hydrogel dressing and a wound in joint skin results in hydrogel shedding, bacterial infection and delayed healing. Therefore, it is of great significance to design and prepare a multifunctional hydrogel with high tensile and tissue-adhesive strength as well as other therapeutic effects for the treatment of joint skin wounds. In this work, a multifunctional hydrogel was reasonably prepared by simply mixing polyvinyl alcohol (PVA), borax, tannic acid (TA) and iron(III) chloride in certain proportions, which was further used to treat the skin wounds at the joint of the hind limb. Acting as the physical crosslinkers, borax and TA dynamically bond with PVA and provide the resulting hydrogel with strong tensile, fast shape-adaptive and self-healing properties. The photothermal bacteriostatic activity of the hydrogel is attributed to the formation of a metallic polyphenol network (MPN) between ferric ions and TA. In addition, the hydrogel exhibits high levels of adhesion, hemostatic performance, antioxidant abilities, and biocompatibility, and shows great potential to promote joint skin wound healing.

Application of Injectable Hydrogels as Delivery Systems in Spinal Cord Injury.

Spinal cord injury (SCI) is a severe neurological injury caused by traffic accidents, trauma, or falls, which leads to significant loss of sensory, motor, and autonomous functions and seriously affects the patient's life quality. Although considerable progress has been made in mitigating secondary injury and promoting the regeneration/repair of SCI, the therapeutic effects need to be improved due to drug availability. Given their good biocompatibility, biodegradability, and low immunogenicity, injectable hydrogels can be used as delivery systems to achieve controlled release of drugs and other substances (cells and proteins, etc.), offering new hope for SCI repair. In this article, we summarized the types of injectable hydrogels, analyzed their application as delivery systems in SCI, and further discussed the mechanisms of hydrogels in the treatment of SCI, such as anti-inflammatory, antioxidant, anti-apoptosis, and pro-neurogenesis. Moreover, we highlighted the potential benefits of hydrogels in the treatment of SCI in combination with therapies, including the recent advances and achievements of these promising tools. Our review may offer new strategies for the development of SCI treatments based on injectable hydrogels as delivery systems.

Correction: Ren et al. Injectable and Antioxidative HT/QGA Hydrogel for Potential Application in Wound Healing. Gels 2021, 7, 204.

In the original publication [...].

PMN-incorporated multifunctional chitosan hydrogel for postoperative synergistic photothermal melanoma therapy and skin regeneration.

Melanoma excision surgery is usually accompanied by neoplasm residual, tissue defect, and bacterial infection, resulting in high tumor recurrence and chronic wound. Nanocomposite hydrogels can satisfy the twin requirements of avoiding tumor recurrence and skin wound healing following skin melanoma surgery due to their photothermal anti-tumor and anti-bacterial activities. In this study, carboxymethyl chitosan, oxidized fucoidan and polyphenol-metal nanoparticle (PMN) of tannic acid capped gold nanoparticles were used to fabricate multifunctional nanocomposite hydrogels through Schiff base reaction. The prepared hydrogel demonstrated outstanding photothermal effect, and the controlled high temperature will rapidly kill melanoma cells as well as bacteria within 10 min. Good injectability, self-healing and adhesion combined with high reactive oxygen species (ROS) scavenging capacity, hemostasis and biocompatibility made this hydrogel platform perfect for the postoperative treatment of melanoma and promoting wound healing. With the assistance of NIR irradiance, hydrogel can inhibit tumor tissue proliferation and promote tumor cell apoptosis, thereby helping to prevent melanoma recurrence after surgical removal of tumors. Simultaneously, the irradiance heat and polyphenol component kill bacteria on the wound surface, eliminate ROS, inhibit inflammatory responses, and promote angiogenesis, collagen deposition, and skin regeneration, all of which help to speed up wound healing.

Application of cell membrane-functionalized biomimetic nanoparticles in the treatment of glioma.

Glioma is one of the most common malignant tumors with characteristics of strong invasion and high postoperative recurrence rate, which seriously threatens human health. Nanoparticles as an emerging drug delivery system have promoted the development of glioma therapy. However, blocking of nanoparticles by the blood-brain barrier is still serious problem for the use of nanoparticles in glioma therapy. In this context, traditional nanoparticles are dressed with natural cell membranes to prepare biomimetic nanoparticles. Biomimetic nanoparticles show longer blood circulation time, excellent homologous targeting and outstanding immune escape capacity, which significantly improve the accumulation of nanoparticles at the tumor site. The therapeutic effect for glioma has been raised to an advanced level. This review focuses on the preparations and applications of cell membrane-functionalized biomimetic nanoparticles, as while as the advantages and problems of biomimetic nanoparticles in the treatment of glioma. In particular, the approach of using biomimetic nanoparticles to cross the blood-brain barrier is analyzed, in the hope of providing new ideas for further developments in crossing the blood-brain barrier and in glioma therapy.

Construction and validation of a novel prognostic signature for cutaneous melanoma based on ferroptosis-related genes.

Ferroptosis, a recently uncovered iron-dependent, non-apoptotic cell death process, has been increasingly linked to cancer development. In this study, our objective was to develop a prognostic model centered on ferroptosis-related genes (FRGs) and assess its efficacy as an overall survival (OS) prediction biomarker. We conducted a systematic analysis of cutaneous melanoma (CM) and devised a novel ferroptosis-related prognostic signature (FRGSig) using the TCGA database. An independent dataset from GSE65904 was employed to corroborate the validity of the FRGSig. Both univariate and multivariate Cox proportional hazard regression analyses were utilized to construct a FRGSig composed of five FRGs. mRNA expression and immunohistochemistry (IHC) analysis demonstrated that the expression of FRGSig genes varied between tumor and normal tissues. According to Kaplan-Meier analysis, patients with elevated FRGsig scores faced a worse prognosis. The predictive accuracy of FRGSig was evaluated using the time-dependent receiver operating characteristic curve (ROC), with the area under the curve (AUC) values for 1, 3, and 5 OS at 0.682, 0.711, 0.735 in the TCGA cohort, and 0.662, 0.695, 0.712 in the validation dataset, respectively. Univariate and multivariate Cox regression analyses demonstrated that FRGSig served as an independent prognostic factor. Further analysis revealed a significant relationship between FRGSig and Tumor Mutational Burden (TMB) as well as immune infiltration levels. Gene set enrichment analysis (GSEA) disclosed functional disparities between high- and low-risk groups, suggesting that immune checkpoint-related pathways could be instrumental in the improved prognosis of the low-risk group. Taken together, the FRGSig has potential guidance for prognosis prediction and clinical treatment of CM.

Ultra-stretchable, tissue-adhesive, shape-adaptive, self-healing, on-demand removable hydrogel dressings with multiple functions for infected wound healing in regions of high mobility.

Bacterial infection in the most mobile area usually leads to delayed healing and functional restriction, which has been a long-term challenge in clinic. Developing hydrogel-based dressings with mechanical flexibly, high adhesive and anti-bacterial properties, will contribute to the healing and therapeutic effects especially for this typical skin wound. In this work, composite hydrogel named PBOF through multi-reversible bonds between polyvinyl alcohol, borax, oligomeric procyanidin and ferric ion demonstrated a 100 times ultra-stretch ability, 24 kPa of highly tissue-adhesive, rapid shape-adaptability within 2 min and self-healing feature within 40 s, was designed as the multifunctional wound dressing for the Staphylococcus aureus-infected skin wound in the mice nape model. Besides, this hydrogel dressing could be easily removed on-demand within 10 min by water. The rapid disassembly of this hydrogel is related to the formation of hydrogen bonds between polyvinyl alcohol and water. Moreover, the multifunctional properties of this hydrogel include strong anti-oxidative, anti-bacteria and hemostasis derived from oligomeric procyanidin and photothermal effect of ferric ion/polyphenol chelate. The killing ratio of the hydrogel on Staphylococcus aureus in infected skin wound reached 90.6% when exposed to 808 nm irradiation for 10 min. Simultaneously, reduced oxidative stress, suppressed inflammation, and promoted angiogenesis all together accelerated wound healing. Therefore, this well-designed multifunctional PBOF hydrogel holds great promise as skin wound dressing especially in the high mobile regions of the body. STATEMENT OF SIGNIFICANCE: An ultra-stretchable, highly tissue-adhesive, and rapidly shape-adaptive, self-healing and on-demand removable hydrogel based on multi-reversible bonds among polyvinyl alcohol, borax, oligomeric procyanidin and ferric ion is designed as dressing material for infected wound healing in the movable nape. The rapid on-demand removal of the hydrogel relates to the formation of hydrogen bonds between polyvinyl alcohol and water. This hydrogel dressing shows strong antioxidant capacity, rapid hemostasis and photothermal antibacterial ability. This is derived from oligomeric procyanidin and thephotothermal effect of ferric ion/polyphenol chelate, which eliminates bacterial infection, reduces oxidative stress, regulates inflammation, promotes angiogenesis, and finally accelerates the infected wound healing in movable part.

Nanoparticle-Based Drug Delivery Systems: An Inspiring Therapeutic Strategy for Neurodegenerative Diseases.

Neurodegenerative diseases are common, incurable neurological disorders with high prevalence, and lead to memory, movement, language, and intelligence impairments, threatening the lives and health of patients worldwide. The blood-brain barrier (BBB), a physiological barrier between the central nervous system and peripheral blood circulation, plays an important role in maintaining the homeostasis of the intracerebral environment by strictly regulating the transport of substances between the blood and brain. Therefore, it is difficult for therapeutic drugs to penetrate the BBB and reach the brain, and this affects their efficacy. Nanoparticles (NPs) can be used as drug transport carriers and are also known as nanoparticle-based drug delivery systems (NDDSs). These systems not only increase the stability of drugs but also facilitate the crossing of drugs through the BBB and improve their efficacy. In this article, we provided an overview of the types and administration routes of NPs, highlighted the preclinical and clinical studies of NDDSs in neurodegenerative diseases, and summarized the combined therapeutic strategies in the management of neurodegenerative diseases. Finally, the prospects and challenges of NDDSs in recent basic and clinical research were also discussed. Above all, NDDSs provide an inspiring therapeutic strategy for the treatment of neurodegenerative diseases.