The STAT1-SLC31A1 axis: Potential regulation of cuproptosis in diabetic retinopathy.

BACKGROUND: By identifying molecular biological markers linked to cuproptosis in diabetic retinopathy (DR), new pathobiological pathways and more accessible diagnostic markers can be developed. METHODS: The datasets related to DR were acquired from the Gene Expression Omnibus database, while genes associated with cuproptosis were sourced from previously published compilations. Consensus clustering was conducted to delineate distinct DR subclasses. Feature genes were identified utilizing weighted correlation network analysis (WGCNA). Additionally, two machine-learning algorithms were employed to refine the selection of feature genes. Finally, we conducted preliminary validation experiments to ascertain the involvement of cuproptosis in DR development and the transcriptional regulation of critical genes using both the streptozotocin-induced diabetic mouse model and the high glucose-induced BV2 model. RESULTS: In the STZ-induced diabetic mouse retinas, a decrease in the expression of cuproptosis signature proteins (FDX1, DLAT, and NDUFS8) suggested the occurrence of cuproptosis in DR. Subsequently, the expression of eight cuproptosis differential genes was validated through the STZ-induced diabetes and oxygen-induced retinopathy (OIR) models, with the key gene SLC31A1 showing upregulation in both models and dataset species. Further analyses, including weighted gene co-expression network analysis, GSVA, and immune infiltration analysis, indicated a close correlation between cuproptosis and microglia function. Additionally, validation in an in vitro model of microglia indicated the occurrence of cuproptosis in microglia under high glucose conditions, alongside abnormal expression of STAT1 with SLC31A1. CONCLUSION: Our findings suggest that STAT1/SLC31A1 may pave the way for a deeper comprehension of the mechanistic basis of DR and offer potential therapeutic avenues.

A thermally reversible injectable adhesive for intestinal tissue repair and anti-postoperative adhesion.

Intestine damage is an acute abdominal disease that usually requires emergency sealing. However, traditional surgical suture not only causes secondary damage to the injured tissue, but also results in adhesion with other tissues in the abdominal cavity. To this end, a thermally reversible injectable gelatin-based hydrogel adhesive (GTPC) is constructed by introducing transglutaminase (TGase) and proanthocyanidins (PCs) into a gelatin system. By reducing the catalytic activity of TGase, the density of covalent and hydrogen bond crosslinking in the hydrogel can be regulated to tune the sol-gel transition temperature of gelatin-based hydrogels above the physiological temperature (42 °C) without introducing any synthetic small molecules. The GTPC hydrogel exhibits good tissue adhesion, antioxidant, and antibacterial properties, which can effectively seal damaged intestinal tissues and regulate the microenvironment of the damaged site, promoting tissue repair and regeneration. Intriguingly, temperature-induced hydrogen bond disruption and reformation confer the hydrogel with asymmetric adhesion properties, preventing tissue adhesion when applied in vivo. Animal experiment outcomes reveal that the GTPC hydrogel can seal the damaged intestinal tissue firmly, accelerate tissue healing, and efficiently prevent postoperative adhesion.

3D printing sequentially strengthening high-strength natural polymer hydrogel bilayer scaffold for cornea regeneration.

3D printing of high-strength natural polymer biodegradable hydrogel scaffolds simultaneously resembling the biomechanics of corneal tissue and facilitating tissue regeneration remains a huge challenge due to the inherent brittleness of natural polymer hydrogels and the demanding requirements of printing. Herein, concentrated aqueous solutions of gelatin and carbohydrazide-modified alginate (Gel/Alg-CDH) are blended to form a natural polymer hydrogel ink, where the hydrazides in Alg-CDH are found to form strong hydrogen bonds with the gelatin. The hydrogen-bonding-strengthened Gel/Alg-CDH hydrogel demonstrates an appropriate thickened viscosity and shear thinning for extrusion printing. The strong hydrogen bonds contribute to remarkably increased mechanical properties of Gel/Alg-CDH hydrogel with a maximum elongation of over 400%. In addition, sequentially Ca2+-physical crosslinking and then moderately chemical crosslinking significantly enhance the mechanical properties of Gel/Alg-CDH hydrogels that ultimately exhibit an intriguing J-shaped stress-strain curve (tensile strength of 1.068 MPa and the toughness of 677.6 kJ/m2). The dually crosslinked Gel-Alg-CDH-Ca2+-EDC hydrogels demonstrate a high transparency, physiological swelling stability and rapid enzymatic degradability, as well as suturability. The growth factor and drug-loaded biomimetic bilayer hydrogel scaffold are customized via a multi-nozzle printing system. This bioactive bilayer hydrogel scaffold considerably promotes regeneration of corneal epithelium and stroma and inhibits cornea scarring in rabbit cornea keratoplasty.

Dough-Kneading-Inspired Design of an Adhesive Cardiac Patch to Attenuate Cardiac Fibrosis and Improve Cardiac Function via Regulating Glycometabolism.

Recently, hydrogel adhesive patches have been explored for treating myocardial infarction. However, achieving secure adhesion onto the wet beating heart and local regulation of pathological microenvironment remains challenging. Herein, a dough-kneading-inspired design of hydrogel adhesive cardiac patch is reported, aiming to improve the strength of prevalent powder-formed patch and retain wet adhesion. In mimicking the polysaccharide and protein components of natural flour, methacrylated polyglutamic acid (PGAMA) is electrostatically interacted with hydroxypropyl chitosan (HPCS) to form PGAMA/HPCS coacervate hydrogel. The PGAMA/HPCS hydrogel is freeze-dried and ground into powders, which are further rehydrated with two aqueous solutions of functional drug, 3-acrylamido phenylboronic acid (APBA)/rutin (Rt) complexes for protecting the myocardium from advanced glycation end product (AGEs) injury by reactive oxygen species (ROS) -responsive Rt release, and hypoxanthine-loaded methacrylated hyaluronic acid (HAMA) nanogels for enhancing macrophage targeting ability to regulate glycometabolism for combating inflammation. The rehydrated powders bearing APBA/Rt complexes and HAMA-hypoxanthine nanogels are repeatedly kneaded into a dough-like gel, which is further subjected to thermal-initiated crosslinking to form a stabilized and sticky patch. This biofunctional patch is applied onto the rats' infarcted myocardium, and the outcomes at 28 days post-surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis.

Wet adhesive hydrogel cardiac patch loaded with anti-oxidative, autophagy-regulating molecule capsules and MSCs for restoring infarcted myocardium.

Hydrogel patch-based stem cell transplantation and microenvironment-regulating drug delivery strategy is promising for the treatment of myocardial infarction (MI). However, the low retention of cells and drugs limits their therapeutic efficacies. Here, we propose a prefixed sponge carpet strategy, that is, aldehyde-dextran sponge (ODS) loading anti-oxidative/autophagy-regulating molecular capsules of 2-hydroxy-ß-cyclodextrin@resveratrol (HP-ß-CD@Res) is first bonded to the rat's heart via capillary removal of interfacial water from the tissue surface, and the subsequent Schiff base reaction between the aldehyde groups on ODS and amino groups on myocardium tissue. Then, an aqueous biocompatible hydrazided hyaluronic acid (HHA) solution encapsulating mesenchymal stem cells (MSCs) is impregnated into the anchored carpet to form HHA@ODS@HP-ß-CD@Res hydrogel in situ via click reaction, thus prolonging the in vivo retention time of therapeutic drug and cells. Importantly, the HHA added to outer surface consumes the remaining aldehydes to contribute to nonsticky top surface, avoiding adhesion to other tissues. The embedded HP-ß-CD@Res molecular capsules with antioxidant and autophagy regulation bioactivities can considerably improve cardiac microenvironment, reduce cardiomyocyte apoptosis, and enhance the survival of transplanted MSCs, thereby promoting cardiac repair by facilitating angiogenesis and reducing cardiac fibrosis.

An anticoagulant/hemostatic indwelling needle for oral glucose tolerance test.

Indwelling needles are widely used in the clinic for their advantages of reducing the pain and discomfort caused by repeated venipuncture. Achieving anticoagulation and hemostasis with one single indwelling needle is highly desired from perspective of implantation patency and the prevention of needle-withdrawal-induced uncontrolled bleeding. Herein, we develop a sophisticated indwelling needle with an anticoagulant/hemostatic dual function by anchoring an anticoagulant heparin coating and a hemostatic hydrogel coating on the inner surface and the outer surface of the indwelling needle, respectively. The results of in vitro tests and continuous blood collections from the rabbit ear vein indicate that the anticoagulant coating can resist the adhesion of proteins and blood cells, and its anticoagulant effect can maintain the patency of the indwelling needle for 3 hours after implantation. Meanwhile, the xerogel-hydrogel transition of the hemostatic coating upon contacting blood promotes the aggregation of blood cells, thus sealing the puncture site to achieve complete hemostasis after needle removal. Importantly, this anticoagulant/hemostatic indwelling needle can replace traditional repeated puncture, and can be used to monitor blood glucose concentration changes in diabetic rats through continuous blood collection, portending its promising application in the oral glucose tolerance test.

An injectable mitochondria-targeted nanodrug loaded-hydrogel for restoring mitochondrial function and hierarchically attenuating oxidative stress to reduce myocardial ischemia-reperfusion injury.

Timely reperfusion is the common treatment for myocardial infarction. However, ischemia-reperfusion (I/R) therapy can lead to oxidative stress and mitochondrial dysfunction that further aggravate myocardial injury, and no effective therapy is currently available for alleviating myocardial I/R injury. Herein, we engineer a mitochondria-targeted Szeto-Schiller (SS31) peptide modified-amphiphilic polymer (PTPS) that self-assembles into nanomicelles (PTPSCs) for loading cyclosporine A (CsA). The PTPSCs are then encapsulated into a pH/ROS dual responsive injectable hydrogel crosslinked with reversible imine and boronic ester bonds. The loaded PTPSCs are controllably delivered from the hydrogel matrix in response to the low pH and high ROS microenvironment of the I/R heart, thus realizing reconstruction of mitochondrial function and unprecedented hierarchical attenuation of oxidative stress. The boronic ester in the hydrogel consumes the ROS in cardiac microenvironment, and the mitochondria-targeted delivery of CsA is revealed to inhibit mitochondria-mediated apoptosis signaling pathway to prevent cardiomyocyte apoptosis, meanwhile attenuating the mitochondrial ROS output to reduce the level of cytosolic ROS. Additionally, SS31 can also serve as an antioxidant to consume ROS in the mitochondria. In rat model of myocardial I/R injury with administration of this injectable hydrogel, the targeted release of PTPSCs efficiently restores mitochondrial and cardiac function.