Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy.

Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in reactive oxygen species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.

Mitochondria-Regulated Information Processing Nanosystem Promoting Immune Cell Communication for Liver Fibrosis Regression.

Liver fibrosis is a coordinated response to tissue injury that is mediated by immune cell interactions. A mitochondria-regulated information-processing (MIP) nanosystem that promotes immune cell communication and interactions to inhibit liver fibrosis is designed. The MIP nanosystem mimics the alkaline amino acid domain of mitochondrial precursor proteins, providing precise targeting of the mitochondria. The MIP nanosystem is driven by light to modulate the mitochondria of hepatic stellate cells, resulting in the release of mitochondrial DNA into the fibrotic microenvironment, as detected by macrophages. By activating the STING signaling pathway, the developed nanosystem-induced macrophage phenotype switches to a reparative subtype (Ly6Clow) and downstream immunostimulatory transcriptional activity, fully restoring the fibrotic liver to its normal tissue state. The MIP nanosystem serves as an advanced information transfer system, allowing precise regulation of trained immunity, and offers a promising approach for effective liver fibrosis immunotherapy with the potential for clinical translation.

A Bioartificial Pancreas with "Immune Stealth" and Continuous Oxygen Supply for Islet Transplantation.

Transplantation of microencapsulated islet cells remains a promising strategy for the normalization of glucose metabolism control in type 1 diabetes mellitus. However, vigorous host immunologic rejection, fibrotic overgrowth around the microcapsules, and poor oxygen supply often lead to graft failure. Herein, a bioartificial pancreas is constructed, which incorporates the "stealth effect" based on polyethylene glycol copolymers and the high oxygen-carrying performance of fluorinated nanoparticles. Polycationic poly(l-lysine)-grafted-poly(ethylene glycol) is successfully coated on the surface of alginate microcapsules through electrostatic interaction, which can not only resist fibrinogen adhesion and avoid excessive fibrosis around the microcapsules but also isolate the host immune system from attacking, achieving a "stealth effect" of microencapsulated islet cells. Furthermore, the coloading of fluoride-based O2 nanocarriers gives them enhanced oxygen-carrying and continuous oxygen supply capabilities, thereby effectively prolonging the survival of islet cells. The intracapsular islet cells still display similar cell viability and almost normal insulin secretion function even in long-term culture under hypoxic conditions. Collectively, here a new approach is opened for microencapsulated islets to efficiently evade host immune attack and improve oxygen supply and a promising strategy is provided for islet transplantation in type 1 diabetes mellitus.

Diabetic ferroptosis plays an important role in triggering on inflammation in diabetic wound.

Impaired wound healing is a major complication of diabetes and involves sustained inflammation and oxidative stress at the wound site. Here, we investigated the potential involvement of ferroptosis, a newly discovered form of cell death characterized by iron-dependent accumulation of lipid peroxides in the pathogenesis of diabetic wound healing. Fibroblasts and vascular endothelial cells exposed to high glucose concentrations in vitro contained elevated levels of reactive oxygen species (ROS), lipid peroxidation products, and ferroptosis-associated proteins and displayed reduced survival and migration. These effects of high glucose were all significantly reduced by treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Similarly, in a rat model of diabetes, direct application of Fer-1 to the wound site reduced the expression of oxidative stress and inflammation markers and accelerated wound healing via activation of the anti-inflammatory phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Our results implicate ferroptosis in wound healing and identify a potential new therapeutic target for difficult-to-treat diabetic wounds.NEW & NOTEWORTHY Ferroptosis-related characteristic changes were found in diabetic wound models. Inhibition of ferroptosis improved inflammatory infiltration of diabetic wounds. PI3K/AKT signal pathway was rescued by restraining of ferroptosis. Mitigation of ferroptosis in diabetic wound promoted the wound healing.

Epithelium-Penetrable Nanoplatform with Enhanced Antibiotic Internalization for Management of Bacterial Keratitis.

A standardized regimen for addressing the adverse effects of bacterial keratitis on vision remains an intractable challenge due to poor epithelial penetration and a short corneal retention time. In this study, a new strategy is proposed to implement the direct transport of antibiotics to bacteria-infected corneas via topical administration of an epithelium-penetrable biodriven nanoplatform, thereby enabling the efficacious treatment of bacterial keratitis. The nanoplatforms were composed of amphiphilic glycopolymers containing boron dipyrromethene and boronic acid moieties with stable fluorescence characteristics and the ability to potentiate epithelial penetration deep into the cornea. The boronic acid-derived nanoplatforms enabled efficient cellular internalization through the high affinity of boric acid groups for the diol-containing bacterial cell wall, resulting in enhanced drug penetration and retention inside the pathogenic bacteria. The bacterial cells formed agglomerations after incorporating the nanoplatforms along with a special mechanism to release the encapsulated cargo in response to in situ bacteria. Compared with the drug alone, this smart system achieved enhanced bacterial mortality and attenuated inflammation associated with Staphylococcus aureus-induced keratitis in rats, demonstrating a paradigm for targeted ocular drug delivery and an alternative strategy for managing bacterial keratitis or other bacterial infections by heightening corneal permeability and transcorneal bioavailability.

A Targeted Photosensitizer Mediated by Visible Light for Efficient Therapy of Bacterial Keratitis.

Bacterial keratitis is a serious bacterial infection of the cornea that can cause sight loss in severe cases because of the sharp decline of efficacious antibiotics. Herein, a targeted photosensitizer based on BODIPY severing as a photobactericidal agent was developed for treating bacterial keratitis. The water solubility of the material was as high as 10 mg/mL, which was attributable to the introduction of pathogen-targeting galactose and fucose. The photosensitizer was able to preferentially bind Pseudomonas aeruginosa instead of mammalian cells and trigger the aggregation of bacteria, which ultimately facilitated effective pathogen ablation upon the generation of reactive oxygen species (ROS) via laser irradiation. Photoexcited targeted photosensitizers can promote wound healing by eradicating P. aeruginosa in rat eyes and reducing the inflammatory response, thus exhibiting the significant therapeutic effect on bacterial keratitis. We also performed molecular level mechanistic studies using the unique field-induced droplet ionization mass spectrometry methodology and confirmed that the generated ROS were mainly singlet oxygen that caused lipid peroxidation (Type II mechanism). We anticipate that the targeted photosensitizer will have great potential in the application of clinical photodynamic therapy to ocular infection.

Comparison of chemiluminescence microparticle immunoassay, indirect immunofluorescence assay, linear immunoassay and multiple microbead immunoassay detecting autoantibodies in systemic lupus erythematosus.

The aim of study was to detect antinuclear antibodies (ANA) using indirect immunofluorescence assay (IIFA), linear immunoassay (LIA), chemiluminescence microparticle immunoassay (CMIA), multiple microbead immunoassay (MBI) and to compare these four methods in the performance of diagnosing systemic lupus erythematosus (SLE). Serum ANA were detected in 147 SLE cases and 42 healthy controls (HCs). The sensitivity, specificity, accuracy, positive predictive value and agreement, the area under the curve of four methods in diagnosing were calculated. Finally, a diagnostic model through logistic regression was constructed. The sensitivity of CMIA and IIFA in diagnosing SLE was 89.08% and 89.12%, higher than other two methods (P < .01), while highest specificity lied in CMIA (95.24%) and LIA (95.24%). The accuracy was highest in CMIA (91.01%), and lowest in LIA (83.07%). CMIA and the other three methods had good agreement, especially with LIA (κ = .798, 95% CI, 0.708-0.88). ANA-IIFA (OR = 1.016, P < .001) and anti-SSA antibodies (OR = 1.017, P = .043) were finally included in the SLE diagnostic model, with AUC value of 0.964 (95% CI, 0.936-0.991). SLE patients exhibited 14 various ANA patterns, especially AC-1, AC-4, and AC-5. Antibodies against SSA and dsDNA were mostly seen with AC-1 and AC-4 patterns, while antibodies against RNP, Sm, SSA, dsDNA, nucleosome and PO were most frequently observed with AC-5 pattern in SLE. CMIA method is a reliable screening test for detections of antibodies related to SLE. Using ANA-IIFA and anti-SSA antibodies by CMIA can discriminate SLE patients from HCs effectively.

Analysis of antinuclear antibody titers and patterns by using HEp-2 and primate liver tissue substrate indirect immunofluorescence assay in patients with systemic autoimmune rheumatic diseases.

BACKGROUND: Indirect immunofluorescence assay (IIFA) is viewed as a preliminary standard to assess antinuclear antibodies (ANAs). Our aim was to explore ANA positivity rate, titers, and patterns in patients with systemic autoimmune rheumatic diseases (SARD), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), and mixed connective tissue disease (MCTD), compared with healthy controls (HC). METHODS: Assess antinuclear antibody titers and patterns were retrospectively identified and compared by IIFA using human epithelial cells (HEp-2) and primate liver tissue substrate according to international consensus in SARD. Serum complement 3 (C3), C4, and immunoglobulin G were compared among subgroups with different ANA titers. The positive predictive values (PPV) for different ANA titers were calculated. RESULTS: There were a total of 3510 samples, including 2034 SLE, 973 RA, 155 SSc, 309 pSS, and 39 MCTD cases. There was no difference in age between HC and SARD, excluding RA. ANA positivity rate in SARD and HC was 78.7% and 12.2%, respectively. A titer of ≥1:320 revealed a PPV of 84.0% in SARD. SLE patients with ANA titers ≥1:320 had significantly lower levels of C3 and C4. AC-4 (31.2%) was the major pattern in patients with SARD, followed by AC-5 (23.9%) and AC-1 (18.8%). SLE mostly presented with AC-4 (30.3%). Several mixed patterns provided a significant hint for SSc and SLE. The major pattern in HC was AC-2 (12.2%). CONCLUSIONS: Assess antinuclear antibody positivity, titers, and patterns display differences in various SARD, contributing to the classification of SARD.

An Antifouling Hydrogel Containing Silver Nanoparticles for Modulating the Therapeutic Immune Response in Chronic Wound Healing.

Patients with diabetic wounds have deficient local and systemic cellular immunity. Herein, a new silver nanoparticle-containing hydrogel with antifouling properties was developed for enhancing the immune response in diabetic wound healing. The antifouling property was obtained by adjusting the composition of cationic chitosan and anionic dextran to approach zero charge. Furthermore, this hybrid hydrogel showed long-lasting and broad-spectrum antibacterial activity. Rapid wound contraction was observed after the treatment with the hydrogel, which suggested its superior healing activity to promote fibroblast migration, granulation tissue formation, and angiogenesis. The upregulation of CD68+ and CD3+ expression levels demonstrated that the hydrogel could trigger immune responses in the treatment of wound healing. These results show that this antifouling hybrid hydrogel as a wound dressing provided a promising strategy for the treatment of diabetic ulcers.

Glutamine Enhances the Hypoglycemic Effect of Insulin in L6 Cells via Phosphatidylinositol-3-Kinase (PI3K)/Protein Kinase B (AKT)/Glucose Transporter 4 (GLUT4) Signaling Pathway.

BACKGROUND Diabetes mellitus (DM) is characterized by a decreased blood level of glutamine (Gln), which may contribute to the disturbance in the effect of insulin on skeletal muscle. Therefore, it is crucial to study how to improve the effect of insulin on skeletal muscle by increasing Gln. In the present study, we investigated the effect of Gln on the hypoglycemic action of insulin in skeletal muscle L6 cells at high glucose levels through the insulin signaling pathway and glycogen synthesis pathway. MATERIAL AND METHODS The L6 cells were cultured in and stimulated by Gln and insulin. The glutamine analogue, L-Gamma-Glutamyl-p-nitroanilide (GPNA), was used for verifying the effect of Gln. The expression of insulin signaling molecules, including phosphatidylinositol-3-kinase (PI3K), 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (AKT), protein kinase C zeta (PKCz), and glucose transporter 4 (GLUT4), were detected by real-time PCR and Western blot analysis, GLUT4 translocation was observed by immunofluorescence staining, glycogen synthase kinase (GSK) was analyzed by Western blotting, and glucose uptake was measured by glucose oxidase method (GOD). RESULTS The results demonstrated that Gln combined with insulin remarkably up-regulated PI3K and PDK1 and also increased AKT and PKCz phosphorylation. The present study shows that Gln enhanced the impact of insulin on GLUT4 and its translocation. The results of glucose uptake and GSK phosphorylation further confirmed the hypoglycemic effect of Gln accompanied with insulin. The hypoglycemic effect of Gln was reversed by GPNA. CONCLUSIONS These findings suggest that Gln enhances the hypoglycemic role of insulin through the PI3K/AKT/GLUT4 signaling pathway and glycogen synthesis pathway.

Antitumor effects evaluation of a novel porphyrin derivative in photodynamic therapy.

In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5,10,15,20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.

Block versus Random Amphiphilic Glycopolymer Nanopaticles as Glucose-Responsive Vehicles.

To explore the effect of polymer structure on their self-assembled aggregates and their unique characteristics, this study was devoted to developing a series of amphiphilic block and random phenylboronic acid-based glycopolymers by RAFT polymerization. The amphiphilic glycopolymers were successfully self-assembled into spherically shaped nanoparticles with narrow size distribution in aqueous solution. For block and random copolymers with similar monomer compositions, block copolymer nanoparticles exhibited a more regular transmittance change with the increasing glucose level, while a more evident variation of size and quicker decreasing tendency in I/I0 behavior in different glucose media were observed for random copolymer nanoparticles. Cell viability of all the polymer nanoparticles investigated by MTT assay was higher than 80%, indicating that both block and random copolymers had good cytocompatibility. Insulin could be encapsulated into both nanoparticles, and insulin release rate for random glycopolymer was slightly quicker than that for the block ones. We speculate that different chain conformations between block and random glycopolymers play an important role in self-assembled nanoaggregates and underlying glucose-sensitive behavior.

An Acid-Triggered Degradable and Fluorescent Nanoscale Drug Delivery System with Enhanced Cytotoxicity to Cancer Cells.

To reduce side-effects of anticancer drugs, development of nanocarriers with precise biological functions is a critical requirement. In this study, the multifunctional nanoparticles combining imaging and therapy for tumor-targeted delivery of hydrophobic anticancer drugs were prepared via self-assembly of amphiphilic copolymers obtained using RAFT polymerization, specifically, acid-labile ortho ester and galactose. First, boron-dipyrromethene dye-conjugated chain transfer agent provides fluorescent imaging capability for diagnostic application. Second, nanoparticles were stable under physiological conditions but degraded in acidic tumor microenvironment, leading to enhanced anticancer efficacy. Third, the application of biocompatible glycopolymers efficiently increased the target-to-background ratio through carbohydrate-protein interactions. Data from cell viability, cellular internalization, flow cytometry, biodistribution and anticancer efficacy tests showed that the drug-loaded nanoparticles were capable of inhibiting cancer cell proliferation with significantly enhanced capacity. Our newly developed multifunctional nanoparticles may thus facilitate the development of effective drug delivery systems for application in diagnosis and therapy of cancer.

Effect of Dental Pulp Stem Cells (DPSCs) in Repairing Rabbit Alveolar Bone Defect.

BACKGROUND: The aim of this research was to analyze the ability of dental pulp stem cells (DPSCs) in repairing rabbit alveolar bone defect. METHODS: First, DPSCs were isolated from the pulp tissue of the anterior teeth and molars of young rabbits and cultured in vitro. Subsequently, cell cloning efficiency, anti-vimentin, and anti-CD44 immunohistochemical staining were investigated. Second, bone defect models were made in rabbit alveolar toothless jaw. The bone defects in the control group were filled with 0.25 g bio-oss bone mixed with PBS solution, while the bone defects in the experimental group were filled with 0.25 g bio-oss bone mixed with 1 x 108 DPSCs/L. Animals were sacrificed six weeks after the surgery, the alveolar tissue was collected for paraffin sections, HE staining, and immunohistochemistry of bone sialoprotein (BSP). RESULTS: The immunocytochemistry results of surface markers showed a positive staining of vimentin and CD44 in the DPSCs forming low density colonies after inoculation. The alveolar tissue of the control group showed a small amount of erythrocytes highlighted by HE staining, with no visible new bone formation except for a few osteoblasts, with a weakly positive BSP immunohistochemical staining. HE staining in the experimental group showed that the inflammatory exudate was significantly absorbed, some new bone tissue was present, with many osteoblasts around the bone defects, and with a strong positive BSP immunohistochemical staining, which was statistically significant compared to the control group (p < 0.05). CONCLUSIONS: DPSCs possess the ability to differentiate into bone cells, promoting the repair and regeneration of alveolar bone defects.

Phenylboronate-diol crosslinked glycopolymeric nanocarriers for insulin delivery at physiological pH.

Research into polymers with glucose-sensitivity in physiological conditions has expanded recently due to their therapeutic potential in diabetes. Herein, to explore the glucose-responsive properties of a new polymer under physiological conditions, we synthesized an amphiphilic block glycopolymer based on phenylboronic acid and a carbohydrate, which was named poly(d-gluconamidoethyl methacrylate-block-3-acrylamidophenylboronic acid) (p(AAPBA-b-GAMA)). Based on the cross-linking between the diol groups of the carbohydrates and phenylboronic acid, the glycopolymers self-assembled to form nanoparticles (NPs). The glucose-sensitivity was revealed by the swelling behavior of the NPs at different glucose concentrations and was found to be dependent on the glucose level. The morphology of the NPs revealed by transmission electron microscopy showed that the NPs were spherical in shape with good dispersity. The cell viability of the NPs investigated by MTT assay was more than 90%, indicating that the glycopolymers had good cytocompatibility. Insulin could be loaded onto the glycopolymer NPs with high efficiency (up to 10%), and insulin release increased with enhancement of the glucose level in the medium. Such a glucose-responsive glycopolymer is an excellent candidate that holds great potential in the treatment of diabetes.

Glucose-sensitive polyelectrolyte nanocapsules based on layer-by-layer technique for protein drug delivery.

The glucose-responsive nanocapsules [CS-NAC/p(GAMA-r-AAPBA)] were readily fabricated with modified chitosan (CS-NAC) and random glycopolymer poly(D-gluconamidoethyl methacrylate-r-3-acrylamidophenylboronic acid) p(GAMA-r-AAPBA) as the alternant multilayered polyelectrolyte hybrid shell via layer-by-layer self-assembly after etching the amino functionalized SiO2 spheres by NH4F/HF. The spherical and hollow structure of nanocapsules was confirmed by TEM analysis and there was no clear collapse found after removal of the sacrificial cores. The reversible zeta potential changes of the nanocapsule materials evaluated the reversible glucose sensitivity. Besides, this system demonstrated a good capacity for encapsulation and loading insulin entrapped in nanocapsules as model protein drug. A good biocompatibility of the material was confirmed by the cell viability. In vitro release of insulin experiments revealed that no obvious release was found in acidic condition and the release could be normally conducted at physiological pH. These results implied that it was feasible for nanocapsules to be used in controlled release drug delivery system.

[Effects of insulin-like growth factor-1 on the myocardium in diabetic rats].

OBJECTIVE: To observe the effects of insulin-like growth factor-1(IGF-1) on myocardial fibrosis and myocardial cell apoptosis in diabetic rats, so as to clarify the potential benefit of IGF-1 on diabetic cardiomyopathy. METHODS: Diabetic rats were induced by caudal injection of STZ, and the diabetic rats were randomly divided into 3 groups:diabetes group, the insulin treatment group and the IGF-1 treatment group.Normal control (NC) group did not receive any therapy. The experiment lasted 10 weeks and the heart weight was recorded to calculate the heart weight index. The serum insulin and IGF-1 level were determined.HE staining and Masson staining were taken on the left ventricular tissue. The cardiomyocyte apoptosis were measured by methods of terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) , the expression levels of IGF-1R in cardiomyocytes were measured by immunohistochemical and Western blot. RESULTS: Compared with diabetes group, the heart weight index of the insulin treatment group and the IGF-1 treatment group were significantly decreased. Serum levels of IGF-1 in diabetes group were significantly decreased compared with NC group, and the levels were significantly increased in IGF-1 treatment group. The results of HE and Masson staining showed that compared with NC group, diabetes rats' myocardial tissue were damaged. Myocardial tissue pathological changes of rats were significantly improved after insulin and IGF-1 treatment. The result of TUNEL indicant cardiomyocyte apoptosis index in diabetes group was obviously increased than the NC group, and that in IGF-1 treatment group were decreased compared with diabetes group. IGF-1R levels in diabetic rats myocardial tissue were rised than the NC group, it was declined in IGF-1 treatment group, but in insulin treatment group the levels had no obvious change. CONCLUSIONS: IGF-1 can inhibite the myocardial fibrosis and cardiomyocyte apoptosis. It maybe have the possible effect on the treatment of diabetic cardiomyopathy.

Targeting ferroptosis promotes diabetic wound healing via Nrf2 activation.

Wound healing impairment is a frequent diabetes problem leading to amputation. Hyperglycemia induces the overproduction of reactive oxygen species (ROS), iron overload and sustained inflammation, resulting in the persistence of chronic wounds. However, the intrinsic mechanisms of impaired diabetic wound healing remain enigmatic. A new non-apoptotic regulatory cellular death called Ferroptosis, is distinguished by iron-driven lipid peroxidation products accumulation along with insufficient antioxidant enzymes. A decline in antioxidant capacity, excess accumulation of peroxidation of iron and lipid have been identified in wound sites of streptozotocin-induced diabetes mellitus (DM) rats and elevated glucose (EG)-cultured macrophages. Additionally, sustained inflammation and increased inflammatory cytokines were observed in DM rats and HG-cultured macrophages. Importantly, ferrostatin-1 (Fer-1) is a ferroptosis suppressor treatment significantly ameliorated diabetes-related ferroptosis and inflammation. This treatment also enhanced cell proliferation and neovascularization, ultimately thereby accelerating diabetic wound healing. Meanwhile, our study demonstrated that an anti-ferroptotic and anti-inflammatory effects of Fer-1 were mediated through stimulation of nuclear erythroid-associated factor 2 (Nrf2). The current study may provide a new rationale for diabetic wound healing.

A Living Microecological Hydrogel with Microbiota Remodeling and Immune Reinstatement for Diabetic Wound Healing.

Dysregulated skin microbiota and compromised immune responses are the major etiological factors for non-healing diabetic wounds. Current antibacterial strategies fail to orchestrate immune responses and indiscriminately eradicate bacteria at the wound site, exacerbating the imbalance of microbiota. Drawing inspiration from the beneficial impacts that probiotics possess on microbiota, a living microecological hydrogel containing Lactobacillus plantarum and fructooligosaccharide (LP/FOS@Gel) is formulated to remodel dysregulated skin microbiota and reinstate compromised immune responses, cultivating a conducive environment for optimal wound healing. LP/FOS@Gel acts as an "evocator," skillfully integrating the skin microecology, promoting the proliferation of Lactobacillus, Ralstonia, Muribaculum, Bacillus, and Allobaculum, while eradicating colonized pathogenic bacteria. Concurrently, LP/FOS@Gel continuously generates lactic acid to elicit a reparative macrophage response and impede the activation of the nuclear factor kappa-B pathway, effectively alleviating inflammation. As an intelligent microecological system, LP/FOS@Gel reinstates the skin's sovereignty during the healing process and effectively orchestrates the harmonious dialogue between the host immune system and microorganisms, thereby fostering the healing of diabetic infectious wounds. These remarkable attributes render LP/FOS@Gel highly advantageous for pragmatic clinical applications.

Adipocyte-Targeted Nanocomplex with Synergistic Photothermal and Pharmacological Effects for Combating Obesity and Related Metabolic Syndromes.

Obesity is a global epidemic which induces a multitude of metabolic disorders. Browning of white adipose tissue (WAT) has emerged as a promising therapeutic strategy for promoting weight loss and improving associated metabolic syndromes in people with obesity. However, current methods of inducing white adipose tissue browning have limited applicability. We developed a nanocomplex pTSL@(P+I), which is a temperature-sensitive liposome (TSL) surface-conjugated with an adipocyte-targeting peptide (p) and loaded with both browning-promoting agents (P) and photosensitizing agents (I). This nanocomplex exhibits adipocyte targeting, as well as synergistic pharmacological and photothermal properties to promote browning. pTSL@(P+I) effectively upregulates UCP1 and COX5B expression by activating the transcription axis of PPARγ/PGC1α and HSF1/PGC1α, thereby promoting white adipose tissue browning and reducing obesity. This novel nanocomplex exhibited a uniform spherical shape, with an average diameter of approximately 200 nm. Additionally, the nanocomplexes exhibited remarkable photothermal properties and biocompatibility. Further, when adipocytes were treated with pTSL@(P+I), their triglyceride content decreased remarkably and intracellular mitochondrial activity increased significantly. When applied to diet-induced obesity (DIO) mice, the nanocomplex exhibited significant efficacy, demonstrating a notable 14.4% reduction in body weight from the initial measurement, a decreased fat/lean mass ratio of 20.8%, and no statistically significant disparities (p > 0.05) in associated side effects when compared to the control group. In summary, implementation of the targeted nanocomplex pTSL@(P+I) to enhance energy expenditure by stimulating white adipose tissue browning offers a promising therapeutic approach for the treatment of obesity and related metabolic syndromes.