Regulation of optimized new Shengmai powder on cardiomyocyte apoptosis and ferroptosis in ischemic heart failure rats: The mediating role of phosphatidylinositol-3-kinase/protein kinase B/tumor protein 53 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Optimized New Shengmai Powder (ONSMP) is a sophisticated traditional Chinese medicinal formula renowned for bolstering vital energy, optimizing blood circulation, and mitigating fluid retention. After years of clinical application, ONSMP has shown a significant impact in improving myocardial injury and cardiac function and has a positive effect on treating heart failure. However, many unknowns exist about the molecular biological mechanisms of how ONSMP exerts its therapeutic effects, which require further research and exploration. AIM OF THE STUDY: Exploring the potential molecular biological mechanisms by which ONSMP ameliorates cardiomyocyte apoptosis and ferroptosis in ischemic heart failure (IHF). MATERIALS AND METHODS: First, we constructed a rat model of IHF by inducing acute myocardial infarction through surgery and using echocardiography, organ coefficients, markers of heart failure, antioxidant markers, and histopathological examination to assess the effects of ONSMP on cardiomyocyte apoptosis and ferroptosis in IHF rats. Next, we used bioinformatics analysis techniques to analyze the active components, signaling pathways, and core targets of ONSMP and calculated the interactions between core targets and corresponding elements. Finally, we detected the positive expression of apoptosis and ferroptosis markers and core indicators of signaling pathways by immunohistochemistry; detected the mean fluorescence intensity of core indicators of signaling pathways by immunofluorescence; detected the protein expression of signaling pathways and downstream effector molecules by western blotting; and detected the mRNA levels of p53 and downstream effector molecules by quantitative polymerase chain reaction. RESULTS: ONSMP can activate the Ser83 site of ASK by promoting the phosphorylation of the PI3K/AKT axis, thereby inhibiting the MKK3/6-p38 axis and the MKK4/7-JNK axis signaling to reduce p53 expression, and can also directly target and inhibit the activity of p53, ultimately inhibiting p53-mediated mRNA and protein increases in PUMA, SAT1, PIG3, and TFR1, as well as mRNA and protein decreases in SLC7A11, thereby inhibiting cardiomyocyte apoptosis and ferroptosis, effectively improving cardiac function and ventricular remodeling in IHF rat models. CONCLUSION: ONSMP can inhibit cardiomyocyte apoptosis and ferroptosis through the PI3K/AKT/p53 signaling pathway, delaying the development of IHF.

Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia.

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.

Simvastatin attenuates silica-induced pulmonary inflammation and fibrosis in rats via the AMPK-NOX pathway.

BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and transforming growth factor-ß1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation.

BACKGROUND: Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. METHODS: FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. RESULTS: The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. CONCLUSION: In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials.

circCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models.

Chronic wounds are a major complication in patients with diabetes. Here, we identify a therapeutic circRNA and load it into small extracellular vesicles (sEVs) to treat diabetic wounds in preclinical models. We show that circCDK13 can stimulate the proliferation and migration of human dermal fibroblasts and human epidermal keratinocytes by interacting with insulin-like growth factor 2 mRNA binding protein 3 in an N6-Methyladenosine-dependent manner to enhance CD44 and c-MYC expression. We engineered sEVs that overexpress circCDK13 and show that local subcutaneous injection into male db/db diabetic mouse wounds and wounds of streptozotocin-induced type I male diabetic rats could accelerate wound healing and skin appendage regeneration. Our study demonstrates that the delivery of circCDK13 in sEVs may present an option for diabetic wound treatment.

Anti-fatigue activity of methyl dihydrojasmonate and linalool in a rat model evaluated by a novel index for neuro-immune and oxidative stress interactions.

Avoiding fatigue is a long-standing challenge in both healthy and diseased individuals. Establishing objective standard markers of fatigue is essential to evaluate conditions in spatiotemporally different locations and individuals and identify agents to fight against fatigue. Herein, we introduced a novel method for evaluating fatigue using nervous system markers (including dopamine, adrenaline, and noradrenaline), various cytokine levels (such as interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, IL-10, IL-2, IL-5 and IL-17A), and oxidative stress markers (such as diacron-reactive oxygen metabolites [d-ROMs] and biological antioxidant potential [BAP]) in a rat fatigue model. Using this method, the anti-fatigue effects of methyl dihydrojasmonate (MDJ) and linalool, the fragrance/flavor compounds used in various products, were assessed. Our method evaluated the anti-fatigue effects of the aforementioned compounds based on the changes in levels of the nerves system markers, cytokines, and oxidative stress markers. MDJ exerted more potent anti-fatigue effects than linalool. In conclusion, the reported method could serve as a useful tool for fatigue studies and these compounds may act as effective therapeutic agents for abrogating fatigue symptoms.

Baicalin nanodelivery system based on functionalized metal-organic framework for targeted therapy of osteoarthritis by modulating macrophage polarization.

Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.

Mesenchymal Stem Cell Exosomes Enhance Posterolateral Spinal Fusion in a Rat Model.

Spinal fusion, a common surgery performed for degenerative lumbar conditions, often uses recombinant human bone morphogenetic protein 2 (rhBMP-2) that is associated with adverse effects. Mesenchymal stromal/stem cells (MSCs) and their extracellular vesicles (EVs), particularly exosomes, have demonstrated efficacy in bone and cartilage repair. However, the efficacy of MSC exosomes in spinal fusion remains to be ascertained. This study investigates the fusion efficacy of MSC exosomes delivered via an absorbable collagen sponge packed in a poly Ɛ-caprolactone tricalcium phosphate (PCL-TCP) scaffold in a rat posterolateral spinal fusion model. Herein, it is shown that a single implantation of exosome-supplemented collagen sponge packed in PCL-TCP scaffold enhanced spinal fusion and improved mechanical stability by inducing bone formation and bridging between the transverse processes, as evidenced by significant improvements in fusion score and rate, bone structural parameters, histology, stiffness, and range of motion. This study demonstrates for the first time that MSC exosomes promote bone formation to enhance spinal fusion and mechanical stability in a rat model, supporting its translational potential for application in spinal fusion.

Novel Inositol 1,4,5-Trisphosphate Receptor Inhibitor Antagonizes Hepatic Stellate Cell Activation: A Potential Drug to Treat Liver Fibrosis.

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, can progress to cirrhosis and increases the risk of liver cancer. Hepatic stellate cells (HSCs) play a pivotal role in fibrosis progression, transitioning from a quiescent to activated state upon liver injury, wherein they proliferate, migrate, and produce ECM. Calcium signaling, involving the inositol 1,4,5-trisphosphate receptor (IP3R), regulates HSC activation. This study investigated the efficacy of a novel IP3R inhibitor, desmethylxestospongin B (dmXeB), in preventing HSC activation. Freshly isolated rat HSCs were activated in vitro in the presence of varying dmXeB concentrations. The dmXeB effectively inhibited HSC proliferation, migration, and expression of fibrosis markers without toxicity to the primary rat hepatocytes or human liver organoids. Furthermore, dmXeB preserved the quiescent phenotype of HSCs marked by retained vitamin A storage. Mechanistically, dmXeB suppressed mitochondrial respiration in activated HSCs while enhancing glycolytic activity. Notably, methyl pyruvate, dimethyl α-ketoglutarate, and nucleoside supplementation all individually restored HSC proliferation despite dmXeB treatment. Overall, dmXeB demonstrates promising anti-fibrotic effects by inhibiting HSC activation via IP3R antagonism without adverse effects on other liver cells. These findings highlight dmXeB as a potential therapeutic agent for liver fibrosis treatment, offering a targeted approach to mitigate liver fibrosis progression and its associated complications.

Cnicus benedictus extract-loaded electrospun gelatin wound dressing for treating diabetic wounds: An in vitro and in vivo study.

In the current study, Cnicus benedictus extract was loaded into electrospun gelatin scaffolds for diabetic wound healing applications. Scaffolds were characterized in vitro by mechanical testing, cell culture assays, electron microscopy, cell migration assay, and antibacterial assay. In vivo wound healing study was performed in a rat model of diabetic wound. In vitro studies revealed fibrous architecture of our developed dressings and their anti-inflammatory properties. In addition, Cnicus benedictus extract-loaded wound dressings prevented bacterial penetration. In vivo study showed that wound size reduction, collagen deposition, and epithelial thickness were significantly greater in Cnicus benedictus extract-loaded scaffolds than other groups. Gene expression studies showed that the produced wound dressings significantly upregulated VEGF and IGF genes expression in diabetic wounds.

MiR-146a reduces fibrosis after glaucoma filtration surgery in rats.

PURPOSE: To explore the impact of microRNA 146a (miR-146a) and the underlying mechanisms in profibrotic changes following glaucoma filtering surgery (GFS) in rats and stimulation by transforming growth factor (TGF)-ß1 in rat Tenon's capsule fibroblasts. METHODS: Cultured rat Tenon's capsule fibroblasts were treated with TGF-ß1 and analyzed with microarrays for mRNA profiling to validate miR-146a as the target. The Tenon's capsule fibroblasts were then respectively treated with lentivirus-mediated transfection of miR-146a mimic or inhibitor following TGF-ß1 stimulation in vitro, while GFS was performed in rat eyes with respective intraoperative administration of miR-146a, mitomycin C (MMC), or 5-fluorouracil (5-FU) in vivo. Profibrotic genes expression levels (fibronectin, collagen Iα, NF-KB, IL-1ß, TNF-α, SMAD4, and α-smooth muscle actin) were determined through qPCR, Western blotting, immunofluorescence staining and/or histochemical analysis in vitro and in vivo. SMAD4 targeting siRNA was further used to treat the fibroblasts in combination with miR-146a intervention to confirm its role in underlying mechanisms. RESULTS: Upregulation of miR-146a reduced the proliferation rate and profibrotic changes of rat Tenon's capsule fibroblasts induced by TGF-ß1 in vitro, and mitigated subconjunctival fibrosis to extend filtering blebs survival after GFS in vivo, where miR-146a decreased expression levels of NF-KB-SMAD4-related genes, such as fibronectin, collagen Iα, NF-KB, IL-1ß, TNF-α, SMAD4, and α-smooth muscle actin(α-SMA). Additionally, SMAD4 is a key target gene in the process of miR-146a inhibiting fibrosis. CONCLUSIONS: MiR-146a effectively reduced TGF-ß1-induced fibrosis in rat Tenon's capsule fibroblasts in vitro and in vivo, potentially through the NF-KB-SMAD4 signaling pathway. MiR-146a shows promise as a novel therapeutic target for preventing fibrosis and improving the success rate of GFS.

Interval training suppresses nod-like receptor protein 3 inflammasome activation to improve cardiac function in myocardial infarction rats by hindering the activation of the transforming growth factor-ß1 pathway.

OBJECTIVE: Myocardial infarction (MI) -induced cardiac dysfunction can be attenuated by aerobic exercises. This study explored the mechanism of interval training (IT) regulating cardiac function in MI rats, providing some theoretical basis for clarifying MI pathogenesis and new ideas for clinically treating MI. METHODS: Rats were subjected to MI modeling, IT intervention, and treatments of the Transforming growth factor-ß1 (TGF-ß1) pathway or the nod-like receptor protein 3 (NLRP3) activators. Cardiac function and hemodynamic indicator alterations were observed. Myocardial pathological damage and fibrosis, reactive oxygen species (ROS) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, MDA content, inflammasome-associated protein levels, and inflammatory factor levels were assessed. The binding between TGF-ß1 and receptor was detected. RESULTS: MI rats exhibited decreased left ventricle ejection fraction (LVEF), left ventricle fractional shortening  (LVFS), left ventricular systolic pressure  (LVSP), positive and negative derivates max/min (dP/dt max/min) and increased left ventricular end-systolic pressure (LVEDP), a large number of scar areas in myocardium, disordered cell arrangement and extensive fibrotic lesions, increased TGF-ß1 and receptor binding, elevated ROS level and MDA content and weakened SOD, CAT and GSH-Px activities, and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD  (ASC) and cleaved-caspase-1 levels, while IT intervention caused ameliorated cardiac function. IT inactivated the TGF-ß1 pathway to decrease oxidative stress in myocardial tissues of MI rats and inhibit NLRP3 inflammasome activation. Activating NLRP3 partially reversed IT-mediated improvement on cardiac function in MI rats. CONCLUSION: IT diminished oxidative stress in myocardial tissues and suppressed NLRP3 inflammasome activation via inactivating the TGF-ß1 pathway, thus improving the cardiac function of MI rats.

Berberine Improves Cancer-Derived Myocardial Impairment in Experimental Cachexia Models by Targeting High-Mobility Group Box-1.

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system.

Hepatocyte-Specific Fads1 Overexpression Attenuates Western Diet-Induced Metabolic Phenotypes in a Rat Model.

Fatty acid desaturase 1 (FADS1) is a rate-limiting enzyme in long-chain polyunsaturated fatty acid (LCPUFA) synthesis. Reduced activity of FADS1 was observed in metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to determine whether adeno-associated virus serotype 8 (AAV8) mediated hepatocyte-specific overexpression of Fads1 (AAV8-Fads1) attenuates western diet-induced metabolic phenotypes in a rat model. Male weanling Sprague-Dawley rats were fed with a chow diet, or low-fat high-fructose (LFHFr) or high-fat high-fructose diet (HFHFr) ad libitum for 8 weeks. Metabolic phenotypes were evaluated at the endpoint. AAV8-Fads1 injection restored hepatic FADS1 protein levels in both LFHFr and HFHFr-fed rats. While AAV8-Fads1 injection led to improved glucose tolerance and insulin signaling in LFHFr-fed rats, it significantly reduced plasma triglyceride (by ~50%) and hepatic cholesterol levels (by ~25%) in HFHFr-fed rats. Hepatic lipidomics analysis showed that FADS1 activity was rescued by AAV8-FADS1 in HFHFr-fed rats, as shown by the restored arachidonic acid (AA)/dihomo-γ-linolenic acid (DGLA) ratio, and that was associated with reduced monounsaturated fatty acid (MUFA). Our data suggest that the beneficial role of AAV8-Fads1 is likely mediated by the inhibition of fatty acid re-esterification. FADS1 is a promising therapeutic target for MASLD in a diet-dependent manner.

Investigating the Relevance of Cyclic Adenosine Monophosphate Response Element-Binding Protein to the Wound Healing Process: An In Vivo Study Using Photobiomodulation Treatment.

Monitoring inflammatory cytokines is crucial for assessing healing process and photobiomodulation (PBM) enhances wound healing. Meanwhile, cAMP response element-binding protein (CREB) is a regulator of cellular metabolism and proliferation. This study explored potential links between inflammatory cytokines and the activity of CREB in PBM-treated wounds. A total of 48 seven-week-old male SD rats were divided into four groups (wound location, skin or oral; treatment method, natural healing or PBM treatment). Wounds with a 6 mm diameter round shape were treated five times with an 808 nm laser every other day (total 60 J). The wound area was measured with a caliper and calculated using the elliptical formula. Histological analysis assessed the epidermal regeneration and collagen expression of skin and oral tissue with H&E and Masson's trichrome staining. Pro-inflammatory (TNF-α) and anti-inflammatory (TGF-ß) cytokines were quantified by RT-PCR. The ratio of phosphorylated CREB (p-CREB) to unphosphorylated CREB was identified through Western blot. PBM treatment significantly reduced the size of the wounds on day 3 and day 7, particularly in the skin wound group (p < 0.05 on day 3, p < 0.001 on day 7). The density of collagen expression was significantly higher in the PBM treatment group (in skin wound, p < 0.05 on day 3, p < 0.001 on day 7, and p < 0.05 on day 14; in oral wound, p < 0.01 on day 7). The TGF-ß/TNF-α ratio and the p-CREB/CREB ratio showed a parallel trend during wound healing. Our findings suggested that the CREB has potential as a meaningful marker to track the wound healing process.

Impact of Thermo-Responsive N-Acetylcysteine Hydrogel on Dermal Wound Healing and Oral Ulcer Regeneration.

This study investigates the efficacy of a thermo-responsive N-acetylcysteine (NAC) hydrogel on wound healing and oral ulcer recovery. Formulated by combining NAC with methylcellulose, the hydrogel's properties were assessed for temperature-induced gelation and cell viability using human fibroblast cells. In vivo experiments on Sprague Dawley rats compared the hydrogel's effects against saline, NAC solution, and a commercial NAC product. Results show that a 5% NAC and 1% methylcellulose solution exhibited optimal outcomes. While modest improvements in wound healing were observed, significant enhancements were noted in oral ulcer recovery, with histological analyses indicating fully regenerated mucosal tissue. The study concludes that modifying viscosity enhances NAC retention, facilitating tissue regeneration. These findings support previous research on the beneficial effects of antioxidant application on damaged tissues, suggesting the potential of NAC hydrogels in improving wound care and oral ulcer treatment.

Microalgae polyphosphate nanoparticles deliver bioavailable calcium against phytate antagonism: Ex vivo and in vivo studies.

Biogenic nanoparticles are promising carriers to deliver essential minerals. Here, calcium-enriched polyphosphate nanoparticles (CaPNPs) with a Ca/P molar ratio > 0.5 were produced by Synechococcus sp. PCC 7002 in the growth medium containing 1.08 g/L CaCl2, and had nearly spherical morphologies with a wide size distribution of 5-75 nm and strongly anionic surface properties with an average ζ-potential of -39 mV, according to dynamic light-scattering analysis, transmission and scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The ex-vivo ligated mouse ileal loop assays found that calcium in CaPNPs was readily available to intestinal absorption via both ion channel-mediated and endocytic pathways, specifically invoking macropinocytic internalization, lysosomal degradation, and transcytosis. Rat oral pharmacokinetics revealed that CaPNPs had a calcium bioavailability approximately 100 % relative to that of CaCl2 and more than 1.6 times of that of CaCO3. CaPNPs corrected the retinoic acid-induced increase in serum calcium, phosphorus, and bone-specific alkaline phosphatase, and decrease in serum osteocalcin, bone mineral content/density, and femoral geometric parameters with an efficacy equivalent to CaCl2 and markedly greater than CaCO3. In contrast to CaCl2, CaPNPs possessed desirable resistance against phytate's antagonistic action on calcium absorption in these ex vivo and in vivo studies. Overall, CaPNPs are attractive as a candidate agent for calcium supplementation, especially to populations on high-phytate diets.

Unlocking renal Restoration: Mesaconine from Aconitum plants restore mitochondrial function to halt cell apoptosis in acute kidney injury.

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. Traditional Chinese medicine has employed Fuzi for kidney diseases; however, concerns about neurotoxicity and cardiotoxicity have constrained its clinical use. This study explored mesaconine, derived from processed Fuzi, as a promising low-toxicity alternative for AKI treatment. In this study, we assessed the protective effects of mesaconine in gentamicin (GM)-induced NRK-52E cells and AKI rat models in vitro and in vivo, respectively. Mesaconine promotes the proliferation of damaged NRK-52E cells and down-regulates intracellular transforming growth factor ß1 (TGF-ß1) and kidney injury molecule 1 (KIM-1) to promote renal cell repair. Concurrently, mesaconine restored mitochondrial morphology and permeability transition pores, reversed the decrease in mitochondrial membrane potential, mitigated mitochondrial dysfunction, decreased ATP production, inhibited inflammatory factor release, and reduced early apoptosis rates. In vivo, GM-induced AKI rat models exhibited elevated AKI biomarkers, in which mesaconine was effectively reduced, indicating improved renal function. Mesaconine enhanced superoxide dismutase activity, reduced malondialdehyde content, alleviated inflammatory infiltrate, mitigated tubular and glomerular lesions, and downregulated NF-κB (nuclear factor-κb) p65 expression, leading to decreased tumor necrosis factor-α (TNF-α) and IL-1ß (interleukin-1ß) levels in GM-induced AKI animals. Furthermore, mesaconine inhibited the expression of renal pro-apoptotic proteins (Bax, cytochrome c, cleaved-caspase 9, and cleaved-caspase 3) and induced the release of the anti-apoptotic protein bcl-2, further suppressing apoptosis. This study highlighted the therapeutic potential of mesaconine in GM-induced AKI. Its multifaceted mechanisms, including the restoration of mitochondrial dysfunction, anti-inflammatory and antioxidant effects, and apoptosis mitigation, make mesaconine a promising candidate for further exploration in AKI management.

Metformin attenuates lung ischemia-reperfusion injury and necroptosis through AMPK pathway in type 2 diabetic recipient rats.

BACKGROUND: Diabetes mellitus (DM) can aggravate lung ischemia-reperfusion (I/R) injury and is a significant risk factor for recipient mortality after lung transplantation. Metformin protects against I/R injury in a variety of organs. However, the effect of metformin on diabetic lung I/R injury remains unclear. Therefore, this study aimed to observe the effect and mechanism of metformin on lung I/R injury following lung transplantation in type 2 diabetic rats. METHODS: Sprague-Dawley rats were randomly divided into the following six groups: the control + sham group (CS group), the control + I/R group (CIR group), the DM + sham group (DS group), the DM + I/R group (DIR group), the DM + I/R + metformin group (DIRM group) and the DM + I/R + metformin + Compound C group (DIRMC group). Control and diabetic rats underwent the sham operation or left lung transplantation operation. Lung function, alveolar capillary permeability, inflammatory response, oxidative stress, necroptosis and the p-AMPK/AMPK ratio were determined after 24 h of reperfusion. RESULTS: Compared with the CIR group, the DIR group exhibited decreased lung function, increased alveolar capillary permeability, inflammatory responses, oxidative stress and necroptosis, but decreased the p-AMPK/AMPK ratio. Metformin improved the function of lung grafts, decreased alveolar capillary permeability, inflammatory responses, oxidative stress and necroptosis, and increased the p-AMPK/AMPK ratio. In contrast, the protective effects of metformin were abrogated by Compound C. CONCLUSIONS: Metformin attenuates lung I/R injury and necroptosis through AMPK pathway in type 2 diabetic lung transplant recipient rats.

Astaxanthin-mediated Nrf2 activation ameliorates glucocorticoid-induced oxidative stress and mitochondrial dysfunction and impaired bone formation of glucocorticoid-induced osteonecrosis of the femoral head in rats.

BACKGROUND: Osteonecrosis of the femoral head caused by glucocorticoids (GIONFH) is a significant issue resulting from prolonged or excessive clinical glucocorticoid use. Astaxanthin, an orange-red carotenoid present in marine organisms, has been the focus of this study to explore its impact and mechanism on osteoblast apoptosis induced by dexamethasone (Dex) and GIONFH. METHODS: In this experiment, bioinformatic prediction, molecular docking and dynamics simulation, cytotoxicity assay, osteogenic differentiation, qRT-PCR analysis, terminal uridine nickend labeling (TUNEL) assay, determination of intracellular ROS, mitochondrial function assay, immunofluorescence, GIONFH rat model construction, micro-computed tomography (micro-CT) scans were performed. RESULTS: Our research demonstrated that a low dose of astaxanthin was non-toxic to healthy osteoblasts and restored the osteogenic function of Dex-treated osteoblasts by reducing oxidative stress, mitochondrial dysfunction, and apoptosis. Furthermore, astaxanthin rescued the dysfunction in poor bone quality, bone metabolism and angiogenesis of GIONFH rats. The mechanism behind this involves astaxanthin counteracting Dex-induced osteogenic damage by activating the Nrf2 pathway. CONCLUSION: Astaxanthin shields osteoblasts from glucocorticoid-induced oxidative stress and mitochondrial dysfunction via Nrf2 pathway activation, making it a potential therapeutic agent for GIONFH treatment.