BV2 Membrane-Coated PEGylated-Liposomes Delivered hFGF21 to Cortical and Hippocampal Microglia for Alzheimer's Disease Therapy.

Microglia-mediated inflammation is involved in the pathogenesis of Alzheimer's disease (AD), whereas human fibroblast growth factor 21 (hFGF21) has demonstrated the ability to regulate microglia activation in Parkinson's disease, indicating a potential therapeutic role in AD. However, challenges such as aggregation, rapid inactivation, and the blood-brain barrier hinder its effectiveness in treating AD. This study develops targeted delivery of hFGF21 to activated microglia using BV2 cell membrane-coated PEGylated liposomes (hFGF21@BCM-LIP), preserving the bioactivity of hFGF21. In vitro, hFGF21@BCM-LIP specifically targets Aß1-42-induced BV2 cells, with uptake hindered by anti-VCAM-1 antibody, indicating the importance of VCAM-1 and integrin α4/ß1 interaction in targeted delivery to BV2 cells. In vivo, following subcutaneous injection near the lymph nodes of the neck, hFGF21@BCM-LIP diffuses into lymph nodes and distributes along the meningeal lymphatic vasculature and brain parenchyma in amyloid-beta (Aß1-42)-induced mice. Furthermore, the administration of hFGF21@BCM-LIP to activated microglia improves cognitive deficits caused by Aß1-42 and reduces levels of tau, p-Tau, and BACE1. It also decreases interleukin-6  (IL-6) and tumor necrosis factor-α (TNF-α) release while increasing interleukin-10 (IL-10) release both in vivo and in vitro. These results indicate that hFGF21@BCM-LIP can be a promising treatment for AD, by effectively crossing the blood-brain barrier and targeting delivery to brain microglia via the neck-meningeal lymphatic vasculature-brain parenchyma pathways.

Efferocytosis-Inspired Biomimetic Nanoplatform for Targeted Acute Lung Injury Therapy.

Acute lung injury (ALI) is a serious inflammatory disease that causes impairment of pulmonary function. Phenotypic modulation of macrophage in the lung using fibroblast growth factor 21 (FGF21) may be a potential strategy to alleviate lung inflammation. Consequently, achieving specific delivery of FGF21 to the inflamed lung and subsequent efficient FGF21 internalization by macrophages within the lung becomes critical for effective ALI treatment. Here, an apoptotic cell membrane-coated zirconium-based metal-organic framework UiO-66 is reported for precise pulmonary delivery of FGF21 (ACM@U-FGF21) whose design is inspired by the process of efferocytosis. ACM@U-FGF21 with apoptotic signals is recognized and internalized by phagocytes in the blood and macrophages in the lung, and then the intracellular ACM@U-FGF21 can inhibit the excessive secretion of pro-inflammatory cytokines by these cells to relieve the inflammation. Utilizing the homologous targeting properties inherited from the source cells and the spontaneous recruitment of immune cells to inflammatory sites, ACM@U-FGF21 can accumulate preferentially in the lung after injection. The results prove that ACM@U-FGF21 effectively reduces inflammatory damage to the lung by modulating lung macrophage polarization and suppressing the excessive secretion of pro-inflammatory cytokines by activated immune cells. This study demonstrates the usefulness of efferocytosis-inspired ACM@U-FGF21 in the treatment of ALI.

Neutrophil membrane-coated therapeutic liposomes for targeted treatment in acute lung injury.

Acute lung injury (ALI) is one of the most common comorbidities associated with sepsis and can lead to acute respiratory distress syndrome. Intense inflammatory response due to excessive activation and uncontrolled infiltration of neutrophils are the central processes in the development of sepsis-induced ALI. In this study, a biomimetic nanoplatform that is a neutrophil membrane-coated liposome-loaded acidic fibroblast growth factor (aFGF@NMLs), which can selectively target the inflamed lung and effectively alleviate sepsis-induced ALI via inflammation suppression, was constructed. In vitro findings revealed that aFGF@NMLs has pro-inflammatory cytokine binding capabilities and can promote cellular uptake, substantially attenuate inflammatory responses, and enhance cellular antioxidant capacity. The in vivo results show that aFGF@NMLs can specifically accumulate in injured lungs in ALI mice after intravenous injection, thereby reducing the secretion of pro-inflammatory cytokines, inhibiting pulmonary cell apoptosis, and promoting lung function recovery. In conclusion, aFGF@NMLs demonstrated anti-inflammatory effects, mitigated the progression of ALI, and contributed to the disease prognosis. This research offers an innovative strategy and concept for the clinical treatment of diseases related to pulmonary inflammation.

Intradermal injection of icariin-HP-ß-cyclodextrin improved traumatic brain injury via the trigeminal epineurium-brain dura pathway.

The lower bioavailability after oral administration limited icariin applications in central nervous system. Icariin/HP-ß-cyclodextrin (HP-ß-CD) inclusion complex was prepared for acute severe opening traumatic brain injury (TBI) via facial intradermal (i.d.) in the mystacial pad. After fluid percussion-induced TBI, icariin/HP-ß-CD at 0.4 mg/kg i.d. preserved more neurons and oligodendrocytes than intranasal injection (i.n.) or intravenous injection via tail vein (i.v.) and decreased microglia and astrocyte activation. Icariin/HP-ß-CD i.d. reduced apoptosis in cortical penumbra while i.n. and i.v. showed weak or no effects. Icariin/HP-ß-CD i.d. reduced Evans blue leakage and altered CD34, ZO-1, Claudin-5, and beta-catenin expression after TBI. Moreover, icariin/HP-ß-CD promoted human umbilical vein endothelial cells proliferation. Thus, Icariin/HP-ß-CD i.d. improved TBI, including blood-brain barrier opening. Fluorescein 5-isothiocyanate (FITC) and 3,3'-Dioctadecyloxacarbocyanine perchlorate (DiOC18(3)) mimic HP-ß-CD and icariin respectively. FITC and DiOC18(3) were similarly delivered to trigeminal epineurium, perineurium and perivascular spaces or tissues, caudal dura mater, and scattered in trigeminal fasciculus, indicating that icariin/HP-ß-CD was delivered to the brain via trigeminal nerve-dura mater-brain pathways. In sum, intradermal injection in mystacial pad might deliver icariin/HP-ß-CD to the brain and icariin/HP-ß-CD improved acute severe opening TBI.

Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury.

Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.

Protective Effects of Chitosan-Bilirubin Nanoparticles Against Ethanol-Induced Gastric Ulcers.

PURPOSE: Gastric ulcers (GU) are a disease of the gastrointestinal tract that can be caused by excessive alcohol consumption and heavy use of nonsteroidal anti-inflammatory drugs. GU manifests predominantly as pathological damage, such as extensive inflammatory erosion and superficial bleeding of the gastric mucosa. Oxidative stress damage and the inflammatory response are now considered important predisposing factors for GU, suggesting that antioxidant and anti-inflammatory drugs could be treatments for GU. Nanoparticle drug carriers offer many advantages over conventional drugs, such as improved drug efficiency, increased drug stability, and increased half-life. METHODS: We designed chitosan-bilirubin conjugate (CS-BR) nanoparticles and assessed the anti-inflammatory and antioxidant abilities of CS-BR in gastric epithelial cells. Then, we evaluated the intragastric retention time and the anti-ulcer effects of CS-BR in vivo. RESULTS: The in vitro data showed that CS-BR nanoparticles protect gastric epithelial cells against oxidative/inflammatory injury. The in vivo study demonstrated that CS-BR nanoparticles accumulate permanently in the stomach and exert powerful antioxidant and anti-inflammatory effects against GU. CONCLUSION: This study applied bilirubin to the treatment of GU and confirmed that CS-BR nanoparticles are effective at alleviating acute GU in an experimental model. The findings provide innovative ideas for prophylaxis against or treatment of GU.

Oxidative stress and activities of caspase-8, -9, and -3 are involved in cryopreservation-induced apoptosis in granulosa cells.

OBJECTIVE: The aim of this study is to determine whether the oxidative stress and the activities of caspase-8, -9, and -3 are involved in cryopreservation-induced apoptosis in granulosa cells. STUDY DESIGN: Granulosa cells from rats were cryopreserved with or without genistein. The level of superoxide dismutase (SOD) was measured. Moreover, the expressions of caspase-8, -9, and -3 in both mRNA and protein were measured. RESULTS: The SOD level in cryopreserved granulosa cells was significantly lower than that in a fresh control group, and the levels of caspase-8, -9, and -3 expression in both mRNA and protein in cryopreserved granulosa cells were significantly higher than those of fresh control granulosa cells. Furthermore, the levels of caspase-8 and -3 expression in both mRNA and protein of granulosa cells cryopreserved in presence of genistein were significant lower than those of granulosa cells cryopreserved in absence of genistein. CONCLUSION: Oxidative stress induced by cryopreservation in granulosa cells is involved in the activation of caspase-8 and -3. Cryopreservation-induced apoptosis in granulosa cells is mediated, at least in part, by activation of caspase-8, -9, and -3 dependent apoptotic pathways.

Optimizing cryoprotectant perfusion conditions for intact ovary: a bovine model.

PURPOSE: The aim of this study was to detect the effects of different perfusion pressure and different length of perfusion period on whole ovarian cryopreservation METHODS: Bovine whole ovaries were vitrified-warmed. The ovaries were divided into the experimental groups according to different perfusion pressure and different length of perfusion period. Follicular viability was assessed using the trypan blue test; the percentage of morphologically normal primordial follicles and the 17-ß estradiol level in the culture supernatants were measured. RESULTS: When perfusion pressure was 100 mmHg, and the length of perfusion period was 40 min, the viability of ovarian tissues in bovine whole ovarian cryopreservation were higher than other protocols. CONCLUSION: Protocol IIb (the perfusion pressure was 100 mmHg, and the length of perfusion period was 40 min) was appropriate for bovine whole ovarian cryopreservation.