Hyaluronic acid modified nanocarriers for aerosolized delivery of verteporfin in the treatment of acute lung injury.

Verteporfin (VER), a photosensitizer used in macular degeneration therapy, has shown promise in controlling macrophage polarization and alleviating inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, its hydrophobicity, limited bioavailability, and side effects hinder its therapeutic potential. In this study, we aimed to enhance the therapeutic potential of VER through pulmonary nebulized drug delivery for ALI/ARDS treatment. We combined hydrophilic hyaluronic acid (HA) with an oil-in-water system containing a poly(lactic acid-co-glycolic acid) (PLGA) copolymer of VER to synthesize HA@PLGA-VER (PHV) nanoparticles with favorable surface characteristics to improve the bioavailability and targeting ability of VER. PHV possesses suitable electrical properties, a narrow size distribution (approximately 200 nm), and favorable stability. In vitro and in vivo studies demonstrated the excellent biocompatibility, safety, and anti-inflammatory responses of the PHV by suppressing M1 macrophage polarization while inducing M2 polarization. The in vivo experiments indicated that the treatment with aerosolized nano-VER (PHV) allowed more drugs to accumulate and penetrate into the lungs, improved the pulmonary function and attenuated lung injury, and mortality of ALI mice, achieving improved therapeutic outcomes. These findings highlight the potential of PHV as a promising delivery system via nebulization for enhancing the therapeutic effects of VER in ALI/ARDS.

Eriodictyol Alleviated LPS/D-GalN-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Cell Apoptosis via PI3K/AKT Signaling Pathway.

Eriodictyol occurs naturally in a variety of fruits and vegetables, and has drawn significant attention for its potential health benefits. This study aims to look into the effects of eriodictyol on acute liver injury (ALI) induced by LPS/D-GalN and elucidate its potential molecular biological mechanisms. A total of 47 targets were predicted for the treatment of ALI with eriodictyol, and the PI3K/AKT signaling pathway played a key role in the anti-ALI processing of this drug. The in vivo experiment showed that eriodictyol can effectively reduce liver function-related biochemical indicators such as ALT, AST, and AKP. Eriodictyol can also up-regulate the levels of SOD and GSH, and inhibit the release of IL-1ß, IL-6, and TNF-α. Additionally, TUNEL staining, immunohistochemistry, and RT-PCR experiments showed that eriodictyol activated the PI3K/AKT pathway and decreased the expression of Bax, caspase3, and caspase8 while increasing the expression of Bcl-2 m-RNA. Finally, molecular docking experiments and molecular dynamics simulations confirmed the stable binding between eriodictyol and PI3K, AKT molecules. This study showed that eriodictyol can activate the PI3K/AKT signaling pathway to alleviate ALI-related oxidative stress and apoptosis.

Swertia cincta Burkill alleviates LPS/D-GalN-induced acute liver failure by modulating apoptosis and oxidative stress signaling pathways.

Swertia cincta Burkill is widely distributed along the southwestern region of China. It is known as "Dida" in Tibetan and "Qingyedan" in Chinese medicine. It was used in folk medicine to treat hepatitis and other liver diseases. To understand how Swertia cincta Burkill extract (ESC) protects against acute liver failure (ALF), firstly, the active ingredients of ESC were identified using liquid chromatography-mass spectrometry (LC-MS), and further screening. Next, network pharmacology analyses were performed to identify the core targets of ESC against ALF and further determine the potential mechanisms. Finally, in vivo experiments as well as in vitro experiments were conducted for further validation. The results revealed that 72 potential targets of ESC were identified using target prediction. The core targets were ALB, ERBB2, AKT1, MMP9, EGFR, PTPRC, MTOR, ESR1, VEGFA, and HIF1A. Next, KEGG pathway analysis showed that EGFR and PI3K-AKT signaling pathways could have been involved in ESC against ALF. ESC exhibits hepatic protective functions via anti-inflammatory, antioxidant, and anti-apoptotic effects. Therefore, the EGFR-ERK, PI3K-AKT, and NRF2/HO-1 signaling pathways could participate in the therapeutic effects of ESC on ALF.

[Effect of Acupuncture Stimulation of Different Acupoint Combinations on Sleep and Expression of Circadian Clock and Bmal 1 Genes in Hypothalamus of Insomnia Rats].

OBJECTIVE: To observe the effect of manual acupuncture stimulation (MAS) of "Baihui"(GV 20)-"Shenmen"(HT 7)or GV 20-"Sanyinjiao"(SP 6) on sleep and expression of circadian rhythm genes (Clock and Bmal 1) in the hypothalamus in insomnia rats, so as to select a better acupoint group for insomnia. METHODS: A total of 53 SD rats were randomly divided into normal control (n=12),insomnia model (n=8), GV 20-HT 7(n=12), GV 20-SP 6(n=11),and GV 20-non-acupoint (n=10) groups. The insomnia model was established by intraperitoneal injection of p-chlorophenylalanine (PCPA,500 mg/kg,100 mg/mL) once daily for 2 days. The MAS (uniform reinforcing-reducing needling) was applied to GV 20-HT 7, GV 20-SP 6 or GV 20-non-acupoint for 30 min,once daily for 7 days. The sleep onset latency and sleep duration were gauged after intraperitoneal injection of pentobarbital sodium (35 mg/kg). The expression levels of Clock mRNA and Bmal 1 mRNA in the hypothalamic tissues containing ventrolateral preoptic area (VLPO) and suprachiasmatic nucleus (SCN) region were detected by fluorescence quantitative real-time PCR. RESULTS: Following administration of pentobarbital sodium,the sleep latency was significantly prolonged and the sleep duration was considerably shortened in rats of the model group(P<0.05). After the treatment, the increased sleep latencies in the GV 20-HT 7, GV 20-SP 6 and GV 20-non-acupoints were all significantly down-regulated (P<0.05), and the decreased sleep duration was significantly increased only in the GV 20-HT 7 group relevant to the model group (P<0.05), but not in the GV 20-SP 6 and GV 20-non-acupoint groups (P<0.05). There were no significant differences in the sleep latency among the 3 treatment groups (P<0.05). The sleep duration was obviously prolonged in the GV 20-HT 7 group than in the GV 20-SP 6 and GV 20-non-acupoint groups (P<0.05). After modeling, the expression levels of Clock mRNA and Bmal 1 mRNA in hypothalamic VLPO and SCN regions were significantly down-regulated relevant to the normal control group (P<0.01). Following the treatment, the expression levels of Clock mRNA in the VLPO and SCN regions of the GV 20-SP 6 and GV 20-HT 7 groups, and those of Bmal 1 mRNA in the VLPO and SCN regions of the 3 treatment groups were considerably increased relevant to the model group (P<0.05, P<0.01). The effects of GV 20-HT 7 were significantly superior to those of GV 20-SP 6 and GV 20-non-acupoint (and also the action of GV 20-SP 6 was evidently superior to that of GV 20-non-acupoint) in up-regulating the expression of Clock mRNA and Bmal 1 mRNA in both VLPO and SCN regions (P<0.05, P<0.01). CONCLUSIONS: Manual acupuncture stimulation of GV 20-HT 7 can improve the sleep latency and duration in insomnia rats,which may be associated with its effects in up-regulating the expression levels of circadian Clock mRNA and Bmal 1 mRNA in hypothalamic VLPO and SCN regions, and the efficacy of GV 20-HT 7 is obviously better than that of GV 20-SP 6 and GV 20-non-acupoint.