Ghrelin inhibits myocardial pyroptosis in diabetic cardiomyopathy by regulating ERS and NLRP3 inflammasome crosstalk through the PI3K/AKT pathway.

AIMS: Endoplasmic reticulum stress(ERS) can induce inflammation mediated by NLRP3 inflammatory bodies and link inflammation with oxidative stress in myocardial tissue. Ghrelin is an endogenous growth hormone-releasing peptide that has been proven to have multiple effects, such as regulating energy metabolism and inhibiting inflammation. However, the role of ghrelin in myocardial injury in diabetic rats and the mechanism have not been reported. RESULTS: We found that ghrelin could improve endoplasmic reticulum stress and inflammatory pyroptosis in the myocardial tissue of diabetic rats and reduce ERS and NLRP3 inflammasome crosstalk in H9C2 cardiomyocytes. Interestingly, ghrelin could activate the PI3K/AKT signalling pathway, playing a role in inhibiting endoplasmic reticulum stress and reducing the expression of pyroptosis-related proteins. However, these protective effects could be largely eliminated by LY294002. CONCLUSIONS: In summary, we demonstrated that ghrelin inhibited myocardial pyroptosis in diabetic cardiomyopathy by regulating ERS and NLRP3 inflammasome crosstalk through the PI3K/AKT pathway. Our results provide new insights into the mechanism of diabetic myocardial injury induced by high glucose and high palmitic acid and ghrelin-mediated anti-inflammatory protection and provide potential therapeutic targets and strategies for diabetic cardiomyopathy.

Ghrelin improves lipid metabolism but not glucose metabolism in rats with diabetic cardiomyopathy.Ghrelin improves cardiac dysfunction and structure disorder in diabetic cardiomyopathy.Ghrelin inhibits cardiomyocyte pyroptosis in diabetic cardiomyopathy by regulating myocardial endoplasmic reticulum stress and NLRP3 inflammasome activation.The protective effect mediated by ghrelin may be related to the activation of PI3K/AKT signal pathway.

Interplay between nuclear factor erythroid 2-related factor 2 and inflammatory mediators in COVID-19-related liver injury.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide. In addition to respiratory symptoms, COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the expression of antioxidant proteins, participating in COVID-19-mediated inflammation and liver injury. Here, we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury. Additionally, we describe some mechanisms and treatment strategies.

Protective effects of poly (butyl) cyanoacrylate nanoparticles containing vasoactive intestinal peptide against 6-hydroxydopamine-induced neurotoxicity in vitro.

The present study investigated brain delivery system of vasoactive intestinal peptide (VIP) adsorbed on poly (butyl cyanoacrylate) nanoparticles coated with polysorbate 80 (P80-poly (butyl) cyanoacrylate (PBCA)-nanoparticles (NPs)) and the neuroprotective effects on the formulation in the model of 6-hydroxydopamine (6-OHDA)-induced Parkinsonian dysfunction in the human neuroblastoma cell line SH-SY5Y. Drug-loaded nanoparticles were prepared by emulsion polymerization method using VIP and PBCA and then stirring with polysorbate 80. The resulting nanoparticles possessed high entrapment efficiency and favorable stability against CaCl2 or fetal bovine serum (FBS)-induced aggregation. Use of fluorescein isothiocyanate (FITC)-conjugated polysorbate 80-PBCA nanoparticles in confocal microscopy revealed that nanoparticles are located inside, while the FITC solution could not penetrate into the cells. The blank nanoparticles showed no significant effects on cell viability, indicating that they had no role in protection; however, polysorbate 80-modified VIP-loading PBCA nanoparticles showed enhanced cell viability compared to free VIP in 6-OHDA-mimic cellular model of Parkinson's disease. In addition, the nanoparticles strikingly increased the anti-apoptosis activity and restored the loss of mitochondrial membrane potential (MMP) significantly after the treatment of 6-OHDA. These results demonstrated that the activity of VIP was enhanced by polysorbate 80-PBCA nanoparticles compared to control solutions, suggesting that PBCA nanoparticles coated with polysorbate 80 could be an effective carrier system for VIP.

Synthesis of thiolated chitosan and preparation nanoparticles with sodium alginate for ocular drug delivery.

PURPOSE: The goal of the present study was to synthesize mucoadhesive polymer - thiolated chitosan (TCS) from chitosan (CS), then prepared CS/TCS-sodium alginate nanoparticles (CS/TCS-SA NPs), determined which was more potential for ocular drug delivery. METHODS: A new method for preparing TCS was developed, and the characteristics were determined using Fourier transform infrared spectroscopy and the degree of thiol immobilized was measured by Ellman's reagent. Human corneal epithelium (HCE) cells were incubated with different concentrations of TCS for 48 h to determine the cell viabilities. CS/TCS-SA NPs were prepared and optimized by a modified ionic gelation method. The particle sizes, zeta potentials, Scanning electron microscopy images, mucoadhesion, in vitro cell uptake and in vivo studies of the two types of NP were compared. RESULTS: The new method enabled a high degree of thiol substitution of TCS, up to 1,411.01±4.02 µmol/g. In vitro cytocompatibility results suggest that TCS is nontoxic. Compared to CS-SA NPs, TCS-SA NPs were more stable, with higher mucoadhesive properties and could deliver greater amounts of drugs into HCE cells in vitro and cornea in vivo. CONCLUSIONS: TCS-SA NPs have better delivery capability, suggesting they have good potential for ocular drug delivery applications.

Metabolism of dl-praeruptorin A in rat liver microsomes using HPLC-electrospray ionization tandem mass spectrometry.

dl-Praeruptorin A (Pd-Ia) is the major active constituent of the traditional Chinese medicine Peucedanum praeruptorum Dunn. Recently it has been identified as a novel agent in the treatment and prevention of cardiovascular diseases. Accordingly, we investigated the metabolism of Pd-Ia in rat liver microsomes. The involvement of cytochrome P450 (CYP) and CYP isoforms were identified using a CYP-specific inhibitor (SKF-525A), CYP-selective inhibitors (α-naphthoflavone, metyrapone, fluvastatin, quinidine, disulfiram, ketoconazole and ticlopidine) and CYP-selective inducers (phenobarbital, dexamethasone and ß-naphthoflavone). Residual concentrations of the substrate and metabolites were determined by HPLC, and further identified by their mass spectra and chromatographic behavior. These experiments showed that CYP450 is involved in Pd-Ia metabolism, and that the major CYP isoform responsible is CYP3A1/2, which acts in a concentration-dependent manner. Four Pd-Ia metabolites (M1, M2, M3, and M4) were detected after incubation with rat liver microsomes. Hydroxylation was the primary metabolic pathway of Pd-Ia, and possible chemical structures of the metabolites were identified. Further research is now needed to link the metabolism of Pd-Ia to its drug-drug interactions.