Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing.

BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

Research progress on pharmacological effects and mechanisms of cepharanthine and its derivatives.

Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid compound found in plants of the Stephania genus, which has biological functions such as regulating autophagy, inhibiting inflammation, oxidative stress, and apoptosis. It is often used for the treatment of inflammatory diseases, viral infections, cancer, and immune disorders and has great clinical translational value. However, there is no detailed research on its specific mechanism and dosage and administration methods, especially clinical research is limited. In recent years, CEP has shown significant effects in the prevention and treatment of COVID-19, suggesting its potential medicinal value waiting to be discovered. In this article, we comprehensively introduce the molecular structure of CEP and its derivatives, describe in detail the pharmacological mechanisms of CEP in various diseases, and discuss how to chemically modify and design CEP to improve its bioavailability. In summary, this work will provide a reference for further research and clinical application of CEP.

Palmitoylethanolamide (PEA) reduces postoperative adhesions after experimental strabismus surgery in rabbits by suppressing canonical and non-canonical TGFß signaling through PPARα.

Postoperative adhesions and scarring are the particular complication after strabismus surgery, for which there is currently no comprehensive treatment available. Preventing inflammation and fibrosis in the extraocular muscle are crucial for treatment of postoperative adhesions. In the present study, we found that administration of palmitoylethanolamide (PEA) attenuated postoperative inflammation and fibroproliferation through activating peroxisome proliferator-activated receptor α (PPARα), thus prevented scar formation. Inhibition of PEA degradation by N-Acylethanolamine acid amidase (NAAA) inhibitor F96 led to the same pharmacological results. PPARα activation suppressed both canonical and non-canonical TGFß signaling. Mechanistically, we found that PPARα directly bound to TGFß-activated kinase 1 (TAK1), thus preventing its hyperphosphorylation and the activation of downstream p38 and JNK1/2 signaling. Taken together, current study suggested that PEA could be a novel therapeutic approach for postoperative adhesions after strabismus surgery.

Fabrication of a novel and simple microcystin-LR photoelectrochemical sensor with high sensitivity and selectivity.

Microcystin-LR (MC-LR), an inert electrochemical species, is difficult to be detected by a simple and direct electrochemical method. In the present work, a novel photoelectrochemical sensor is developed on highly ordered and vertically aligned TiO(2) nanotubes (TiO(2) NTs) with convenient surface modification of molecularly imprinted polymer (MIP) (denoted as MIP@TiO(2) NTs) for highly sensitive and selective determination of MC-LR in solutions. Molecularly imprinted polypyrrole (PPy) of MC-LR is chosen as the recognition element. The designed MIP@TiO(2) NTs photoelectrochemical sensor presents excellent applicability in MC-LR determination, with linear range from 0.5 to 100 µg L(-1) and limit of detection of 0.1 µg L(-1). Moreover, the sensor exhibits outstanding selectivity while used in coexisting systems containing 2,4-dichorophenoxyacetic acid, atrazine, paraquat, or monosultap with high concentration, 100 times that of MC-LR. The sensor presents good photoelectric conversion efficiency and detection sensitivity, as well as broad linear detection range, mainly because of the high specific surface area and photoelectric activity of TiO(2) NTs and the π bond delocalized electron system of PPy that promotes the separation of electron-holes. The prominent selectivity is from the MIP by forming multiple hydrogen bonds between PPy and MC-LR. Mechanisms for photoelectrochemical analysis and selective recognition are also discussed.