Inhibition of LSD1 via SP2509 attenuated the progression of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Lysine-specific demethylase 1 (LSD1), an enzyme involved in transcriptional regulation, has an unclear role in synovial inflammation, fibroblast-like synoviocytes migration, and invasion during RA pathogenesis. In this study, we observed increased LSD1 expression in RA synovial tissues and in TNF-α-stimulated MH7A cells. SP2509, an LSD1 antagonist, directly reduced LSD1 expression and reversed the elevated levels of proteins associated with inflammation, apoptosis, proliferation, and autophagy induced by TNF-α. Furthermore, SP2509 inhibited the migratory capacity of MH7A cells, which was enhanced by TNF-α. In CIA models, SP2509 treatment ameliorated RA development, reducing the expression of pro-inflammatory cytokines and alleviating joint pathological symptoms. These findings underscore the significance of LSD1 in RA and propose the therapeutic potential of SP2509.

Silencing CoREST inhibits the viability and migration of fibroblast-like synoviocytes in TNF-α-induced rheumatoid arthritis.

Fibroblast-like synoviocytes (FLSs) have functions in the pathogenesis of rheumatoid arthritis (RA) through the onset of synovitis, the growth of pannus and the destruction of cartilage and bone. The significant increase in the proliferation, migration and invasion of FLSs induces the onset and advancement of RA. To date, the exact function of corepressor element-1 silencing transcription factor (CoREST) in RA remains unclear, but its expression has been determined in RA synovial tissues. In this study, the effects of CoREST were investigated in a TNF-α-induced FLS activation model. Following the silencing of CoREST expression with small interfering (si)RNA, the viability and migration of FLSs were evaluated. Furthermore, the possible molecular mechanisms were explored by detecting the expression of key factors, including matrix metalloproteinases (MMPs), lysine-specific histone demethylase 1 (LSD1) and associated cytokines, via reverse transcription-quantitative PCR and western blotting. CoREST expression increased not only in the RA synovial tissues, but also in the TNF-α-induced FLS activation model. Following the silencing of CoREST in the FLSs treated with TNF-α, cell viability was inhibited, and the migratory capacity of FLSs was suppressed, which was accompanied by the reduced expression of MMP-3 and MMP-9. The expression of LSD1 was also downregulated. There was a notable decrease in the synthesis of interferon-γ and interleukin (IL)-17, while IL-10 expression was increased. The knockdown of CoREST inhibited the viability and migration of FLSs stimulated with TNF-α. Thus, the suppression of CoREST may have crucial roles in the occurrence and development of RA.

A Multiple Stimuli-Sensitive Low-Molecular-Weight Gel with an Aggregate-Induced Emission Effect for Sol-Gel Transition Detection.

A low-molecular-weight gel (LMWG) with a hydrazone moiety and an aggregate-induced emission (AIE) unit was fabricated; the self-assembly and disassembly of the LMWG under different stimuli conditions were studied. The LMWG exhibited multiple stimuli sensitivity with temperature, light, ions, and ionic strength. The hydrazone was integrated into the gelator to act as ion sensing sites and hydrogen bond donor groups to fulfil the task of ion recognition of Ni2+, BH4-, and OH-, as well as ion-controlled reversible sol-gel recovery by adding H+ for deprotonation; it also broke under UV irradiation to evoke light-sensitivity. In addition, the sol-gel transition of the gel was detected by the AIE effect. The research provided an effective strategy in fabricating multiple stimuli-sensitive LMWGs for potential biomedical applications.

In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy.

Injectable low molecular weight gels (LMWGs) based on the derivatives of phenylboronic acid were prepared and used as substrates for efficient in situ chemotherapy. The gelators as well as LMWGs were characterized by (1)H NMR, UV-vis, FTIR, MS and SEM. Anticancer drug doxorubicin hydrochloride (DOX) was encapsulated in the gels. The rheological properties and rapid recovery capability of both blank and drug-loaded gels were tested. The LMWGs were non-toxic to both 3T3 fibroblasts and 4T1 breast cancer cells. The gels were formed rapidly after injected in vivo. The in vivo anticancer activities of DOX-loaded LMWGs were investigated in breast cancer bearing mice. The intratumoral injection of DOX loaded LMWGs with dose of 30 mg/kg revealed that the gels could coat around the tumor tissues to release DOX sustainingly and maintain effective DOX concentration for chemotherapy. The systemic toxicity of DOX was reduced significantly with the in situ administration of LMWGs formulations. The injectable LMWGs exhibited excellent therapeutic efficacy and low side effects in local chemotherapy.

Low molecular weight gels induced differentiation of mesenchymal stem cells.

Four low molecular weight gels (LMWGs) with different moduli were fabricated as scaffolds to investigate the differentiation of mesenchymal stem cells (MSCs). The MSCs differentiated to osteoblasts in rigid LMWGs and to chondrocytes in soft LMWGs. The critical modulus to induce the different differentiations was between 10 and 20 kPa.