Circular RNAs (circRNAs) are a new class of noncoding single-stranded RNAs that differ from linear microRNAs (miRNAs), since they form covalently closed loop structures without free 3′ poly(A) tails or 5′ caps. circRNAs are the competitive endogenous RNAs (ceRNAs) by binding to miRNA through miRNA response elements (MREs) (i.e., “miRNA sponge”), thereby reducing the quantity of miRNA available to target mRNA, subsequently promoting mRNA stability or protein expression, which involves the initiation and progress of human diseases. Owing to these features of abundance, stability, conservative property, and tissue and stage specificity, widely distributing in the extracellular space and in various bodily fluids, circRNAs can be considered as potential biomarkers for various diseases. Here, we reviewed the promising circRNAs being disease biomarkers, focused on their regulatory function by acting as miRNA sponges, and described their roles in cancer, cardiovascular or neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, diabetes, and other human aging-related diseases, which provide a new direction for pathogenesis, diagnosis, and treatment of human aging-related diseases.

Gaultheria yunnanensis (Franch.) Rehder is a kind of traditional Chinese herbal medicine used for the treatments of rheumatoid arthritis, swelling and pain. Two methyl salicylate glycosides, namely methyl benzoate-2-O-b-D-xylopyranosyl(1-6)-O-b-D-gluco-pyranoside (J12122) and methyl benzoate-2-O-β-D-xylopyranosyl(1-2)[O-β-D-xylopyranosyl(1-6)]-O-β-D-glucopyranoside (J12123), are natural salicylic derivatives isolated from Gaultheria yunnanensis. In this study, we investigated the anti-inflammatory activity of J12122 and J12123 on LPS-induced RAW264.7 macrophage cells by measuring the production of pro-inflammatory cytokines, accumulation of nitric oxide (NO), and level of reactive oxygen species (ROS). The results showed that both methyl salicylate glycosides dose-dependently inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, respectively. Consistent with these observations, J12122 and J12123 significantly suppressed the accumulation of NO, with an inhibitory rate of 56.20% and 51.72% at 3.0 μg/mL concentration, respectively. Furthermore, the two methyl salicylate glycosides reduced the level of ROS induced by LPS. These results showed that the isolated compounds possess anti-inflammatory properties through inhibition the production pro-inflammatory cytokines, NO, and ROS.

Janus kinases (JAKs) play a critical role in immune responses by relaying signals from more than 50 cytokines, making them attractive therapeutic targets for autoimmune diseases. Although approved JAK inhibitors have demonstrated clinical efficacy, they target a broad spectrum of cytokines, which results in side effects. Therefore, next-generation inhibitors maintain efficacy, while sparing adverse events need to be developed. Among members of the JAK family, JAK3 only regulates a narrow spectrum of γc cytokines and becomes a potentially ideal target. Here, a highly JAK3-selective inhibitor Z583 is developed, which showed a potent inhibition of JAK3 with an IC ₅₀ of 0.1 nM and exhibited a 4500-fold selectivity for JAK3 than other JAK subtypes. Furthermore, Z583 completely inhibited the γc cytokine signaling and sufficiently blocked the development of inflammatory response in RA model, while sparing hematopoiesis. Collectively, the highly selective JAK3 inhibitor Z583 is a promising candidate with significant therapeutic potential for autoimmune diseases.

Background: Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer's disease (AD). Activation of microglia and astrocytes is a characteristic of brain inflammation. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) delays the onset of AD and suppresses its progression. Methyl salicylate-2-O-β-D-lactoside (DL0309) is a new molecule chemically related to salicylic acid. The present study aimed to evaluate the anti-inflammatory effects of DL0309. Findings: Our studies show that DL0309 significantly inhibits lipopolysaccharide (LPS)-induced release of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the expression of the inflammation-related proteins iNOS, COX-1, and COX-2 by microglia and astrocytes. At a concentration of 10 μM, DL0309 prominently inhibited LPS-induced activation of NF-κB in glial cells by blocking phosphorylation of IKK and p65, and by blocking IκB degradation. Conclusions: We demonstrate here for the first time that DL0309 exerts anti-inflammatory effects in glial cells by suppressing different pro-inflammatory cytokines and iNOS/NO. Furthermore, it also regulates the NF-κB signaling pathway by blocking IKK and p65 activation and IκB degradation. DL0309 also acts as a non-selective COX inhibitor in glial cells. These studies suggest that DL0309 may be effective in the treatment of neuroinflammatory disorders, including AD.

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system (CNS) due to the critical roles of these cells in the production of proinflammatory cytokines, differentiation of T-helper (Th) cells, and antigen presentation. The JAK–STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines signaling. However, the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis (MS) is unclear. Here, we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis (EAE), a model for MS. JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6C^hi monocytes and monocyte-derived dendritic cells in EAE mice. In parallel, the proportion of GM-CSF⁺CD4⁺ T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition, which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue damage. Together, our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes.

Tolerogenic dendritic cells (tolDCs) facilitate the suppression of autoimmune responses by differentiating regulatory T cells (Treg). The dysfunction of immunotolerance results in the development of autoimmune diseases, such as rheumatoid arthritis (RA). As multipotent progenitor cells, mesenchymal stem cells (MSCs), can regulate dendritic cells (DCs) to restore their immunosuppressive function and prevent disease development. However, the underlying mechanisms of MSCs in regulating DCs still need to be better defined. Simultaneously, the delivery system for MSCs also influences their function. Herein, MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ, maximizing efficacy in vivo. The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines. In the collagen-induced arthritis (CIA) mice model, alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39⁺CD73⁺ on MSCs. These enzymes hydrolyze ATP to adenosine and activate A_2A/2B receptors on immature DCs, further promoting the phenotypic transformation of DCs to tolDCs and regulating naïve T cells to Tregs. Therefore, encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression. This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.