Inflammatory depression is closely related to neuroinflammation. However, current anti-inflammatory drugs have low permeability to cross blood–brain barrier with difficulties reaching the central nervous system to provide therapeutic effectiveness. To overcome this limitation, the nano-based drug delivery technology was used to synthesize melanin-like polydopamine nanoparticles (PDA NPs) (~ 250 nm) which can cross the blood–brain barrier. Importantly, PDA NPs with abundant phenolic hydroxyl groups function as excellent free radical scavengers to attenuate cell damage caused by reactive oxygen species or acute inflammation. In vitro experiments revealed that PDA NPs exhibited excellent antioxidative properties. Next, we aimed to investigate the therapeutic effect of PDA NPs on inflammatory depression through intraperitoneal injection to the lipopolysaccharide-induced inflammatory depression model in mice. PDA NPs significantly reversed the depression-like behavior. PDA NPs was also found to reduce the peripheral and central inflammation induced by LPS, showing that alleviated splenomegaly, reduced serum inflammatory cytokines, inhibited microglial activation and restored synaptic loss. Various experiments also showed that PDA NPs had good biocompatibility both in vivo and in vitro. Our work suggested that PDA NPs may be biocompatible nano-drugs in treating inflammatory depression but their clinical application requires further study. Graphical Abstract

Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease of the intestines with a significant increase in global incidence in recent years. Oxidative stress and inflammation are two hallmarks of UC pathogenesis. Anemoside B4 (AB4), a pentacyclic triterpenoid saponin, exhibits significant antioxidant and anti-inflammatory properties and shows potential for preventing UC. Here, an animal model induced by dextran sodium sulfate (DSS) was used to investigate the effect of AB4 on UC. The results demonstrated that AB4 significantly reduces intestinal oxidative stress and inflammation in UC mice, while also protecting intestinal barrier function. Furthermore, AB4 helps restore intestinal microbial balance primarily by modulating the abundance of Lactobacillus, which enhances the metabolism of short-chain fatty acids and upregulates the production of butyric acid (BA). Pseudogerm-free mice and fecal microbiota transplantation (FMT) demonstrated that AB4 significantly mitigated UC in a gut microbe-dependent manner. Both AB4 and BA markedly activate the aromatic hydrocarbon receptor (AhR). The intestinal organoid results suggest BA may activate the AhR to inhibit ROS production and activation of NLRP3 inflammasome, thereby protecting intestinal integrity. Administration of AhR antagonists abolished the protective effects, thus confirming the involvement of AhR in the underlying mechanism. Overall, these results indicate that AB4 is an effective agent against UC mainly by activating the AhR through gut microbial short-chain fatty acid metabolites to inhibit intestinal oxidative stress and inflammation.

Extracellular vesicles (EVs), which carry bioactive components such as proteins and nucleic acids, reflect the physiological state of their parent cells and play a key role in mediating complex intercellular signaling. Leveraging these unique characteristics, researchers have explored their potential applications in cell therapy, non-invasive biopsies, and tissue regeneration. Therefore, standardized and scalable methods for EVs production and purification are crucial for clinical application and therapeutic settings. However, the limited yields of traditional production and isolation methods have hampered full potential of EVs. In this review, we will introduce strategies aimed at enhancing EV production include optimizing cell yield, expanding cell culture scale, and exploring alternative EVs production sources such as non-mammalian organisms and artificially produced vesicles. Various approaches as well as the bioreactors for controlling cell culture to enhance EVs production, will be introduced in detail. These approaches include regulation of culture parameters, culture medium components, and external stimuli. Additionally, the comparison between traditional ultracentrifugation methods and advance microfluidic isolating methods will be analyzed and discussed. Finally, we will introduce the potential challenges of transitioning EVs from basic research to clinical application and further discuss the future prospects. As the technology advances and different methods are integrated, there is significant potential to enable large-scale EVs production and improve their clinical translation.

Background: Preclinical studies have indicated that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is a rapid-acting antidepressant drug with limited dissociation properties and low abuse potential. However, its effects and molecular mechanisms remain unclear. In this work, we examined the involvement of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and Narp in the antidepressant-like actions of (2R,6R)-HNK in a chronic restraint stress (CRS) mouse model. Methods: C57BL/6 male mice were subjected to CRS for 8 h per day for 14 consecutive days. Open field, forced swimming, novelty suppressed feeding, and tail suspension tests were performed after administering (2R,6R)-HNK (10 mg/kg), a combination of (2R,6R)-HNK and NBQX (an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist; 10 mg/kg), or a combination of (2R,6R)-HNK and ANA-12 (a TrkB receptor antagonist; 0.5 mg/kg). The mRNA levels of Bdnf and Narp in the hippocampus were determined by quantitative reverse transcription-PCR (qRT–PCR). Western blotting was used to determine the hippocampal protein levels of GluA1, GluA2, BDNF, Narp, PSD95, and synaptophysin, as well as the p-TrkB/TrkB protein ratio. Results: (2R,6R)-HNK had rapid antidepressant-like effects in CRS mice. Furthermore, (2R,6R)-HNK significantly ameliorated CRS-induced downregulation of GluA1, GluA2, BDNF, Narp, PSD95, and the p-TrkB/TrkB protein ratio in the hippocampus. The effects of (2R,6R)-HNK were blocked by combinations with NBQX or ANA-12. Conclusion: BDNF-TrkB signaling-mediated upregulation of Narp in the hippocampus may play a key role in the antidepressant-like effect of (2R,6R)-HNK in the CRS model of depression.

Tissue engineering is a great alternative to repair and regenerate damaged tissues and organs. Hydrogels are promising materials for tissue repair, but optimizing their various functions—such as adhesion, mechanical properties, and vascularization—to suit the complexity of different organs and tissues remains a significant challenge. In this study, we explore a tough and adhesive polydopamine (PDA)‐silk‐polyacrylamide (PAM) hydrogel inspired by the mussel‐inspired adhesion of PDA and the vascularization potential of silk. Through a Schiff base reaction, self‐polymerization occurs between the free dopamine and the conjugated dopamine on the silk chains, resulting in the formation of a PDA/silk prepolymer. The presence of PDA in the prepolymer endows the resulting PDA‐silk‐PAM hydrogel with excellent adhesiveness, strong mechanical properties, and good water absorption. By adjusting the degree of crosslinking, the hydrogel also demonstrates impressive deformability, making it suitable for engineering thicker and more complex tissues and organs. Moreover, benefiting from the vascularization capabilities of silk and the adhesive properties of PDA, the PDA‐silk‐PAM hydrogel effectively promotes vascularization and accelerates wound healing in full‐thickness skin wounds on the backs of Sprague‐Dawley rats. Overall, our study provides a straightforward approach to create versatile medical hydrogel with strong potential for clinical applications.

Ulcerative colitis (UC) is an inflammatory bowel disease that significantly impacts patients’ quality of life. The pathogenesis of UC remains incompl