β-Hydroxybutyrate induces microglial M2 polarization by inhibiting the NF-κB/NLRP3 pathway to ameliorate cerebral ischemia–reperfusion injury

Thymosin β4 Mitigates Acute Cerebral Infarction Via Inhibition of the TLR4/NF-κB Pathway and Suppression of Neuronal Pyroptosis.

β-hydroxybutyrate regulates microglia M1/M2 polarization and phagocytosis through the JAK1/STAT1 pathway to reduce neuroinflammation and exert anti-epileptic effects.

11β-HSD1 may Aggravate Sepsis-associated Endothelial Dysfunction by Activating the NF-κB/MAPK Pathway and NLRP3 Inflammasome.

BACKGROUND Endothelial dysfunction is a major contributor to sepsis-related organ dysfunction, but the underlying molecular mechanism of endothelial damage remains poorly understood. OBJECTIVE This study aimed to investigate whether 11β-HSD1 promotes sepsis-induced endothelial dysfunction by activating the NF-κB/MAPK pathway and NLRP3 inflammasome. METHODS Lipopolysaccharide (LPS)-stimulated human microvascular endothelial cells (HMEC-1) and a cecal ligation and puncture (CLP)-induced mouse model were used as in vitro and in vivo models of sepsis, respectively. The involvement of specific pathways was examined using the 11β-HSD1 inhibitor BVT.2733, along with NLRP3 knockdown and knockout models. Inflammatory cytokines were quantified by ELISA, while endothelial injury- and inflammasome-related molecules were assessed by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, serum cortisol (COR) and NLRP3 levels were measured in patients with sepsis. RESULTS In LPS-treated HMEC-1 cells and aortic tissues from CLP-induced septic mice, 11β-HSD1 expression was significantly upregulated, accompanied by decreased levels of eNOS and VE-cadherin, increased release of inflammatory cytokines, and activation of NF-κB/MAPK signaling and the NLRP3 inflammasome. Treatment with BVT.2733 or NLRP3 blockade partially reversed these changes and attenuated endothelial damage. Clinically, serum cortisol (COR) and NLRP3 levels were elevated in septic patients, and this elevation was more pronounced in non-survivors. CONCLUSION 11β-HSD1 may exacerbate sepsis-associated endothelial dysfunction by promoting NF-κB/MAPK signaling and NLRP3 inflammasome activation. Targeting this axis represents a potential therapeutic approach for sepsis-related endothelial injury, though further validation is warranted.

Pentoxifylline targets TLR4/MyD88/NF-κB signaling to ameliorate neuroinflammation and metabolic dysfunction in a rat model of chronic hypoperfusion-induced vascular cognitive impairment

Pentoxifylline concurrently mitigates hypoperfusion-associated neuroinflammation, neuronal injury, and glucose hypometabolism via inhibition of the TLR4/MyD88/NF-κB axis, supporting PTX as a readily translatable candidate for early VCI intervention.

Taraxerol Alleviates Cerebral Ischemia–Reperfusion Induced Inflammation and Ferroptosis via Regulating AKT/NF‐κB Pathway

Taraxerol (Tar) is a natural triterpenoid which exhibited anti‐inflammatory and neuroprotective properties. Whereas, the roles of Tar in cerebral ischemia–reperfusion injury (CIRI) remain incompletely understood. The research investigated the protective effects and regulatory mechanism of Tar in CIRI. The middle cerebral artery occlusion (MCAO) model was established in vivo. Effects of Tar on brain injury and MCAO rats motor function were detected by HE staining and TUNEL assay. PC12 cells were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) and irritated with 20, 40, 80, and 160 μM Tar; the intracellular Fe2+, MDA, and ROS levels were detected utilizing interrelated assay kits. The pro‐inflammatory cytokines and ferroptosis‐related factors were examined through qRT‐PCR and western blot assay. Cell viability and apoptosis of PC12 cells were examined by CCK‐8 and flow cytometry assays. The AKT agonist (SC79) was used to investigate the regulatory functions of the AKT/NF‐κB pathway in OGD/R‐treated PC12 cells. Tar alleviated brain injury and motor function in MCAO rats. Tar eased inflammation, oxidative stress, and ferroptosis in MCAO rats. In vitro, OGD/R exposure reduced cell viability, promoted apoptosis, elevated IFN‐γ, TNF‐α, IL‐6, Fe2+, MDA, and ROS levels but declined GPX4 and SLC7A11 in PC12 cells. But, the above‐mentioned tendency of OGD/R‐triggered PC12 cells injury was overturned by Tar. Mechanistically, Tar treatment inactivated the AKT/NF‐κB pathway and decreased nuclear translocation of NF‐κB in OGD/R‐induced PC12 cells. The AKT agonist SC79 reversed the protective effects of Tar in OGD/R‐induced PC12 cells. Tar improved CIRI induced inflammation and ferroptosis through regulating the AKT/NF‐κB pathway.

SGLT2i Canagliflozin Exerts Neuroprotection in Diabetic Retinopathy by Inhibiting Microglial Proinflammatory Cytokine Release by Downregulating the TLR4/NF-κB/NLRP3 Pathway.

PURPOSE Diabetic retinopathy (DR) is the leading cause of preventable blindness among working-age adults. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), first-line treatments for diabetes mellitus (DM), have demonstrated efficacy in decelerating DR progression. However, the mechanisms remain unclear. This study investigates how canagliflozin (CANA), an SGLT2 inhibitor, exerts neuroprotective effects in DR by suppressing microglial proinflammatory cytokine release. MATERIALS AND METHODS Using high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice and BV-2 microglial cells under high glucose (HG) conditions, we elucidate the mechanistic link between CANA and neuroinflammation suppression in DR. Retinal structure and function were assessed using optical coherence tomography and electroretinography. Protein was evaluated via Western blotting, immunostaining, and enzyme-linked immunosorbent assay. Cell viability was measured using the Cell Counting Kit-8 assay. RESULTS CANA demonstrated significant neuroprotective effects in diabetic retinopathy (DR) by attenuating microglia-mediated neuroinflammation. In HFD and STZ-induced diabetic mice, the ganglion cell complex thickness and a-wave and b-wave amplitudes decreased (p < 0.05). CANA upregulated the ganglion cell complex thickness (p < 0.05) and TSPO expression (p < 0.05), and tended to increase a-wave and b-wave amplitudes (p > 0.05) in retinas in DM mice. In BV-2 cells, HG activated BV-2 cells, downregulated TSPO expression, and promoted proinflammatory cytokine release, toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and nuclear translocation of p65 and phosphorylated p65 (p < 0.05). CANA reduced BV-2 cell viability, upregulated TSPO, while suppressing proinflammatory cytokine release, TLR4 and NLRP3 expression, and nuclear translocation of p65 and phosphorylated p65 (p < 0.05). Notably, CANA inhibited the TLR4/NF-κB/NLRP3 pathway, evidenced by reduced TLR4/NLRP3 protein levels and diminished nuclear translocation of p65 and phosphorylated p65 in microglia. CONCLUSIONS These findings identify CANA as a promising therapeutic candidate for DR, acting through TLR4/NF-κB/NLRP3-dependent modulation of microglial activation.