Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

Saturated fatty acids were proposed to activate the NLRP3 inflammasome, a molecular platform that mediates the processing of interleukin (IL)-1β and IL-18. However, the mechanisms underlying the miRNA-mediated regulation of palmitate (PA)-induced inflammasome activation are unclear. We examined the role of miR-132 in PA-induced NLRP3 inflammasome activation in THP-1 cells. To understand the regulatory role of miR-132 in inflammasome activation, we either overexpressed or suppressed miR-132 in THP-1 cells that expressed the NLRP3 inflammasome in response to stimulation by PA. We analyzed the mRNA and protein levels of NLRP3, caspase-1 p10, IL-18, and IL-1β; caspase-1 activity; and IL-1β secretion. The presence of PA activated the NLRP3 inflammasome and increased miR-132 expression. Overexpression of miR-132 reduced caspase-1 p10, IL-18, and IL-1β, while the suppression of miR-132 enhanced inflammasome activation. In addition, miR-132 regulated the mRNA and protein expression of FOXO3, which is a potential target of miR-132 in these cells. FOXO3 suppression by small interfering RNA decreased NLRP3 inflammasome activity stimulated by PA. Knockdown of FOXO3 attenuated NLRP3 inflammasome activation by the miR-132 inhibitor. Based on these findings, we conclude that miR-132 negatively regulates PA-induced NLRP3 inflammasome activation through FOXO3 down-regulation in THP-1 cells.

Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) = 0.957 and mean accuracy = 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (p = 0.034). When we performed a pathway enrichment analysis, the cell cycle and cellular senescence pathways were related to the upregulation of intrinsic genes in LUAD. The intrinsic signature of LUAD also showed a positive correlation with other immune checkpoint targets, including CD274, LAG3, and PDCD1LG2 (Spearman correlation coefficient > 0.25). PD-1 inhibitor-related intrinsic gene patterns differed significantly between LUAD and LUSC and may be a particularly useful biomarker in LUAD.

Lactoferrin (LF) is a potent antiviral, anti-inflammatory, and antibacterial agent found in cow and human colostrum which acts as an osteogenic growth factor. This study aimed to investigate whether LF-anchored tannylated mesoporous silica nanomaterials (TA-MSN-LF) function as a bone fusion material in a rat model. In this study, we created TA-MSN-LF and measured the effects of low (1 μg) and high (100 μg) TA-MSN-LF concentrations in a spinal fusion animal model. Rats were assigned to four groups in this study: defect, MSN, TA-MSN-LF-low (1 μg/mL), and TA-MSN-LF-high (100 μg/mL). Eight weeks after surgery, a greater amount of radiological fusion was identified in the TA-MSN-LF groups than in the other groups. Hematoxylin and eosin staining showed that new bone fusion was induced in the TA-MSN-LF groups. Additionally, osteocalcin, a marker of bone formation, was detected by immunohistochemistry, and its intensity was induced in the TA-MSN-LF groups. The formation of new vessels was induced in the TA-MSN-LF-high group. We also confirmed an increase in the serum osteocalcin level and the mRNA expression of osteocalcin and osteopontin in the TA-MSN-LF groups. TA-MSN-LF showed effective bone fusion and angiogenesis in rats. We suggest that TA-MSN-LF is a potent material for spinal bone fusion.

Background: Traumatic liver injury in severe trauma and temporary abdominal closure can lead to postoperative intestinal edema and inflammation. Hyperbaric oxygen therapy (HBOT) may mitigate these effects by modulating inflammatory pathways. This study investigated the effects of HBOT on mucosal preservation, with villus height and the villus-to-crypt (V/C) ratio as primary outcomes and mechanistic analyses of the NLRP3/caspase-1 pathway. Methods: Twenty male Sprague–Dawley rats (aged 7 weeks, weighing 260–300 g) were randomly assigned to HBOT (n = 10) or non-HBOT groups (n = 10) and underwent midline laparotomy (3–5 cm) with 50% left lateral lobe liver resection. After 4 min, the liver was packed with 2 × 2 cm aseptic gauze and the abdomen was temporarily sutured. After 24 h, the small intestine was isolated and flushed with phosphate-buffered saline. The primary outcomes were villus height and the V/C ratio, measured in the proximal jejunum. Secondary outcomes included villus width, crypt depth, villous surface area, and the Dvorak histological injury grade. Additional analyses included NLRP3, AIM2, pro-caspase-1, cleaved caspase-1, IL-1β, and IL-18 expression in bowel tissue (Western blot); plasma IL-1β and IL-18 (ELISA); and peripheral blood mononuclear cell catalase activity, cell viability (CCK-8), and LDH release. Results: The HBOT group demonstrated greater villus height compared with the non-HBOT group (347.68 ± 42.48 μm vs. 290.43 ± 43.47 μm; p = 0.008), corresponding to a 19.7% increase. The V/C ratio was significantly higher in the HBOT group (2.56 ± 0.31 vs. 2.12 ± 0.23; p = 0.002). Villus width was significantly reduced in the HBOT group (64.65 ± 4.24 μm vs. 73.93 ± 9.49 μm; p = 0.015). Pathological findings indicated that the HBOT group showed attenuated lamina propria edema and separation. In the intestinal tissue samples, NLRP3 expression was significantly lower in the HBOT group (0.09 [0.09, 0.12] vs. 1.00 [0.92, 1.06]; p < 0.001), and AIM2, IL-1β, IL-18, and cleaved caspase-1 followed similar trends. Conclusions: HBOT preserved intestinal villus structure after traumatic liver injury, as evidenced by greater villus height and a higher villus-to-crypt ratio. At the molecular level, HBOT suppressed NLRP3, AIM2, and cleaved caspase-1 protein expression in bowel tissue and reduced IL-1β and IL-18 protein levels. By limiting inflammasome activation and interstitial edema, HBOT may help preserve intestinal structural integrity after damage-control surgery.