OBJECTIVE: To explore the mechanism by which ω-3 polyunsaturated fatty acids (hereinafter referred to as "ω-3") exert antioxidant stress protection and promote osteogenic differentiation in MC3T3-E1 cells, and to reveal the relationship between ω-3 and the key antioxidant stress pathway involving nuclear factor E2-related factor 2 (Nrf2) and NAD (P) H quinone oxidoreductase 1 (NQO1) in MC3T3-E1 cells. METHODS: The optimal concentration of H ₂O ₂ (used to establish the oxidative stress model of MC3T3-E1 cells in vitro) and the optimal intervention concentrations of ω-3 were screened by cell counting kit 8. MC3T3-E1 cells were divided into blank control group, oxidative stress group (H ₂O ₂), low-dose ω-3 group (H ₂O ₂+low-dose ω-3), and high-dose ω-3 group (H ₂O ₂+high-dose ω-3). After osteoblastic differentiation for 7 or 14 days, the intracellular reactive oxygen species (ROS) level was measured by fluorescence staining and flow cytometry, and the mitochondrial morphological changes were observed by biological transmission electron microscope; the expression levels of Nrf2, NQO1, heme oxygenase 1 (HO-1), Mitofusin 1 (Mfn1), and Mfn2 were detected by Western blot to evaluate the cells' antioxidant stress capacity; the expression levels of Runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) were detected by immunofluorescence staining and Western blot; osteogenic potential of MC3T3-E1 cells was evaluated by alkaline phosphatase (ALP) staining and alizarin red staining. RESULTS: Compared with the oxidative stress group, the content of ROS in the low and high dose ω-3 groups significantly decreased, and the protein expressions of Nrf2, NQO1, and HO-1 significantly increased ( P<0.05). At the same time, the mitochondrial morphology of MC3T3-E1 cells improved, and the expressions of mitochondrial morphology-related proteins Mfn1 and Mfn2 significantly increased ( P<0.05). ALP staining and alizarin red staining showed that the low-dose and high-dose ω-3 groups showed stronger osteogenic ability, and the expressions of osteogenesis-related proteins RUNX2 and OCN significantly increased ( P<0.05). And the above results showed a dose-dependence in the two ω-3 treatment groups ( P<0.05). CONCLUSION ω-3 can enhance the antioxidant capacity of MC3T3-E1 cells under oxidative stress conditions and upregulate their osteogenic activity, possibly through the Nrf2/NQO1 signaling pathway.
Oxidative Stress/drug effects* ; NF-E2-Related Factor 2/metabolism* ; NAD(P)H Dehydrogenase (Quinone)/metabolism* ; Animals ; Mice ; Osteogenesis/drug effects* ; Cell Differentiation/drug effects* ; Fatty Acids, Omega-3/pharmacology* ; Signal Transduction/drug effects* ; Osteoblasts/drug effects* ; Reactive Oxygen Species/metabolism* ; Cell Line ; Hydrogen Peroxide/pharmacology* ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Antioxidants/pharmacology* ; Heme Oxygenase-1/metabolism*

The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5-NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5-NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5-NEK7 interaction.

Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.

The most common medications for the treatment of zoonotic toxoplasmosis are pyrimethamine and sulfadiazine, which may cause serious undesirable side effects. Thus, there is an urgent need to develop novel therapeutics. Baicalein (BAI, C₁₅H₁₀O₅) has been shown to perform well against protozoan parasites including Leishmania and Cryptosporidium. In this study, the inhibition efficacy of BAI on Toxoplasma gondii was evaluated using plaque, invasion, and intracellular proliferation assays. BAI effectively inhibited T. gondii (half-maximum inhibitory concentration (IC₅₀)=6.457×10^-5 mol/L), with a reduced invasion rate (33.56%) and intracellular proliferation, and exhibited low cytotoxicity (half-maximum toxicity concentration (TC₅₀)=5.929×10^-4 mol/L). Further investigation using a mouse model shed light on the inhibitory efficacy of BAI against T. gondii, as well as the potential mechanisms underlying its anti-parasitic effects. The survival time of T. gondii-infected ICR mice treated with BAI was remarkably extended, and their parasite burdens in the liver and spleen were greatly reduced compared with those of the negative control group. Histopathological examination of live sections revealed effective therapeutic outcomes in the treatment groups, with no notable pathological alterations observed. Furthermore, alterations in cytokine levels indicated that BAI not only effectively suppressed the growth of T. gondii but also prevented excessive inflammation in mice. Collectively, these findings underscore the significant inhibitory efficacy of BAI against T. gondii, positioning it as a promising alternative therapeutic agent for toxoplasmosis.
Animals ; Toxoplasma/drug effects* ; Flavanones/therapeutic use* ; Mice ; Antiparasitic Agents/therapeutic use* ; Mice, Inbred ICR ; Toxoplasmosis/drug therapy* ; Female

OBJECTIVES: To investigate the inhibitory effect of multimerin-2 (MMRN2) overexpression on growth and metastasis of cutaneous melanoma cells. METHODS: Clinical data of patients with cutaneous melanoma were obtained from the GEO database to compare MMRN2 expressions between normal and tumor tissues. A protein-protein interaction network was constructed using the STRING database, and the intersecting genes from GEPIA2.0 were subjected to GO and KEGG enrichment analysis. The prognostic relevance of MMRN2 expression level was assessed using Cox regression and "timeROC". The correlations of MMRN2 expression level with immune infiltration and angiogenesis-related genes were analyzed using GSCA database and the ssGSEA algorithm. Colony-forming assay, Transwell assay, and wound healing assay were used to examine the changes in proliferation and migration of cultured cutaneous melanoma cells following MMRN2 knockdown. In a mouse model bearing cutaneous melanoma xenograft, the effect of MMRN2 knockdown on vital organ pathologies, survival of the mice and GM-CSF, CXCL9, and TGF‑β1 protein expressions were analyzed. RESULTS: MMRN2 was significantly upregulated in metastatic cutaneous melanoma (P<0.001). Protein interaction network analysis identified 15 intersecting genes, which were enriched in endothelium development and cell-cell junctions. In patients with cutaneous melanoma, a high MMRN2 expression was correlated with a poor prognosis, an advanced T stage, a greater Breslow depth, and ulceration (P<0.05). MMRN2 expression level was strongly correlated with 24 immune cell types (P<0.001), fibroblasts, endothelial cells, and expressions of the pro-angiogenic genes (KCNJ8, SLCO2A1, NRP1, and COL3A1; P<0.001). In cultured B16F10 cells, MMRN2 knockdown significantly suppressed cell proliferation, migration and invasion and caused remo-deling of the immunosuppressive microenvironment. CONCLUSIONS MMRN2 overexpression drives progression of cutaneous melanoma by enhancing tumor metastasis, angiogenesis and immune evasion, highlighting its potential as a therapeutic target for melanomas.
Humans ; Melanoma/metabolism* ; Animals ; Cell Movement ; Prognosis ; Skin Neoplasms/metabolism* ; Mice ; Cell Proliferation ; Neoplasm Invasiveness ; Cell Line, Tumor ; Protein Interaction Maps

Neurodegenerative diseases encompass a diverse array of disorders that have a profoundly detrimental impact on human health, characterized by their intricate and multifaceted pathogenesis. In the recent past, a growing body of scientific research has begun to shed light on the critical involvement of the neuro-immune axis in the onset and advancement of these debilitating conditions. This comprehensive review article delves into the intricate composition of the neuro-immune axis, elucidating the complex mechanisms through which it exerts its influence in the context of neurodegenerative diseases. Furthermore, it explores the potential therapeutic applications of targeting the neuro-immune axis for the management and treatment of these diseases. This extensive examination aims to offer new perspectives and innovative strategies that could pave the way for more effective treatments for neurodegenerative diseases, thereby providing hope for those afflicted by these challenging conditions.
Humans ; Neurodegenerative Diseases/metabolism* ; Animals ; Neuroimmunomodulation/physiology*

Macrophages are important immune cells involved in innate immunity,with significant heterogeneity and polarization.Macrophages can polarize into different phenotypes(mainly M1 and M2)under stimulation by various factors in the microenvironment,leading to different roles and functions.Macrophages play an important role in the pathophysiological mechanism of renal ischemia-reperfusion injury(RIRI).An excessive immune response will inevitably lead to tissue damage.M1 macrophages are pro-inflammatory cells involved in the clearance of pathogens,while M2-type macrophages have anti-inflammatory effects and participate in the repair and remodeling of renal tissue after RIRI.The balance between these macrophage phenotypes is thus an important factor affecting the outcome and treatment of RIRI.This review considers the pathophysiologic mechanism of macrophages in RIRI and the latest treatments from the perspective of macrophage polarization,with the aim of supporting further studies of the function of macrophage polarization in RIRI and adjusting the macrophage polarization process to improve RIRI treatment strategies.

Objective To investigate the effect of lateral wedge insoles (LWI) with different heights on lower limb biomechanical characteristics during single-leg landing in patients with chronic ankle in? stability (CAI). Methods Thirty CAI undergraduates (15 males and 15 females) were recruited. All participants were required to perform a single-leg landing task from a height of 30 cm. They first un? derwent the test with flat insoles (FI),followed by tests with 3 mm and 6 mm LWI in a randomized order. A Qualisys 3D motion capture system and Kistler force platform were used to synchronously col? lect data. Kinematic and kinetic data of the lower limb tri-joints (hip,knee and ankle) were ana? lyzed from the moment of ground contact to the body stabilization phase. Results(1) Kinematically,compared with the FI group,the 3 mm and 6 mm LWI groups showed greater hip and knee flexion angles (P<0.001),smaller hip adduction (P<0.05,P<0.01),ankle plantarflexion (P<0.05,P<0.001),and knee valgus angles (P<0.05,P<0.001) at the moment of ground contact. The 6 mm LWI group had larger hip/knee flexion angles (P<0.001) and smaller ankle plantarflexion angles (P<0.001) at contact than the 3 mm LWI group. Additionally,compared with the FI group,the 6 mm LWI group showed significantly smaller ankle eversion angles (P<0.05). The 6 mm LWI group showed larger peak knee flexion angle (P<0.05) and peak ankle eversion angle (P<0.01) than the FI group,while the 3 mm LWI group also had a greater peak ankle eversion angle (P<0.05) than the FI group. Meanwhile,the 3 mm and 6 mm LWI groups had a larger knee flexion-extension range of motion (ROM)(P<0.05,P<0.01) but smaller ankle flexion-extension ROM (P<0.001) than the FI group. The 6 mm LWI group showed a significantly greater hip adduction-abduction ROM (P<0.001,P<0.05) than the other groups,with a smaller ankle plantar flexion-extension ROM (P<0.05) than the 3 mm LWI group. (2) The peak vertical ground reaction force (peak vGRF) of the LWI groups was signifi? cantly lower than the FI group (P<0.01),with that of the 6 mm LWI group significantly lower than the 3 mm LWI group (P<0.001). Moreover,there were significantly greater peak hip flexion moment (P<0.01) and smaller peak ankle plantarflexion moment of the LWI groups than the FI group (P<0.001),with a smaller peak ankle plantarflexion moment of the 6 mm LWI group than the 3 mm LWI group (P<0.05). (3) Significantly greater subjective comfort was observed in the 6 mm LWI group than the FI group (P<0.01). Conclusion LWI can improve landing patterns in CAI patients,re? duce their ground reaction forces,and lower the risk of ankle sprain. The 6 mm LWI outperforms the 3 mm LWI in improving flexion angles of the lower limb tri-joints at ground contact,ankle flexion-ex? tension ROM,peak vGRF,and peak ankle plantarflexion moment during single-leg landing tasks. Therefore,LWI can be used as a wearable protective device during rehabilitation to prevent recurrent ankle sprains among such patients.

Objective:To study the influence of surgical margins on the prognosis of anatomical hepatectomy in patients with hepatocellular carcinoma (HCC) based on a propensity score-matched (PSM) analysis.Methods:Clinical data of 200 patients with HCC undergoing anatomical hepatectomy at the Affiliated Cancer Hospital of Guangxi Medical University from December 2019 to December 2023 were retrospectively analyzed, including 169 males and 31 females, aged 53.4±12.0 years. Patients were divided into the narrow margin group (surgical margin ≤10 mm, n=133) and wide margin group (>10 mm, n=67) according to the width of the surgical margin. PSM was used to compare preoperative indicators such as the maximum diameter of the tumor, the integrity of the tumor capsule, sublesions, and the clinical stage of Barcelona liver cancer (BCLC), perioperative indicators such as intraoperative blood loss, and 24-hour postoperative laboratory indicators such as alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase between the two groups of patients. The prognosis was analyzed by the Kaplan-Meier method, and the postoperative recurrence-free survival rate of the two groups was compared by the log-rank test. Yates corrected chi-square test was used to analyze the postoperative liver function of the two groups of patients. Results:Before PSM, 133 cases were included in the narrow margin group and 67 cases in the wide margin group. There were statistically significant differences in the clinical stage of BCLC, intraoperative blood loss, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase between the two groups (all P<0.05). After PSM, 55 cases were included in both the narrow margin group and the wide margin group. There were no statistically significant differences in the clinical stage, intraoperative blood loss, alanine aminotransferase and other indicators of BCLC between the two groups (all P>0.05). The 1-year, 2-year, and 3-year recurrence-free survival rates of the wide margin group were 94.2%, 80.1%, and 75.1% respectively, which were higher than those of the narrow margin group (71.8%, 52.9%, and 44.1%), the difference was statistically significant ( χ2=6.25, P=0.012). After PSM, a total of 12 patients (10.9%, 12/110) in the two groups developed liver dysfunction after the operation, among which 10 cases (18.2%, 10/55) were in the wide margin group and 2 cases (3.6%, 2/55). The incidence of postoperative liver dysfunction in the wide margin group was higher than that in the narrow margin group, the difference was statistically significant difference ( χ2=4.58, P=0.032). Conclusion:A surgical margin >10 mm can improve the relapse free survival rate, but it will increase the incidence of postoperative liver dysfunction.

Objective To analyze the characteristics of the crown-root ratios of the anterior teeth in subjects with different periodontal phenotypes in healthy population.Methods A total of 100 periodontally healthy young volunteers were selected,there were 53 females and 47 males,totaling 594 anterior teeth were included in the study.The periodontal probe method was used to determine the periodontal phenotypes of different tooth positions,with 108 cases of thick gingival type and 90 cases of thin gingival type in mesial incisors;95 teeth of thick gingival type and 103 teeth of thin gingival type in lateral incisors,and 98 teeth of thick gingival type and 100 teeth of thin gingival type in cuspids.Panoramic radiographs were taken,crown length and root length of upper anterior teeth were calculated,and crown-root ratio was calculated,to compare and analyze the differences between the results of the two groups.Results The crown-to-root ratio in thin gingival group of mesial incisors and lateral incisors were higher than those in thick gingival group,and the root length was smaller than thick gingival group.The difference was statistically significant(P＜0.05).The keratinized gingival width of thin gingival group was less than that of thick gingival group,and the difference was statistically significant(P＜0.05).Conclusion The relatively high crown-to-root ratio of mesial incisors and lateral incisors in patients with thin gingival phenotypes and the lesser width of keratinized gingiva in thin gingival phenotypes than thick gingival phenotypes.and risk assessment should be taken into account in the restorative system as well as in the orthodontic design of the anterior tooth movement.