HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease.

Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An in vivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an in vitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with ß-glycerophosphate (ß-GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and ß-GP-induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α-SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The in vitro results also demonstrated that ß-GP-induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3-MA blocked HDAC2's protective effect on osteogenic differentiation in ß-GP-treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.

PRMT3 methylates HIF-1α to enhance the vascular calcification induced by chronic kidney disease.

BACKGROUND: Medial vascular calcification is commonly identified in chronic kidney disease (CKD) patients and seriously affects the health and life quality of patients. This study aimed to investigate the effects of protein arginine methyltransferase 3 (PRMT3) on vascular calcification induced by CKD. METHODS: A mice model of CKD was established with a two-step diet containing high levels of calcium and phosphorus. Vascular smooth muscle cells (VSMCs) were subjected to ß-glycerophosphate (ß-GP) treatment to induce the osteogenic differentiation as an in vitro CKD model. RESULTS: PRMT3 was upregulated in VSMCs of medial artery of CKD mice and ß-GP-induced VSMCs. The inhibitor of PRMT3 (SGC707) alleviated the vascular calcification and inhibited the glycolysis of CKD mice. Knockdown of PRMT3 alleviated the ß-GP-induced osteogenic transfomation of VSMCs by the repression of glycolysis. Next, PRMT3 interacted with hypoxia-induced factor 1α (HIF-1α), and the knockdown of PRMT3 downregulated the protein expression of HIF-1α by weakening its methylation. Gain of HIF-1α reversed the PRMT3 depletion-induced suppression of osteogenic differentiation and glycolysis of VSMCs. CONCLUSION: The inhibitory role of PRMT3 depletion was at least mediated by the regulation of glycolysis upon repressing the methylation of HIF-1α.

Identification of osteogenic differentiation-related miRNA-mRNA regulatory network of human periodontal ligament stem cells.

This study aimed to investigate the hub genes and miRNA-mRNA regulatory network around periodontal ligament stem cells (PDLSC) for osteogenic differentiation through bioinformatic analysis. The dataset with osteogenic differentiation of human PDLSC was downloaded from the GEO database. The Weighted gene coexpression network analysis (WGCNA) was performed to identify key modules and hub genes. In addition, differentially expressed genes (DEGs) analysis was conducted with limma. The functional enrichment of differentially expressed hub genes was implemented with KEGG and GSEA analysis. The targeted genes of differentially expressed miRNA were predicted based on miRWalk database. The miRNA-mRNA interaction network of osteogenic differentiation of PDLSC was constructed and visualized. The WGNCA results showed that the light-cyan module was positively correlated with osteogenic differentiation (r=0.98, P<0.05). A total of 3125 hub genes and 1426 differentially expressed hub genes were detected in OG group. Innate immune-related signaling pathways and metabolic pathways were involved in the osteogenic differentiation. In addition, total of 2 upregulated miRNAs with 63 targeted DEGs and 6 downregulated miRNAs with 214 targeted DEGs were detected, which contributed to osteogenic differentiation by regulating amino acid metabolism signaling pathway. We identified hub genes and miRNA-mRNA regulatory network contributing to osteogenic differentiation of human PDLSC, which will provide novel strategy for periodontal disease therapy.

Deciphering resveratrol's role in modulating pathological pain: From molecular mechanisms to clinical relevance.

Pathological pain, a multifaceted and debilitating ailment originating from injury or post-injury inflammation of the somatosensory system, poses a global health challenge. Despite its ubiquity, reliable therapeutic strategies remain elusive. To solve this problem, resveratrol, a naturally occurring nonflavonoid polyphenol, has emerged as a potential beacon of hope owing to its anti-inflammatory, antioxidant, and immunomodulatory capabilities. These properties potentially position resveratrol as an efficacious candidate for the management of pathological pain. This concise review summaries current experimental and clinical findings to underscore the therapeutic potential of resveratrol in pathological pain, casting light on the complex underlying pathophysiology. Our exploration suggests that resveratrol may exert its analgesic effect by the modulating pivotal signaling pathways, including PI3K/Akt/mTOR, TNFR1/NF-κB, MAPKs, and Nrf2. Moreover, resveratrol appears to attenuate spinal microglia activation, regulate primary receptors in dorsal root sensory neurons, inhibit pertinent voltage-gated ion channels, and curb the expression of inflammatory mediators and oxidative stress responses. The objective of this review is to encapsulate the pharmacological activity of resveratrol, including its probable signaling pathways, pharmacokinetics, and toxicology pertinent to the treatment of pathological pain. Hopefully, we aim to map out promising trajectories for the development of resveratrol as a potential analgesic.

Preparation and characterization of zein-caseinate-pectin complex nanoparticles for encapsulation of curcumin: pectin extracted by high-speed shearing from passion fruit (Passiflora edulis f. flavicarpa) peel.

BACKGROUND: Pectin extracted by high-speed shearing from passion fruit peel (HSSP) is a potentially excellent wall material for encapsulating curcumin, which has multiple advantages over pectin prepared by heated water extraction. HSSP was used to fabricate complex nanoparticles of zein-sodium caseinate-pectin for encapsulation of curcumin in this study. The influence of heating on the physicochemical properties of the composite nanoparticles was also investigated, as well as the effect of composite nanoparticles on the encapsulation efficiency, antioxidant activity and release characteristics of curcumin. RESULTS: The nanoparticles were formed through electrostatic interactions, hydrogen bonds and hydrophobic interactions between the proteins and HSSP. A temperature of 50 °C was more favorable for generating compact and small-sized nanoparticles, which could effectively improve the encapsulation efficiency and functional properties. Moreover, compared to other pectin used in the study, the nanoparticles prepared with HSSP showed the best functionality with a particle size of 234.28 ± 0.85 nm, encapsulation rate of 90.22 ± 0.54%, free radical scavenging rate of 78.97% and strongest protective capacity in simulated gastric fluid and intestinal release effect. CONCLUSION: Zein-sodium caseinate-HSSP is effective for encapsulating and delivering hydrophobic bioactive substances such as curcumin, which has potential applications in the functional food and pharmaceutical industries. © 2024 Society of Chemical Industry.

Influence mechanisms of linoleic acid and oleic acid on the gel properties of egg yolk protein.

BACKGROUND: Gel property is among the crucial functional properties of egg yolk (EY), which determines the texture and flavor of EY products. In the present study, the effects of two unsaturated fatty acids [monounsaturated fatty acid oleic acid (OA) and diunsaturated fatty acid linoleic acid (LA)] on the gel properties of EY protein were investigated. RESULTS: Compared with the blank group, the addition of LA and OA (10-50 g kg-1) improved the gel hardness (from 270.54 g to 385.85 g and 414.38 g, respectively) and viscosity coefficient (from 0.015 Pa.sn to 11.892 Pa.sn and 1.812 Pa.sn, respectively). The surface hydrophobicity of EY protein increased to a maximum value of 40 g kg-1 with the addition of both fatty acids (39.06 µg and 41.58 µg, respectively). However, excess unsaturated fatty acids (≥ 50 g kg-1) disrupted the completeness of the gel matrix and weakened the structural properties of the EY gel. CONCLUSION: Both fatty acids improved the gel properties of EY protein. At the same addition level, OA was superior to LA in improving gel properties. The present study provides a theoretical underpinning for the sensible application of unsaturated fatty acids in improving EY gel properties. © 2024 Society of Chemical Industry.

Prognostic analysis of uveal melanoma based on the characteristic genes of M2-type macrophages in the tumor microenvironment.

Uveal melanoma arises from stromal melanocytes and is the most prevalent primary intraocular tumor in adults. It poses a significant diagnostic and therapeutic challenge due to its high malignancy and early onset of metastases. In recent years, there has been a growing interest in the role of diverse immune cells in tumor cell development and metastasis. Using The Cancer Genome Atlas and the gene expression omnibus databases, and the CIBERSORT method, we investigated the topography of intra-tumor immune infiltration in uveal melanoma in this research. We evaluated the prognosis of uveal melanoma patients using the M2 macrophage immune cell infiltration score in conjunction with clinical tumor patient data. We built a prognostic model based on the distinctive genes of M2 macrophages and combined it with patients' clinical data in the database; we ran a survival prognostic analysis to authenticate the model's accuracy. The functional study revealed the importance of macrophage-associated genes in the development of uveal melanoma. Moreover, the reliability of our prediction model was verified by combining tumor mutational load, immune checkpoint, and drug sensitivity, respectively. Our study provides a reference for the follow-up study of uveal melanoma.

The interaction of global small vessel disease burden and Alzheimer's disease pathologies do not change the independent association of amyloid-beta with hippocampal volume: A longitudinal study on mild cognitive impairment subjects.

The purpose of this study was to investigate whether the co-existence of global small vessel disease (SVD) burdens and Alzheimer's disease (AD) pathologies change hippocampal volume (HV) and cognitive function of mild cognitive impairment (MCI) subjects. We obtained MRI images, cerebrospinal fluid biomarkers (Aß1-42 and p-tau), and neuropsychological tests of 310 MCI subjects from ADNI. The global SVD score was assessed. We used linear regression and linear mixing effect to analyze the effects of global SVD burdens, AD pathologies, and their interactions (SVD*AD) on baseline and longitudinal HV and cognition respectively. We used simple mediation effect to analyze the influencing pathways. After adjusting for global SVD and SVD*AD, Aß remained independently correlated with baseline and longitudinal HV (std ß = 0.294, p = .007; std ß = 0.292, p < .001), indicating that global SVD did not affect the correlation between Aß and HV. Global SVD score was correlated with longitudinal but not baseline HV (std ß = 0.470, p = .050), suggesting that global SVD may be more representative of long-term permanent impairment. Global SVD, AD pathologies, and SVD*AD were independently correlated with baseline and longitudinal cognitions, in which the association of Aß (B = 0.005, 95% CI: 0.005; 0.024) and p-tau (B = -0.002, 95% CI: -0.004; -0.000) with cognition were mediated by HV, suggesting that HV is more likely to explain the progression caused by AD pathology than SVD. The co-existence of global SVD and AD pathologies did not affect the individual association of Aß on HV; HV played a more important role in the influence of AD pathology on cognition than in SVD.

Enhancement of bioavailability and bioactivity of diet-derived flavonoids by application of nanotechnology: a review.

Flavonoids, which are a class of polyphenols widely existing in food and medicine, have enormous pharmacological effects. The functional properties of flavonoids are mainly distributed to their anti-oxidative, anticancer, and anti-inflammatoryeffects, etc. However, flavonoids' low bioavailability limits their clinical application, which is closely related to their intestinal absorption and metabolism. In addition, because of the short residence time of oral bioactive molecules in the stomach, low permeability and low solubility in the gastrointestinal tract, flavonoids are easy to be decomposed by the external environment and gastrointestinal tract after digestion. To tackle these obstacles, technological approaches like microencapsulation have been developed and applied for the formulation of flavonoid-enriched food products. In the light of these scientific advances, the objective of this review is to establish the structural requirements of flavonoids for appreciable anticancer, anti-inflammatory, and antioxidant effects, and elucidate a comprehensive mechanism that can explain their activity. Furthermore, the novelty in application of nanotechnology for the safe delivery of flavonoids in food matrices is discussed. After a literature on the flavonoids and their health attributes, the encapsulation methods and the coating materials are presented.

Effects of branched-chain amino acids on Shiraia perylenequinone production in mycelium cultures.

BACKGROUND: Perylenequinones from Shiraia fruiting bodies are excellent photosensitizers and widely used for anti-cancer photodynamic therapy (PDT). The lower yield of Shiraia perylenequinones becomes a significant bottleneck for their medical application. Branched-chain amino acids (BCAAs) not only serve as important precursors for protein synthesis, but also are involved in signaling pathway in cell growth and development. However, there are few reports concerning their regulation of fungal secondary metabolism. In present study, the eliciting effects of BCAAs including L-isoleucine (L-Ile), L-leucine (L-Leu) and L-valine (L-Val) on Shiraia perylenequinone production were investigated. RESULTS: Based on the analysis of the transcriptome and amino acid contents of Shiraia in the production medium, we revealed the involvement of BCAAs in perylenequinone biosynthesis. The fungal conidiation was promoted by L-Val treatment at 1.5 g/L, but inhibited by L-Leu. The spore germination was promoted by both. The production of fungal perylenequinones including hypocrellins A (HA), HC and elsinochromes A-C (EA-EC) was stimulated significantly by L-Val at 1.5 g/L, but sharply suppressed by L-Leu. After L-Val treatment (1.5 g/L) in Shiraia mycelium cultures, HA, one of the main bioactive perylenequinones reached highest production 237.92 mg/L, about 2.12-fold than that of the control. Simultaneously, we found that the expression levels of key genes involved in the central carbon metabolism and in the late steps for perylenequinone biosynthesis were up-regulated significantly by L-Val, but most of them were down-regulated by L-Leu. CONCLUSIONS: Our transcriptome analysis demonstrated that BCAA metabolism was involved in Shiraia perylenequinone biosynthesis. Exogenous BCAAs exhibit contrasting effects on Shiraia growth and perylenequinones production. L-Val could promote perylenequinone biosynthesis via not only enhancing the central carbon metabolism for more precursors, but also eliciting perylenequinone biosynthetic gene expressions. This is the first report on the regulation of BCAAs on fungal perylenequinone production. These findings provided a basis for understanding physiological roles of BCAAs and a new avenue for increasing perylenequinone production in Shiraia mycelium cultures.

Indirect Comparison of Cryoablation and Radiofrequency Ablation as Initial Therapy for Symptomatic Paroxysmal Atrial Fibrillation: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Data on first-line ablation treatment for patients with symptomatic atrial fibrillation (AF) are scarce. This study indirectly compared the efficacy and safety of cryoballoon ablation (CBA) versus radiofrequency ablation (RFA) as initial therapy for symptomatic AF. METHODS: We searched the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) that compared CBA or RFA with antiarrhythmic drugs (AADs) as first-line treatment for AF from the time of database establishment up to December 2021. The odds ratio (OR) with a 95% confidence interval (CI) was used as a measure of the treatment effect. RESULTS: Six RCTs (3 CBA, 3 RFA) that enrolled a total of 1,215 patients were included in this analysis. There were no significant differences in atrial arrhythmia (AA) (OR 0.993, 95% CI: 0.602-1.638), symptomatic AA (OR 0.638, 95% CI: 0.344-1.182), or serious adverse events (OR 1.474, 95% CI: 0.404-5.376) between the two ablation techniques. The incidences of additional CBA therapy (OR 2.693, 95% CI: 1.277-5.681) and patients who crossed over to AAD therapy (OR 0.345, 95% CI: 0.179-0.664) in the CBA group were significantly lower than those in the RFA group. CONCLUSION: Among patients with paroxysmal AF receiving initial therapy, CBA and RFA share a similar efficacy and safety profile. When pulmonary vein isolation is performed by CBA, study crossover and the need for additional ablation are substantially lower.

Evaluation of immune microenvironment in IgG4-related sialadenitis.

IgG4-related sialadenitis is a systemic autoimmune disease that can lead to fibro-inflammatory conditions. This study aims to investigate the immune microenvironment and potential signaling pathways associated with IgG4-related sialadenitis. Datasets related to IgG4-related sialadenitis were retrieved from the GEO database. Immune cell infiltration analysis was conducted using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) method. Differentially immune-related expressed genes (DIEG) and immune-related functional enrichment were identified. Moreover, potential treatment targets for IgG4-related sialadenitis were predicted using The Connectivity Map. Only two datasets from GEO were included for further analysis. The CIBERSORT results indicated dominant immune cell populations in IgG4-related sialadenitis, including CD8+ T cells, resting NK cells, monocytes, and naïve B cells in peripheral blood mononuclear cells. Additionally, high abundance of plasma cells was observed in labial salivary gland tissues. Furthermore, a total of 42 DIEGs were identified, with tumor necrosis factor (TNF) signaling via the NF-Kappa B signaling pathway and the p53 signaling pathway being highly enriched. Autophagy inhibitors and DNA topoisomerase inhibitors were strongly associated with potential targets for the treatment of IgG4-related sialadenitis (P<0.05). This study reveals altered immune microenvironment in peripheral blood mononuclear cells and labial salivary gland tissues in IgG4-related sialadenitis. Autophagy inhibitors and DNA topoisomerase inhibitors show promise as potential targets for treating IgG4-related sialadenitis, providing a novel therapeutic strategy for this disease.

Efficacy and safety of EGFR-TKIs in combination with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: For patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Even with a high disease control rate, a majority of patients develop acquired EGFR-TKIs resistance and eventually advance. To increase the benefits of treatment, clinical trials are increasingly exploring the value of EGFR-TKIs combined with angiogenesis inhibitors as a first-line treatment in advanced NSCLC carrying EGFR mutations. METHOD: Using PubMed, EMBASE and Cochrane Library, to locate published full-text articles in print or online, a thorough literature search was done from the database's inception to February 2021. Additionally, oral presentation RCTs from ESMO and ASCO were obtained. We sifted out RCTs that used EGFR-TKIs along with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant NSCLC. ORR, AEs, OS, and PFS were the endpoints. Review Manager version 5.4.1 was used for data analysis. RESULTS: One thousand eight hundred twenty-one patients were involved in 9 RCTs. According to the results, combining EGFR-TKIs with angiogenesis inhibitors therapy prolonged PFS of advanced EGFR-mutation NSCLC patients on the whole [HR:0.65 (95%CI: 0.59~0.73, P<0.00001)]. No significant statistical difference was identified between the combination group and single drug group in OS(P=0.20) and ORR (P=0.11). There are more adverse effects when EGFR-TKIs are used in combination with angiogenesis inhibitors than when used alone. CONCLUSION: The combination of EGFR-TKIs and angiogenesis inhibitors prolonged PFS in patients with EGFR-mutant advanced NSCLC, but the OS and ORR benefit was not significant, and the risk of adverse events was higher, more pronounced with hypertension and proteinuria; PFS in subgroups suggested that the combination was associated with better PFS in the smoking, liver metastasis, and no brain metastasis groups, and the included studies suggested that the smoking group , liver metastasis group, and brain metastasis group may have a potential OS benefit.

Clinical Evaluation of Femoral Head Fractures: Which Classification Systems Have the Best Universality, Reliability, and Reproducibility?

BACKGROUND: Femoral head fractures are rare but potentially disabling injuries, and classifying them accurately and consistently can help surgeons make good choices about their treatment. However, there is no consensus as to which classification of these fractures is the most advantageous; parameters that might inform this choice include universality (the proportion of fractures that can be classified), as well as, of course, interobserver and intraobserver reproducibility. QUESTIONS/PURPOSES: (1) Which classification achieves the best universality (defined as the proportion of fractures that can be classified)? (2) Which classification delivers the highest intraobserver and interobserver reproducibility in the clinical CT assessment of femoral head fractures? (3) Based on the answers to those two questions, which classifications are the most applicable for clinical practice and research? METHODS: Between January 2011 and January 2023, 254 patients with femoral head fractures who had CT scans (CT is routine at our institution for patients who have experienced severe hip trauma) were potentially eligible for inclusion in this study, which was performed at a large Level I trauma center in China. Of those, 9% (23 patients) were excluded because of poor-quality CT images, unclosed physes, pathologic fractures, or acetabular dysplasia, leaving 91% (231 patients with 231 hips) for analysis here. Among those, 19% (45) were female. At the time of injury, the mean age was 40 ± 17 years. All fractures were independently classified by four observers according to the Pipkin, Brumback, AO/Orthopaedic Trauma Association (OTA), Chiron, and New classifications. Each observer repeated his classifications again 1 month later to allow us to ascertain intraobserver reliability. To evaluate the universality of classifications, we characterized the percentage of hips that could be classified using the definitions offered in each classification. The kappa (κ) value was calculated to determine interrater and intrarater agreement. We then compared the classifications based on the combination of universality and interobserver and intraobserver reproducibility to determine which classifications might be recommended for clinical and research use. RESULTS: The universalities of the classifications were 99% (228 of 231, Pipkin), 43% (99 of 231, Brumback), 94% (216 of 231, AO/OTA), 99% (228 of 231, Chiron), and 100% (231 of 231, New). The interrater agreement was judged as almost perfect (κ 0.81 [95% CI 0.78 to 0.84], Pipkin), moderate (κ 0.51 [95% CI 0.44 to 0.59], Brumback), fair (κ 0.28 [95% CI 0.18 to 0.38], AO/OTA), substantial (κ 0.79 [95% CI 0.76 to 0.82], Chiron), and substantial (κ 0.63 [95% CI 0.58 to 0.68], New). In addition, the intrarater agreement was judged as almost perfect (κ 0.89 [95% CI 0.83 to 0.96]), substantial (κ 0.72 [95% CI 0.69 to 0.75]), moderate (κ 0.51 [95% CI 0.43 to 0.58]), almost perfect (κ 0.87 [95% CI 0.82 to 0.91]), and substantial (κ 0.78 [95% CI 0.59 to 0.97]), respectively. Based on these findings, we determined that the Pipkin and Chiron classifications offer near-complete universality and sufficient interobserver and intraobserver reproducibility to recommend them for clinical and research use, but the other classifications (Brumback, AO/OTA, and New) do not. CONCLUSION: Based on our findings, clinicians and clinician-scientists can use either the Pipkin or Chiron classification systems to classify femoral head fractures based on CT images, with equal confidence. It seems unlikely that any new classifications will substantially outperform these, and the other available systems either lacked sufficient universality or reproducibility to recommend them for general use. LEVEL OF EVIDENCE: Level III, diagnostic study.

Regulation of Bimetallic Coordination Centers in MOF Catalyst for Electrochemical CO2 Reduction to Formate.

Electrocatalytic reduction of CO2 to valuable chemicals can alleviate the energy crisis, and solve the greenhouse effect. The key is to develop non-noble metal electrocatalysts with high activity, selectivity, and stability. Herein, bimetallic metal organic frameworks (MOFs) materials (BiZn-MOF, BiSn-MOF, and BiIn-MOF) were constructed by coordinating the metals Zn, In, Sn, and Bi with the organic ligand 3-amino-1H-1,2,4-triazole-5-carboxylic acid (H2atzc) through a rapid microwave synthesis approach. The coordination centers in bimetallic MOF catalyst were regulated to optimize the catalytic performance for electrochemical CO2 reduction reaction (CO2RR). The optimized catalyst BiZn-MOF exhibited higher catalytic activity than those of Bi-MOF, BiSn-MOF, and BiIn-MOF. BiZn-MOF exhibited a higher selectivity for formate production with a Faradic efficiency (FE = 92%) at a potential of -0.9 V (vs. RHE, reversible hydrogen electrode) with a current density of 13 mA cm-2. The current density maintained continuous electrolysis for 13 h. The electrochemical conversion of CO2 to formate mainly follows the *OCHO pathway. The good catalytic performance of BiZn-MOF may be attributed to the Bi-Zn bimetallic coordination centers in the MOF, which can reduce the binding energies of the reaction intermediates by tuning the electronic structure and atomic arrangement. This study provides a feasible strategy for performance optimization of bismuth-based catalysts.

Osteocytes Exposed to Titanium Particles Inhibit Osteoblastic Cell Differentiation via Connexin 43.

Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the osteocyte-selective Cx43 (CKO)-deficient and wild-type (WT) mice were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in CKO mice. The expression of ß-catenin and osteogenesis markers increased significantly in CKO mice. In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, ß-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and ß-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, ß-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased ß-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the ß-catenin expression, and the over-expression of Cx43 decreased the ß-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased ß-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of ß-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO.

Fabrication and characterization of gelatin-EGCG-pectin ternary complex: formation mechanism, emulsion stability, and structure.

BACKGROUND: Protein-polyphenol-polysaccharide ternary complex particles have better emulsion interfacial stability compared to protein-polysaccharide binary complexes. However, knowledge is scarce when it comes to the fabrication of protein-polyphenol-polysaccharide ternary complexes as interfacial stabilizers and the interactions between the three substances. In the present work, ternary complexes were prepared using gelatin, high methoxyl pectin, and epigallocatechin gallate (EGCG) as raw materials. The effect of different influencing factors on the formation process of ternary complexes was investigated by varying different parameters. physicochemical stability, emulsifying properties, and structural characteristics were analyzed. RESULTS: The ternary complex had a smaller particle size (275 nm) and polydispersity index (0.112) when the mass concentration ratio of gelatin to high methoxyl pectin was 9:1, addition of EGCG was 0.05%, pH value was 3.0, and ionic strength was 10 mmol L-1 . Meanwhile, the complex had the highest emulsifying stability index (691.75 min) and emulsifying activity index (22.96 m2 g-1 ). Scanning electron microscopical observation demonstrated that the addition of EGCG promoted the dispersion of ternary complex more uniformly, and effectively reduced the agglomeration phenomenon. The discrepancy in fluorescence intensity suggested that interactions between EGCG and gelatin occurred, which altered the protein spatial conformation of gelatin. Fourier transform infrared spectroscopic analysis elucidated that hydrogen bond interaction was the primary non-covalent interaction between EGCG and gelatin-high methoxyl pectin binary complex. CONCLUSION: The aforementioned results purposed to provide some theoretical reference and basis for the rational design of stable protein-polyphenol-polysaccharide ternary complexes. © 2022 Society of Chemical Industry.

Bamboo polysaccharides elicit hypocrellin A biosynthesis of a bambusicolous fungus Shiraia sp. S9.

Hypocrellin A (HA), a fungal perylenequinone from bambusicolous Shiraia species, is a newly developed photosensitizer for photodynamic therapy in cancer and other infectious diseases. The lower yield of HA is an important bottleneck for its biomedical application. This study is the first report of the enhancement of HA production in mycelium culture of Shiraia sp. S9 by the polysaccharides from its host bamboo which serve as a strong elicitor. A purified bamboo polysaccharide (BPSE) with an average molecular weight of 34.2 kDa was found to be the most effective elicitor to enhance fungal HA production and characterized as a polysaccharide fraction mainly composed of arabinose and galactose (53.7: 36.9). When BPSE was added to the culture at 10 mg/L on day 3, the highest HA production of 422.8 mg/L was achieved on day 8, which was about 4.0-fold of the control. BPSE changed the gene expressions mainly responsible for central carbon metabolism and the cellular oxidative stress. The induced generation of H2O2 and nitric oxide was found to be involved in both the permeabilization of cell membrane and HA biosynthesis, leading to enhancements in both intra- and extracellular HA production. Our results indicated the roles of plant polysaccharides in host-fungal interactions and provided a new elicitation technique to improve fungal perylenequinone production in mycelium cultures.

Optimizing glucocorticoid therapy for Behçet's uveitis: efficacy, adverse effects, and advances in combination approaches.

Behçet's uveitis (BU) is a debilitating manifestation of Behçet's disease, often requiring prompt and aggressive treatment to prevent vision loss. Glucocorticoids (GCS) serve as a first-line therapy for BU; however, their long-term, high-dose use can result in significant adverse effects. This review summarizes the efficacy, adverse effects, and advances in combination therapy involving GCS for the management of BU. We discuss the benefits and drawbacks of various GCS administration routes, including periocular and intravitreal injections, intravitreal sustained-release devices, and systemic therapy, highlighting the role of fluocinolone acetonide and dexamethasone as primary sustained-release formulations. Moreover, we underscore the importance of combining GCS with immunosuppressive drugs and biological agents to minimize adverse reactions and optimize therapeutic outcomes. The review concludes that, while GCS remain a crucial component of BU treatment, careful consideration of their administration and combination with other therapies is essential to achieve long-term remission and improved visual outcomes for patients with BU.

[Association between infant and young child feeding indicators and the nutritional status of children aged 6-23 months in rural areas of Hunan Province in 2019].

OBJECTIVE: To estimate the status of complementary feeding among infants and young children aged 6-23 months in rural areas of Hunan Province. The association between infant and young child feeding indicators and child undernutrition were assessed. METHODS: A total of 1220 infants and young children aged 6-23 months from 24 investigated places of 6 cities in Hunan Province were selected by multi-stage stratified sampling for physical measurement, hemoglobin(Hb) test and caregiver interview. Complementary diet was analyzed according to the World Health Organization's definition of infant and young child feeding indicators. Z-scores were used to elevate nutrition status. Logistic regression models were used to explore the influencing factors of the nutritional status. RESULTS: The prevalence rates of underweight, stunting, wasting, overweight, obesity and anemia were 3.6%, 4.8%, 2.7%, 10.5%, 2.0% and 16.3%. The percentage of infants and young children aged 6-23 months in rural areas of Hunan Province who get minimum dietary diversity, minimum meal frequency, and minimum acceptable diet was 43.3%, 68.5% and 28.1%. None of the individual infant and young child feeding indicators showed significant association with undernutrition, except minimum meal frequency for obesity and anemia. CONCLUSION: The nutritional status of infants and young children in rural areas of Hunan Province has improved, but the anemia problem is still serious. Complementary feeding frequency is closely associated with anemia for infants and young children.