Epigallocatechin gallate protects MC3T3-E1 cells from cadmium-induced apoptosis and dysfunction via modulating PI3K/AKT/mTOR and Nrf2/HO-1 pathways.

Epigallocatechin gallate (EGCG), an active constituent of tea, is recognized for its anticancer and anti-inflammatory properties. However, the specific mechanism by which EGCG protects osteoblasts from cadmium-induced damage remains incompletely understood. Here, the action of EGCG was investigated by exposing MC3T3-E1 osteoblasts to EGCG and CdCl2 and examining their growth, apoptosis, and differentiation. It was found that EGCG promoted the viability of cadmium-exposed MC3T3-E1 cells, mitigated apoptosis, and promoted both maturation and mineralization. Additionally, CdCl2 has been reported to inhibit both the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and nuclear factor erythroid 2-related factor 2/heme oxygenase-1(Nrf2/HO-1) signaling pathways. EGCG treatment attenuated cadmium-induced apoptosis in osteoblasts and restored their function by upregulating both signaling pathways. The findings provide compelling evidence for EGCG's role in attenuating cadmium-induced osteoblast apoptosis and dysfunction through activating the PI3K/AKT/mTOR and Nrf2/HO-1 pathways. This suggests the potential of using EGCG for treating cadmium-induced osteoblast dysfunction.

Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling.

Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. Sulforaphane (SFN) has been shown to have anti-inflammatory and antioxidant properties. In this study, we investigated the effects of SFN on a mouse model of psoriasis induced by imiquimod (IMQ) and its underlying molecular mechanism. Mice treated with SFN showed significant improvement in psoriatic symptoms, including reduced erythema, scales, and cutaneous thickness. Histopathological analysis and immunohistochemical staining revealed decreased expression of K16, K17, and Ki67 in SFN-treated mice, indicating reduced abnormal differentiation of keratinocytes and cutaneous inflammation. SFN treatment also reduced the activation of STAT3 and NF-κB pathways and downregulated pro-inflammatory cytokines IL-1ß, IL-6, and CCL2. In vitro experiments using HaCaT cells demonstrated that SFN inhibited IL-22 and TNF-α-induced activation of inflammatory pathways and keratinocyte proliferation. Network pharmacology analysis suggested that the KEAP1-NRF2 pathway might be involved in the protective effects of SFN on psoriasis. We observed reduced NRF2 expression in human psoriatic lesions, and subsequent experiments showed that SFN activated KEAP1-NRF2 pathway in vivo and in vitro. Importantly, NRF2-deficient mice exhibited aggravated psoriasis-like symptoms and reduced response to SFN treatment. Our findings indicate that SFN ameliorates psoriasis symptoms and inflammation through the KEAP1-NRF2 pathway, suggesting a potential therapeutic role for SFN in the treatment of psoriasis.

Isopsoralen suppresses receptor activator of nuclear factor kappa-ß ligand-induced osteoclastogenesis by inhibiting the NF-κB signaling.

Osteoporosis is a serious systemic metabolic bone system disease.This study aimed to identify the target genes of isopsoralen and the signaling pathways involved in the differential expression of the genes involved in osteoclast differentiation. We hypothesized that isopsoralen may inhibit osteoclast differentiation by blocking the nuclear factor kappa-B (NF-κB) signaling pathway and verified our hypothesis through basic experiments. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to detect the effect of isopsoralen on the proliferation and viability of primary mouse bone marrow monocytes (BMMCs). The effect of isopsoralen on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation was determined by using tartrate-resistant acid phosphatase (TRAP) staining. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the expression of the related genes and proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of isopsoralen target genes were obtained through comprehensive analysis using the STITCH database, Cytoscape 3.8.2, and R-Studio software. Differentially expressed genes (DEGs) were found in osteoclasts induced by RANKL before and after 3 days using R-Studio, following which KEGG analysis was performed. Next, enrichment analysis was performed on the KEGG pathway shared by the target genes of isopsoralen and the differentially expressed genes during osteoclast differentiation to predict the signaling pathway underlying the inhibition of osteoclast differentiation by isopsoralen. Finally, Western blot was used to detect the effect of isopsoralen on the activation of signaling pathways to verify the results of our bioinformatics analysis. Based on the enrichment analysis of isopsoralen target genes and differentially expressed genes during osteoclastogenesis, we believe that isopsoralen can inhibit RANKL-induced osteoclastogenesis by inhibiting the NF-κB signaling pathway.

Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis: A systematic review and meta-analysis of randomized controlled trials.

Introduction: Vitamin K (VK) as a nutrient, is a cofactor in the carboxylation of osteocalcin (OC), which can bind with hydroxyapatite to promote bone mineralization and increase bone strength. However, some studies have been inconsistent on whether vitamin K2 (VK2) can maintain or improve bone mineral density (BMD) and reduce the incidence of fractures in postmenopausal women. Therefore, the main objective of this meta-analysis was to determine the effect of VK2 as a nutritional supplement on BMD and fracture incidence in postmenopausal women. Methods: We searched PubMed, EMBASE, and Cochrane Library databases (published before March 17, 2022) and then extracted and pooled data from all randomized controlled trials (RCTs) that met the inclusion criteria. Results: Sixteen RCTs with a total of 6,425 subjects were included in this meta-analysis. The overall effect test of 10 studies showed a significant improvement in lumbar spine BMD (BMD LS) (P = 0.006) with VK2. The subgroup analysis of VK2 combination therapy showed that BMD LS was significantly maintained and improved with the administration of VK2 (P = 0.03). The overall effect test of the six RCTs showed no significant difference in fracture incidence between the two groups (RR=0.96, P=0.65). However, after excluding one heterogeneous study, the overall effect test showed a significant reduction in fracture incidence with VK2 (RR = 0.43, P = 0.01). In addition, this meta-analysis showed that VK2 reduced serum undercarboxylated osteocalcin (uc-OC) levels and the ratio of uc-OC to cOC in both subgroups of VK2 combined intervention and alone. However, for carboxylated osteocalcin (cOC), both subgroup analysis and overall effect test showed no significant effect of VK2 on it. And the pooled analysis of adverse reactions showed no significant difference between the VK2 and control groups (RR = 1.03, 95%CI 0.87 to 1.21, P = 0.76). Conclusions: The results of this meta-analysis seem to indicate that VK2 supplementation has a positive effect on the maintenance and improvement of BMD LS in postmenopausal women, and it can also reduce the fracture incidence, serum uc-OC levels and the ratio of uc-OC to cOC. In conclusion, VK2 can indirectly promote bone mineralization and increase bone strength.

NRF2 is a critical regulator and therapeutic target of metal implant particle-incurred bone damage.

Aseptic metal implant loosening due to wear particle-induced bone damage is a major complication of total joint arthroplasty often leading to revision surgery, of which the key regulators mediating the processes are not clearly defined. Here we reported that in a mouse model of calvarial osteolysis, titanium particles (TiPs) and cobalt-chromium-molybdenum particles induced severe osteolysis accompanied by marked suppression of a master redox transcriptional factor NRF2 (Nuclear factor erythroid derived 2-related factor 2). Nfe2l2 knockout mice treated with TiPs developed worse osteolytic alterations compared with wild-type mice. On the contrary, NRF2 restoration by an NRF2 agonist TBHQ (tert-butylhydroquinone) effectively alleviated the osteolysis and the abnormal expression of NRF2 downstream antioxidant enzymes, inflammatory cytokines and osteogenic factors. Further, TiPs induced adverse osteoblastogenesis and osteoclastogenesis in cultured bone cells, which were substantially blocked by TBHQ in an NRF2 inhibition-sensitive manner. Consistently, the osteoprotective effects of TBHQ observed in wild-type mice were largely limited in Nfe2l2 knockout mice. Collectively, our data suggest that NRF2 suppression is a critical causal event of metal wear particle-incurred osteolysis, and the strategies reinstating NRF2 are effective to lessen the bone damage and potentially reduce the incidence of metal implant loosening.

Comparison of different segments in the fixation of thoracolumbar fractures: a Bayesian network meta-analysis.

BACKGROUND: Posterior internal fixation (PIF) is commonly used in the treatment of thoracolumbar fracture (TLF), but there is still no standard for the number of fixed segments. The objective of this meta-analysis was to evaluate the efficacy and safety of short segment (SS), intermediate segment (IS) and long segment (LS) in the fixation of TLF. METHODS: Two authors independently searched through PubMed, Embase, Cochrane Library and Web of Science for studies of thoracolumbar fracture treated by posterior internal fixation, which were published until the end of April 2021. The Aggregate Data Drug Information System (ADDIS) software was used for data evaluation according to the Markov chain Monte Carlo (MCMC) method based on the Bayesian theorem. RESULTS: Nineteen trials evaluating a total of 970 patients were enrolled in these studies, of which 340 in the SS group, 429 in the IS group and 201 in the LS group. For anterior vertebral height ratio (AVHR), IS had the highest AVHR, LS had the second highest AVHR. IS also ranked first in reducing visual analogue scale (VAS), SS ranked second. For sagittal Cobb's angle (SCA), LS had the lowest SCA and IS had the second lowest SCA. In terms of adverse events, IS had the lowest implant failure rate and LS had the second lowest implant failure rate. CONCLUSIONS: IS may be the most desirable treatment option for TLF in reducing SCA, implant failure rate, VAS, and improving AVHR. However, more randomized controlled trials are needed to verify these results.

Reversal of Epigenetic Peroxisome Proliferator-Activated Receptor-γ Suppression by Diacerein Alleviates Oxidative Stress and Osteoarthritis in Mice.

Aims: The pathogenesis of osteoarthritis (OA) is characterized by oxidative stress (OS) and sustained inflammation that are substantially associated with epigenetic DNA methylation alterations of osteogenic gene expression. Diacerein as an anthraquinone anti-OA drug exhibits multiple chondroprotective properties, but less clarified pharmacological actions. Since anthraquinone contain an epigenetic modulating property, in this study we investigate whether the anti-OA functions of diacerein involve DNA methylation modulation and antioxidant signaling. Results: The OA mice incurred by destabilization of medial meniscus exhibited marked suppression of peroxisome proliferator-activated receptor-gamma (PPARγ), a chondroprotective transcription factor with anti-inflammation and OS-balancing properties, aberrant upregulations of DNA methyltransferase (DNMT)1/3a, and PPARγ promoter hypermethylation in knee joint cartilage. Diacerein treatment mitigated the cartilage damage and significantly inhibited the DNMT1/3a upregulation, the PPARγ promoter hypermethylation, and the PPARγ loss, and it effectively corrected the adverse expression of antioxidant enzymes and inflammatory cytokines. In cultured chondrocytes, diacerein reduced the interleukin-1ß-induced PPARγ suppression and the abnormal expression of its downstream antioxidant enzymes in a gain of DNMT and PPARγ inhibition-sensitive manner, and in PPARγ knockout mice, the anti-OA effects of diacerein were significantly reduced. Innovation: Our work reveals a novel anti-OA pharmacological property of diacerein and identifies the aberrant DNMT elevation and the resultant PPARγ suppression as an important epigenetic pathway that mediates diacerein's anti-OA activities. Conclusion: DNA methylation aberration and the resultant PPARγ suppression contribute significantly to epigenetic OA pathogenesis, and targeting PPARγ suppression via DNA demethylation is an important component of diacerein's anti-OA functions. Antioxid. Redox Signal. 37, 40-53.

Clinical Outcomes of Thoracolumbar Burst Fracture Treated by Trans-Kambin triangle versus Transpedicular Bone Grafting Combined with Posterior Internal Fixation.

OBJECTIVE: The ideal management of thoracolumbar burst fracture (TLBF) remains controversial. We conducted this study to compare the effectiveness and safety of trans-Kambin triangle versus transpedicular bone grafting combined with posterior internal fixation (PIF) for TLBF. METHODS: Fifty-four patients were retrospectively analyzed and divided into 2 groups: the observation group (PIF combined with bone grafting via the Kambin triangle, n = 28) and the control group (PIF combined with bone grafting via transpedicular, n = 26). The anterior vertebral height ratio, sagittal Cobb angle, visual analog scale score, Oswestry Disability Index, bone healing rate, and neurologic complications were measured. RESULTS: All patients were followed up regularly for a mean period of 17.94 months (12 - 24 months). The anterior vertebral height ratio in the observation group was higher than that in the control group (93.93 ± 2.92 vs. 89.90 ± 5.54%, P = 0.006), and the loss of correction was lower (1.59 ± 1.20 vs. 3.00 ± 1.98%, P = 0.008). The observation group had lower sagittal Cobb angle at final follow-up (8.68 ± 3.75 vs. 11.33 ± 4.77 degrees, P = 0.046) and less correction loss (1.96 ± 1.32 ± 1.15 vs. 3.90 ± 2.39 degrees, P = 0.002). The visual analog scale score and Oswestry Disability Index in the observation group were lower (0.61 ± 0.43 vs. 0.92 ± 0.38, P = 0.016; 15.86 ± 4.11 vs. 19.18 ± 4.04, P = 0.010), while the fracture healing rate showed no significant difference (P > 0.05). No internal fixation failure or neurologic complications occurred in both groups during the follow-up. CONCLUSIONS: Bone grafting via the Kambin triangle combined with PIF is a safe and effective technology for thoracolumbar burst fracture.

Wound infiltration of dexmedetomidine as an adjunct to local anesthesia in postoperative analgesia for lumbar surgery.

INTRODUCTION: Most patients undergoing lumbar surgery experience varying degrees of incision pain, leading to prolonged postoperative recovery and poor satisfaction with treatment. The objective of this meta-analysis was to evaluate the efficacy and safety of dexmedetomidine as an adjunct to local anesthesia for postoperative pain control after lumbar surgery. EVIDENCE ACQUISITION: Two authors independently searched eligible random controlled trials in electronic databases, including PubMed, Embase, Cochrane Library, Web of Science, CNKI (China National Knowledge Infrastructure), CBM (The Chinese BioMedical database) using the search terms "dexmedetomidine," "infiltration," and "lumbar." The random-effect model was used to perform the meta-analysis based on deviance information criteria. EVIDENCE SYNTHESIS: Six trials evaluating a total of 330 patients were included in this review. Wound infiltration with dexmedetomidine significantly reduced the postoperative VAS scores (4th hour static VAS scores (MD=-1.03; 95% CI: -1.58 to -0.47; P=0.0003); 24th hour static VAS scores (MD=-0.66; 95% CI: -0.91 to -0.40; P<0.00001); 6th hour dynamic VAS scores (MD=-1.84; 95% CI: -2.23 to -1.45; P<0.00001) and total supplemental analgesic consumption (SMD=-2.01; 95% CI: -3.04 to -0.98; P<0.00001), prolonged the median time to first rescue analgesia (SMD=3.53; 95% CI:2.31 to 4.76; P<0.00001), and reduced the incidence of nausea or vomiting (RR=0.40; 95% CI: 0.17 to 0.93; P<0.05). CONCLUSIONS: Dexmedetomidine infiltration appears to be a promising and safe adjunct for postoperative pain control after lumbar surgery. However, more studies are needed to assess the prevalence of other side effects.

Clinical Effect of Suture Anchor and Double-Pulley Technique in the Treatment of Inferior Patellar Fracture.

OBJECTIVE: To evaluate the efficacy of suture anchor combined with double-pulley technique for subpatellar comminuted fractures compared with wire vertical suture and Krachow in the treatment of subpatellar fractures. METHODS: Retrospectively selected 48 patients with subpatellar pole comminuted fracture admitted in our hospital from February 2013 to July 2019, 25 patients with double-pulley technique (group A), and 23 patients with vertical wire suture with Krachow suture. Patient age, gender, AT/OTA typing, injury mechanism, follow-up time, surgical time, bleeding volume, mean fracture healing time, and postoperative complications were recorded. The Insall-Salvati index immediately and 6 weeks after surgery. Bostman scores and knee activity were recorded at each follow-up, and month 12 was taken as the final result. RESULTS: Time of surgery in group A (46.52 min) was significantly shorter than in group B (76.30 min). Intraoperative bleeding in group 15.1 ml, B, group 15.9 ml. Both incisions healed in stage I, averaging clinical healing of patella fracture within 10 weeks. There was no significant difference in mean Bostman score and knee activity at month 12 (group A: 28.4, 124.8°; group B: 28.1, 125.7°). There was no significant statistical difference in the Insall-Salvati index immediately or 6 weeks between the two groups. Group B patients had two wire fractures, fracture healing and the wire removed one year after surgery, and the remaining patients had no complications such as internal fixation loosening, fracture, delayed healing, or nonhealing of fracture. CONCLUSION: Compared with the treatment of subpatellar fracture with wire vertical suture and Krachow method, suture anchor with double-pulley technique has short operation time, reliable fixation, and less complications. Patients can have early functional exercise and good knee function recovery without secondary surgery. It can be considered as an alternative therapy for this fracture and deserves clinical adoption and promotion.

Intraoperative Use of Topical Retropharyngeal Steroids for Dysphagia after Anterior Cervical Fusion: A Systematic Review and Meta-Analysis.

PURPOSE: The anterior cervical approach is commonly used clinically for cervical spondylosis, but it also results in frequent postoperative dysphagia, which can increase the risk of complications and poor treatment satisfaction in severe cases. Intraoperative local application of retropharyngeal steroids has an impact on reducing the occurrence and severity of dysphagia; however, the results of current studies vary. The meta-analysis of this randomized trial was to evaluate the effectiveness and safety of intraoperative topical retropharyngeal steroids for the control of dysphagia after anterior cervical spine surgery. METHODS: Two authors searched electronic databases such as PubMed, MEDLINE, EMBASE, Cochrane Library, and Google Scholar, respectively. The search terms were "Dysphagia," "Steroids," "Anterior Cervical Discectomy and Fusion," etc. A random effects model was used to conduct a meta-analysis based on deviance information criteria. RESULTS: A total of 8 studies were included in this meta-analysis after screening of 792 studies. Bazaz scores were not significantly different in the steroid group at one day postoperatively (P = 0.38), and dysphagia was significantly improved at 14 days postoperatively (95% CI: 0.15 to 0.64; P = 0.002). PSTSI was significantly improved one day (P = 0.03) and 14 days after surgery (P < 0.0001). VAS scores were all lower versus controls (P < 0.001). CONCLUSION: Perioperative local retropharyngeal steroid administration as an adjunct to anterior cervical spine surgery reduces the incidence and severity of dysphagia compared with placebo control. However, future high-quality randomized controlled studies could incorporate nonsubjective dysphagia measures and long-term follow-up on the occurrence of associated complications or other side effects.