ED-71 ameliorates bone regeneration in type 2 diabetes by reducing ferroptosis in osteoblasts via the HIF1α pathway.

Eldecalcitol (ED-71), a novel active form of vitamin D, shows potential in treating osteoporosis. However, its underlying mechanisms of action remain to be determined. This study aimed to investigate the effect of ED-71 on bone regeneration and to illustrate its mode of action. The in-vitro model was developed using rat primary osteoblasts cultured under high-glucose conditions, and these cells were treated with ED-71. Additionally, an in vivo model of cranial bone defects was established in type 2 diabetic rats, and ED-71 was administered by gavage. The results demonstrated that ED-71 prevented osteoblast cell death, enhanced rat primary osteoblasts' osteogenic capacity, and attenuated the overexpression of hypoxia-inducible factor 1α (HIF1α) induced by high glucose levels. Furthermore, ED-71 increased glutathione peroxidase 4 (GPX4) levels and inhibited ferroptosis in response to hyperglycemic stimulation. Notably, interference with the HIF1α activator and ferroptosis activator Erastin significantly reduced the therapeutic effects of edetate osteolysis. These findings were further tested in vivo experiments. These results suggest that ED-71 activates the HIF1α pathway in vivo and in vitro, effectively relieving the ferroptosis induced by high glucose. Significantly, ED-71 may improve osteogenic disorders caused by diabetes.

Maresin1: A multifunctional regulator in inflammatory bone diseases.

Inflammation plays a crucial role in the physical response to danger signals, the elimination of toxic stimuli, and the restoration of homeostasis. However, dysregulated inflammatory responses lead to tissue damage, and chronic inflammation can disrupt osteogenic-osteoclastic homeostasis, ultimately leading to bone loss. Maresin1 (MaR1), a member of the specialized pro-resolving mediators (SPMs) family, has been found to possess significant anti-inflammatory, anti-allergic, pro-hemolytic, pro-healing, and pain-relieving properties. MaR1 is synthesized by macrophages (Mφs) and omega-3 fatty acids, and it may have the potential to promote bone homeostasis and treat inflammatory bone diseases. MaR1 has been found to stimulate osteoblast proliferation through leucine-rich repeat G protein-coupled receptor 6 (LGR6). It also activates Mφ phagocytosis and M2-type polarization, which helps to control the immune system. MaR1 can regulate T cells to exert anti-inflammatory effects and inhibit neutrophil infiltration and recruitment. In addition, MaR1 is involved in antioxidant signaling, including nuclear factor erythroid 2-related factor 2 (NRF2). It has also been found to promote the autophagic behavior of periodontal ligament stem cells, stimulate Mφs against pathogenic bacteria, and regulate tissue regeneration and repair. In summary, this review provides new information and a comprehensive overview of the critical roles of MaR1 in inflammatory bone diseases, indicating its potential as a therapeutic approach for managing skeletal metabolism and inflammatory bone diseases.

The burden of diabetes on the soft tissue seal surrounding the dental implants.

Soft tissue seal around implant prostheses is considered the primary barrier against adverse external stimuli and is a critical factor in maintaining dental implants' stability. Soft tissue seal is formed mainly by the adhesion of epithelial tissue and fibrous connective tissue to the transmembrane portion of the implant. Type 2 diabetes mellitus (T2DM) is one of the risk factors for peri-implant inflammation, and peri-implant disease may be triggered by dysfunction of the soft tissue barrier around dental implants. This is increasingly considered a promising target for disease treatment and management. However, many studies have demonstrated that pathogenic bacterial infestation, gingival immune inflammation, overactive matrix metalloproteinases (MMPs), impaired wound healing processes and excessive oxidative stress may trigger poor peri-implant soft tissue sealing, which may be more severe in the T2DM state. This article reviews the structure of peri-implant soft tissue seal, peri-implant disease and treatment, and moderating mechanisms of impaired soft tissue seal around implants due to T2DM to inform the development of treatment strategies for dental implants in patients with dental defects.

Maresin1 Suppresses High-Glucose-Induced Ferroptosis in Osteoblasts via NRF2 Activation in Type 2 Diabetic Osteoporosis.

Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator produced from polyunsaturated fatty acids and is believed to have antioxidant and anti-inflammatory properties. The objective of this study was to estimate MaR1's impact on type 2 diabetic osteoporosis (T2DOP) and its pharmacological mode of action. An in vitro high-glucose model of the osteoblast cell line MC3T3-E1 was constructed and stimulated with MaR1. Type 2 diabetic rats were used to establish in vivo models of calvarial defects and were treated in situ with MaR1. The results revealed that, aside from preventing mortality and promoting the osteogenic capacity of MC3T3-E1 cells, MaR1 increased nuclear factor erythroid-2 related factor 2 (NRF2) signaling as well as the activity of glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11) and caused the restraint of ferroptosis under hyperglycemic stimulation. However, the therapeutic impact of MaR1 was significantly diminished due to NRF2-siRNA interference and the ferroptosis activator Erastin. Meanwhile, these results were validated through in vivo experiments. These findings imply that MaR1 activated the NRF2 pathway in vivo and in vitro to alleviate high-glucose-induced ferroptosis greatly. More crucially, MaR1 might effectively reduce the risk of T2DOP.

Optimization of deep eutectic solvent-based ultrasound-assisted extraction of polysaccharides from Dioscorea opposita Thunb.

In this study, deep eutectic solvents were proposed for the ultrasound-assisted extraction of polysaccharides from Dioscorea opposita Thunb. Several deep eutectic solvents were prepared for the extraction of polysaccharides, among which the deep eutectic solvent composed of choline chloride and 1,4-butanediol was proved to be suitable for the extraction. Based on the screening of single-factor experiment design and orthogonal experiment design, three experimental factors were optimized for the Box-Behnken experimental design combined with response surface methodology, which gave the optimal extraction conditions: water content of 32.89%(v/v), extraction temperature of 94.00°C, and the extraction time of 44.74min. The optimal extraction conditions could supply higher extraction yield than those of hot water extraction and water-based ultrasound-assisted extraction. Therefore, deep eutectic solvents were an excellent extraction solvent alternative to the extraction of polysaccharides from sample matrices.

ANTI-INFLAMMATORY ACTIVITY OF PLATYCODIN D ON ALCOHOL-INDUCED FATTY LIVER RATS VIA TLR4-MYD88-NF-κB SIGNAL PATH.

BACKGROUND: The current study was designed to evaluate the effect of Platycodin D (PD), triterpenoid saponins extracted from the roots of Platycodon grandiflorum (PG) on alcohol-induced fatty liver (AFL) and investigate the possible mechanism. METHODS AND MATERIALS: A rat model was set up by feeding ethanol and fish oil to experimental rats, which then were treated with PD of 10, 20, 30 mg/kg body weight/day for 4 weeks, respectively, whereafter, liver function enzymes, endotoxin of serum and liver lipid were assayed by biochemical methods, cytokines, histochemistry of hepatic tissue, the protein expression of CD14 and TLR4, the mRNA expression of MD-2, MyD 88 and TRAF-6 were assayed. RESULTS: Treatment with PD on AFL rats significantly decreased the levels of serum ALT, AST and TBIL, coefficient of liver index and the hepatic tissue contents of TG, additionally and dramatically decreased serum endotoxin levels, down-regulated MD-2 and CD14 levels, as well as the mRNA expression of TLR4, MyD88 and TRAF-6, accordingly suppressed NF-κB: p65 as well as endotoxin-mediated inflammatory factors such as TNF-α and IL-6. CONCLUSIONS: Treatment with PD effectively protects against AFL through anti-inflammatory and anti-endotoxic process, and the confirmed mechanism is that PD treatment ameliorate alcoholic-induced liver injury mainly via TLR4-MyD88-NF-K: B signal path in AFL rat. List of Abbreviations: AFL: alcoholic-induced fatty liver, CD14: cluster of differentiation 14, LPS: lipopolysaccharide, LBP: lipopolysaccharide-binding protein, TLR4: toll-like receptor 4, MD-2: molecule myeloid differential protein-2, MyD 88: myeloid differentiation primary response protein 88, TRAF-6: TNF-receptor associated factor-6, NF-κB: nuclear transcription factor kappa B, IL-6: interleukin-6, TNF-α: tumor necrosis factor-α, PG: Platycodon grandiflorum, PD: Platycodin D.

PEG-based ultrasound-assisted enzymatic extraction of polysaccharides from Ginkgo biloba leaves.

In this study, one kind of environmentally friendly solvents named polyethylene glycol (PEG) was developed for the ultrasound-assisted enzymatic extraction (UAEE) of polysaccharides from Gingko biloba leaves (GBLP). Box-Behnken design (BBD) was used to optimize the UAEE conditions of GBLP. Results showed that the optimal extraction conditions were: a pH of 4.34, an extraction temperature of 51.88 °C and an extraction time of 37.13 min. Under these optimal extraction conditions, the GBLP yield was 7.29±0.21%, which was well in agreement with the value predicted by the mathematical model.

Giant congenital melanocytic nevi in neonates: report of two cases.

Giant congenital melanocytic nevi are rare, with an estimated incidence of approximately 1 in 20,000 live births. They increase the lifetime risk for malignant melanoma and neurological deficits, including leptomeningeal melanocytosis and epilepsy. Recently, we encountered two patients in whom giant congenital melanocytic nevi were noted at birth. Case 1 presented with the largest nevus spreading across the posterior scalp, neck, chest wall, shoulder and upper back. At the age of 2 months, magnetic resonance imaging (MRI) was performed and no leptomeningeal melanocytosis was found. Case 2 presented with a huge nevus covering most parts of the lower abdomen, lower back, buttocks and bilateral upper thighs. She also had normal MRI findings in the newborn period. At the age of 7 years, leptomeningeal thickening on the surface of the junction between the pons and midbrain was found on brain MRI although she was neurologically asymptomatic. Here, we describe these two cases with congenital melanocytic nevi and review the literature about its clinical manifestations, outcomes, risks for malignant melanoma and neurocutaneous melanosis, and possible surgical interventions.

Inhibition of 11beta-hydroxysteroid dehydrogenase in guinea pig kidney by three bioflavonoids and their interactions with gossypol.

AIM: To study the effects of some bioflavonoids on the gossypol-induced hypokalemia. METHODS: The 11beta-hydroxysteroid dehydrogenase (11beta-OHSD) protein was prepared from guinea pig kidney. The activity of 11beta-OHSD with NAD as the coenzyme was measured by HPLC. The drug interaction was analysed by isobolographic method. RESULTS: The 11beta-OHSD can be inhibited by some bioflavonoids. The IC50 (95 % confidence limits) values were: quercetin 164 (79 - 341) micromol/L, morin 913 (385 - 2173) micromol/L, and naringenin 2193 (1114 - 4315) micromol/L. When the 11beta-OHSD was treated with quercetin, tangeretin, morin, naringenin plus gossypol, the combination index (CI) values were 0.92, 0.85, 0.98, and 1.01 respectively. CONCLUSION: The interaction of some bioflavonoids with gossypol might be one of the factors for gossypol-induced hypokalemia.