Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve damage, Schwann cells (SCs) are thought to play a key role in repairing peripheral nerve injury, suggesting that functional deficits occurring in SCs may potentially exhibit their pathogenic roles in DN. Therefore, elucidating the mechanisms that underlie this pathology can be used to develop novel therapeutic targets. In this regard, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently attracted great attention in ameliorating SCs’ dysfunction. However, the detailed mechanisms remain uncertain. In the present study, we investigated how GLP-1 RA Liraglutide protects against RSC96 SCs dysfunction through a diabetic condition mimicked by high glucose and high free fatty acid (FFA). Our results showed that high glucose and high FFAs reduced the viability of RSC96 SCs by up to 51%, whereas Liraglutide reduced oxidative stress by upregulating antioxidant enzymes, and thus protected cells from apoptosis. Liraglutide also inhibited NFκB-mediated inflammation, inducing SCs to switch from pro-inflammatory cytokine production to anti-inflammatory cytokine production. Moreover, Liraglutide upregulated the production of neurotrophic factors and myelination-related proteins, and these protective effects appear to be synergistically linked to insulin signaling. Taken together, our findings demonstrate that Liraglutide ameliorates diabetes-related SC dysfunction through the above-mentioned mechanisms, and suggest that modulating GLP-1 signaling in SCs may be a promising strategy against DN.

Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 10⁷ β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells.

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including αSyn. This study aims to evaluate AMBX’s neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive fat accumulation in the liver. Intracellular oxidative stress induced by lipid accumulation leads to various hepatocellular injuries including fibrosis. However, no effective method for mitigating MASLD without substantial side effects currently exists. Molecular hydrogen (H₂) has garnered attention due to its efficiency in neutralizing harmful reactive oxygen species (ROS) and its ability to penetrate cell membranes. Some clinical evidence suggests that H₂ may alleviate fatty liver disease, but the precise molecular mechanisms, particularly the regulation of lipid droplet (LD) metabolism, remain unclear. This study utilized an in vitro model of hepatocyte lipid accumulation induced by free fatty acids (FFAs) to replicate MASLD in HepG2 cells. The results demonstrated a significant increase in LD accumulation due to elevated FFA levels. However, the addition of hydrogen-rich water (HRW) effectively reduced LD accumulation. HRW decreased the diameter of LDs and reduced lipid peroxidation and FFA-induced oxidative stress by activating the AMPK/Nrf2/HO-1 pathway. Overall, our findings suggest that HRW has potential as an adjunctive supplement in managing fatty liver disease by reducing LD accumulation and enhancing antioxidant pathways, presenting a novel strategy for impeding MASLD progression.

Variable techniques in periacetabular osteotomy have been formulated for the treatment of acetabular dysplasia. However, few studies have compared the radiographic outcomes between different osteotomy types. This study compared modified triple innominate (MTI) osteotomy and Ganz osteotomy with respect to radiographic outcomes. Patients receiving MTI osteotomies and Ganz osteotomies at any time between 2006 and 2018 in a tertiary medical centre were recruited. Only patients with unilateral osteotomies were recruited to eliminate potential influence from the contralateral hip following periacetabular osteotomy. Patients having hip-joint dislocation, receiving simultaneous proximal femoral osteotomy, or having fewer than 2 years of follow-up were excluded. The radiographic parameters of preoperative and postoperative anteroposterior radiographs of the pelvis were measured, and Sharp’s angle (SA), the lateral centre-edge angle (CE angle), the femoral head extrusion index (FHEI), and the centre-head distance discrepancy (CHDD) were included for comparison. Among 55 participants, 23 received MTI osteotomies and 32 received Ganz osteotomies. The mean age at which patients underwent surgery was 21.9 years in the Ganz osteotomy group and 21.1 years in the MTI group. The mean follow-up length was 2.5 years. The preoperative radiographic parameters between groups differed only slightly and nonsignificantly. Both groups exhibited significantly improved SA, LCEA, and FHEI after surgery. The Ganz osteotomy group exhibited more favourable postoperative FHEI (13.5 vs. 24.3, p < 0.0001), CHDD (3.7 vs. 11.5, p < 0.0001), Sharp angle (45.0 vs. 41.8, p = 0.0489) and CE angles (28.3 vs. 21.1, p = 0.029) compared with the MTI osteotomy group. Notably, CHDD became better and worse following Ganz and MTI osteotomies, respectively; this suggests that the femoral head is pushed laterally in modified triple osteotomy. With respect to femoral head coverage and the medialization of the femoral head, Ganz osteotomy exhibits more favourable corrections in postoperative radiographic parameters than does MTI osteotomy.

Aims: The aim of this study was to compare outcomes of guided growth and varus osteotomy in treating Kalamchi type II avascular necrosis (AVN) after open reduction and Pemberton acetabuloplasty for developmental dysplasia of the hip (DDH). Methods: This retrospective study reviewed patients undergoing guided growth or varus osteotomy for Kalamchi type II AVN between September 2009 and January 2019. All children who had undergone open reduction and Pemberton acetabuloplasty for DDH with a minimum two-year follow-up were enrolled in the study. Demographic and radiological data, which included the head-shaft angle (HSA), neck-shaft angle (NSA), articulotrochanteric distance (ATD), Sharp angle (SA), and lateral centre-edge angle (LCEA) at baseline, two years, and at the extended follow-up, were compared. Revision rates were evaluated. Clinical outcomes using the Harris Hip Score were assessed two years postoperatively. Results: A total of 24 patients underwent guided growth and 19 underwent varus osteotomy, over a mean period of 3.3 years (95% confidence interval (CI) 2.8 to 3.8) and 5.2 years (95% CI 4.5 to 6.0), respectively. There were no differences in demographic and preoperative radiological data, except for a younger age at time of acetabuloplasty and larger ATD for the osteotomy group. The HSA did not differ at two years and the extended follow-up because of postoperative rebound in the osteotomy group. The NSA of the osteotomy group remained smaller postoperatively. There were no significant differences in the follow-up ATD, SA, and LCEA, except for a smaller two-year ATD of the osteotomy group. Seven patients (29.2%) in the guided growth group underwent revision surgery and none in the osteotomy group. The Harris Hip Score was similar between groups. Conclusion: Guided growth and varus osteotomy had comparable results in improving caput valgum deformity, given the rebound of lateral tilting of the physis after osteotomy correction. There were no differences in clinical outcomes at two years postoperatively. Cite this article: Bone Joint J 2022;104-B(7):902–908.