Abstract
Background
Steroid-induced avascular necrosis of the femoral head (SANFH) is characterized by osteoblast apoptosis, leading to a loss of bone structure and impaired hip joint function. It ...has been demonstrated that erythropoietin (EPO) performs a number of biological roles.
Objective
We examined the effects of EPO on SANFH and its regulation of the STAT1-caspase 3 signaling pathway.
Method
In vitro, osteoblasts were treated with dexamethasone (Dex) or EPO. We identified the cytotoxicity of EPO by CCK-8, the protein expression of P-STAT1, cleaved-caspase9, cleaved-caspase3, Bcl-2, BAX, and cytochrome c by Western blotting, and evaluated the apoptosis of osteoblasts by flow cytometry. In vivo, we analyzed the protective effect of EPO against SANFH by hematoxylin and eosin (H&E), Immunohistochemical staining, and Micro-computed tomography (CT).
Results
In vitro, EPO had no apparent toxic effect on osteoblasts. In Dex-stimulated cells, EPO therapy lowered the protein expression of BAX, cytochrome c, p-STAT1, cleaved-caspase9, and cleaved-caspase3 while increasing the expression of Bcl-2. EPO can alleviate the apoptosis induced by Dex. In vivo, EPO can lower the percentage of empty bone lacunae in SANFH rats.
Conclusion
The present study shows that EPO conferred beneficial effects in rats with SANFH by inhibiting STAT1-caspase 3 signaling, suggesting that EPO may be developed as a treatment for SANFH.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: Osteochondral repair poses a significant challenge due to its unique pathological mechanisms and complex repair processes, particularly in bacterial tissue conditions resulting from ...open injuries, infections, and surgical contamination. This study introduces a biomimetic honeycomb-like scaffold (Zn-AlgMA@Mg) designed for osteochondral repair. The scaffold consists of a dicalcium phosphate dihydrate (DCPD)-coated porous magnesium scaffold (DCPD Mg) embedded within a dual crosslinked sodium alginate hydrogel (Zn-AlgMA). This combination aims to synergistically exert antibacterial and osteochondral integrated repair properties. Methods: The Zn-AlgMA@Mg scaffold was fabricated by coating porous magnesium scaffolds with DCPD and embedding them within a dual crosslinked sodium alginate hydrogel. The structural and mechanical properties of the DCPD Mg scaffold were characterized using scanning electron microscopy (SEM) and mechanical testing. The microstructural features and hydrophilicity of Zn-AlgMA were assessed. In vitro studies were conducted to evaluate the controlled release of magnesium and zinc ions, as well as the scaffold’s osteogenic, chondrogenic, and antibacterial properties. Proteomic analysis was performed to elucidate the mechanism of osteochondral integrated repair. In vivo efficacy was evaluated using a rabbit full-thickness osteochondral defect model, with micro-CT evaluation, quantitative analysis, and histological staining (hematoxylin-eosin, Safranin-O, and Masson’s trichrome). Results: The DCPD Mg scaffold exhibited a uniform porous structure and superior mechanical properties. The Zn-AlgMA hydrogel displayed consistent microstructural features and enhanced hydrophilicity. The Zn-AlgMA@Mg scaffold provided controlled release of magnesium and zinc ions, promoting cell proliferation and vitality. In vitro studies demonstrated significant osteogenic and chondrogenic properties, as well as antibacterial efficacy. Proteomic analysis revealed the underlying mechanism of osteochondral integrated repair facilitated by the scaffold. Micro-CT evaluation and histological analysis confirmed successful osteochondral integration in the rabbit model. Discussion: The biomimetic honeycomb-like scaffold (Zn-AlgMA@Mg) demonstrated promising results for osteochondral repair, effectively addressing the challenges posed by bacterial tissue conditions. The scaffold’s ability to release magnesium and zinc ions in a controlled manner contributed to its significant osteogenic, chondrogenic, and antibacterial properties. Proteomic analysis provided insights into the scaffold’s mechanism of action, supporting its potential for integrated osteochondral regeneration. The successful in vivo results highlight the scaffold’s efficacy, making it a promising biomaterial for future applications in osteochondral repair.
Osteoarthritis (OA) is a type of joint disorder that is marked by the gradual breakdown of cartilage and persistent inflammation of the synovial membrane, and is a leading cause of disability among ...elderly people worldwide. Oldenlandia diffusa (OD) is a member of the Rubiaceae family, and various researches have revealed that it possesses antioxidant, anti-inflammatory, and anti-tumor properties. Extracts of Oldenlandia diffusa is commonly used in traditional oriental medicine to treat various illnesses, including inflammation and cancer.
This study is aimed at investigating the anti-inflammatory and anti-apoptosis effects of OD and its potential mechanisms on IL-1β-induced mouse chondrocytes, as well as its characteristics in a mouse osteoarthritis model.
In this study, the key targets and potential pathways of OD were determined through network pharmacology analysis and molecular docking. The potential mechanism of OD in osteoarthritis was verified by in vitro and in vivo studies.
The results of network pharmacology showed that Bax, Bcl2, CASP3, and JUN are key candidate targets of OD for the treatment of osteoarthritis. There is a strong correlation between apoptosis and both OA and OD. Additionally, molecular docking results show that β-sitosterol in OD can strongly bind with CASP3 and PTGS2. In vitro experiments showed that OD pretreatment inhibited the expression of pro-inflammatory factors induced by IL-1β, such as COX2, iNOS, IL-6, TNF-α, and PGE2. Furthermore, OD reversed IL-1β-mediated degradation of collagen II and aggrecan within the extracellular matrix (ECM). The protective effect of OD can be attributed to its inhibition of the MAPK pathway and inhibition of chondrocyte apoptosis. Additionally, it was found that OD can alleviate cartilage degradation in a mouse model of knee osteoarthritis.
Our study showed that β-sitosterol, one of the active components of OD, could alleviate the inflammation and cartilage degeneration of OA by inhibiting chondrocyte apoptosis and MAPK pathway.
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•OD attenuates IL-1β-induced apoptosis in chondrocytes.•OD can reduce IL-1β induced mouse chondrocyte inflammation and degradation of extracellular matrix.•OD mediates its cellular effect by inhibiting the activation of MAPK signaling pathway.
Osteoarthritis (OA) is a complicated disease that involves apoptosis and mitophagy. MST1 is a pro‐apoptotic factor. Hence, decreasing its expression plays an anti‐apoptotic effect. This study aims to ...investigate the protective effect of MST1 inhibition on OA and the underlying processes. Immunofluorescence (IF) was used to detect MST1 expression in cartilage tissue. Western Blot, ELISA and IF were used to analyse the expression of inflammation, extracellular matrix (ECM) degradation, apoptosis and mitophagy‐associated proteins. MST1 expression in chondrocytes was inhibited using siRNA and shRNA in vitro and in vivo. Haematoxylin–Eosin, Safranin O‐Fast Green and alcian blue staining were used to evaluate the therapeutic effect of inhibiting MST1. This study discovered that the expression of MST1 was higher in OA patients. Inhibition of MST1 reduced inflammation, ECM degradation and apoptosis and enhanced mitophagy in vitro. MST1 inhibition slows OA progression in vivo. Inhibiting MST1 suppressed apoptosis, inflammation and ECM degradation via promoting Parkin‐mediated mitophagy and the Nrf2‐NF‐κB axis. The results suggest that MST1 is a possible therapeutic target for the treatment of osteoarthritis as its inhibition delays the progression of OA through the Nrf2‐NF‐κB axis and mitophagy.
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•Asiatic Acid (AA) has therapeutic potential for glucocorticoid-induced osteonecrosis of the femoral head (GIONFH).•AA prevents GIONFH may related to anti-apoptosis and alleviation of ...oxidative stress.•AA can inhibit GIONFH by modulating the PI3K/AKT signaling pathway.
Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) represents a predominant etiology of non-traumatic osteonecrosis, imposing substantial pain, restricting hip mobility, and diminishing overall quality of life for affected individuals. Centella asiatica (L.) Urb. (CA), an herbal remedy deeply rooted in traditional oriental medicine, has exhibited noteworthy therapeutic efficacy in addressing inflammation and facilitating wound healing. Drawing from CA's historical applications, its anti-inflammatory, anti-apoptotic, and antioxidant attributes may hold promise for managing GIONFH. Asiatic acid (AA), a primary constituent of CA, has been substantiated as a key contributor to its anti-apoptotic, antioxidant, and anti-inflammatory capabilities, showcasing a close association with orthopedic conditions.
For the investigation of whether AA could alleviate GIONFH through suppressing oxidative stress, apoptosis, and to delve into its potential cellular and molecular mechanisms, the connection between AA and disease was analyzed through network pharmacology. DEX-induced apoptosis in rat osteoblasts and GIONFH in rat models, got utilized for the verification in vitro/vivo, on underlying mechanism of AA in GIONFH. Network pharmacology analysis reveals a robust correlation between AA and GIONFH in multiple target genes. AA has demonstrated the inhibition of DEX-induced osteoblast apoptosis by modulating apoptotic factors like BAX, BCL-2, Cleaved-caspase3, and cleaved-caspase9. Furthermore, it effectively diminishes the ROS overexpression and regulates oxidative stress through mitochondrial pathway. Mechanistic insights suggest that AA's therapeutic effects involve phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) pathway activation. Additionally, AA has exhibited its potential to ameliorate GIONFH progression in rat models. Our findings revealed that AA mitigated DEX-induced osteoblast apoptosis and oxidative stress through triggering PI3K/AKT pathway. Also, AA can effectively thwart GIONFH occurrence and development in rats.
•Bioinspired EM from SIM-pretreatment MSCs improves GIONFH treatment.•SIM-MSCs-EM exhibits better osteogenesis and angiogenesis ability than MSCs-EM.•SIM-MSCs-EM delivers miR-29b-3p to silence PTEN ...and activate PI3K/AKT pathway.
Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long-term or excessive glucocorticoid use. Promoting osteogenesis and angiogenesis simultaneously is the key to prevent or treat GIONFH at early stage. Recently, exosomes secreted by mesenchymal stem cells (MSCs) have played a significant role in preventing GIONFH by enhancing osteogenesis and angiogenesis. However, poor yield, difficulty in purification and unpredictable therapeutic effect of exosomes have been obstacles for widespread use in clinical practices. Here, this study reported bioinspired exosome mimetics (EM) derived from simvastatin (SIM)-pretreatment MSCs (SIM-MSCs-EM) by an extrusion approach. Our results demonstrated SIM-MSCs-EM exhibited better osteogenesis and angiogenesis ability compared to EM derived from MSCs (MSCs-EM), alleviating the progression of GIONFH in vivo. Due to the unique endogenous miRNA cargos, SIM-MSCs-EM deliver miR-29b-3p to silence the target gene phosphatase and tensin homolog (PTEN) and then activate the PI3K/AKT pathway, which exerts a vital role in osteogenesis and angiogenesis. Taken together, our study proposed that SIM-enhanced bioinspired EM could be a feasible approach by regulating osteogenesis and angiogenesis for the treatment of GIONFH and other avascular osteonecrosis disease.
•Stevioside can suppress IL-1β-induced cartilage metabolic imbalance, inflammation and apoptosis.•Stevioside can delay disease progression in a mice osteoarthritis model.•Stevioside mediates its ...cellular effect by inhibiting the activation of MAPK and NF-κB signaling pathways.
Osteoarthritis (OA) is a joint disease that is characterized by articular cartilage degeneration and destruction. Stevioside (SVS) is a diterpenoid glycoside extracted from Stevia rebaudiana Bertoni with some specific effects against inflammatory and apoptotic, whereas it is still unclear what function SVS has in osteoarthritis. This study focuses on the anti-inflammatory and anti-apoptosis functions of SVS on chondrocytes induced by interleukin (IL)-1beta, and the role of SVS in an osteoarthritis model for mice. We can detect the production of inflammatory factors such as nitric oxide (NO) and prostaglandin E2 (PGE2) using real-time quantitative polymerase chain reaction (RT-qPCR), the Griess reaction, and enzyme linked immunosorbent assay (ELISA). On the basis of Western blot, we have observed the protein expressions of cartilage matrix metabolism, inflammatory factors, and apoptosis of chondrocytes. Simultaneously, the pharmacological effects of SVS in mice were evaluated by hematoxylin and eosin (HE), toluidine blue, Safranin O, and immunohistochemical staining. The results show that SVS slows extracellular matrix degradation and chondrocyte apoptosis. In addition, SVS mediates its cellular effect by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways. Meanwhile, molecular docking studies revealed that SVS has excellent binding capabilities to p65, extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The study suggests that SVS can be developed as a potential osteoarthritis treatment.
Glucocorticoid‐induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long‐term or excessive use of glucocorticoids (GCs). Taxifolin (TAX) is a natural antioxidant ...with various pharmacological effects, such as antioxidative stress and antiapoptotic properties. The purpose of this study was to explore whether TAX could regulate oxidative stress and apoptosis in GIONFH by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway. We conducted qRT‐PCR, Western blotting, TUNEL assays, flow cytometry, and other experiments in vitro. Microcomputed tomography analysis, hematoxylin–eosin staining, and immunohistochemical staining were performed to determine the therapeutic effect of TAX in vivo. TAX mitigated the overexpression of ROS and NOX gene expression induced by DEX, effectively reducing oxidative stress. Additionally, TAX could alleviate DEX‐induced osteoblast apoptosis, as evidenced by qRT‐PCR, Western blotting, and other experimental techniques. Our in vivo studies further demonstrated that TAX mitigates the progression of GIONFH in rats by combating oxidative stress and apoptosis. Mechanistic exploration revealed that TAX thwarts the progression of GIONFH through the activation of the Nrf2 pathway. Overall, our research herein reports that TAX‐mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of GIONFH.
Spinal cord injury (SCI) is a severe medical condition with lasting effects. The efficacy of numerous clinical treatments is hampered by the intricate pathophysiological mechanism of SCI. Fibroblast ...growth factor 18 (FGF-18) has been found to exert neuroprotective effects after brain ischaemia, but its effect after SCI has not been well explored. The aim of the present study was to explore the therapeutic effect of FGF-18 on SCI and the related mechanism. In the present study, a mouse model of SCI was used, and the results showed that FGF-18 may significantly affect functional recovery. The present findings demonstrated that FGF-18 directly promoted functional recovery by increasing autophagy and decreasing pyroptosis. In addition, FGF-18 increased autophagy, and the well-known autophagy inhibitor 3-methyladenine (3MA) reversed the therapeutic benefits of FGF-18 after SCI, suggesting that autophagy mediates the therapeutic effects of FGF-18 on SCI. A mechanistic study revealed that after stimulation of the protein kinase B (AKT)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin signalling pathway, the FGF-18-induced increase in autophagy was mediated by the dephosphorylation and nuclear translocation of transcription factor E3 (TFE3). Together, these findings indicated that FGF-18 is a robust autophagy modulator capable of accelerating functional recovery after SCI, suggesting that it may be a promising treatment for SCI in the clinic.
Diabetes is a metabolic disorder characterized by hyperglycemia, resulting in low-grade systemic inflammation. Diabetic cardiomyopathy (DCM) is a common complication among diabetic patients, and the ...mechanism underlying its induction of cardiac remodeling and dysfunction remains unclear. Numerous experimental and clinical studies have suggested that adaptive immunity, especially T lymphocyte-mediated immunity, plays a potentially important role in the pathogenesis of diabetes and DCM. Metallothioneins (MTs), cysteine-rich, metal-binding proteins, have antioxidant properties. Some potential mechanisms underlying the cardioprotective effects of MTs include the role of MTs in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant activity. Moreover, metal homeostasis, especially MT-regulated zinc homeostasis, is essential for immune function. This review discusses aberrant immune regulation in diabetic heart disease with respect to endothelial insulin resistance and the effects of hyperglycemia and hyperlipidemia on tissues and the different effects of intracellular and extracellular MTs on adaptive immunity. This review shows that intracellular MTs are involved in naïve T-cell activation and reduce regulatory T-cell (Treg) polarization, whereas extracellular MTs promote proliferation and survival in naïve T cells and Treg polarization but inhibit their activation, thus revealing potential therapeutic strategies targeting the regulation of immune cell function by MTs.
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