Inhibition of protein disulfide isomerase mitigates steroid-induced osteonecrosis of the femoral head by suppressing osteoclast activity through the reduction of cellular oxidative stress.

Osteonecrosis of the femoral head (ONFH) is a devastating and irreversible hip disease usually associated with increased oxidative stress due to the clinical application of high-dose or long-term glucocorticoids (GCs). Previous publications have demonstrated protein disulfide isomerase (PDI) plays a critical role in regulating cellular production of reactive oxygen species (ROS). We therefore ask whether interfering PDI could affect GCs-stimulated osteoclastogenesis. To test the hypothesis, we conducted bioinformatics and network analysis based on potential gene targets of steroid-induced osteonecrosis of the femoral head (SIONFH) in light of multiple databases and concomitantly verified the associated biological effect via the in vitro model of dexamethasone (DEX)-stimulated osteoclastogenesis. The results revealed 70 potential gene targets for SIONFH intervention, including the P4HB gene that encodes PDI. Further analysis based on network topology-based analysis techniques (NTA), protein-protein interaction (PPI) networks, and mouse cell atlas database identified the importance of PDI in regulating the cellular redox state of osteoclast during ONFH. Western blotting (WB) validations also indicated that PDI may be a positive regulator in the process of DEX-stimulated osteoclastogenesis. Hence, various PDI inhibitors were subjected to molecular docking with PDI and their performances were analyzed, including 3-Methyltoxoflavin (3 M) which inhibits PDI expression, and ribostamycin sulfate (RS) which represses PDI chaperone activity. The binding energies of DEX, 3 M, and RS to PDI were -5.3547, -4.2324, and -5.9917 kcal/mol, respectively. The Protein-Ligand Interaction Profiler (PLIP) analysis demonstrated that both hydrogen bonds and hydrophobic interactions were the key contributions to the DEX-PDI and 3M-PDI complexes, while only hydrogen bonds were identified as the predominant driving forces in the RS-PDI complex. Subsequent experiments showed that both 3 M and RS reduced osteoclast differentiation and bone resorption activity by stifling the expression of osteoclastic markers. This reduction was primarily due to the PDI inhibitors boosting the antioxidant system, thereby reducing the production of intracellular ROS. In conclusion, our results supported PDI's involvement in SIONFH progression by regulating ROS in osteoclasts and highlighted PDI inhibitors may serve as potential options for SIONFH treatment.

Corydaline attenuates osteolysis in rheumatoid arthritis via mitigating reactive oxygen species production and suppressing calcineurin-Nfatc1 signaling.

AIM OF THE STUDY: Osteolysis in Rheumatoid arthritis (RA) is principally provoked by osteoclast hyperactivity. This study aims to employ Corydaline (Cory), a plant extract, as an osteoclast inhibitor in treating RA-inflicted osteolysis while unveiling the corresponding mechanism. MATERIALS AND METHODS: Osteoclasts were derived from mouse bone marrow-derived monocytes (BMMs) stimulated with M-CSF and RANKL. Subsequently, utilizing network pharmacology, we performed a thorough analysis of Cory's molecular structure and discerned its preliminary therapeutic potential. Subsequently, LPS was used to simulate and establish an in vitro model of RA, and the biological effect of Cory on osteoclast behaviors was evaluated through various staining methods, RT-qPCR, and Western blot. In addition, a collagen-induced arthritis (CIA) mouse model was developed to evaluate the therapeutic effects of Cory in vivo. RESULTS: The results from network pharmacology indicated a significant correlation between Cory, oxidative stress, and calcium signaling. Subsequent in vitro experiments demonstrated Cory's capacity to inhibit the formation and function of osteoclast under inflammatory stimuli, thereby protecting against abnormal bone resorption. This effect is achieved by activating the Nrf2 signaling pathway, mitigating the generation of reactive oxygen species (ROS), and modulating the calcineurin-Nfatc1 signaling. Furthermore, this therapeutic effect of Cory on RA-associated osteolysis was proved in CIA mice models. CONCLUSIONS: Cory demonstrates the potential to activate the Nrf2 signaling pathway, effectively countering oxidative stress, and simultaneously inhibit the calcineurin-Nfatc1 signaling pathway to regulate the terminals of calcium signaling. These dual effects collectively reduce osteoclast activity, ultimately contributing to a therapeutic role in RA osteolysis. Therefore, our study presents Cory as a novel pharmaceutical candidate for the prevention and treatment of RA.

Factors Influencing the Self-Management Stages of Older Patients With Chronic Pain: A Cross-Sectional Study.

PURPOSE: To investigate the current status and related influencing factors of self-management stages in older patients with chronic pain. DESIGN: A cross-sectional study. METHODS: A total of 326 older patients with chronic pain were selected as the study subjects in five city districts from December 2022 to June 2023. We used a general information survey form, a numerical rating scale, a pain stages of change questionnaire, a health literacy assessment instrument for patients with chronic pain, and a psychological inflexibility in pain scale to collect relevant information from participants. Univariate analysis and multiple ordinal logistic regression analysis were conducted to identify the relevant influencing factors of the self-management stages. RESULTS: The self-management stages of older patients with chronic pain were as follows: precontemplation stage (n = 52; 16.0%), contemplation stage (n = 103; 31.6%), action stage (n = 62; 19.0%), and maintenance stage (n = 109; 33.4%). Regression results showed that average monthly household income, smoking history, pain duration, health literacy, and psychological inflexibility were the influencing factors for the self-management stages of older patients with chronic pain. CONCLUSIONS: In this study, the self-management stages of older patients with chronic pain still needed to be improved. Suitable personalized pain self-management strategies should be developed based on identified factors affecting patients to improve their self-management stages. CLINICAL IMPLICATIONS: Nursing professionals can use research survey findings to identify patients at low levels of self-management stage and develop personalized intervention strategies based on various influencing factors. For example, nurses can provide practical smoking cessation guidance to assist older chronic pain patients in improving their lifestyle. Nurses can also seek support from family members to collectively offer better medical care and nursing services for the patient if financially feasible. Secondly, as our study has demonstrated, patients' health literacy and psychological flexibility were poor. Nurses can utilize available clinical resources to offer educational materials, such as portable handbooks and online videos, covering pain-related knowledge, managing pain medication, and coping strategies like massage and exercise. Combining this approach with mental health education, such as relaxation therapy, can help patients better understand their pain and actively participate in their self-management. In addition, nursing staff should pay more attention to the self-management stages of older chronic pain patients, and the assessment of self-management stages can be included in clinical pain management for patients. Regular assessment will help track more patients needing attention and make timely adjustments to their pain management plans.

Crebanine mitigates glucocorticoid-induced osteonecrosis of the femoral head by restoring bone remodelling homeostasis via attenuating oxidative stress.

The onset of osteonecrosis of the femoral head (ONFH) is intimately associated with the extensive administration of glucocorticoids (GCs). Long-term stimulation of GCs can induce oxidative stress in both osteoclasts (OCs) and osteoblasts (OBs), resulting in the disturbance of bone remodelling. An alkaloid named crebanine (CN) demonstrates pharmacological properties including anti-inflammation and reactive oxygen species (ROS) modulation. Our objective is to assess the therapeutic potential of CN in treating ONFH and elucidate the associated underlying mechanisms. The network pharmacology analysis uncovered that CN played a role in regulating ROS metabolism. In vitro, CN demonstrated its ability to reduce the dexamethasone (DEX)-stimulated generation of OCs and suppress their resorptive function by downregulating the level of osteoclast marker genes. Concurrently, CN also mitigated DEX-induced damage to OBs, facilitating the restoration of osteoblast marker gene expression, cellular differentiation and function. These effects were achieved by CN augmenting the antioxidant system to reduce intracellular ROS levels. Furthermore, in vitro results were corroborated by micro-CT and histological data, which also showed that CN attenuated MPS-induced ONFH in mice. This study highlights the therapeutic potential of CN in counteracting GCs-induced ONFH.

Suppressing ERp57 diminishes osteoclast activity and ameliorates ovariectomy-induced bone loss via the intervention in calcium oscillation and the calmodulin/calcineurin/Nfatc1 pathway.

Background: Increased osteoclast activity constitutes the primary etiology of excessive bone erosion in postmenopausal osteoporosis. ERp57, otherwise referred to as protein disulfide isomerase A3 (PDIA3), plays a crucial role in the regulation of intracellular calcium signaling. This is documented to exert a profound impact on osteoclast differentiation and functionality. Methods: To ascertain the potential role of ERp57 in disease progression, prevention, and treatment, network pharmacology and bioinformatics analyses were conducted in relation to postmenopausal osteoporosis and ERp57 inhibitor (Loc14). Then, subsequent experimental verifications were employed in vitro on osteoclast and osteoblast, and in vivo on ovariectomy (OVX) mice models. Results: Multiple enrichment analyses suggested that the "calcium signaling pathway" may constitute a potential avenue for therapeutic intervention by Loc14 in the treatment of postmenopausal osteoporosis. In vitro experiments demonstrated inhibition of ERp57 could block osteoclast differentiation and function by interfering with the expression of osteoclast marker genes (Traf6, Nfatc1, and Ctsk). Further mechanisms studies based on calcium imaging, qPCR, and WB established that ERp57 inhibitor (Loc14) could obstruct calcium oscillation in osteoclast precursor cells (OPCs) by limiting the entry sources of cytosolic Ca2+ and interfering with calmodulin/calcineurin/Nfatc1 pathway. Evidence from Micro-CT scanning and double calcein labeling confirmed that the application of Loc14 in vivo could alleviate bone loss and partially reversed the osteogenic impairment caused by OVX in mice. Conclusions: Our findings proved the suppressive effects of Loc14 on osteoclastogenesis via attenuating calcium oscillation and associated singling pathways, providing ERp57 as a potential therapeutic target for postmenopausal osteoporosis.

Effects of olfactory and/or gustatory stimuli on feeding of preterm infants: A systematic review and meta-analysis.

AIM: To evaluate the effect of olfactory and/or gustatory stimulation interventions on feeding outcomes in preterm infants. METHODS: We conducted systematic searches across various academic databases, including PubMed, Embase, Web of Science, the Cochrane Library, the Chinese Biomedical Literature Service System, China National Knowledge Infrastructure, the Wanfang Database, and the Wipu Database. These searches aimed to identify randomized controlled trials investigating the impact of olfactory and/or gustatory stimulation on preterm infants. The search period spanned from the inception of the databases until December 2022. Two independent evaluators autonomously reviewed the literature, extracted pertinent data, assessed the quality of the included studies, and conducted a meta-analysis using RevMan 5.3 software. RESULTS: A total of 7 randomized controlled trials or quasi-experimental studies were included, with a total of 871 participants. Olfactory and gustatory stimulation demonstrated a reduction in the time to full enteral feeds in preterm infants when compared to usual care (MD = -1.60 days; 95% CI = -2.31, -0.89; p<0.0001). No substantial evidence was identified regarding the influence of olfactory and gustatory stimulation on the duration of gastric tube placement, length of hospitalization, incidence of necrotizing enterocolitis, or occurrence of spontaneous bowel perforation in preterm infants. CONCLUSIONS: Olfactory and gustatory stimulation show potential benefits for preterm infants. However, due to the low to very low level of certainty associated with the available data, our ability to assess the effects is limited. Further trials and studies are essential to enhance our understanding of the mechanisms and effectiveness of olfactory and gustatory stimulation therapies.

Loneliness in nursing homes: A qualitative meta-synthesis of older people's experiences.

BACKGROUND: Older people in the nursing home environment are much less mobile and capable of taking care of themselves as they age, and most of them face the plight of loneliness, which seriously affects the quality of life of older people in their later years. AIMS: A systematic review and synthesis of older people's experiences of loneliness in nursing homes. DESIGN: Following ENTREQ, do a systematic evaluation and synthesis of qualitative investigations. METHODS: A search of PubMed, Cochrane Library, Web of Science, Embase, the Chinese biomedical literature service system, the China National Knowledge Infrastructure, the Wanfang Database and the Wipu Database for qualitative studies of older people's experiences of loneliness in nursing homes was conducted with a search time frame of March 2023. Evaluation of the quality of the literature using the Joanna Briggs Institute's Australian Centre for Evidence-Based Health Care Quality Assessment Criteria for Qualitative Research, And the data were synthesised using Thomas and Harden's method of thematic and content analysis. RESULTS: A total of 13 papers were included, and 36 research findings were distilled and integrated into three themes: causes of loneliness; feelings of loneliness; coping with loneliness; and seven sub-themes: aging and loss; environmental transformation; loneliness is a pain; loneliness is a choice; participation; strengthening social ties; and diverting attention. CONCLUSIONS: Older people in nursing homes face varying degrees of loneliness, which is a subjective feeling influenced by the interplay between personal awareness and the external environment, so future care interventions should be developed in a comprehensive manner, taking into account the characteristics of the older people themselves and their external environment. NO PATIENT OR PUBLIC CONTRIBUTION: This study is a meta-synthesis and does not require relevant contributions from patients or the public.