Targeted delivery of anti-osteoporosis therapy: Bisphosphonate-modified nanosystems and composites.

Osteoporosis (OP) constitutes a significant health concern that profoundly affects individuals' quality of life. Bisphosphonates, conventional pharmaceuticals widely employed in OP treatment, encounter limitations related to inadequate drug targeting and a short effective duration, thereby compromising their clinical efficacy. The burgeoning field of nanotechnology has witnessed the development and application of diverse functional nanosystems designed for OP treatment. Owing to the bone tissue affinity of bisphosphonates, these nanosystems are modified to address shortcomings associated with traditional drug delivery. In this review, we explore the potential of bisphosphonate-modified nanosystems as a promising strategy for addressing osteoporotic conditions. With functional modification, these nanosystems exhibit a targeted and reversible effect on osteoporotic remodeling, presenting a promising solution to enhance precision in drug delivery. The synthesis methods, physicochemical properties, and in vitro/in vivo performance of bisphosphonate-modified nanosystems are comprehensively examined in this review. Through a thorough analysis of recent advances and accomplishments in this field, we aim to provide insights into the potential applications and future directions of bisphosphonate-modified nanosystems for targeted and reversible osteoporotic remodeling.

A prospective observational study comparing outcomes application of low-frequency pulse electrical combined with target-oriented rehabilitation therapy in postoperative nerve function rehabilitation of patients with distal humeral fracture and radial nerve injury.

Objective: The aim of the present study was to compare the effect of low-frequency pulse electrical stimulation combined with target-oriented rehabilitation therapy and single low-frequency pulse electrical stimulation therapy on postoperative neurological improvement in patients with radial nerve injury and humeral condylar fracture. Methods: A total of 88 patients with humeral condyle fracture and radial nerve injury admitted to our hospital from April 2019 to January 2022 were randomly divided into a combined group and a control group, with 44 patients in each group. The patients in the combined group received low-frequency pulse electrical stimulation combined with target-oriented rehabilitation therapy, while those in the control group received low-frequency pulse electrical stimulation therapy. The recovery rate of radial nerve function, the recovery of finger extensor and wrist extensor muscle strength, and the occurrence of postoperative complications were evaluated in all patients. Results: After treatment, the recovery rate in the combined group (77.27%) was higher than that in the control group (50.00%) (p < 0.05). There was no significant difference in finger extensor and wrist extensor muscle strength before treatment between the two groups (p > 0.05). After treatment, both groups showed improvement compared to before treatment (p < 0.05), and the recovery in the combined group was better than that in the control group (p < 0.05). There was no significant difference in MCV and amplitude before treatment between the two groups (p > 0.05). After treatment, both groups showed improvement compared to before treatment (p < 0.05), and the recovery in the combined group was better than that in the control group (p < 0.05). The fracture healing time in the combined group was shorter than that in the control group (p < 0.05). During the treatment period, there was one case of infection and one case of joint pain in the combined group, with a complication rate of 4.55%. In the control group, there was one case of infection and two cases of joint pain, with a complication rate of 6.82%. There was no significant difference in the complication rate between the two groups (p > 0.05). The DHI score in the combined group was better than that in the control group (p < 0.05). The ESCA score in the combined group was better than that in the control group (p < 0.05). Conclusion: Low-frequency pulse electrical stimulation combined with target-oriented rehabilitation therapy can promote muscle strength and functional recovery after radial nerve injury, accelerate fracture healing time, and no additional risk of complications. Clinical trial registration: https://www.researchregistry.com/, researchregistry9461.

Nanoparticle-Facilitated Therapy: Advancing Tools in Peripheral Nerve Regeneration.

Peripheral nerve injuries, arising from a diverse range of etiologies such as trauma and underlying medical conditions, pose substantial challenges in both clinical management and subsequent restoration of functional capacity. Addressing these challenges, nanoparticles have emerged as a promising therapeutic modality poised to augment the process of peripheral nerve regeneration. However, a comprehensive elucidation of the complicated mechanistic foundations responsible for the favorable effects of nanoparticle-based therapy on nerve regeneration remains imperative. This review aims to scrutinize the potential of nanoparticles as innovative therapeutic carriers for promoting peripheral nerve repair. This review encompasses an in-depth exploration of the classifications and synthesis methodologies associated with nanoparticles. Additionally, we discuss and summarize the multifaceted roles that nanoparticles play, including neuroprotection, facilitation of axonal growth, and efficient drug delivery mechanisms. Furthermore, we present essential considerations and highlight the potential synergies of integrating nanoparticles with emerging technologies. Through this comprehensive review, we highlight the indispensable role of nanoparticles in propelling advancements in peripheral nerve regeneration.

How Advancing is Peripheral Nerve Regeneration Using Nanofiber Scaffolds? A Comprehensive Review of the Literature.

Peripheral nerve injuries present significant challenges in regenerative medicine, primarily due to inherent limitations in the body's natural healing processes. In response to these challenges and with the aim of enhancing peripheral nerve regeneration, nanofiber scaffolds have emerged as a promising and advanced intervention. However, a deeper understanding of the underlying mechanistic foundations that drive the favorable contributions of nanofiber scaffolds to nerve regeneration is essential. In this comprehensive review, we make an exploration of the latent potential of nanofiber scaffolds in augmenting peripheral nerve regeneration. This exploration includes a detailed introduction to the fabrication methods of nanofibers, an analysis of the intricate interactions between these scaffolds and cellular entities, an examination of strategies related to the controlled release of bioactive agents, an assessment of the prospects for clinical translation, an exploration of emerging trends, and thorough considerations regarding biocompatibility and safety. By comprehensively elucidating the intricate structural attributes and multifaceted functional capacities inherent in nanofiber scaffolds, we aim to offer a prospective and effective strategy for the treatment of peripheral nerve injury.

Advances in diagnosis and treatment of Madelung's deformity.

In this paper, a review of the literature was performed to critically evaluate relevant published research on diagnosis and treatment of Madelung's deformity. Madelung's deformity is a metaphyseal dysplasia of the distal radius, where the distal radial joint tilts to the volar and ulnar sides, combined with distal ulnar subluxation and elbow dislocation. The main pathogenic factors of this disease include idiopathic, hereditary and acquired factors. So far, it is believed that Madelung's deformity is mainly associated with trauma, epiphyseal dysplasia, nutritional disorders, and gene deletion or mutation. It is more common in females, and is an autosomal dominant inheritance disease. Most patients suffer from this disease bilaterally. Madelung's deformity may occur as a complication of Leri-Weill dyschondrosteosis. Most patients usually have no clinical symptoms in the early stage, and some patients come to the hospital due to wrist pain, stiffness, deformity and a shorter forearm. X-ray film is the main diagnostic method for this disease. Magnetic resonance imaging can show local soft tissue and bone abnormalities in the early stage, so it is used for the early diagnosis of this disease. The ulnar angle can be classified into different types based on the size of the distal radius palmar angle. For severe deformity and symptoms, surgical treatment is often required, including soft tissue release, distal radius osteotomy, ulnar shortening osteotomy, distal ulnar resection, and distal radioulnar joint fusion. Some procedures have better clinical results in relieving pain and improving mobility.

Influential articles on shoulder arthroplasty: bibliometric analysis and visualized study.

BACKGROUND: Shoulder arthroplasty has had increasing global demand, technical development, and research interest in the past few decades, with the publication of numerous articles. However, little is known about the characteristics and evaluation of these articles. Our objective was to study and analyze the top 100 cited articles in shoulder arthroplasty research. MATERIALS AND METHODS: Publications on shoulder arthroplasty from inception to 2022 were retrieved from the Web of Science. The top 100 publications were defined by the number of citations, and their characteristics were recorded and analyzed. A visualized study of the articles was performed using VOSviewer software. RESULTS: The top 100 cited articles were published between 1981 and 2018, with the 2000s the most productive decade. Citations per article ranged from 103 to 822. The countries with the most articles were the United States followed by France and Switzerland. Most of the articles were level III evidence. The keywords for the articles were primarily in 5 clusters: infection, fracture, osteoarthritis, perioperative complications, and prosthetic design. CONCLUSIONS: The characteristics of influential articles on shoulder arthroplasty were thoroughly analyzed. Most studies focused on surgical techniques and perioperative complications with a relatively low level of evidence.

Fibrolipomatous hamartoma of the median nerve: a case report and literature review / Hamartoma fibrolipomatoso del nervio mediano: reporte de un caso y revisión de la literatura

Abstract Fibrolipomatous hamartoma (FLH) of the nerve, also known as lipomatosis of the nerve, neurofibrillary lipomatous lesion, or intraneural lipoma, is a rare benign soft tissue tumor which mainly occurs in the nerves of the upper limb, especially in the median nerve. In April 2021, a 30-year-old male patient was secondly admitted to our hospital and underwent his third surgery, due to the recurrence of a mass and pain in the right palm, noticeable swelling and numbness of the right index and ring fingers, and limited flexion and extension activities of the right ring finger. He first visited our hospital in December 2017 due to a mass and pain in the right palm and swelling and numbness of the right index and ring fingers. When the clinician asked for the patient medical history, his parents stated that his right middle finger was swollen after birth. When the patient was ten years old; he was diagnosed with "macrodactyly" at the local county hospital, not in our hospital, and subsequently, the middle finger was amputated at the metacarpophalangeal joint level at the local county hospital. The postoperative pathological examination was not performed at that time, which was the first surgery the patient received. FLH is clinically rare, and its exact epidemiology and etiology are poorly understood. FLH is highly suspected in cases where a painless mass is present in the wrist, combined with macrodactyly. Magnetic resonance imaging and pathological examination are helpful in clarifying the diagnosis. Although FLH is a benign tumor, an individual treatment plan is the best choice according to the severity of the patient's symptoms. Therefore, further exploration and understanding of this disease by clinicians radiologists, and pathologists is necessary.

Resumen El hamartoma fibrolipomatoso (FLH) del nervio, también conocido como lipomatosis del nervio, lesión neurofibrilar lipomatosa, o lipointraneural, es un tumor benigno de tejido blando poco frecuente, que se presenta principalmente en los nervios del miembro superior, especialmente en el nervio mediano. En abril de 2021, un paciente masculino de 30 años fue ingresado por segunda vez en nuestro hospital y sometido a su tercera cirugía debido a la recurrencia de una masa y dolor en la palma derecha, evidente hinchazón y entumecimiento de los dedos índice y anular derecho y limitadas actividades de flexión y extensión del dedo anular derecho. En diciembre de 2017, visitó por primera vez nuestro hospital debido a una masa y dolor en la palma derecha, y a la hinchazón y entumecimiento de los dedos índice y anular derecho. Cuando el clínico preguntó la historia clínica del paciente, sus padres declararon que su dedo medio derecho estaba hinchado después del nacimiento, y cuando el paciente tenía 10 años, fue diagnosticado con "macrodactilia" en el hospital local del condado, no en nuestro hospital Posteriormente, el dedo medio fue amputado a nivel de la articulación metacarpofalángica en el hospital comarcal local, pero no se realizó la patología postoperatoria en ese momento, siendo ésta la primera cirugía a la cual se sometió el paciente. La FLH es clínicamente rara, y su epidemiología y etiología exactas no se entienden bien. En los casos que presentan una masa indolora en la muñeca, combinada con macrodactilia, se sospecha de FLH. La resonancia magnética y la patología son útiles para aclarar el diagnóstico. Aunque la FLH es un tumor benigno, el plan de tratamiento individual es la mejor opción de acuerdo con la gravedad de los síntomas del paciente. Por lo tanto, es necesaria una mayor exploración y comprensión de esta enfermedad por parte de médicos, radiólogos y patólogos.

Activation of PGRN/MAPK axis stimulated by the hypoxia-conditioned mesenchymal stem cell-derived HIF-1α facilitates osteosarcoma progression.

BACKGROUND: Progranulin (PGRN) is an important survival factor in the progression of multiple cancers. PURPOSE: To explore the effects and mechanisms of PGRN on malignant biological behavior of osteosarcoma (OS) cells and the effects of mesenchymal stem cells (MSCs) and the hypoxic microenvironment on PGRN alteration. MATERIAL AND METHODS: The expression pattern of PGRN in OS were evaluated in OS tissues and cell lines. Next, a loss-of-function assay investigated the function of PGRN on the proliferation, migration and cell death of OS cells. The activation of MAPK signaling in the process was examined by western blot and functional experiments accompanied by skatole. Additionally, we internally silenced hypoxia-inducible factor-1α (HIF-1α) in MSCs along with exogenously added HIF-1α (exo-HIF-1α) to explore how MSCs affect PGRN alteration and the malignant behavior of OS cells. RESULTS: An aberrantly high expression of PGRN was observed in OS and associated with the poor prognosis of OS patients. PGRN knockdown repressed the proliferation, migration and induced cell death of OS cells, and activating MAPK pathway reversed these effects. Further evidence showed that MSCs regulated PGRN to mediate the malignant biological behavior of OS cells. Hypoxia enhanced HIF-1α expression in MSCs. HIF-1α silencing in MSCs under hypoxia suppressed the oncogenic effects of MSCs and reduced PGRN expression in OS cells, while the treatment of exo-HIF-1α reversed the depressive effects of HIF1α silencing on OS progression. CONCLUSION: Overall, we concluded that PGRN, which was activated by the increase of hypoxic-MSCs-derived HIF-1α, promoted OS progression through the activation of MAPK signaling.

A comprehensive analysis of G-protein-signaling modulator 2 as a prognostic and diagnostic marker for pan-cancer.

Background: G-protein signaling modulator 2 (GPSM2) maintains cell polarization and regulates the cell cycle. Recent studies have shown that it is highly expressed in various tumors, but its pan-cancer analysis has not been reported. Methods: First, we analyzed the differential GPSM2 expression in normal and cancer tissues by the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Human Protein Atlas databases and investigated its expression effect on the survival of cancer patients by gene expression profiling interactive analysis 2 (GEPIA2). Second, we analyzed the GPSM2 phosphorylation level using the clinical proteomic tumor analysis consortium dataset. In addition, we investigated GPSM2 gene mutations in human tumor specimens and the impact of gene mutations on patient survival. Finally, we analyzed the relationship between GPSM2 expression and cellular immune infiltration through the TIMER 2.0 database. Meanwhile, the possible signaling pathway of the gene was analyzed by the Gene Ontology (GO)| Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to explore its potential mechanism. Results: GPSM2 is overexpressed in most cancers, which leads to reduced overall survival (OS) and disease-free survival in patients. The results of phosphorylation analysis suggest that tumor development involves a complex GPSM2 phosphorylation process. We identified GPSM2 mutation loci with the highest frequency of mutations in uterine corpus endometrial carcinoma (UCEC), and this mutation increased progression-free survival and overall survival in uterine corpus endometrial carcinoma patients. Finally, we found that the role of GPSM2 in tumors may be associated with cellular immune infiltration. Gene Ontology|KEGG pathway analysis showed that the enrichment pathways were mainly "mitotic nuclear division," "chromosome segregation," and "spindle." Conclusions: Our pan-cancer analysis provides a comprehensive overview of the oncogenic roles and potential mechanisms of GPSM2 in multiple human cancers.

Integrated analysis of anti-tumor roles of BAP1 in osteosarcoma.

Background: This study aims to screen out differentially expressed genes (DEGs) regulated by BRCA1-associated protein 1 (BAP1) in osteosarcoma cells, and to analyze their biological functions. Methods: The microarray dataset GSE23035 of BAP1-knockdown osteosarcoma cells was obtained from Gene Expression Omnibus (GEO) database, consisting of shControl, shBAP1#1 and shBAP1#2 samples. The DEGs between the BAP1-knockdown osteosarcoma cells and the untreated osteosarcoma cells were screened with limma package, and then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Gene Set Enrichment Analysis (GSEA) was also performed for the three groups of samples. Hub genes in a protein-protein interaction (PPI) network of DEGs was filtered, and then subjected to prognostic analysis and correlation analysis with BAP1 in Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Besides, the correlation between BAP1 and biological processes/pathways was analyzed by Gene Set Variation Analysis (GSVA) method and the correlation between BAP1 and immune infiltration by CIBERSORT and ESTIMATE methods. The roles of BAP1 in regulating proliferation and epithelial-mesenchymal transition (EMT) were validated by CCK-8 and western blot. Results: 58 upregulated DEGs and 81 downregulated DEGs were obtained with |logFC| ≥ 1 and adj.p < 0.05. Cell cycle, DNA repair, and focal adhesion were associated with BAP1 in datasets. Further, BAP1 was negatively correlated with naïve CD4 T cells infiltration. In vitro, BAP1 inhibited proliferation and EMT. Conclusion: BAP1 might be a tumor suppressor in osteosarcoma and a promising therapeutic target.

lncRNA AC007207.2 Promotes Malignant Properties of Osteosarcoma via the miR-1306-5p/SIRT7 Axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been implicated in initiation and development of numerous cancers. In the present study, we explored the role of lncRNAs AC007207.2 in osteosarcoma (OS). METHODS: Gene expression data of OS tissues was downloaded from the TARGET database. All the experiments were repeated at least three times. Data were analyzed using Perl, R, SPSS v12.0 and GraphPad Prism 8 software. RESULTS: We found lncRNA AC007207.2 was over-expressed in OS tissues and cell lines, and this phenomenon was associated with the worse prognosis of OS. Moreover, we found that AC007207.2 promotes proliferation and metastasis of OS cells via the miR-1306-5p/SIRT7 axis. Meanwhile, we found miR-1306-5p remarkably inhibits the malignant behavior of OS cells. CONCLUSION: lncRNA AC007207.2 promotes progression of OS by upregulating SIRT7 expression through miR-1306-5p sponging. Thus, lncRNA AC007207.2/miR-1306-5p/SIRT7 axis is a promising therapeutic target for OS treatment.

Blocking Smad2 signalling with loganin attenuates SW10 cell cycle arrest induced by TNF-α.

The activity of Schwann cells (SWCs) is very important in trauma-induced nerve repair, and tumour necrosis factor-α (TNF-α) produced during tissue injury inhibits the viability of SWCs, which delays the repair of peripheral nerves. Loganin is an iridoid glycoside that has been shown to alleviate a variety of cytotoxic effects. In the current study, we evaluated the potential efficacy and the mechanism of action of loganin in TNF-α-induced cytotoxicity in SW10 cells. The experimental results indicated that loganin blocked TNF-α-mediated Smad2 activation, downregulated the expression of the G1 phase cell cycle inhibitor p15IN4KB, and upregulated the expression of the G1 phase cell cycle activator cyclin D1-CDK4/6, which upregulated E2F-1-dependent survivin expression and relieved TNF-α-induced apoptosis in SW10 cells. The protective effect of loganin on SWCs has potential medicinal value in the promotion of peripheral nerve repair and is significant for studies in the field of tissue regeneration.

MiR-34a and miR-203 Inhibit Survivin Expression to Control Cell Proliferation and Survival in Human Osteosarcoma Cells.

Elevated expression of survivin is observed in a number of cancer types, including human osteosarcoma. Few studies have demonstrated that survivin expression levels can be considered an independent predictor of survival for human osteosarcoma patients. However, the underlying molecular mechanisms of survivin in the process of human osteosarcoma carcinogenesis remain unclear. In the current study, we evaluated the biological effects of survivin knockdown on osteosarcoma cell proliferation, colony formation rate, and sensitivity to the chemotherapeutic agent cisplatin. We found that two different osteosarcoma cell lines, U2OS and Saos-2, have relatively higher expression levels of survivin, and specific knockdown of survivin resulted in a number of effects, such as inhibition of cell proliferation, decreased colony formation rate, cell cycle arrest at G2/M phase, induction of apoptosis, and increased sensitivity to cisplatin. In addition, we identified two microRNAs, miR-34a and miR-203, that are aberrantly expressed in human osteosarcoma cells and specifically target survivin by inhibiting its expression, therefore repressing osteosarcoma cell maintenance and proliferation.

Adenosine A2B receptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells.

Angiogenesis is critical to wound repair due to its role in providing oxygen and nutrients that are required to support the growth and function of reparative cells in damaged tissues. Adenosine receptors are claimed to be of paramount importance in driving wound angiogenesis by inducing VEGF. However, the underlying mechanisms for the regulation of adenosine receptors in VEGF as well as eNOS remain poorly understood. In the present study, we found that adenosine and the non-selective adenosine receptor agonists (NECA) induced tube formation in HMEC-1 in a dose-dependent manner. Adenosine or NECA (10 µmol/L) significantly augmented the number and length of the segments in comparison with the control. Simultaneously, VEGF and eNOS were significantly upregulated following the administration of 10 µmol/L NECA, while they were suppressed after A2B AR genetic silencing and pharmacological inhibition by MRS1754. In addition, VEGF expression and eNOS bioavailability elimination significantly reduced the formation of capillary-like structures. Furthermore, the activation of A2B AR by NECA significantly increased the intracellular cAMP levels and concomitant CREB phosphorylation, eventually leading to the production of VEGF in HMEC-1. However, the activated PKA-CREB pathway seemed to be invalidated in the induction of eNOS. Moreover, we found that the elicited PI3K/AKT signaling in response to the induction of NECA assisted in regulating eNOS but failed to impact on VEGF generation. In conclusion, the A2B AR activation-driven angiogenesis via cAMP-PKA-CREB mediated VEGF production and PI3K/AKT-dependent upregulation of eNOS in HMEC-1.