Pregabalin-induced delayed cutaneous hypersensitivity reaction occurring after 40 days of use: a case report.

Pregabalin is the first-line treatment for neuropathic pain. Cases of cutaneous hypersensitivity reactions caused by pregabalin generally occur within 2 weeks of initiating medication. We report a rare case of a delayed cutaneous hypersensitivity reaction caused by pregabalin, which was confirmed by a drug provocation test. A 72-year-old man with severe herpes zoster neuralgia developed maculopapular drug eruption covering 80% to 90% of his total body surface area after 40 days of combined multidrug analgesia. A drug provocation test for pregabalin was positive. The time interval between initiating medication and the onset of the patient's rash was the longest and he also had the largest area of skin affected compared with patients with a similar condition in previous related reports. Remaining vigilant for possible adverse cutaneous hypersensitivity reactions during treatment is important because of the long-term course of pregabalin treatment for neuropathic pain.

Origin of Interfacial Orbital Reconstruction in Perovskite Superlattices.

The competition between on-site electronic correlation and local crystal field stands out as a captivating topic in research. However, its physical ramifications often get overshadowed by influences of strong periodic potential and orbital hybridization. The present study reveals this competition may become more pronounced or even dominant in two-dimensional systems, driven by the combined effects of dimensional confinement and orbital anisotropy. This leads to electronic orbital reconstruction in certain perovskite superlattices or thin films. To explore the emerging physics, we investigate the interfacial orbital disorder-order transition with an effective Hamiltonian and how to modulate this transition through strains.

Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Hsa_circTCF25 Facilitates Oncogenesis in Gastric Cancer Cells by Modulating miR-149 Expression.

BACKGROUND/AIM: Circular RNA (circRNA) is related to gastric carcinogenesis and progression. This study explored the effects of circTCF25 on gastric cancer cell proliferation, migration, invasion, and cancer stem cell markers, as well as the potential network of circTCF25-miR and miR-149. MATERIALS AND METHODS: circTCF25 expression was detected in tissue specimens and cells by real-time quantitative reverse transcription polymerase chain reaction. Cell Counting Kit-8 and transwell assays were used to measure the effects of circTCF25 knockdown on proliferation, migration and invasion. The potential network of circTCF25 was analyzed using bioinformatic analysis. RESULTS: circTCF25 was overexpressed in human gastric cancer tissues, and a series of cancer cell lines, and was associated with shorter overall survival. Interfering with circTCF25 reduced gastric cancer cell proliferation, migration, invasion and expression of cancer stem cell markers. CircTCF25 reduced expression of miR-149, apparently by acting as a miR-149 sponge. A new circTCF25-miR-149 competitive endogenous RNA network in gastric cancer was constructed, and most core genes were associated with the malignant growth and metastatic behavior of gastric cancer. CONCLUSION: circTCF25 may have prognostic value and an oncogenic role in gastric cancer. A circTCF25-miR-149 RNA regulatory network was established which may provide novel biomarkers or potential therapeutic targets for treating gastric cancer.

Bioinformatics Analysis and Experimental Validation of Mitochondrial Autophagy Genes in Knee Osteoarthritis.

Background: Mitochondrial autophagy is closely related to the pathogenesis of osteoarthritis, In order to explore the role of mitochondrial autophagy related genes in knee osteoarthritis (KOA) and its molecular mechanism. Methods: KOA-related transcriptome data were extracted from the Gene Expression Omnibus (GEO) database. Differentially expressed mitochondrial autophagy gene (DEMGs) were screened in patients with KOA by differential expression analysis. The STRING website was used to construct a protein-protein interaction (PPI) network among DEMGs. Molecular complex detection (MCODE) method in Cytoscape software was performed to identify hub DEMGs. Support vector machine recursive feature elimination (SVM-RFE) method was used to construct the hub DEMG diagnosis model. Genes with diagnostic value were identified as biomarkers by plotting receiver operating characteristic (ROC) curves and Expression validation. CIBERSORT algorithm was used to calculate the proportion of 22 immune cells in each sample in the GSE114007 dataset. Finally, biomarker expression was verified by qPCR. Results: A total of 15 DEMGs were obtained and enrichment analyses showed that these DEMG strains were mainly enriched in the mitophagy-animal, shigellosis, autophagy-animal and FoxO signal pathways. The PPI network unveiled 13 DEMGs with interactions. In addition, 8 hub DEMGs (ULK1, CALCOCO2, MAP1LC3B, BNIP3L, GABARAPL1, BNIP3, FKBP8 and FOXO3) were obtained for KOA. And 5 model DEMGs (BNIP3L, BNIP3, MAP1LC3B, ULK1 and FOXO3) were screened. The ROC curves revealed that BNIP3 and FOXO3 has strong diagnostic value in these models of DEMG. Immune-infiltration and correlation analysis showed that BNIP3 and FOXO3 were significantly correlated with three different immune cells, including primary B cells, M0 macrophage and M2 macrophage. The cartilage tissue samples qPCR verification results show that FOXO3 and BNIP3 were all down-regulated in KOA (p < 0.01), and the validation results are consistent with the above analysis. Conclusion: BNIP3 and FOXO3 have been identified as biomarkers for the diagnosis of KOA, which might supply a new insight for the pathogenesis and treatment of KOA.

The Fecal Redox Potential in Healthy and Diarrheal Pigs and Their Correlation with Microbiota.

The redox potential plays a critical role in sustaining the stability of gut microbiota. This study measured the fecal redox potential in healthy and diarrheal pigs using direct and dilution methods and investigated their correlation with microbiota. The results showed that the fluctuations in the redox potential of healthy pig feces were consistent using two different methods and the two methods are equivalent based on an equivalence test. The redox potential was positively correlated with the number of fungi and negatively related to the total bacteria. The relative or absolute abundances of many bacteria at the phyla and genus levels were associated with redox potential. In diarrheal pigs, the potentiometric trends of the two methods demonstrated an opposing pattern and the correlation with total bacteria was reversed. Precipitously elevated redox potential was detected post-diarrhea using dilution methods. The absolute abundance of Escherichia-Shigella and Fuurnierella was positively correlated with redox potential, while both relative and absolute abundances of Limosilactobacillus were positively correlated. These results suggest that both methods are suitable for detecting gut redox potential in healthy pigs, while the dilution method is more suitable for diarrheal pigs. The findings on the correlation of Limosilactobacillus, Prevotella, and Escherichia-Shigella with redox potential offer novel insights for targeted modulation of intestinal health.

Bioactive VS4-based sonosensitizer for robust chemodynamic, sonodynamic and osteogenic therapy of infected bone defects.

BACKGROUND: Most bone defects caused by bone disease or trauma are accompanied by infection, and there is a high risk of infection spread and defect expansion. Traditional clinical treatment plans often fail due to issues like antibiotic resistance and non-union of bones. Therefore, the treatment of infected bone defects requires a strategy that simultaneously achieves high antibacterial efficiency and promotes bone regeneration. RESULTS: In this study, an ultrasound responsive vanadium tetrasulfide-loaded MXene (VSM) Schottky junction is constructed for rapid methicillin-resistant staphylococcus aureus (MRSA) clearance and bone regeneration. Due to the peroxidase (POD)-like activity of VS4 and the abundant Schottky junctions, VSM has high electron-hole separation efficiency and a decreased band gap, exhibiting a strong chemodynamic and sonodynamic antibacterial efficiency of 94.03%. Under the stimulation of medical dose ultrasound, the steady release of vanadium element promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The in vivo application of VSM in infected tibial plateau bone defects of rats also has a great therapeutic effect, eliminating MRSA infection, then inhibiting inflammation and improving bone regeneration. CONCLUSION: The present work successfully develops an ultrasound responsive VS4-based versatile sonosensitizer for robust effective antibacterial and osteogenic therapy of infected bone defects.

A Janus-ROS Healing System Promoting Infectious Bone Regeneration via Sono-Epigenetic Modulation.

Elimination of bacterial infections and simultaneously promoting osteogenic differentiation are highly required for infectious bone diseases. Massive reactive oxygen species (ROS) can damage cells, while low ROS concentrations as a molecular signal can regulate cellular fate. In this study, a Janus-ROS healing system is developed for infectious bone regeneration. An alendronate (ALN)-mediated defective metal-organic framework (MOF) sonosensitizer is prepared, which can effectively clear Methicillin-resistant Staphylococcus aureus (MRSA) infections and promote osteogenic differentiation under differential ultrasonic irradiation. In the presence of zirconium-phosphate coordination, the ALN-mediated porphyrin-based MOF (HN25) with a proper defect has great sonodynamic antibacterial efficiency (98.97%, 15 min) and bone-targeting ability. Notably, under low-power ultrasound irradiation, HN25 can increase the chromatin accessibility of ossification-related genes and FOXO1 to promote bone repair through low ROS concentrations. Animal models of paravertebral infection, fracture with infection, and osteomyelitis demonstrate that HN25 successfully realizes the targeted and potent repair of various infectious bone tissues through rapid MRSA elimination, inhibiting osteoclast activity and promoting bone regeneration. The results show that high catalytic efficiency and bioactive MOF can be constructed using pharmaceutical-mediated defect engineering. The Janus-ROS treatment is also a promising therapeutic mode for infectious tissue regeneration.

SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.

Nucleus pulposus (NP) cell function-loss is one main contributor during intervertebral disc degeneration (IDD) progression. Both mitochondria and endoplasmic reticulum (ER) play vital roles in sustaining NP cell homeostasis, while the precise function of ER-mitochondria tethering and cross talk in IDD remain to be clarified. Here, we demonstrated that a notable disruption of mitochondria-associated ER membrane (MAM) was identified in degenerated discs and TBHP-induced NP cells, accompanied by mitochondrial Zn2+ overload and NP cell senescence. Importantly, experimental coupling of MAM contacts by MFN2, a critical regulator of MAM formation, could enhance NLRX1-SLC39A7 complex formation and mitochondrial Zn2+ homeostasis. Further using the sequencing data from TBHP-induced degenerative model of NP cells, combining the reported MAM proteomes, we demonstrated that SYNJ2BP loss was one critical pathological characteristic of NP cell senescence and IDD progression, which showed close relationship with MAM disruption. Overexpression of SYNJ2BP could facilitate MAM contact organization and NLRX1-SLC39A7 complex formation, thus promoted mitochondrial Zn2+ homeostasis, NP cell proliferation and intervertebral disc rejuvenation. Collectively, our present study revealed a critical role of SYNJ2BP in maintaining mitochondrial Zn2+ homeostasis in NP cells during IDD progression, partially via sustaining MAM contact and NLRX1-SLC39A7 complex formation.

Heterostructured piezocatalytic nanoparticles with enhanced ultrasound response for efficient repair of infectious bone defects.

Infection of bone defects remains a challenging issue in clinical practice, resulting in various complications. The current clinical treatments include antibiotic therapy and surgical debridement, which can cause drug-resistance and potential postoperative complications. Therefore, there is an urgent need for an efficient treatment to sterilize and promote bone repair in situ. In this work, an ultrasound responsive selenium modified barium titanate nanoparticle (Se@BTO NP) was fabricated, which exhibited significant antibacterial and bone regeneration effects. Selenium nanoparticle (Se NP) was modified on the surface of barium titanate nanoparticle (BTO NP) to form heterostructure, which facilitated the second distribution of piezo-induced carriers under ultrasound (US) irradiation and improved the separation of electron-hole pairs. The Se@BTO NPs exhibited remarkable antibacterial efficiency with an antibacterial rate of 99.23 % against Staphylococcus aureus (S.aureus) and significantly promoted the osteogenic differentiation under ultrasound irradiation. The in vivo experiments exhibited that Se@BTO NPs successfully repaired the femoral condylar bone defects of rats infected by S.aureus, resulting in significant promotion of bone regeneration. Overall, this work provided an innovative strategy for the utilization of US responsive nanomaterials in efficient bacteria elimination and bone regeneration. STATEMENT OF SIGNIFICANCE: Infectious bone defects remain a challenging issue in clinical practice. Current antibiotic therapy and surgical debridement has numerous limitations such as drug-resistance and potential complications. Herein, we designed an innovative ultrasound responsive selenium modified barium titanate nanoparticle (Se@BTO NP) to achieve efficient non-invasive bacteria elimination and bone regeneration. In this work, Se@BTO nanoparticles can enhance the separation of electrons and holes, facilitate the transfer of free carriers due to the cooperative effect of ultrasound induced piezoelectric field and heterojunction construction, and thus exhibit remarkable antibacterial and osteogenesis effect. Overall, our study provided a promising strategy for the utilization of piezocatalytic nanomaterials in efficient antibacterial and bone regeneration.

The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.

Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn2+ trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.Abbreviations: 3-MA: 3-methyladenine; Baf-A1: bafilomycin A1; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; DNM1L/DRP1: dynamin 1 like; EdU: 5-Ethynyl-2'-deoxyuridine; HE: hematoxylin-eosin; IDD: intervertebral disc degeneration; IL1B/IL-1ß: interleukin 1 beta; IL6: interleukin 6; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MKI67/Ki67: marker of proliferation Ki-67; LBP: low back pain; MMP: mitochondrial membrane potential; MFN1: mitofusin 1; MFN2: mitofusin 2; MFF: mitochondrial fission factor; NP: nucleus pulposus; NLRX1: NLR family member X1; OMA1: OMA1 zinc metallopeptidase; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxidative species; SASP: senescence-associated secretory phenotype; SA-GLB1/ß-gal: senescence-associated galactosidase beta 1; SO: safranin o; TBHP: tert-butyl hydroperoxide; TP53/p53: tumor protein p53; SLC39A7/ZIP7: solute carrier family 39 member 7; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23.

Sequential Correction versus Conventional Correction for Severe and Rigid Kyphoscoliosis: A Retrospective Case Control Study.

OBJECTIVE: Conventional correction techniques were challenging and of high risk of neurological complications for the correction of severe and rigid kyphoscoliosis. A new technical note we developed and named as sequential correction, was used to treat severe and rigid kyphoscoliosis. The present study was to compare the clinical outcomes of sequential correction versus conventional correction for the treatment of severe and rigid kyphoscoliosis. METHODS: This is a respectively case-control study. Between January 2014 and December 2019, 36 adults underwent the surgical correction of severe and rigid kyphoscoliosis and were included in the present study. Among them, 20 adults underwent conventional correction, 16 adults underwent sequential correction. Major curve Cobb angle, kyphotic angle, coronal imbalance, and sagittal vertical axis were compared between two groups. The patient-reported health-related quality of life outcomes, including the Oswestry disability index score, and SRS-22 questionnaire, were recorded. Independent samples t-test, Mann-Whitney U test, and Wilcoxon signed-rank test, were used to compare the differences between two groups according to the results of normal distribution test. RESULTS: In conventional correction group, the mean major curve Cobb angle was 122.50° preoperatively, 40.35° immediately after surgery, and 43.95° at final follow-up postoperatively; the mean kyphotic angle was 97.45° preoperatively, 34.45° immediately after surgery, and 38.30° at final follow-up postoperatively. In the sequential correction group, the mean major angle was 134.44° preoperatively, 44.56° immediately after surgery, and 46.25° at final follow-up postoperatively; the mean kyphotic angle was 112.31° preoperatively, 39.00° immediately after surgery, and 40.38° at final follow-up postoperatively. The mean major curve Cobb angle and kyphotic angle of both groups were improved significantly, while there were no significant differences between two groups (p > 0.001). Improved self-reported quality of life scores were achieved postoperatively and at final follow-up postoperatively, and there were no significant differences between the two groups. The total complication rate of the patients underwent conventional correction was 55%, and the total complication rate of the patients underwent sequential correction was 43.75%. The complication rate of the two groups showed no significant difference. CONCLUSIONS: Sequential correction is an excellent and safe treatment for severe and rigid kyphoscoliosis in adults, with similar clinical outcomes with conventional correction. The total complication rate of the patients who underwent sequential correction was slightly lower than conventional correction.

Sonodynamic amplification of cGAS-STING activation by cobalt-based nanoagonist against bone and metastatic tumor.

The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by 'cold' tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating stimulator of interferon genes (STING) confers promising antitumor immunity even in 'cold' tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor.

Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration.

Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking and transcriptional activity. Here, we demonstrate that TFEB activity is controlled by protein methylation in degenerated nucleus pulposus cells (NPCs), even though TFEB itself is incapable of undergoing methylation. Specifically, protein phosphatase 1 catalytic subunit alpha (PPP1CA), newly identified to dephosphorylate TFEB, contains a K141 mono-methylated site. In degenerated NPCs, increased K141-methylation of PPP1CA disrupts its interaction with TEFB and subsequently blocks TEFB dephosphorylation and nuclear translocation, which eventually leads to autophagy deficiency and NPC senescence. In addition, we found that the PPP1CA-mediated targeting of TFEB is facilitated by the protein phosphatase 1 regulatory subunit 9B (PPP1R9B), which binds with PPP1CA and is also manipulated by K141 methylation. Further proteomic analysis revealed that the protein lysine methyltransferase suppressor of variegation 3-9 homologue 2 (SUV39H2) is responsible for the K141 mono-methylation of PPP1CA. Targeting SUV39H2 effectively mitigates NPC senescence and IDD progression, providing a potential therapeutic strategy for IDD intervention.

Sequential correction of severe and rigid kyphoscoliosis: a new technical note and preliminary results.

OBJECTIVE: The present study is to evaluate the clinical outcomes of the sequential correction of severe and rigid kyphoscoliosis. METHODS: Between January 2014 and December 2020, 27 adults with severe and rigid kyphoscoliosis underwent sequential correction combined with posterior grade 4 or grade 5 spinal osteotomy. Radiological parameters, including the major curve Cobb angle, kyphotic angle, coronal imbalance, and sagittal vertical axis (SVA), were compared. Patient self-reported health-related quality of life (HRQOL) scores were used to evaluate clinical outcomes. RESULTS: The mean major curve Cobb angle improved from 134.30 ± 13.24° to 44.48 ± 9.34° immediately after surgery and to 46.11 ± 8.94° at the final follow-up. The mean kyphotic angle improved from 112.15 ± 20.28° to 38.63 ± 15.00° immediately after surgery and to 39.85 ± 14.92° at the final follow-up. The mean preoperative major curve Cobb angle of grade 5 spinal osteotomy group was higher than that of grade 4 spinal osteotomy group. Coronal imbalance and SVA slightly improved. The patient self-reported HRQOL scores improved postoperatively and at the final follow-up. Activity, appearance and total scores of the SRS-22 of the grade 5 spinal osteotomy group at the final follow-up were significantly better than those of the grade 4 spinal osteotomy group. CONCLUSIONS: Sequential correction combined with posterior grade 4 or grade 5 spinal osteotomies is an excellent and safe treatment for severe and rigid kyphoscoliosis in adults. Sequential correction combined with posterior grade 5 spinal osteotomies can be used to correct severe and rigid kyphoscoliosis with higher major curve Cobb angle.

Copper Ion-Modified Germanium Phosphorus Nanosheets Integrated with an Electroactive and Biodegradable Hydrogel for Neuro-Vascularized Bone Regeneration.

Severe bone defects accompanied by vascular and peripheral nerve injuries represent a huge orthopedic challenge and are often accompanied by the risk of infection. Thus, biomaterials with antibacterial and neurovascular regeneration properties are highly desirable. Here, a newly designed biohybrid biodegradable hydrogel (GelMA) containing copper ion-modified germanium-phosphorus (GeP) nanosheets, which act as neuro-vascular regeneration and antibacterial agents, is designed. The copper ion modification process serves to improve the stability of the GeP nanosheets and offers a platform for the sustained release of bioactive ions. Study findings show that GelMA/GeP@Cu has effective antibacterial properties. The integrated hydrogel can significantly boost the osteogenic differentiation of bone marrow mesenchymal stem cells, facilitate angiogenesis in human umbilical vein endothelial cells, and up-regulate neural differentiation-related proteins in neural stem cells in vitro. In vivo, in the rat calvarial bone defect mode, the GelMA/GeP@Cu hydrogel is found to enhance angiogenesis and neurogenesis, eventually contributing to bone regeneration. These findings indicate that in the field of bone tissue engineering, GelMA/GeP@Cu can serve as a valuable biomaterial for neuro-vascularized bone regeneration and infection prevention.

Stiff Substrate Induces Nucleus Pulposus Cell Ferroptosis via YAP and N-Cadherin Mediated Mechanotransduction.

Increased tissue stiffness is associated with various pathological processes, such as fibrosis, inflammation, and aging. The matrix stiffness of the nucleus pulposus (NP) tissues increases gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In this study, the results indicate that ferroptosis is involved in stiff substrate-induced NP cell death. The expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) increases in NP cells of the stiff group, which mediates lipid peroxidation and ferroptosis in NP cells. In addition, stiff substrate activates the hippo signaling cascade and induces the nuclear translocation of yes-associated protein (YAP). Interestingly, inhibition of YAP is efficient to reverse the increase of ACSL4 expression caused by matrix stiffness. Furthermore, stiff substrate suppresses the expression of N-cadherin in NP cells. N-cadherin overexpression can inhibit YAP nuclear translocation via the formation of the N-cadherin/ß-catenin/YAP complex, and reverse matrix stiffness-induced ferroptosis in NP cells. Finally, the effects of YAP inhibition and N-cadherin overexpression on IDD progression are further illustrated in animal models. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for the treatment of IDD.

Biomechanical comparison of intramedullary nail and plate osteosynthesis for extra-articular proximal tibial fractures with segmental bone defect.

Purpose: Proximal tibial fractures are common, but the current available internal fixation strategies remain debatable, especially for comminuted fractures. This study aimed to compare the biomechanical stability of three internal fixation strategies for extra-articular comminuted proximal tibial fractures. Methods: A total of 90 synthetic tibiae models of simulated proximal tibial fractures with segmental bone defects were randomly divided into three groups: Single lateral plating (LP), double plating (DP) and intramedullary nailing (IN). Based on the different number of fixed screws, the above three groups were further divided into nine subgroups and subjected to axial compression, cyclic loading and static torsional testing. Results: The subgroup of intramedullary nailing with five proximal interlocking screws showed the highest axial stiffness of 384.36 ± 35.00 N/mm. The LP group obtained the lowest axial stiffness performance with a value of 96.59 ± 16.14 N/mm. As expected, the DP group offered significantly greater biomechanical stability than the LP group, with mean static axial stiffness and mean torque increasing by approximately 200% and 50%, respectively. According to static torsional experiments, the maximum torque of the DP subgroup was 3,308.32 ± 286.21 N mm, which outperformed all other groups in terms of torsional characteristics. Conclusion: Utilizing more than four distal screws did not provide improved biomechanical stability in the LP or DP groups, while a substantial increase in the biomechanical stability of DP was obtained when an additional medial plate was used. For the intramedullary nailing group, increasing the number of proximal interlocking screws could significantly improve biomechanical stability, and the intramedullary nailing with three proximal interlocking screws had similar static and cyclic stiffness as the DP group. The intramedullary nailing with five proximal screws had better axial stability, whereas DP had better torsional stability.

Augmenting Intracellular Cargo Delivery of Extracellular Vesicles in Hypoxic Tissues through Inhibiting Hypoxia-Induced Endocytic Recycling.

As mesenchymal stem-cell-derived small extracellular vesicles (MSC-sEVs) have been widely applied in treatment of degenerative diseases, it is essential to improve their cargo delivery efficiency in specific microenvironments of lesions. However, the interaction between the microenvironment of recipient cells and MSC-sEVs remains poorly understood. Herein, we find that the cargo delivery efficiency of MSC-sEVs was significantly reduced under hypoxia in inflammaging nucleus pulposus cells due to activated endocytic recycling of MSC-sEVs. Hypoxia-inducible factor-1 (HIF-1)-induced upregulated RCP (also known as RAB11FIP1) is shown to promote the Rab11a-dependent recycling of internalized MSC-sEVs under hypoxia via enhancing the interaction between Rab11a and MSC-sEV. Based on this finding, si-RCP is loaded into MSC-sEVs using electroporation to overcome the hypoxic microenvironment of intervertebral disks. The engineered MSC-sEVs significantly inhibit the endocytic recycling process and exhibit higher delivery efficiency under hypoxia. In a rat model of intervertebral disk degeneration (IDD), the si-RCP-loaded MSC-sEVs successfully treat IDD with improved regenerative capacity compared with natural MSC-sEV. Collectively, the findings illustrate the intracellular traffic mechanism of MSC-sEVs under hypoxia and demonstrate that the therapeutic capacity of MSC-sEVs can be improved via inhibiting endocytic recycling. This modifying strategy may further facilitate the application of extracellular vesicles in hypoxic tissues.