Insulin-Like Growth Factor 1 Activates PI3k/Akt Signaling to Antagonize Lumbar Disc Degeneration.

BACKGROUND/AIMS: The pathogenesis of Lumbar disc degeneration (LDD) has been extensively studied in the past. In particular, a role of matrix metalloproteinase 3 (MMP3) in the disease initiation and progression has been recently reported. However, an involvement of Insulin-like growth factor 1 (IGF-I)-stimulated phosphatidylinositol-3 kinase (PI3k) / Akt signaling pathway-mediated control of MMP3 in LDD has not been acknowledged. METHODS: We examined the serum IGF-1 levels and activation of the receptor for IGF-1 (IGF-1R) in resected discs in patients with LDD, compared to the fractured discs from traumatized, non-LDD subjects as a control. We analyzed the effects of IGF-1 on the activation of IGF-1R, Akt and MMP3 in a human nucleus pulposus SV40 cell line (HNPSV). We transfected HNPSV cells with a constitutive nuclear FoxO1, and analyzed its effect on the activation of IGF-1R, Akt and MMP3. RESULTS: LDD patients had significantly lower levels of serum IGF-1, and LDD discs had significantly lower levels of activated IGF-1R. IGF-1 induced phosphorylation of IGF-1R, and then phosphorylation of its downstream factor Akt in the HNPSV cells, resulting in significantly inhibition of MMP3. Further, FoxO1 nuclear retention completely abolished the inhibitory effects of IGF-1 on MMP3 in HNPSV cells. CONCLUSION: Together, IGF-1/Akt/FoxO1/MMP3 regulatory machinery may control the development of LDD.

Reactive Oxygen Species Induced Upregulation of TRPV1 in Dorsal Root Ganglia Results in Low Back Pain in Rats.

Background: Dorsal root ganglia (DRGs) contain sensory neurons that innervate intervertebral discs (IVDs) and may play a critical role in mediating low-back pain (LBP), but the potential pathophysiological mechanism needs to be clarified. Methods: A discogenic LBP model in rats was established by penetration of a lumbar IVD. The severity of LBP was evaluated through behavioral analysis, and the gene and protein expression levels of pro-algesic peptide substance P (SP) and calcitonin gene-related peptide (CGRP) in DRGs were quantified. The level of reactive oxygen species (ROS) in bilateral lumbar DRGs was also quantified using dihydroethidium staining. Subsequently, hydrogen peroxide solution or N-acetyl-L-cysteine was injected into DRGs to evaluate the change in LBP, and gene and protein expression levels of transient receptor potential vanilloid-1 (TRPV1) in DRGs were analyzed. Finally, an inhibitor or activator of TRPV1 was injected into DRGs to observe the change in LBP. Results: The rats had remarkable LBP after disc puncture, manifesting as mechanical and cold allodynia and increased expression of the pro-algesic peptides SP and CGRP in DRGs. Furthermore, there was significant overexpression of ROS in bilateral lumbar DRGs, while manipulation of the level of ROS in DRGs attenuated or aggravated LBP in rats. In addition, excessive ROS in DRGs stimulated upregulation of TRPV1 in DRGs. Finally, activation or inhibition of TRPV1 in DRGs resulted in a significant increase or decrease of discogenic LBP, respectively, suggesting that ROS-induced TRPV1 has a strong correlation with discogenic LBP. Conclusion: Increased ROS in DRGs play a primary pathological role in puncture-induced discogenic LBP, and excessive ROS-induced upregulation of TRPV1 in DRGs may be the underlying pathophysiological mechanism to cause nerve sensitization and discogenic LBP. Therapeutic targeting of ROS or TRPV1 in DRGs may provide a promising method for the treatment of discogenic LBP.

Synergistic dual-phase air electrode enables high and durable performance of reversible proton ceramic electrochemical cells.

Reversible proton ceramic electrochemical cells are promising solid-state ion devices for efficient power generation and energy storage, but necessitate effective air electrodes to accelerate the commercial application. Here, we construct a triple-conducting hybrid electrode through a stoichiometry tuning strategy, composed of a cubic phase Ba0.5Sr0.5Co0.8Fe0.2O3-δ and a hexagonal phase Ba4Sr4(Co0.8Fe0.2)4O16-δ. Unlike the common method of creating self-assembled hybrids by breaking through material tolerance limits, the strategy of adjusting the stoichiometric ratio of the A-site/B-site not only achieves strong interactions between hybrid phases, but also can efficiently modifies the phase contents. When operate as an air electrode for reversible proton ceramic electrochemical cell, the hybrid electrode with unique dual-phase synergy shows excellent electrochemical performance with a current density of 3.73 A cm-2 @ 1.3 V in electrolysis mode and a peak power density of 1.99 W cm-2 in fuel cell mode at 650 °C.

Rapid Gas-Phase Synthesis of the Perovskite-Type BaCe0.7Zr0.1Y0.1Yb0.1O3-δ Proton-Conducting Nanocrystalline Electrolyte for Intermediate-Temperature Solid Oxide Fuel Cells.

Perovskite-type proton-conducting materials, such as BaCe0.7Zr0.1Y0.1Yb0.1O3-δ (BCZYYb), are very attractive for the next-generation equipment of electrochemical energy conversion and storage owing to their excellent conductivity in the intermediate-temperature range (300-750 °C), as well as good thermo-chemical stability, coking resistance, and sulfur tolerance. However, the lack of a reliable and cost-effective synthesis method for such multi-component co-doping oxides limits their large-scale application. In this study, for the first time, we successfully synthesize BCZYYb electrolyte nanopowders by using a rapid, scalable flame-based gas-phase synthesis method with two different barium precursors Ba(NO3)2 and Ba(CH3COO)2, named as BCZYYb (N) and BCZYYb (CA). The as-synthesized nanoparticles exhibit good crystallinity of the pure orthorhombic perovskite BCZYYb phase. BCZYYb (CA) shows more uniform doping with the element ratio of 1:0.74:0.12:0.08:0.1, which is very close to the theoretical value. The shrinkage and surface SEM (scanning electron microscope) results indicate that the flame-made powders have superior sinterability compared to the sol-gel-made powders because of the smaller primary particle size (∼20 nm). Electrochemical impedance spectroscopy tests show that BCZYYb (CA) sintered at 1450 °C has the highest protonic conductivity of 1.31 × 10-2 S cm-1 in wet H2 when operating at 600 °C and still maintains a high-level conductivity of 1.19 × 10-2 S cm-1 even when the sintering temperature is reduced to 1350 °C, which is mainly attributed to uniform doping and good sinterability. The activation energy for the conductivity of BCZYYb (CA) is also significantly lower than that of conventional electrolytes, which suggests much better conductivity in the intermediate (∼600 °C) and even lower operating temperature. The excellent conductivity performance combined with the high-throughput production capability makes the swirling spray flame a promising synthesis method for promoting the BCZYYb electrolytes from lab to industrial-scale solid oxide fuel cells.

High-Entropy Perovskite Oxide: A New Opportunity for Developing Highly Active and Durable Air Electrode for Reversible Protonic Ceramic Electrochemical Cells.

Reversible proton ceramic electrochemical cell (R-PCEC) is regarded as the most promising energy conversion device, which can realize efficient mutual conversion of electrical and chemical energy and to solve the problem of large-scale energy storage. However, the development of robust electrodes with high catalytic activity is the main bottleneck for the commercialization of R-PCECs. Here, a novel type of high-entropy perovskite oxide consisting of six equimolar metals in the A-site, Pr1/6La1/6Nd1/6Ba1/6Sr1/6Ca1/6CoO3-δ (PLNBSCC), is reported as a high-performance bifunctional air electrode for R-PCEC. By harnessing the unique functionalities of multiple elements, high-entropy perovskite oxide can be anticipated to accelerate reaction rates in both fuel cell and electrolysis modes. Especially, an R-PCEC utilizing the PLNBSCC air electrode achieves exceptional electrochemical performances, demonstrating a peak power density of 1.21 W cm-2 for the fuel cell, while simultaneously obtaining an astonishing current density of - 1.95 A cm-2 at an electrolysis voltage of 1.3 V and a temperature of 600 °C. The significantly enhanced electrochemical performance and durability of the PLNBSCC air electrode is attributed mainly to the high electrons/ions conductivity, fast hydration reactivity and high configurational entropy. This research explores to a new avenue to develop optimally active and stable air electrodes for R-PCECs.

Prevention of lumbar disc degeneration through co-manipulation of insulin-like growth factor 1 and vascular endothelial growth factor.

BACKGROUND: Associated with abnormal angiogenesis and disc dysfunction, lumbar disc degeneration (LDD) appears to be an important disease suffered by elderly people. Previous studies have highlighted the importance of insufficient insulin-like growth factor 1 (IGF1) and excessive vascular endothelial growth factor (VEGF) in the development and progression of LDD, though a practical therapeutic strategy is lacking. METHODS: The expression of IGF1 and VEGF was assessed in LDD specimens compared to normal disc tissue as a control. A gene therapy approach was performed, in which an adeno-associated virus (AAV) carrying both IGF1 and shVEGF (AAV-IGF1/shVEGF) was orthotopically injected to the rats that had undergone LDD. The alterations in IGF1 and VEGF levels in the treated disc tissue were confirmed by immunohistochemistry. The outcome of this therapy was assessed by disc cell death using an annexin V-FITC assay and by assessing lumbar proteoglycan and collagen II levels using ELISA. RESULTS: IGF1 expression was significantly downregulated in LDD, while VEGF expression was significantly upregulated in LDD, compared to normal controls. Combined AAV-IGF1/shVEGF treatment simultaneously corrected the insufficient IGF1 and the excessive VEGF in LDD rats. Moreover, AAV-IGF1/shVEGF significantly reduced disc cell death in the vertebral pulp and annulus fibrosus and significantly enhanced the lumbar proteoglycan and collagen II levels. CONCLUSIONS: The simultaneous increase in IGF1 and depletion of VEGF effectively prevented the development of LDD, suggesting its potential as a novel therapeutic approach for LDD which is clinically translatable.

Minimally invasive treatment of unstable pelvic ring injuries with modified pedicle screw-rod fixator.

Objective To evaluate the clinical application of the minimally invasive modified pedicle screw-rod fixator for unstable pelvic ring injuries, including its feasibility, merits, and limitations. Methods Twenty-three patients (13 males, 10 females; average age, 36.3 years) with unstable pelvic ring injuries underwent anterior fixation using a modified pedicle screw-rod fixator with or without posterior fixation using a transiliac internal fixator. The clinical findings were assessed using Majeed scores. The quality of reduction was evaluated using the Matta criteria. Results Clinical results at 1 year postoperatively were excellent in 14 patients, good in 7, and fair in 2. The two patients with fair results had intermittent pain at the sacroiliac joint because of the posterior implant. One woman complained of persistent pain at the pubic tubercle during sexual intercourse. Iatrogenic neuropraxia of the unilateral lateral femoral cutaneous nerve occurred in three patients. Unilateral femoral nerve palsy occurred in one patient. The quality of fracture reduction was excellent in 12 patients, good in 8, and fair in 3. Heterotopic ossification occurred in eight patients; all were asymptomatic. Conclusions Minimally invasive modified pedicle screw-rod fixation is an effective alternative treatment for pelvic ring injuries.

Modified pedicle screw-rod fixation as a minimally invasive treatment for anterior pelvic ring injuries: an initial case series.

BACKGROUND: Unstable pelvic ring injuries often involve high mortality and morbidity. This study was aimed to evaluate the modified minimally invasive pedicle screw-rod fixation for anterior pelvic ring injuries, in the respects of its feasibility, merits, and limitations. METHODS: Twenty-three patients with unstable pelvic ring injuries underwent the modified anterior pedicle screw-rod fixation, with or without posterior fixation. The clinical outcomes were assessed using Majeed scores, and the quality of reduction was evaluated according to the criteria of Matta. RESULTS: Majeed scores showed that the clinical outcomes at postoperatively 1 year were excellent in 14 patients, good in 7, and fair in 2. One woman complained of persistent pain at the pubic tubercle during sexual intercourse. Iatrogenic neuropraxia of the unilateral lateral femoral cutaneous nerve occurred in 3 patients. Unilateral femoral nerve palsy occurred in 1 patient. The reduction was found to be excellent in 12 patients, good in 8, and fair in 3. Heterotopic ossification occurred in 8 patients, all being asymptomatic. CONCLUSIONS: The modified pedicle screw-rod fixation with the minimally invasive technique offered an effective alternative for unstable anterior pelvic ring injuries.

[Therapeutic observation of subcutaneous pedicle screw-rod system with modified placement for Tile B pelvic fractures].

OBJECTIVE: To investigate the feasibility and therapeutic effect of subcutaneous pedicle screw-rod system with modified placement in treatment of Tile B pelvic fractures. METHODS: From June 2014 to August 2015, 14 patients with Tile B pelvic fractures were treated by subcutaneous pedicle screw-rod system with modified placement in the anterior inferior iliac spine and pubic tubercle. There were 8 males and 6 females, aged from 23 to 65 years with an average of 42 years. Operative time, intraoperative blood loss, fracture healing and postoperative complication were observed and clinical effects were evaluated by Matta reduction standard and Majeed score. RESULTS: All patients were followed up from 8 to 15 months with an average of 10.5 months. Operative time was 25 to 45 min with an average of 32 min;intraoperative blood loss was 10 to 35 ml with an average of 18 ml. All fractures got primary healing and healed time was 9 to 14 weeks with an average of 12.5 weeks. No postoperative incision infection, internal fixation failure and ectopic ossification were found, 4 cases occurred unilateral lateral femoral cutaneous nerve injury and 1 case occurred unilateral femoral nerve paralysis, but all restored finally. According to Matta criteria, reduction was excellent in 7 cases, good in 5 cases, fair in 2 case. According to Majeed score system, the functional evaluation at last follow-up was excellent in 5 cases, good in 7 cases, fair in 2 cases with the average score of 81.50±8.05. CONCLUSIONS: Subcutaneous pedicle screw-rod system with modified placement in the anterior inferior iliac spine and pubic tubercle have advantages of strong reduction, less trauma and complications, and is a promising surgical method in the treatment of Tile B pelvic fractures.

Insulin-like growth factor 1 antagonizes lumbar disc degeneration through enhanced autophagy.

Autophagy has been shown to antagonize the development of Lumbar disc degeneration (LDD), whereas the molecular regulation of autophagy is unknown. We recently reported a potential role of Insulin-like growth factor 1 receptor (IGF1R)/phosphatidylinositol-3 kinase (PI3k)/Akt signaling in the initiation and progression of LDD. Here, we studied the effects of IGF1R signaling on disc cell autophagy. We showed a correction of activation of IGF1R and disc cell autophagy in the resected discs in LDD patients. In vitro, activation of IGF1R signaling antagonized the decreases in cell viability of human disc cells, HNPSV, through suppression of apoptosis and enhancement of autophagy. Suppression of IGF1R signaling or inhibition of autophagy abolished the effects of activation of IGF1R signaling on disc cell survival upon compression. Together, our data suggest that activation of IGF1R may antagonize LDD, at least partially through enhanced autophagy.

Regulation of insulin-like growth factor 1 receptor signaling by microRNA-4458 in the development of lumbar disc degeneration.

A potential role of Insulin-like growth factor 1 (IGF1) receptor/phosphatidylinositol-3 kinase (PI3k)/Akt signaling in the initiation and progression of Lumbar disc degeneration (LDD) has been recently reported. However, the regulation of IGF1 receptor (IGF1R) at post-transcriptional levels in the development of LDD remains unknown. Here, we studied the effects of microRNA-4458 on the expression of IGF1R. We examined the IGF1R levels and microRNA-4458 (miR-4458) levels in the resected LDD discs, compared with the traumatized, non-LDD discs. We analyzed the binding of miR-4458 to the 3'-UTR of IGF1R mRNA and its effects on IGF1R translation by bioinformatics analysis and by luciferase-reporter assay, respectively. We modified miR-4458 levels in a human nucleus pulposus SV40 cell line (HNPSV), and examined the effects of miR-4458 on the expression of IGF1R and Akt, as well as their phosphorylation. We found that the levels of miR-4458 were significantly higher and the levels of IGF1R were significantly lower in LDD discs, compared with the control non-LDD discs. The levels of IGF1R inversely correlated with the levels of miR-4458 in LDD discs. Moreover, miR-4458 was found to bind to the 3'-UTR of IGF1R mRNA to prevent its translation. In miR-4458-modified HNPSV cells, we found that miR-4458 decreased both total IGF1R and phosphorylated IGF1R, resulting in deceases in phosphorylated Akt. Thus, these data suggest that miR-4458 may suppress PI3k/Akt signaling pathway through 3'-UTR-inhibtion of IGF1R mRNA to promote development of LDD.