Evaluating the pro-survival potential of apoptotic bodies derived from 2D- and 3D- cultured adipose stem cells in ischaemic flaps.

In the realm of large-area trauma flap transplantation, averting ischaemic necrosis emerges as a pivotal concern. Several key mechanisms, including the promotion of angiogenesis, the inhibition of oxidative stress, the suppression of cell death, and the mitigation of inflammation, are crucial for enhancing skin flap survival. Apoptotic bodies (ABs), arising from cell apoptosis, have recently emerged as significant contributors to these functions. This study engineered three-dimensional (3D)-ABs using tissue-like mouse adipose-derived stem cells (mADSCs) cultured in a 3D environment to compare their superior biological effects against 2D-ABs in bolstering skin flap survival. The findings reveal that 3D-ABs (85.74 ± 4.51) % outperform 2D-ABs (76.48 ± 5.04) % in enhancing the survival rate of ischaemic skin flaps (60.45 ± 8.95) % (all p < 0.05). Mechanistically, they stimulated angiogenesis, mitigated oxidative stress, suppressed apoptosis, and facilitated the transition of macrophages from M1 to M2 polarization (all p < 0.05). A comparative analysis of microRNA (miRNA) profiles in 3D- and 2D-ABs identified several specific miRNAs (miR-423-5p-up, miR30b-5p-down, etc.) with pertinent roles. In summary, ABs derived from mADSCs cultured in a 3D spheroid-like arrangement exhibit heightened biological activity compared to those from 2D-cultured mADSCs and are more effective in promoting ischaemic skin flap survival. These effects are attributed to their influence on specific miRNAs.

Comparison of the clinical and radiographic outcomes of cortical bone trajectory and traditional trajectory pedicle screw fixation in transforaminal lumbar interbody fusion: a randomized controlled trial.

PURPOSE: To compare the clinical outcomes and radiographic outcomes of cortical bone trajectory (CBT) and traditional trajectory (TT) pedicle screw fixation in patients treated with single-level transforaminal lumbar interbody fusion (TLIF). METHODS: This trial included a total of 224 patients with lumbar spine disease who required single-level TLIF surgery. Patients were randomly assigned to the CBT and TT groups at a 1:1 ratio. Demographics and clinical and radiographic data were collected to evaluate the efficacy and safety of CBT and TT screw fixation in TLIF. RESULTS: The baseline characteristic data were similar between the CBT and TT groups. Back and leg pain for both the CBT and TT groups improved significantly from baseline to 24 months postoperatively. The CBT group experienced less pain than the TT group at one week postoperatively. The postoperative radiographic results showed that the accuracy of screw placement was significantly increased in the CBT group compared with the TT group (P < 0.05). The CBT group had a significantly lower rate of FJV than the TT group (P < 0.05). In addition, the rate of fusion and the rate of screw loosening were similar between the CBT and TT groups according to screw loosening criteria. CONCLUSION: This prospective, randomized controlled analysis suggests that clinical outcomes and radiographic characteristics, including fusion rates and caudal screw loosening rates, were comparable between CBT and TT screw fixation. Compared with the TT group, the CBT group showed advantages in the accuracy of screw placement and the FJV rate. CLINICAL TRIALS REGISTRATION: This trial has been registered at the US National Institutes of Health Clinical Trials Registry: NCT03105167.

Elamipretide alleviates pyroptosis in traumatically injured spinal cord by inhibiting cPLA2-induced lysosomal membrane permeabilization.

Spinal cord injury (SCI) is a devastating injury that may result in permanent motor impairment. The active ingredients of medications are unable to reach the affected area due to the blood‒brain barrier. Elamipretide (SS-31) is a new and innovative aromatic cationic peptide. Because of its alternating aromatic and cationic groups, it freely crosses the blood‒brain barrier. It is also believed to decrease inflammation and protect against a variety of neurological illnesses. This study explored the therapeutic value of SS-31 in functional recovery after SCI and its possible underlying mechanism. A spinal cord contusion injury model as well as the Basso Mouse Scale, footprint assessment, and inclined plane test were employed to assess how well individuals could function following SCI. The area of glial scarring, the number of dendrites, and the number of synapses after SCI were confirmed by HE, Masson, MAP2, and Syn staining. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were employed to examine the expression levels of pyroptosis-, autophagy-, lysosomal membrane permeabilization (LMP)- and MAPK signalling-related proteins. The outcomes showed that SS-31 inhibited pyroptosis, enhanced autophagy and attenuated LMP in SCI. Mechanistically, we applied AAV vectors to upregulate Pla2g4A in vivo and found that SS-31 enhanced autophagy and attenuated pyroptosis and LMP by inhibiting phosphorylation of cPLA2. Ultimately, we applied asiatic acid (a p38-MAPK agonist) to test whether SS-31 regulated cPLA2 partially through the MAPK-P38 signalling pathway. Our group is the first to suggest that SS-31 promotes functional recovery partially by inhibiting cPLA2-mediated autophagy impairment and preventing LMP and pyroptosis after SCI, which may have potential clinical application value.

Piperine attenuates the inflammation, oxidative stress, and pyroptosis to facilitate recovery from spinal cord injury via autophagy enhancement.

Spinal cord injury (SCI) is a serious injury that can lead to irreversible motor dysfunction. Due to its complicated pathogenic mechanism, there are no effective drug treatments. Piperine, a natural active alkaloid extracted from black pepper, has been reported to influence neurogenesis and exert a neuroprotective effect in traumatic brain injury. The aim of this study was to investigate the therapeutic effect of piperine in an SCI model. SCI was induced in mice by clamping the spinal cord with a vascular clip for 1 min. Before SCI and every 2 days post-SCI, evaluations using the Basso mouse scale and inclined plane tests were performed. On day 28 after SCI, footprint analyses, and HE/Masson staining of tissues were performed. On a postoperative Day 3, the spinal cord was harvested to assess the levels of pyroptosis, reactive oxygen species (ROS), inflammation, and autophagy. Piperine enhanced functional recovery after SCI. Additionally, piperine reduced inflammation, oxidative stress, pyroptosis, and activated autophagy. However, the effects of piperine on functional recovery after SCI were reversed by autophagy inhibition. The study demonstrated that piperine facilitated functional recovery after SCI by inhibiting inflammatory, oxidative stress, and pyroptosis, mediated by the activation of autophagy.

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis.

Stimulator of interferons genes (STING), which is crucial for the secretion of type I interferons and proinflammatory cytokines in response to cytosolic nucleic acids, plays a key role in the innate immune system. Studies have revealed the participation of the STING pathway in unregulated inflammatory processes, traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid haemorrhage (SAH) and hypoxic-ischaemic encephalopathy (HIE). STING signalling is markedly increased in CNS injury, and STING agonists might facilitate the pathogenesis of CNS injury. However, the effects of STING-regulated signalling activation in CNS injury are not well understood. Aberrant activation of STING increases inflammatory events, type I interferon responses, and cell death. cGAS is the primary pathway that induces STING activation. Herein, we provide a comprehensive review of the latest findings related to STING signalling and the cGAS-STING pathway and highlight the control mechanisms and their functions in CNS injury. Furthermore, we summarize and explore the most recent advances toward obtaining an understanding of the involvement of STING signalling in programmed cell death (autophagy, necroptosis, ferroptosis and pyroptosis) during CNS injury. We also review potential therapeutic agents that are capable of regulating the cGAS-STING signalling pathway, which facilitates our understanding of cGAS-STING signalling functions in CNS injury and the potential value of this signalling pathway as a treatment target.

Bone-targeting delivery of platelet lysate exosomes ameliorates glucocorticoid-induced osteoporosis by enhancing bone-vessel coupling.

BACKGROUND: Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs. RESULTS: In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs' stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo. CONCLUSIONS: PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP.

Maslinic acid prevents IL-1ß-induced inflammatory response in osteoarthritis via PI3K/AKT/NF-κB pathways.

Osteoarthritis (OA) is a degenerative joint disease characterized by destruction of articular cartilage. The inflammatory response is the most important factor affecting the disease process. As interleukin-1ß (IL-1ß) stimulates several key mediators in the inflammatory response, it plays a major role in the pathogenesis of OA. Maslinic acid (MA) is a natural compound distributed in olive fruit. Previous studies have found that maslinic acid has an inhibitory effect on inflammation, but its specific role in the progression of OA disease has not been studied so far. In this study, we aim to assess the protective effect of MA on OA progression by in vitro and in vivo experiments. Our results indicate that, in IL-1ß-induced inflammatory response, MA is effective in attenuating some major inflammatory mediators such as nitric oxide (NO) and prostaglandin E2, and inhibits the expression of IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner. Also, MA downregulated the expression levels of thrombospondin motif 5 (ADAMTS5) and matrix metalloproteinase 13 in chondrocytes, resulting in reduced degradation of its extracellular matrix. Mechanistically, MA exhibits an anti-inflammatory effect by inactivating the PI3K/AKT/NF-κB pathway. In vivo, the protective effect of MA on OA development can be detected in a surgically induced mouse OA model. In summary, these findings suggest that MA can be used as a safe and effective potential OA therapeutic strategy.

Risk of pedicle and spinous process violation during cortical bone trajectory screw placement in the lumbar spine.

BACKGROUND: Previous studies have confirmed the feasibility of the cortical bone trajectory (CBT) technique. However, there are few reports on spinous process violation and screw penetration during the screw insertion. The purpose of this study was to evaluate the incidence of spinous process violation and screw penetration through the pedicle during CBT screw insertion. METHODS: Computed tomography (CT) scans with normal lumbar structures were consecutively obtained and three-dimensional (3D) reconstructions of the lumbar spine were created. Bilateral CBT screw placement was simulated on each segment using a screw diameter of 4.5 mm, 5.0 mm, or 5.5 mm. Incidences of these complications were recorded and analyzed. RESULTS: A total of 90 patients were enrolled. Spinous process violation was observed in 68.3, 53.3, 25.5, 1.7, and 0% from L1 to L5, respectively, using 4.5 mm screws. A significant difference was found among the five segments but this was unconnected to gender or screw diameter. The incidence of screw penetration through the inner wall decreased from L1 to L4; in turn, L1 (16.7-35.5%), L2 (12.7-34.4%), L3 (2.8-23.8%) and L4 (1.1-6.7%). This trend was reversed in L5 (6.7-16.7%). Moreover, screw penetration through the outer wall was rare. The incidence of screw penetration varied with screw size as well as lumbar level, but not with gender. CONCLUSIONS: There are more difficulties of CBT screw fixation in upper lumbar spine. The low rate of screw penetration, using 4.5 mm screws, suggests the safety for CBT fixation in the lumbar spine. Larger screws (5.0 mm or 5.5 mm) are more recommended for use in the lower lumbar spine. Moreover, CBT fixation in L5 deserves greater attention because of the unique morphology of the pedicle.

The protective effect of sinapic acid in osteoarthritis: In vitro and in vivo studies.

The anti-inflammatory effect of sinapic acid (SA) has been reported in several studies. However, whether SA has the same effect on osteoarthritis (OA) has yet to be clearly elucidated. We designed a series of in vitro and in vivo procedures to verify the above conjecture. Compared with controls, SA-pretreated human chondrocytes showed lower levels of interleukin (IL)-1ß-induced IL-6, prostaglandin E2 (PGE2), nitric oxide (NO) and tumour necrosis factor-α (TNF-α) in vitro. Meanwhile, SA could also reverse the degradation of type II collage and aggrecan, as well as the overproduction of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-13 (MMP-13), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and a disintegrin and metalloproteinase thrombospondin motifs (ADAMTS)-5. Furthermore, activation of nuclear factor κB (NF-κB), which was induced by IL-1ß, was also inhibited by SA through the pathway of nuclear factor-erythroid 2-related factor-2 (Nrf2)/heme oxygenase 1. In vivo, SA could delay the progress of mice OA models. We propose that SA may be applied as a potential therapeutic drug in OA treatment.

Inhibition of PI3K/Akt/NF-κB signaling with leonurine for ameliorating the progression of osteoarthritis: In vitro and in vivo studies.

Osteoarthritis (OA) is characterized as the degeneration and destruction of articular cartilage. In recent decades, leonurine (LN), the main active component in medical and edible dual purpose plant Herba Leonuri, has been shown associated with potent anti-inflammatory effects in several diseases. In the current study, we examined the protective effects of LN in the inhibition of OA development as well as its underlying mechanism both in vitro and in vivo experiments. In vitro, interleukin-1 beta (IL-1ß) induced over-production of prostaglandin E2, nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6 and tumor necrosis factor alpha were all inhibited significantly by the pretreatment of LN at a dose-dependent manner (5, 10, and 20 µM). Moreover, the expression of thrombospondin motifs 5 (ADAMTS5) and metalloproteinase 13 (MMP13) was downregulated by LN. All these changes led to the IL-1ß induced degradation of extracellular matrix. Mechanistically, the LN suppressed IL-1ß induced activation of the PI3K/Akt/NF-κB signaling pathway cascades. Meanwhile, it was also demonstrated in our molecular docking studies that LN had strong binding abilities to PI3K. In addition, LN was observed exerting protective effects in a surgical induced model of OA. To sum up, this study indicated LN could be applied as a promising therapeutic agent in the treatment of OA.

The Protective Effect of Ligustilide in Osteoarthritis: An in Vitro and in Vivo Study.

BACKGROUND/AIMS: Osteoarthritis is a degenerative joint disease characterized by cartilage degeneration and a chondrocyte inflammatory response that induces an inflammatory environment closely linked to extracellular matrix (ECM) degradation. Ligustilide (LIG) is a major component of the herb Radix Angelicae Sinensis, with demonstrated anti-inflammatory effects. To confirm whether LIG has an equally inhibitory effect on inflammation in human osteoarthritis chondrocytes, we performed in vivo and in vitro experiments to validate the above conjectures and determine the relevant mechanisms. METHODS: Quantitative realtime PCR and western blotting were performed to evaluate the expression of MMP-3, MMP-13, ADAMTS-5, iNOS, and COX-2 at both gene and protein levels. An enzyme-linked immunosorbent assay was used to evaluate the levels of other inflammatory factors (PGE2, TNF-α, and IL-6). The PI3K/AKT and nuclear factor kappa B (NF-κB) signaling pathways were also analyzed by western blotting, whereas immunofluorescence was used to assess the expression of collagen II and aggrecan. The in vitro effect of LIG was evaluated by intraperitoneal injection into a mouse osteoarthritis model induced by destabilization of the medial meniscus. RESULTS: LIG lowered the phosphorylation levels of p65, IκBα, and IKKα/ß and suppressed the IL-1ß-induced expression of MMP-3, ADAMTS-5, iNOS, and COX-2 and the inflammatory factors PGE2, TNF-α, and IL-6. LIG markedly decreased IL-1ß-induced degradation of collagen II and aggrecan. In vivo results showed that LIG-treated mouse cartilage showed less damage than the control group; the Osteoarthritis Research Society International (OARSI) score was also lower. LIG further reduced the thickness of the subchondral bone plate and alleviated the synovitis. CONCLUSION: LIG may act as a promising therapeutic agent for osteoarthritis by attenuating IL-1ß-induced inflammation in chondrocytes and ECM degradation via suppression of NF-κB activation by the PI3K/AKT pathway.

Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression in dexamethasone-induced osteoblasts apoptosis and slows the progression of steroid-induced avascular necrosis of the femoral head in rats.

Steroid-induced avascular necrosis of the femoral head (SANFH) is a major limitation of long-term or excessive clinical administration of glucocorticoids. Fludarabine, which is a compound used to treat various hematological malignancies, such as chronic lymphocytic leukemia, acts by down-regulating signal transducer and activator of transcription 1 (STAT1) by inhibiting STAT1 phosphorylation in both normal and cancer cells. This study assessed the effects of fludarabine in vitro (primary murine osteoblasts) and in vivo (rat SANFH model). In vitro, pretreatment with fludarabine significantly inhibited Dexamethasone (Dex)-induced apoptosis in osteoblasts, which was examined by TUNEL staining. Treatment with Dex caused a remarkable decrease in the expression of Bcl-2; an increase in cytochrome c release; activation of BAX, caspase-9, and caspase-3; and an obvious enhancement in STAT1 phosphorylation. However, treatment resulted in the up-regulation of caspase-3 expression. Enhanced P-STAT1 activity and up-regulation of caspase-3 expression were also observed in osteoblasts. In vivo, the subchondral trabeculae in fludarabine-treated rats exhibited less bone loss and a lower ratio of empty lacunae. Taken together, our results suggest that STAT1-mediated up-regulation of caspase-3 is involved in osteoblast apoptosis induced by Dex and indicates that fludarabine may serve as a potential agent for the treatment of SANFH.

The location of Modic changes in the lumbar spine: a meta-analysis.

PURPOSE: This meta-analysis was to study the location of Modic changes in the lumbar spine. METHODS: The electronic databases including MEDLINE, Web of science, Cochrane Central Register of Controlled Trials, OVID, CBM were searched. Relevant studies that described the patients with Modic Changes were included. Data were extracted and analysed using the version 12.0 STATA software. RESULTS: Thirty-one studies were selected and analyzed (2346 total patients). No significant differences of the incidence of MC were identified between superior and the inferior end plates adjacent to discs [RR = 1.04, 95 % CI (0.74, 1.53)], the same result was detected for the distribution of MC type I between L4/5 and L5/S1 [RR = 0.80, 95 % CI (0.64, 1.02)]. While lower lumbar spine (L4/5, L5/S1) had significant greater incidence of MC [RR = 0.20, 95 % CI (0.15, 0.25)], especially in L5/S1 [RR = 0.82, 95 % CI (0.72, 0.92)]. For MC type II, it also significantly appeared in L5/S1 [RR = 0.80, 95 % CI (0.67, 0.95), P = 0.010]. CONCLUSIONS: In this study, Modic Changes was more common in the lowest two levels, especially in L5/S1. Additionally, the sub-types (type I and type II) were also more likely to appear in L5/S1. It appeared that there existed a correlation between MC and biomechanics. And it seemed that local biomechanical stress might contributed to the distribution of MC and the conversion of type I to type II for the patients treated conservatively.

Percutaneous posterior transdiscal oblique screw fixation with lateral interbody fusion: a radiological and cadaveric study.

PURPOSE: To design and investigate a novel technique of percutaneous posterior transdiscal oblique screw fixation with lateral interbody fusion. METHODS: CT scans of 45 patients were collected and imported into Mimics software for three-dimensional (3D) reconstruction. Cylinders were drawn to simulate the trajectory of the oblique screw. Six measurements were obtained for each unit to design a right size cage: a the distance between the intersection of the simulated trajectory of the screw with the inferior border of the upper vertebra and its anteroinferior corner; b the distance between the intersection of the simulated trajectory of the screw with the superior border of the inferior vertebra and its anterosuperior corner; h the height of the intervertebral space; θ the angle between simulated trajectory of screw and the upper endplate of inferior vertebra; uw: the width of the inferior endplate of upper vertebra; iw: the width of upper endplate of inferior vertebra. Three intact adult fresh-frozen cadaveric specimens were obtained, percutaneous posterior transdiscal oblique screw fixation was performed under X-ray apparatus, and interbody cage was implanted by assistance with special self-retaining retractor system and endoscope. RESULTS: According to the results of data measured from 3D images, trapezoid shape interbody cages with suitable size were designed. Percutaneous posterior oblique screw fixation with lateral interbody fusion was performed on three cadaveric specimens successfully. CONCLUSION: Using specially designed trapezoid shape interbody cages, assisted by intra-operative image intensification and endoscope, it is feasible to perform percutaneous posterior transdiscal oblique screw fixation with lateral interbody fusion technique.

DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury.

BACKGROUND AND PURPOSE: Autophagy is a protective factor for controlling neuronal damage, while necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (D-Ala2 , D-Leu5 ]-enkephalin) is a selective agonist for delta (δ) opioid receptor and has been identified as a promising drug for neuroprotection. The aim of this study was to investigate the mechanism/s by which DADLE causes locomotor recovery following SCI. EXPERIMENTAL APPROACH: Spinal cord contusion model was used and DADLE was given by i.p. (16 mg·kg-1 ) in mice for following experiments. Motor function was assessed by footprint and Basso mouse scale (BMS) score analysis. Western blotting used to evaluate related protein expression. Immunofluorescence showed the protein expression in each cell and its distribution. Network pharmacology analysis was used to find the related signalling pathways. KEY RESULTS: DADLE promoted functional recovery after SCI. In SCI model of mice, DADLE significantly increased autophagic flux and inhibited necroptosis. Concurrently, DADLE restored autophagic flux by decreasing lysosomal membrane permeabilization (LMP). Additionally, chloroquine administration reversed the protective effect of DADLE to inhibit necroptosis. Further analysis showed that DADLE decreased phosphorylated cPLA2 , overexpression of cPLA2 partially reversed DADLE inhibitory effect on LMP and necroptosis, as well as the promotion autophagy. Finally, AMPK/SIRT1/p38 pathway regulating cPLA2 is involved in the action DADLE on SCI and naltrindole inhibited DADLE action on δ receptor and on AMPK signalling pathway. CONCLUSION AND IMPLICATION: DADLE causes its neuroprotective effects on SCI by promoting autophagic flux and inhibiting necroptosis by decreasing LMP via activating δ receptor/AMPK/SIRT1/p38/cPLA2 pathway.

FGF-18 Protects the Injured Spinal cord in mice by Suppressing Pyroptosis and Promoting Autophagy via the AKT-mTOR-TRPML1 axis.

Spinal cord injury (SCI) is a severe medical condition with lasting effects. The efficacy of numerous clinical treatments is hampered by the intricate pathophysiological mechanism of SCI. Fibroblast growth factor 18 (FGF-18) has been found to exert neuroprotective effects after brain ischaemia, but its effect after SCI has not been well explored. The aim of the present study was to explore the therapeutic effect of FGF-18 on SCI and the related mechanism. In the present study, a mouse model of SCI was used, and the results showed that FGF-18 may significantly affect functional recovery. The present findings demonstrated that FGF-18 directly promoted functional recovery by increasing autophagy and decreasing pyroptosis. In addition, FGF-18 increased autophagy, and the well-known autophagy inhibitor 3-methyladenine (3MA) reversed the therapeutic benefits of FGF-18 after SCI, suggesting that autophagy mediates the therapeutic effects of FGF-18 on SCI. A mechanistic study revealed that after stimulation of the protein kinase B (AKT)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin signalling pathway, the FGF-18-induced increase in autophagy was mediated by the dephosphorylation and nuclear translocation of transcription factor E3 (TFE3). Together, these findings indicated that FGF-18 is a robust autophagy modulator capable of accelerating functional recovery after SCI, suggesting that it may be a promising treatment for SCI in the clinic.

Ginsenoside-Rh2 Promotes Functional Recovery after Spinal Cord Injury by Enhancing TFEB-Mediated Autophagy.

Background: Following spinal cord injury (SCI), autophagy plays a positive role in neuronal protection, whereas pyroptosis triggers an inflammatory response. Ginsenoside-Rh2 (GRh2), known for its neuroprotective effects, is considered a promising drug. However, the exact molecular mechanisms underlying these protective effects remain unclear. Aim of the Study: Explore the therapeutic value of GRh2 in SCI and its potential mechanisms of action. Materials and Methods: An SCI mouse model was established, followed by random grouping and drug treatments under different conditions. Subsequently, the functional recovery of SCI mice after GRh2 treatment was assessed using hematoxylin and eosin, Masson's trichrome, and Nissl staining, footprint analysis, Basso Mouse Scale scoring, and inclined plane tests. The expression levels of relevant indicators in the mice were detected using Western blotting, immunofluorescence, and a quantitative polymerase chain reaction. Network pharmacology analysis was used to identify the relevant signaling pathways through which GRh2 exerts its therapeutic effects. Results: GRh2 promoted functional recovery after SCI. GRh2 significantly inhibits pyroptosis by enhancing autophagy in SCI mice. Simultaneously, the neuroprotective effect of GRh2, achieved through the inhibition of pyroptosis, is partially reversed by 3-methyladenine, an autophagy inhibitor. Additionally, the increase in autophagy induced by GRh2 is mediated by the promotion of transcription factor EB (TFEB) nuclear translocation and dephosphorylation. Partial attenuation of the protective effects of GRh2 was observed after TFEB knockdown. Additionally, GRh2 can modulate the activity of TFEB in mice post-SCI through the EGFR-MAPK signaling pathway, and NSC228155 (an EGFR activator) can partially reverse the effect of GRh2 on the EGFR-MAPK signaling pathway. Conclusions: GRh2 improves functional recovery after SCI by upregulating TFEB-mediated autophagic flux and inhibiting pyroptosis, indicating its potential clinical applicability.

[Reasons and strategies of reoperation after oblique lateral interbody fusion].

OBJECTIVE: To summarize the reasons and management strategies of reoperation after oblique lateral interbody fusion (OLIF), and put forward preventive measures. METHODS: From October 2015 to December 2019, 23 patients who underwent reoperation after OLIF in four spine surgery centers were retrospectively analyzed. There were 9 males and 14 females with an average age of (61.89±8.80) years old ranging from 44 to 81 years old. The index diagnosis was degenerative lumbar intervertebral dics diseases in 3 cases, discogenic low back pain in 1 case, degenerative lumbar spondylolisthesis in 6 cases, lumbar spinal stenosis in 9 cases and degenerative lumbar spinal kyphoscoliosis in 4 cases. Sixteen patients were primarily treated with Stand-alone OLIF procedures and 7 cases were primarily treated with OLIF combined with posterior pedicle screw fixation. There were 17 cases of single fusion segment, 2 of 2 fusion segments, 4 of 3 fusion segments. All the cases underwent reoperation within 3 months after the initial surgery. The strategies of reoperation included supplementary posterior pedicle screw instrumentation in 16 cases;posterior laminectomy, cage adjustment and neurolysis in 2 cases, arthroplasty and neurolysis under endoscope in 1 case, posterior laminectomy and neurolysis in 1 case, pedicle screw adjustment in 1 case, exploration and decompression under percutaneous endoscopic in 1 case, interbody fusion cage and pedicle screw revision in 1 case. Visual analogue scale (VAS) and Oswestry disability index (ODI) index were used to evaluate and compare the recovery of low back pain and lumbar function before reoperation and at the last follow-up. During the follow-up process, the phenomenon of fusion cage settlement or re-displacement, as well as the condition of intervertebral fusion, were observed. The changes in intervertebral space height before the first operation, after the first operation, before the second operation, 3 to 5 days after the second operation, 6 months after the second operation, and at the latest follow-up were measured and compared. RESULTS: There was no skin necrosis and infection. All patients were followed up from 12 to 48 months with an average of (28.1±7.3) months. Nerve root injury symptoms were relieved within 3 to 6 months. No cage transverse shifting and no dislodgement, loosening or breakage of the instrumentation was observed in any patient during the follow-up period. Though the intervertebral disc height was obviously increased at the first postoperative, there was a rapid loss in the early stage, and still partially lost after reoperation. The VAS for back pain recovered from (6.20±1.69) points preoperatively to (1.60±0.71) points postoperatively(P<0.05). The ODI recovered from (40.60±7.01)% preoperatively to (9.14±2.66)% postoperatively(P<0.05). CONCLUSION: There is a risk of reoperation due to failure after OLIF surgery. The reasons for reoperation include preoperative bone loss or osteoporosis the initial surgery was performed by Stand-alone, intraoperative endplate injury, significant subsidence of the fusion cage after surgery, postoperative fusion cage displacement, nerve damage, etc. As long as it is discovered in a timely manner and handled properly, further surgery after OLIF surgery can achieve better clinical results, but prevention still needs to be strengthened.

Complications in degenerative lumbar disease treated with a dynamic interspinous spacer (Coflex).

PURPOSE: The purpose of this study was to quantify the intra- and postoperative complications of an interspinous process device (Coflex) in managing degenerative lumbar diseases and to investigate corresponding therapeutic strategies. METHODS: Between January 2008 and December 2012, we retrospectively analysed a total of 131 patients who underwent decompressive surgery along with the Coflex system for the treatment of degenerative lumbar diseases. The related complications were reported, and appropriate measures were taken. Clinical outcomes and radiological data were collected and analysed, and clinical outcomes were evaluated with paired-samples T test. RESULTS: Related complications occurred in 11 patients. Among them, six cases were found with surgical technique-related complications, including device-related complications in three cases: spinal process fracture (n = 1), Coflex loosening (n = 1), fixed-wing breakage (n = 1), dura mater tear in two cases and superficial wound infection in one case. All of them received corresponding conservative treatment and obtained a good result. The other five cases had non-device-related complications and required additional spinal surgery. The conservative therapy group had apparent improvement of VAS score and ODI, and remained well to final follow-up (P < 0.05). The second operation group also improved postoperatively (each P < 0.05). CONCLUSION: The Coflex dynamic interspinous process device shows a low complication and re-operation rate. Standard operation and strict follow-up observation can effectively avoid surgical technique-related complications. The key points to ensure surgical effect and to reduce non-device-related complications are mastering surgical indications and thorough intra-operative decompression.

[Discectomy and discectomy plus Coflex fixation for lumbar disc herniation, a clinical comparison study].

OBJECTIVE: To compare clinical efficacy between discectomy and discectomy plus Coflex fixation for lumbar disc herniation. METHODS: From December 2007 to August 2008, 50 patients (31 males and 19 females) were treated by surgery of discectomy and discectomy plus Coflex fixation. The average age was 52.5 years (range, 30 - 72 years). There were 24 cases in the group of discectomy plus Coflex fixation and 26 cases in the group of discectomy. Preoperative and postoperative visual analogue scales (VAS), Japanese Orthopadic Association (JOA) and Oswestry disability index (ODI) were recorded, as well as radiological index. And use a paired t-test and one-way analysis of variance (one-way ANOVA) statistical method to evaluate the Coflex dynamic stabilization system in value in the treatment of lumbar disc herniation. RESULTS: Both groups received significant improvement of JOA, ODI and VAS (t = -33.2 - 64.5, P < 0.01), but the group of discectomy was found with deterioration of ODI at last follow-up, 12 months after surgery 6.7 ± 1.5 to 10.2 ± 2.3 (t = -19.3, P < 0.05). The group of discectomy plus Coflex fixation was found with significant increase of height of dorsal intervertebral discs (HD), distance across the two adjacent spinous processes (DS), distance of intervertebral foramina (DIF) and spinal canal area(SA) (t = -34.4 - 4.5, P < 0.05). In contrast, the group of discectomy was found with significant decrease of HD, DS, DIF and SA (t = 3.4 - 52.8, P < 0.05). Coflex fixed group in HD, DIF, DS significant difference with simple discectomy group, with a statistically significant (F = 14.1 - 25.6, P < 0.05). CONCLUSIONS: Both discectomy and discectomy plus Coflex fixation are apparently effective when treating lumbar disc herniation. Coflex can significantly increase the HD and DIF when used for lumbar disc herniation, and it has positive influence for keeping height of lumbar vertebral space and treating the nerve root symptom of lumbar disc herniation. Discectomy plus Coflex is better than pure discectomy in preventing lumbar degeneration.