The blockage of autophagic flux in chondrocytes has been considered as a major reason for the excessive cellular apoptosis and senescence in osteoarthritis (OA) development; however, the molecular ...mechanism and therapeutic strategy for interrupted autophagic flux is still not clear. Most recently, the transcription factor EB (TFEB) is identified as a master regulator for autophagic flux via initiating the expression of multiple autophagy-related genes and lysosomal biogenesis. This research was performed to confirm whether TFEB expression and activity are impacted in OA development and to confirm the effect of genetic up-regulation of TFEB on autophagic flux and cellular protection in the in vitro and in vivo models of OA. We demonstrated that the expression and nuclear localization of TFEB is decreased in human and mouse OA cartilage as well as in tert-Butyl hydroperoxide (TBHP)-treated chondrocytes. Applying lentivirus to transfect chondrocytes, we found that TFEB overexpression rescues the TBHP-induced the autophagic flux damage, lysosome dysfunction and protects chondrocyte against TBHP induced apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Our destabilized medial meniscus (DMM) mouse OA model shows that TFEB overexpression ameliorates the surgery-induced cartilage degradation, restrains the apoptosis and senescence of chondrocyte, and enhances the autophagic flux. In summary, our study indicates that the activity of TFEB in chondrocyte is involved in OA development, also TFEB overexpression may be a promising strategy for OA treatment.
Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and ...considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti‐inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV‐2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS‐induced M1 BV‐2 microglia, also the inflammatory secretion phenotype of M1 BV‐2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK‐/mTOR‐mediated autophagic flux stimulation.
The pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. Secondary injury is a major target for SCI therapy, whereas microglia play an important role in secondary ...injury. The immunoresponsive gene 1 (Irg-1) has been recorded as one of the most significantly upregulated genes in SCI tissues in gene chip data; however, its role in SCI remains unclear. This study aims to illustrate the role of Irg-1 as well as its regulated metabolite itaconate in SCI. It was demonstrated that the expression of Irg-1 was increased in spinal cord tissues in mice as well as in microglia stimulated by lipopolysaccharides (LPS). It was also shown that overexpression of Irg-1 may suppress LPS-induced inflammation in microglia, while these protective effects were attenuated by Nrf2 silencing. In vivo, overexpression of Irg-1 was shown to suppress neuroinflammation and improve motor function recovery. Furthermore, treatment of microglia with itaconate demonstrated similar inflammation suppressive effects as Irg-1 overexpression in vitro and improved motor function recovery in vivo. In conclusion, the current study shows that Irg-1 and itaconate are involved in the recovery process of SCI, either Irg-1 overexpression or itaconate treatment may provide a promising strategy for the treatment of SCI.
Objective
This study was performed to depict the patterns of change in the perioperative hemoglobin (Hb) concentration and hematocrit (Hct) and to identify the optimal timing of Hb and Hct ...measurement in patients undergoing total knee arthroplasty (TKA).
Methods
This prospective observational study involved 302 consecutive patients who underwent TKA. The patients were kept in hospital for 1 full week postoperatively. Hb and Hct measurements were performed preoperatively and on days 1 to 7 postoperatively and then during clinic visits at 1, 3, and 6 months postoperatively.
Results
The Hb concentration and Hct decreased during the first few days postoperatively and reached a nadir on postoperative day 4 and 3, respectively; they then recovered in the following days. Significant differences in the Hb concentration and Hct were detected between the preoperative period and day 1, between days 1 and 2, between days 2 and 3, between day 7 and 1 month, and between 1 and 3 months. A significant difference in the Hct was also detected between 3 and 6 months.
Conclusion
The optimal timing of Hb and Hct measurement is on postoperative day 3 or 4. This timing accurately reflects ongoing hidden blood loss to better guide blood transfusions.
Diabetes (DB) is a risk factor for osteoarthritis progression. High glucose (HG) is one of the key pathological features of DB and has been demonstrated to induce apoptosis and senescence in ...chondrocytes. Autophagy is an endogenous mechanism that can protect cells against apoptosis and senescence. The effects of HG on autophagy in cells including chondrocytes have been studied; however, the results have been inconsistent. The current study aimed to elucidate the underlying mechanisms, which could be associated with the contrasting outcomes. The present study revealed that HG can induce apoptosis and senescence in chondrocytes, in addition to regulating autophagy dynamically. The present study demonstrated that HG can cause oxidative stress in chondrocytes and suppress the AMPK pathway in a dose-dependent manner. Elimination of oxidative stress by Acetylcysteine, also called N-acetyl cysteine (NAC), downregulated autophagy and alleviated HG-stimulated apoptosis and senescence, while activation of the AMPK signaling pathway by AICAR not only upregulated autophagy but also alleviated HG-stimulated apoptosis and senescence. A combined treatment of NAC and AICAR was superior to treatment with either NAC or AICAR. The study has demonstrated that HG can suppress autophagy through the AMPK pathway and induce autophagy via oxidative stress in chondrocytes.
Wound healing is delayed in diabetic patients. Increased apoptosis and endothelial progenitor cell (EPC) dysfunction are implicated in delayed diabetic wound healing. Melatonin, a major secretory ...product of the pineal gland, promotes diabetic wound healing; however, its mechanism of action remains unclear. Here, EPCs were isolated from the bone marrow of mice. Treatment of EPCs with melatonin alleviated advanced glycation end product (AGE)-induced apoptosis and cellular dysfunction. We further examined autophagy flux after melatonin treatment and found increased light chain 3 (LC3) and p62 protein levels in AGE-treated EPCs. However, lysosome-associated membrane protein 2 expression was decreased, indicating that autophagy flux was impaired in EPCs treated with AGEs. We then evaluated autophagy flux after melatonin treatment and found that melatonin increased the LC3 levels, but attenuated the accumulation of p62, suggesting a stimulatory effect of melatonin on autophagy flux. Blockage of autophagy flux by chloroquine partially abolished the protective effects of melatonin, indicating that autophagy flux is involved in the protective effects of melatonin. Furthermore, we found that the AMPK/mTOR signaling pathway is involved in autophagy flux stimulation by melatonin. An in vivo study also illustrated that melatonin treatment ameliorated impaired wound healing in a streptozotocin-induced diabetic wound healing model. Thus, our study shows that melatonin protects EPCs against apoptosis and dysfunction via autophagy flux stimulation and ameliorates impaired wound healing in vivo, providing insight into its mechanism of action in diabetic wound healing.
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.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, ...is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 μM) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1α signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD.
Surgeons often encounter recurrent kyphosis of Cobb angle following thoracolumbar burst fracture surgery. Some factors affecting postoperative correction loss have been studied in previous studies, ...but few have examined the relationship between laminar fractures and postoperative loss of correction.
The clinical data of 86 patients with thoracolumbar burst fracture who met the inclusion criteria and were admitted to our Department of Spine Surgery between 2013 and 2020 was retrospectively analyzed. To examine the association between laminar fracturs and postoperative correction loss, demographic and radiographic characteristics of the two groups were analyzed.
The presence or absence of laminar fractures was statistically different between the two groups (P < 0.05). Binary logistic regression analysis showed that laminar fractures and preoperative Cobb were statistically significant in the two groups. There were statistically significant differences in the degree of injury of laminar fractures in the coronal plane between the two groups (P < 0.05).
This study investigated that the presence or absence of laminar fractures and preoperative Cobb contribute to loss of correction after thoracolumbar burst fracture surgery. There was a statistically significant difference between full-length and partial-length laminar fractures on the loss of postoperative correction of thoracolumbar burst fractures with laminar fractures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intervertebral disc degeneration (IVDD) is the main cause of cervical and lumbar spondylosis. Over the past few years, the relevance between cellular senescence and IVDD has been widely studied, and ...the senescence-associated secretory phenotype (SASP) produced by senescent cells is found to remodel extracellular matrix (ECM) metabolism and destruct homeostasis. Elimination of senescent cells by senolytics and suppression of SASP production by senomorphics/senostatics are effective strategies to alleviate degenerative diseases including IVDD. Here, we review the involvement of senescence in the process of IVDD; we also discuss the potential of senolytics on eliminating senescent disc cells and alleviating IVDD; finally, we provide a table listing senolytic drugs and small molecules, aiming to propose potential drugs for IVDD therapy in the future.
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