Remodeling of the Intra-Conduit Inflammatory Microenvironment to Improve Peripheral Nerve Regeneration with a Neuromechanical Matching Protein-Based Conduit.

Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein-based conduits. Moreover, the NGC can gradually regulate the intra-conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.

Excessive mechanical strain accelerates intervertebral disc degeneration by disrupting intrinsic circadian rhythm.

Night shift workers with disordered rhythmic mechanical loading are more prone to intervertebral disc degeneration (IDD). Our results showed that circadian rhythm (CR) was dampened in degenerated and aged NP cells. Long-term environmental CR disruption promoted IDD in rats. Excessive mechanical strain disrupted the CR and inhibited the expression of core clock proteins. The inhibitory effect of mechanical loading on the expression of extracellular matrix genes could be reversed by BMAL1 overexpression in NP cells. The Rho/ROCK pathway was demonstrated to mediate the effect of mechanical stimulation on CR. Prolonged mechanical loading for 12 months affected intrinsic CR genes and induced IDD in a model of upright posture in a normal environment. Unexpectedly, mechanical loading further accelerated the IDD in an Light-Dark (LD) cycle-disrupted environment. These results indicated that intrinsic CR disruption might be a mechanism involved in overloading-induced IDD and a potential drug target for night shift workers.

Decorin inhibits nucleus pulposus apoptosis by matrix-induced autophagy via the mTOR pathway.

Decorin (Dcn) is a member of the class I small leucine-rich proteoglycans, whose expression in the nucleus pulposus (NP) of intervertebral discs (IVDs) has been shown to increase with aging in humans and sheep. Dcn induces autophagy in endothelial cells; however, its precise role in NP and IVD degeneration during aging is not well understood. We addressed this question in the present study by treating rat nucleus pulposus cells (NPCs) with different concentrations of Dcn. The Western blot analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling assay results showed that Dcn treatment induced autophagy and decreased apoptosis caused by interleukin (IL)-1ß application. This effect was dependent on the protein kinase B/mechanistic target of rapamycin (mTOR)/p70 S6 kinase signaling. Dcn treatment also decreased the expression of matrix metalloproteinase-3 and -13 and decreased the IL-1ß-induced attenuation of collagen type II and aggrecan levels. The role of Dcn in stimulating autophagy was further supported by the fact that the observed effects were abrogated by knocking down autophagy-related protein 7 with Atg7 small interfering RNA. Thus, Dcn protects NPCs in IVDs from IL-1ß-induced apoptosis and degeneration by promoting autophagy through mTOR signaling.

Experimental study of airway pressure release ventilation in the treatment of acute respiratory distress syndrome.

Airway pressure release ventilation (APRV) is a ventilator mode which has demonstrated potential benefits in acute respiratory distress syndrome (ARDS) patients. We therefore sought to compare relevant pulmonary data and safety outcomes of this mode to the conventional ventilation and sustained inflation. Canines admitted after intravenous injection of oleic acid requiring mechanical ventilation were randomly divided into 3 groups (n=6), namely conventional ventilation group, low tidal volume ventilation with recruitment group (LTV+SI) and APRV group. The changes of oxygenation, ventilation, airway pressure, inflammatory reaction and hemodynamics at the basic state were observed at 0, 1, 2 and 4 h during the experiment. The levels of PaO2/FiO2 in APRV group were higher than LTV+SI group at 2 and 4 h (P<0.05). In APRV group, the PCO2 levels at 1, 2 and 4 h is much lower than LTV+SI group (P<0.05). Outcome variables showed no differences between APRV, LVT+SI and conventional mechanical ventilation for plateau airway pressure (24±1 vs. 29±3 vs. 25±4), mean arterial pressure (92.9±16.5 vs. 85.8±21.4 vs. 88.7±24.4), cardiac index (4.3±1.7 vs. 3.5±1.9 vs. 3.4±2.1), ERO2 (13.4±10.3 vs. 16.1±6.8 vs. 17.6±9.1), lac (2.5±1.7 vs. 3.1±1.6 vs. 3.9±1.9), tumor necrosis factor (TNF)-α (132±11 vs. 140±6 vs. 195±13) and matrix metalloproteinase (MMP)-9. For canines sustaining acute respiratory distress syndrome requiring mechanical ventilation, APRV can significantly improve oxygenation and keep hemodynamic stability compared with LTV+SI. The results of TNF-α and MMP-9 suggest that APRV could be as protective for ARDS as LTV with recruitment group.

Effect of the Shenfu Injection Combined with Early Goal-Directed Therapy on Organ Functions and Outcomes of Septic Shock Patients.

Shenfu injection (SFI) derived from traditional Chinese medicine has been widely used in cardiovascular diseases. The objective of this study was to determine the effect of SFI and conventional early goal-directed therapy (EGDT) on organ functions and outcomes of septic shock patients. For this purpose, a total of 45 septic shock patients were randomly divided into control group A (24 patients on EGDT) and experimental group B (21 patients on SFI + EGDT). SFI was administered (100@20 mL/h) twice daily. Hemodynamic status, lactic acid, and vasoactive drug use were observed before and after treatment. Other indicators included ventilator weaning time, ICU stay time, free of organ failure time, and 28-day hospital mortality. Regarding experimental group, compared with controls, BUN/creatinine decreased significantly at 3, 5, and 7 days while PaO2/FiO2 increased at 1 and 3 days (P < 0.05). APACHE-II and SOFA scores decreased in both groups at 3, 5, and 7 days (P < 0.05), whereas SOFA scores improved more in experimental group as compared with controls. Ventilator weaning time and ICU stay were significantly shorter in experimental group as compared with controls. In both groups, mean arterial pressure/systemic vascular resistance index post-treatment levels increased and lactic acid decreased at 6, 12, 24, 48, and 72 h (P < 0.05). Heart rate decreased at 24, 48, and 72 h (P < 0.05); while gamma-glutamyl transpeptidase and glutamate oxaloacetate transaminase levels increased at 1 day and 1 and 3 days, respectively (P < 0.05). Combined use of SFI and EGDT can improve hemodynamics, reduce the damage to vital organs, and shorten ventilation and ICU stay times in septic shock patients.