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ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. α-MG-4, featuring an allyl group at C3 of the lead compound α-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although α-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that α-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. α-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA)’s resistance to multiple antibiotics poses significant health and safety concerns. A novel α-mangostin (α-MG) derivative, α-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of α-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function.

Objectives To evaluate the safety and clinical efficacy of One-Stage 360 degree circular decompression for thoracic ossification of the posterior longitudinal ligament (TOPLL) assisted by piezosurgery. Materials and methods The present study enrolled 36 patients with TOPLL between August 2016 and February 2019. The average intraoperative bleeding volume of all 36 patients in this study is 1058.61 ±737.66 ml. Results All patients did not experience any intraoperative complications such as spinal cord and nerve injuries, and 22 other complications related to decompression of OPLL cited in other literature; all of which were relieved after treatment. The resection time of single laminectomy was 3.43 ±0.49 min, and circular decompression was 42.06 ±14.22 min. At the last follow-up, the modified Japanese Orthopaedic Association (mJOA) score was 8.89 ±1.56, the recovery rate of spinal cord function was 64.2 ±21.2%, and the number of cases of spinal cord function deterioration was 0 (0%). The mJOA score of the last follow-up was negatively correlated with the time of circular decompression (r = 0.368, p ＜ 0.01) and age (r = 0.412, p = 0.026). The recovery rate of the spinal cord function was negatively correlated with the operation time of circular decompression (r = -0.325, p = 0.041) and the amount of intraoperative blood loss (r = -0.555, p = 0.028). Conclusions The use of piezosurgery can safely and effectively complete one-stage simple posterior TOPLL with 360-degree circular decompression. The incidence of complications is not high, and a good outcome can be obtained.

Purpose: To analyze the relationships between coronal and sagittal spinopelvic parameters in degenerative lumbar kyphoscoliosis (DLKS). Methods: We enrolled 75 patients with DLKS for a radiographic study between January 2016 and September 2018. Correlations between coronal and sagittal spinopelvic radiographic parameters were analyzed. Then patients were divided into 2 groups: sagittal balanced group (SVA< = 5 cm, 30 patients) and sagittal imbalanced group (SVA >5 cm, 45 patients), and relevant parameters were compared. Results: The Cobb angle and lumbar lordosis of the DLKS patients were 24.87 ± 11.59° and 17.26 ± 12.24°, respectively. The average age was 68 years old (range: 42-82), and the sex ratio was 2.6:1 (female: 54 patients; male: 21 patients). 50 patients (66.7%) located convexity of the curve at left side, while 25 patients (33.3%) at right side. The Cobb angle correlated with LL-TK (r = −0.228, p = 0.049), LL (r = −0.255, p = 0.027) and SS (r = −0.232, p = 0.045). There were significant differences in PI-LL (t = −3.484, P = 0.001), LL-TK (t = 2.354, P = 0.023), PI (t = −3201, P = 0.002) and PT (t = −2.521, P = 0.014) between sagittal balanced and imbalanced group. Conclusions: In degenerative lumbar kyphoscoliosis, there are some correlations between coronal and sagittal spinopelvic parameters. Moreover, PI-LL, LL-TK, PI, PT were significantly different between sagittal balanced and imbalanced DLKS patients.

In this study, we examined the metabolism of [(3)H]N-hexanoylsphingosine [C(6)-ceramide (Cer)] in neutrophils, erythrocytes, platelets and mononuclear cells. [(3)H]C(6)-Cer, exogenously added and incorporated into the inside of the cell, was found to be converted to other radioactive sphingolipids in these differentiated blood cells, except erythrocytes, which were unable to metabolize C(6)-Cer. Only in neutrophils was a specific radioactive band, comigrating with a standard C(6)-Cer 1-phosphate (C(6)-Cer-1-P) on thin layer chromatography, observed in a time-dependent manner. This metabolite was confirmed to be C(6)-Cer-1-P by its sensitivity to acid treatment and resistance to mild alkaline hydrolysis. Neutrophil [(3)H]C(6)-Cer conversion into [(3)H]C(6)-Cer-1-P, reflecting Cer kinase activity, was not affected by cell stimulation. Furthermore, extracellular release of [(3)H]C(6)-Cer-1-P was not observed either. Exogenous addition of C(8)-Cer-1-P failed to induce intracellular Ca(2+) mobilization or affect the response induced by the formyl peptide. Furthermore, neutrophil morphology was not affected by C(8)-Cer-1-P. Although specific expression of Cer kinase suggests an important role for Cer-1-P in neutrophils, its functional role(s) remain to be clarified., (Copyright 2003 S. Karger AG, Basel)

Since blood platelets release sphingosine 1-phosphate (Sph-1-P) upon activation, it is important to examine the effects of this bioactive lipid on vascular endothelial cell functions from the viewpoint of platelet-endothelial cell interactions. In the present study, we examined Sph-1-P-stimulated signaling pathways related to human umbilical vein endothelial cell (HUVEC) motility, with a special emphasis on the cytoskeletal docking protein Crk-associated substrate (Cas). Sph-1-P stimulated tyrosine phosphorylation of Cas, which was inhibited by the G(i) inactivator pertussis toxin but not by the Rho inactivator C3 exoenzyme or the Rho kinase inhibitor Y-27632. Fyn constitutively associated with and phosphorylated Cas, suggesting that Cas tyrosine phosphorylation may be catalyzed by Fyn. Furthermore, upon HUVEC stimulation with Sph-1-P, Crk, through its SH2 domain, interacted with tyrosine-phosphorylated Cas, and the Cas-Crk complex translocated to the cell periphery (membrane ruffles), through mediation of G(i) (Fyn) but not Rho. In contrast, tyrosine phosphorylation of focal adhesion kinase, and formation of stress fibers and focal adhesion were mediated by Rho but not G(i) (Fyn). Finally, Sph-1-P-enhanced HUVEC motility, assessed by a phagokinetic assay using gold sol-coated plates and a Boyden's chamber assay, was markedly inhibited not only by pertussis toxin (or the Fyn kinase inhibitor PP2) but also by C3 exoenzyme (or Y-27632). In HUVECs stimulated with Sph-1-P, these data suggest the following: (i) cytoskeletal signalings may be separable into G(i)-mediated signaling pathways (involving Cas) and Rho-mediated ones (involving FAK), and (ii) coordinated signalings from both pathways are required for Sph-1-P-enhanced HUVEC motility. Since HUVECs reportedly express the Sph-1-P receptors EDG-1 (coupled with G(i)) and EDG-3 (coupled with G(13) and G(q)) and the EDG-3 antagonist suramin was found to block specifically Rho-mediated responses, it is likely that Cas-related responses following G(i) activation originate from EDG-1, whereas Rho-related responses originate from EDG-3.

The serum-borne lysophospholipid mediators sphingosine 1-phosphate (Sph-1-P) and lysophosphatidic acid (LPA) have been shown to be released from activated platelets and to act on endothelial cells. In this study, we employed the repeated lipid extraction (under alkaline and acidic conditions), capable of detecting Sph-1-P, LPA, and possibly structurally similar lysophospholipids, whereby a marked formation of [(32)P]Sph-1-P, but not [(32)P]LPA, was observed in [(32)P]orthophosphate-labeled platelets. Platelet Sph-1-P release, possibly mediated by protein kinase C, was greatly enhanced in the presence of albumin, which formed a complex with Sph-1-P. This finding suggests that platelet Sph-1-P may become accessible to depletion by albumin when its transbilayer movement (flipping) across the plasma membrane is enhanced by protein kinase C. Although human umbilical vein endothelial cells expressed receptors for both Sph-1-P and LPA, Sph-1-P acted much more potently than LPA on the cells in terms of intracellular Ca(++) mobilization, cytoskeletal reorganization, and migration. The results suggest that Sph-1-P, rather than LPA, is a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells, under the conditions in which critical platelet-endothelial interactions (including thrombosis, angiogenesis, and atherosclerosis) occur. Furthermore, albumin-bound Sph-1-P may account for at least some of the serum biological activities on endothelial cells, which have been ascribed to the effects of albumin-bound LPA, based on the similarities between LPA and serum effects.