Effectiveness of robotic-assisted gait training on cardiopulmonary fitness and exercise capacity for incomplete spinal cord injury: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine the effects of robotic-assisted gait training on cardiopulmonary fitness and exercise capacity for people with incomplete spinal cord injury. METHODS: PubMed, Embase, Web of Science, PEDro, CENTRAL and CINAHL were searched from inception until September 4, 2022. Randomized controlled trials that evaluated the effects of robotic-assisted gait training on cardiopulmonary fitness and exercise capacity for individuals with incomplete spinal cord injury were selected. Mean differences (MD) with 95% confidence interval (CI) were calculated. The methodological quality was evaluated by the Cochrane Risk of Bias 2.0 tool. Subgroup analyses were conducted according to the time since injury. RESULTS: In total 19 studies involving 770 patients were eligible for analysis. Individuals with acute incomplete spinal cord injury in robotic-assisted gait training groups showed significantly greater improvements in 6-minute walking test (MD 53.32; 95% CI 33.49 to 73.15; P < 0.001), lower extremity motor scale (MD 5.22; 95% CI 3.63 to 6.80; P < 0.001) and walking index for spinal cord injury II (MD 3.18; 95% CI 1.34 to 5.02; P < 0.001). Robotic-assisted gait training improved peak oxygen consumption to a greater degree for chronic incomplete spinal cord injury patients (MD 4.90; 95% CI 0.96 to 8.84; P = 0.01). CONCLUSION: Robot-assisted gait training may be a feasible and effective intervention in terms of cardiopulmonary fitness and exercise capacity for individuals with incomplete spinal cord injury.

CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction.

BACKGROUND: Since angiogenesis occurs as the pathological process following myocardial infarction to alleviate ischemia, therapeutic angiogenesis has been proposed to be a cardioprotective strategy. CD44 has been implicated in endothelial cell functions and its role has been well established in angiogenesis for years. Although recent studies indicate the close correlation between CD44 and exosome, as well as the two being implicated in myocardial ischemia pathological processes, the effect and the underlying mechanism of CD44 and its regulated plasma exosome in pathological angiogenesis post-myocardial infarction have not been fully elucidated. METHODS: In this study, we used CD44 knockout mice to study the in vivo impacts of CD44 on ischemic angiogenesis in myocardial infarction. Mouse cardiac function was measured by echocardiography, histological changes were observed by Evans Blue and TTC-double staining and Masson's trichrome staining, and molecular changes were detected by immunofluorescence. In the in vitro study, CD44 knockout HUVECs were generated and CD44 inhibitor was used to study the mechanism of CD44 on angiogenesis. We performed the immunoprecipitation, proximity ligation assay, and super-resolution imaging to study the mechanistic regulation of FGFR2 signaling transduction by CD44. Importantly, we also isolated plasma exosomes from myocardial infarction model mice and studied the effect of plasma exosomes on the activation of the FGFR2 signaling pathway and the related phenotypic alterations, including exosomes uptake and angiogenic function in primary mouse microvascular endothelial cells, and further discovered the regulation mechanism of exosomal miRNAs. RESULTS: We observed that the expression of CD44 in the border zone of the infarcted heart was tightly related to pathological angiogenesis following myocardial ischemia. The depletion of CD44 impaired angiogenesis and impacts biogenesis and proangiogenic function of plasma exosomes. Subsequently, we found that CD44 mediated the activation of the FGFR2 signaling pathway as well as the caveolin 1-dependent uptake of exosomes in vascular endothelial cells. Most importantly, the proangiogenic therapeutic effect of plasma exosomal miRNAs depended upon the participation of CD44/FGFR2 signaling transduction in vascular endothelial cells. CONCLUSION: CD44 and its regulated plasma exosomes have crucial potent angiogenic activity. Our studies elucidate that CD44 plays a key role in plasma exosomal miRNA-enhanced angiogenic FGFR2 singling transduction and ischemic angiogenesis in the early stage of myocardial infarction.

Efficacy of pulsed electromagnetic field on pain and physical function in patients with low back pain: A systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of pulsed electromagnetic field (PEMF) on pain and physical function in patients with low back pain. DATA SOURCES: A search of PubMed, Embase, Cochrane Library, and Web of Science was conducted up to December 2021. METHODS: We included randomized controlled trials that investigated the effectiveness of PEMF in patients with low back pain. The primary outcome was pain intensity and the secondary outcome was physical function, both were evaluated by assessment scales. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for the summary statistics analysis. The registration number of this systematic review in PROSPERO is CRD42020213829. RESULTS: Fourteen trials involving 618 participants were included. The PEMF treatment showed more significant pain alleviation than placebo or other therapy alone in patients with low back pain (SMD = -1.01, 95% CI -1.42 to -0.6, P < 0.001, I2 = 31%; SMD = -0.36, 95% CI -0.62 to -0.11, P = 0.005, I2 = 37%, respectively.) In addition, a significant difference in pain alleviation was observed in patients with chronic low back pain (SMD = -0.6, 95%CI - 0.94 to -0.25, p < 0.001, I2 = 67%), whereas no significant difference was observed in patients with acute low back pain (SMD = -0.46, 95%CI - 0.99 to 0.07, p = 0.09, I2 = 0%). PEMF did not improve physical function compared with the control treatment (SMD = -0.45, 95% CI - 0.98 to 0.07, p = 0.09, I2 = 86%). CONCLUSION: PEMF is beneficial for alleviating pain in patients with chronic low back pain despite having no advantage in improving physical function.

Curcumin-mediated Photodynamic Therapy Inhibits the Phenotypic Transformation, Migration, and Foaming of Oxidized Low-density Lipoprotein-treated Vascular Smooth Muscle Cells by Promoting Autophagy.

ABSTRACT: Vascular smooth muscle cells (VSMCs) are becoming a hot spot and target of atherosclerosis research. This study aimed to observe the specific effects of curcumin (CUR)-mediated photodynamic therapy (CUR-PDT) on oxidized low-density lipoprotein (ox-LDL)-treated VSMCs and confirm whether these effects are mediated by autophagy. In this study, the mouse aortic smooth muscle cell line and A7r5 cell lines were used for parallel experiments. VSMC viability was evaluated by Cell Counting Kit-8 assay. VSMCs were treated with ox-LDL to establish a model of atherosclerosis in vitro. The autophagy level and the expression of proteins related to phenotypic transformation were detected by western blotting. The migration ability of the cells was detected by using transwell assay. The presence of intracellular lipid droplets was detected by Oil Red O staining. The results showed that VSMCs transformed from the contraction phenotype to the synthetic phenotype when stimulated by ox-LDL, during which autophagy was inhibited. However, CUR-PDT treatment significantly promoted the level of autophagy and inhibited the process of phenotypic transformation induced by ox-LDL. In addition, ox-LDL significantly promoted VSMC migration and increased the number of lipid droplets, whereas CUR-PDT treatment significantly reduced the ox-LDL-induced increase in the migration ability of, and lipid droplet numbers in, VSMCs. When the VSMCs were pretreated with the autophagy inhibitor 3-methyladenine for 24 hours, the effects of CUR-PDT were reversed. Therefore, our study indicated that CUR-PDT can inhibit the phenotypic transformation, migration, and foaming of ox-LDL-treated VSMCs by inducing autophagy.

Efficacy of Extracorporeal Shockwave Therapy on Pain and Function in Myofascial Pain Syndrome of the Trapezius: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the effect of extracorporeal shockwave therapy (ESWT) on pain and function in myofascial pain syndrome (MPS) of the trapezius. DATA SOURCES: PubMed, EMBASE, Web of Science, Physiotherapy Evidence Database, and The Cochrane Central Register of Controlled Trials were systematically searched from the time of their inception to September 2019. STUDY SELECTION: Randomized controlled trials comparing the effects of ESWT on MPS of the trapezius were included in this review. DATA EXTRACTION: Data related to study participants, intervention, follow-up period, measure time, and outcomes were extracted. The Physiotherapy Evidence Database scale and the Cochrane Collaboration Tool for Assessing Risk of Bias were used to assess study quality and risk of bias. DATA SYNTHESIS: In total, 10 articles (n=477 patients) met our criteria and were included in this study. The overall effectiveness was calculated using a meta-analysis method. The meta-analysis revealed that ESWT exhibited significant improvement in pain reduction compared with sham ESWT or ultrasound treatment, but no significant effect when compared with conventional treatments (dry needling, trigger point injection, laser therapy) as for pain intensity and neck disability index. CONCLUSIONS: ESWT appears to benefit patients with MPS of the trapezius by alleviating pain. ESWT may not be an ideal therapeutic method to replace conventional therapies but could serve as an adjunct therapeutic method to those treatments.

MPPa-PDT suppresses breast tumor migration/invasion by inhibiting Akt-NF-κB-dependent MMP-9 expression via ROS.

BACKGROUND: Breast cancer is one of the most commonly diagnosed cancers in women, with high morbidity and mortality. Tumor metastasis is implicated in most breast cancer deaths; thus, inhibiting metastasis may provide a therapeutic direction for breast cancer. In the present study, pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPa-PDT) was used to inhibit metastasis in MCF-7 breast cancer cells. METHODS: Uptake of MPPa was detected by fluorescence microscopy. Cell viability was evaluated by the Cell Counting Kit-8 (CCK-8). ROS generation was detected by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The migration of cells was assessed by wound healing assay, and invasion ability was assessed by Matrigel invasion assay. Levels of MMP2 and MMP9 were measured by PCR. Akt, phospho-Akt (Ser473), phospho-NF-κB p65 (Ser536) and NF-κB p65 were measured by western blotting. The F-actin cytoskeleton was observed by immunofluorescence. Lung tissue was visualized by hematoxylin and eosin staining. RESULTS: Following MPPa-PDT, migration and invasion were decreased in the MCF-7 cells. MPPa-PDT downregulated the expression of MMP2 and MMP9, which are responsible for the initiation of metastasis. MPPa-PDT reduced the phosphorylation of Akt and NF-κB. MPPa-PDT also reduced the expression of F-actin in cytoskeleton in MCF-7 cells. These effects were blocked by the reactive oxygen species scavenger NAC or the Akt activator SC79, while the PI3K inhibitor LY294002 or the Akt inhibitor triciribine enhanced these effects. Moreover, MPPa-PDT inhibited tumor metastasis and destroyed F-actin in vivo. CONCLUSION: Taken together, these results demonstrate that MPPa-PDT inhibits the metastasis of MCF-7 cells both in vitro and in vivo and may be involved in the Akt/NF-κB-dependent MMP-9 signaling pathway. Thus, MPPa-PDT may be a promising treatment to inhibit metastasis.

Progressive cationic functionalization of chlorin derivatives for antimicrobial photodynamic inactivation and related vancomycin conjugates.

It is known that multiple cationic charges are required to produce broad-spectrum antimicrobial photosensitizers (PS) for photodynamic inactivation (aPDI) or photodynamic therapy of bacteria and fungi. In the present study we describe the synthesis and aPDI testing of a set of derivatives prepared from the parent pheophytin molecule with different numbers of attached side arms (1-3) each consisting of five quaternized cationic groups (pentacationic), producing the corresponding [Zn2+]pheophorbide-a-N(C2N+C1C3)5 (Zn-Phe-N5+, 5 charges), [Zn2+]chlorin e6-[N(C2N+C1C3)5]2 (Zn-Chl-N10+, 10 charges) and [Zn2+]mesochlorin e6-[N(C2N+C1C3)5]3 (Zn-mChl-N15+, 15 charges). Moreover, a conjugate between Zn-Phe-N5+ and the antibiotic vancomycin called Van-[Zn2+]-m-pheophorbide-N(C2N+C1C3)5 (Van-Zn-mPhe-N5+) was also prepared. The aPDI activities of all compounds were based on Type-II photochemistry (1O2 generation). We tested these compounds against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative Escherichia coli, and the fungal yeast Candida albicans. All three compounds were highly active against MRSA, giving eradication (≥6 logs of killing) with <1.0 µM and 10 J cm-2 of 415 nm light. The order of activity was Zn-Phe-N5+ > Zn-Chl-N10+ > Zn-mChl-N15+. In the case of E coli the activity was much lower (eradication was only possible with 50 µM Zn-mChl-N15+ and 20 J cm-2). The order of activity was the reverse of that found with MRSA (Zn-mChl-N15+ > Zn-Chl-N10+ > Zn-Phe-N5+). Activity against C. albicans was similar to E. coli with Zn-mChl-N15+ giving eradication. The activity of Van-Zn-mPhe-N5+ was generally lower than that of Zn-Phe-N5+ (except for E. coli). Red (660 nm) light was also effective as might be expected from the absorption spectra. An initial finding that Van-Zn-mPhe-N5+ might have higher activity against vancomycin resistant Enterococcus fecium (VRE) strains (compared to vancomycin sensitive strains) was disproved when it was found that VRE strains were also more sensitive to aPDI with Zn-Phe-N5+. The minimum inhibitory concentrations of Van-Zn-mPhe-N5+ were higher than those of Van alone, showing that the antibiotic properties of the Van moiety were lessened in the conjugate. In conclusion, Zn-Phe-N5+ is a highly active PS against Gram-positive species and deserves further testing. Increasing the number of cationic charges increased aPDI efficacy on C. albicans and Gram-negative E. coli.

CXCL12 and CXCR4 polymorphisms and expressions in peripheral blood from patients of hepatocellular carcinoma.

AIM: To determine if CXCL12 (rs1801157) and CXCR4 (rs2228014) polymorphisms are associated with hepatocellular carcinoma (HCC) susceptibility, and detect their expressions in peripheral blood. METHODS: 206 HCC patients, 252 chronic hepatitis B patients, 221 liver cirrhosis patients and 275 healthy volunteers were recruited. Genes CXCL12 and CXCR4 were amplified and genotyped. Their expression in peripheral blood were detected. RESULTS: CXCL12 rs1801157 and CXCR4 rs2228014 polymorphisms were associated with increased susceptibility of HCC, and genotypes GA/AA and CT/TT may be risk factors of HCC (all p < 0.05). Expressions of CXCL12 and CXCR4 in peripheral blood from HCC patients increased significantly (p < 0.05). CONCLUSION: CXCL12 and CXCR4 polymorphisms may be risk factors for HCC, and they may be potential HCC markers.

Bacterial photodynamic inactivation mediated by methylene blue and red light is enhanced by synergistic effect of potassium iodide.

The inexorable increase of antibiotic resistance occurring in different bacterial species is increasing the interest in developing new antimicrobial treatments that will be equally effective against multidrug-resistant strains and will not themselves induce resistance. One of these alternatives may be photodynamic inactivation (PDI), which uses a combination of nontoxic dyes, called photosensitizers (PS), excited by harmless visible light to generate reactive oxygen species (ROS) by type 1 (radical) and type 2 (singlet oxygen) pathways. In this study, we asked whether it was possible to improve the efficacy of PDI in vitro and in vivo by addition of the inert salt potassium iodide (KI) to a commonly investigated PS, the phenothiazinium dye methylene blue (MB). By adding KI, we observed a consistent increase of red light-mediated bacterial killing of Gram-positive and Gram-negative species in vitro and in vivo. In vivo, we also observed less bacterial recurrence in wounds in the days posttreatment. The mechanism of action is probably due to formation of reactive iodine species that are produced quickly with a short lifetime. This finding may have a relevant clinical impact by reducing the risk of amputation and, in some cases, the risk of death, leading to improvement in the care of patients affected by localized infections.

Photochemical activation of TRPA1 channels in neurons and animals.

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans.

Medium-term comparison of uterus preservation versus hysterectomy in pelvic organ prolapse treatment with Prolift™ mesh.

INTRODUCTION AND HYPOTHESIS: We conducted a medium-term assessment of clinical outcomes and complications after surgical repair of pelvic organ prolapse (POP) using Prolift™ mesh, and sought to determine whether concomitant hysterectomy clinically influenced the outcome of pelvic reconstruction in patients without a prior history of urogenital surgery. METHODS: Patients diagnosed with POP-Q stage 3/4 uterine prolapse at a tertiary referral urogynecology unit in South Taiwan who had undergone POP repair with Prolift mesh from May 2007 to July 2010 were identified by chart review. Concomitant hysterectomy was performed in 24 patients (hysterectomy group), and uterus-sparing surgery in 78 (uterus-sparing group) Preoperative and postoperative subjective assessments of urinary and prolapse symptoms, objective POP-Q score, urodynamic examination, and postoperative adverse events were compared between the groups. RESULTS: The mean follow-up periods were 25.7 months (range 6.2 - 73.1 months) and 31.7 months (range 6.0 - 78.4 months) in the concomitant hysterectomy and uterus-sparing groups, respectively. There were no between-group differences in functional and anatomic outcomes after surgery. No statistically significant differences were found in postoperative adverse events between the groups. CONCLUSIONS: Pelvic reconstruction using Prolift with concomitant hysterectomy and uterus-sparing surgery have similar anatomic and functional results at 2.5 years. Therefore, we consider uterus-sparing surgery to be an alternative to hysterectomy in uterine prolapse repair.

Evaluation of the single-incision Elevate system to treat pelvic organ prolapse: follow-up from 15 to 45 months.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the 2-year clinical outcomes of pelvic reconstructive surgery with the single-incision Elevate system (American Medical Systems, Minnetonka, MN, USA). METHODS: This retrospective study was conducted from November 2010 to August 2013, and included 210 patients with pelvic organ prolapse stage 3 or 4 who underwent pelvic reconstructive surgery with an Elevate system and were followed for 1 to 3 years postoperatively. Assessments included pre- and postoperative Pelvic Organ Prolapse Quantification (POP-Q) stage, Urogenital Distress Inventory (UDI-6), Incontinence Impact Questionnaire (IIQ-7) and multi-channel urodynamic examinations. Anatomical success was defined as postoperative POP-Q stage 0 or I. RESULTS: The anatomical success rates were 95 % for the anterior vaginal wall, 99 % for the posterior vaginal wall and 94 % for the apical vaginal wall after a median 27 months of follow-up. POP-Q, UDI-6 and IIQ-7 scores, maximal flow rate and post-voiding residual urine all improved significantly after surgery. Complications included 1 case of internal bleeding, 4 cases of mesh exposure, 5 cases of recurrent prolapse that required salvage operations, and 3 cases of urine retention that required intermittent catheterization. There were no bladder or bowel injuries during surgery. CONCLUSIONS: Pelvic reconstructive surgery with the Elevate system yielded good anatomical outcomes and symptom improvement after 2 years of follow-up.

A Continuous Volatility Forecasting Model Based on Neural Differential Equations and Scale-Similarity.

Volatility forecasting is a problem in finance that attracts the attention of both academia and industry. While existing approaches typically utilize a discrete-time latent process that governs the volatility to forecast its future level, volatility is considered to evolve continuously, which makes discrete-time modeling inevitably lose some critical information about the evolution of volatility. In this article, a novel neural-network-based model, Continuous Volatility Forecasting Model, CVFM is proposed to tackle this problem. First, CVFM introduces a continuous-time latent process, whose evolution is modeled with neural differential equations (NDEs), to govern volatility, which effectively captures the continuous evolutionary behavior of volatility in a data-driven way. Second, a scale-similarity-based mechanism is designed to calibrate the evolution equation of the latent process with real-world observations in the absence of high-frequency data. CVFM is tested on six real-world stock index datasets. The main experimental results show that CVFM can significantly outperform existing models in terms of both forecasting accuracy and high-volatility recognition.

Clinical aPDT's effect on Candida albicans: Antifungal susceptibility, virulence gene expression, and correlation with leukocyte and neutrophil counts.

BACKGROUND: Our previous clinical trial demonstrated that antimicrobial photodynamic therapy (aPDT) with methylene blue (MB) and potassium iodide (KI) effectively killed Candida albicans (C. albicans) in adult AIDS patients with oral candidiasis, regardless of biofilm formation or 25S rDNA genotype. This study evaluated changes in antifungal susceptibility and virulence gene expression in C. albicans before and after aPDT, and explored factors related to clinical aPDT efficacy. METHODS: Twenty-one adult AIDS patients with C. albicans oral candidiasis were divided into Group a (400 µM MB, N = 11) and Group b (600 µM MB, N = 10). Both groups received two aPDT treatments, where MB was applied for 5 min, followed by 300 mM KI, and illuminated for 30 min (37.29 J/cm²). C. albicans isolates were collected before and after treatment to assess antifungal susceptibility (fluconazole, itraconazole, flucytosine, amphotericin B) and gene expression (CAT1, HWP1). Peripheral blood tests were analyzed for correlations with aPDT efficacy. RESULTS: aPDT reduced minimum inhibitory concentration (MIC) values for amphotericin B, fluconazole, and flucytosine, with significant reductions primarily after the first treatment. MIC reductions differed between groups, with Group a showing greater decreases in flucytosine and fluconazole MICs, and Group b in amphotericin B MICs. No significant changes in CAT1 or HWP1 expression were observed. Clinical efficacy of aPDT negatively correlated with leukocyte and neutrophil levels. CONCLUSIONS: aPDT effectively reduces MICs of antifungal drugs against C. albicans isolated from treated patients, particularly after the first treatment. The concentration of MB required to reduce MICs varies among different antifungal drugs. aPDT does not alter CAT1 or HWP1 expression, and its clinical efficacy in eradicating C. albicans is negatively associated with leukocyte and neutrophil levels.

Use of the traditional Chinese medicine "compound healthy ear agent" to protect against age-related hearing loss in mice: A proteomics study.

Background: Previous studies have shown that the traditional Chinese medicine (TCM) called "compound healthy ear agent" (CHEA) had anti-apoptosis effects in cochlear hair cells and spiral ganglion neurons, and could protect mice hearing against presbycusis or age-related hearing loss (AHL), as well as aminoglycoside antibiotic-induced ototoxicity. Because its mechanisms of action are still unclear, we investigated the mechanism of action of CHEA against AHL in mice using proteomics techniques. Methods: Eighteen C57BL/6J mice at 1 month of age were randomly divided into three groups: (A) drinking water until 2 months of age, K2M); (B) drinking water until 7 months of age to induce AHL, K7M; (C) drinking water containing CHEA daily until 7 months of age as treatment group, Z7M. At 2 or 7 months mice were sacrificed and their cochleae were removed for proteomics analysis. Results: The numbers of proteins with a false discovery rate (FDR) < 1% were respectively 5873 for qualitative and 5492 for quantitative statistics. The numbers of proteins with differential enrichment at least 1.5-fold (p < 0.05) were respectively 351 for K7M vs K2M groups, 52 for Z7M vs K7M groups, 264 for Z7M vs K2M groups. The differentially expressed proteins in the Z7M group were involved in synaptic molecular transmission, energy metabolism, immune response, antioxidant defenses, and anti-apoptosis. Conclusion: The TCM CHEA played a protective role against AHL in mice by regulating the expression of specific proteins and genes in cochlear hair cells and spiral ganglion neurons. Besides the pathways expected to be involved (antioxidant and anti-apoptosis), proteins related to immune response is a new finding of the present study.

Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: Advances and challenges.

Spinal cord injury (SCI) is a devastating condition with complex pathological mechanisms that lead to sensory, motor, and autonomic dysfunction below the site of injury. To date, no effective therapy is available for the treatment of SCI. Recently, bone marrow-derived mesenchymal stem cells (BMMSCs) have been considered to be the most promising source for cellular therapies following SCI. The objective of the present review is to summarize the most recent insights into the cellular and molecular mechanism using BMMSC therapy to treat SCI. In this work, we review the specific mechanism of BMMSCs in SCI repair mainly from the following aspects: Neuroprotection, axon sprouting and/or regeneration, myelin regeneration, inhibitory microenvironments, glial scar formation, immunomodulation, and angiogenesis. Additionally, we summarize the latest evidence on the application of BMMSCs in clinical trials and further discuss the challenges and future directions for stem cell therapy in SCI models.

Phenylalanine-Arginine-ß-Naphthylamide Enhances the Photobactericidal Effect of Methylene Blue on Pseudomonas aeruginosa.

Objective: To investigate the effectiveness, dosing sequence, concentration, and mechanism of antimicrobial photodynamic inactivation (aPDI) using methylene blue (MB) plus phenylalanine-arginine-ß-naphthylamide (PAßN) against Pseudomonas aeruginosa. Methods: P. aeruginosa bacterial suspension was incubated with MB for different times (5-240 min), and then, 10 J/cm2 red light was irradiated. The efflux pump inhibitor (EPI) PAßN (10-100 µg/mL) was combined with MB (1-20 µM) in different sequences (PAßN-first, PAßN+MB, PAßN-after). Colony-forming units were then determined by serial dilution. Results: Using MB 10 µM plus 10 J/cm2, the killing effect of MB-aPDI on P. aeruginosa increased first and then decreased with longer incubation time. The killing effect of MB+PAßN-aPDI on P. aeruginosa was better than that of MB-aPDI (p < 0.05) by up to 2 logs. PAßN-first had the best killing effect, whereas PAßN-after had the worst killing effect. The killing effect increased with PAßN concentration and at 100 µg/mL reached 5.1 logs. Conclusions: The EPI PAßN enhanced the bactericidal effect of MB-aPDI on P. aeruginosa, especially when added before MB. It is proposed that MB is a substrate of the resistance-nodulation-division family efflux pump.

Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway.

Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.

Type I and Type II mechanisms of antimicrobial photodynamic therapy: an in vitro study on gram-negative and gram-positive bacteria.

BACKGROUND AND OBJECTIVES: Antimicrobial photodynamic therapy (APDT) employs a non-toxic photosensitizer (PS) and visible light, which in the presence of oxygen produce reactive oxygen species (ROS), such as singlet oxygen ((1) O(2), produced via Type II mechanism) and hydroxyl radical (HO(.), produced via Type I mechanism). This study examined the relative contributions of (1) O(2) and HO(.) to APDT killing of Gram-positive and Gram-negative bacteria. STUDY DESIGN/MATERIALS AND METHODS: Fluorescence probes, 3'-(p-hydroxyphenyl)-fluorescein (HPF) and singlet oxygen sensor green reagent (SOSG) were used to determine HO(.) and (1) O(2) produced by illumination of two PS: tris-cationic-buckminsterfullerene (BB6) and a conjugate between polyethylenimine and chlorin(e6) (PEI-ce6). Dimethylthiourea is a HO(.) scavenger, while sodium azide (NaN(3)) is a quencher of (1) O(2). Both APDT and killing by Fenton reaction (chemical generation of HO(.)) were carried out on Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa). RESULTS: Conjugate PEI-ce6 mainly produced (1) O(2) (quenched by NaN(3)), while BB6 produced HO(.) in addition to (1) O(2) when NaN(3) potentiated probe activation. NaN(3) also potentiated HPF activation by Fenton reagent. All bacteria were killed by Fenton reagent but Gram-positive bacteria needed a higher concentration than Gram-negatives. NaN(3) potentiated Fenton-mediated killing of all bacteria. The ratio of APDT killing between Gram-positive and Gram-negative bacteria was 2 or 4:1 for BB6 and 25:1 for conjugate PEI-ce6. There was a NaN(3) dose-dependent inhibition of APDT killing using both PEI-ce6 and BB6 against Gram-negative bacteria while NaN(3) almost failed to inhibit killing of Gram-positive bacteria. CONCLUSION: Azidyl radicals may be formed from NaN(3) and HO(.). It may be that Gram-negative bacteria are more susceptible to HO(.) while Gram-positive bacteria are more susceptible to (1) O(2). The differences in NaN(3) inhibition may reflect differences in the extent of PS binding to bacteria (microenvironment) or differences in penetration of NaN(3) into cell walls of bacteria.

Low-level laser therapy for closed-head traumatic brain injury in mice: effect of different wavelengths.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) affects millions worldwide and is without effective treatment. One area that is attracting growing interest is the use of transcranial low-level laser therapy (LLLT) to treat TBI. The fact that near-infrared light can penetrate into the brain would allow non-invasive treatment to be carried out with a low likelihood of treatment-related adverse events. LLLT may treat TBI by increasing respiration in the mitochondria, causing activation of transcription factors, reducing inflammatory mediators and oxidative stress, and inhibiting apoptosis. STUDY DESIGN/MATERIALS AND METHODS: We tested LLLT in a mouse model of closed-head TBI produced by a controlled weight drop onto the skull. Mice received a single treatment with continuous-wave 665, 730, 810, or 980 nm lasers (36 J/cm(2) delivered at 150 mW/cm(2)) 4-hour post-TBI and were followed up by neurological performance testing for 4 weeks. RESULTS: Mice with moderate-to-severe TBI treated with 665 and 810 nm laser (but not with 730 or 980 nm) had a significant improvement in Neurological Severity Score that increased over the course of the follow-up compared to sham-treated controls. Morphometry of brain sections showed a reduction in small deficits in 665 and 810 nm laser treated mouse brains at 28 days. CONCLUSIONS: The effectiveness of 810 nm agrees with previous publications, and together with the effectiveness of 660 nm and non-effectiveness of 730 and 980 nm can be explained by the absorption spectrum of cytochrome oxidase, the candidate mitochondrial chromophore in transcranial LLLT.