Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of ...the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right-prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness.
Melanoma is a malignant tumor with aggressive behavior. Vemurafenib, a BRAF inhibitor, is clinically used in melanoma, but resistance to melanoma cytotoxic therapies is associated with BRAF ...mutations. Curcumin can effectively inhibit numerous types of cancers. However, there are no reports regarding the correlation between curcumin and vemurafenib‐resistant melanoma cells. In this study, vemurafenib‐resistant A375.S2 (A375.S2/VR) cells were established, and the functional mechanism of the epidermal growth factor receptor (EGFR), serine–threonine kinase (AKT), and the extracellular signal‐regulated kinase (ERK) signaling induced by curcumin was investigated in A375.S2/VR cells in vitro. Our results indicated that A375.S2/VR cells had a higher IC50 concentration of vemurafenib than the parental A375.S2 cells. Moreover, curcumin reduced the viability and confluence of A375.S2/VR cells. Curcumin triggered apoptosis via reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential (ΔΨm), and intrinsic signaling (caspase‐9/‐3‐dependent) pathways in A375.S2/VR cells. Curcumin‐induced apoptosis was also mediated by the EGFR signaling pathway. Combination treatment with curcumin and gefitinib (an EGFR inhibitor) synergistically potentiated the inhibitory effect of cell viability in A375.S2/VR cells. The present study provides new insights into the therapy of vemurafenib‐resistant melanoma and suggests that curcumin might be an encouraging therapeutic candidate for its drug‐resistant treatment.
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•Plumbagin does not affect the cell viability of human EPCs.•Plumbagin suppresses VEGF-promoted EPC migration and tube formation.•Plumbagin reduces VEGF-induced promotion of PLC, Akt ...and ERK activation.•Plumbagin inhibits VEGF-induced promotion of NF-κB and HIF-1 activation in EPCs.•Plumbagin suppress EPC expression and angiogenesis in vivo.
Plumbagin, a naturally occurring naphthoquinone component isolated from the root of Plumbago zeylanica, reduces angiogenesis in human umbilical vein endothelial cells; whether plumbagin also has anti-angiogenic activity in human endothelial progenitor cells (EPCs) has remained unclear. Importantly, the recruitment of bone marrow-derived EPCs promotes physiological and pathological neovascularization. In this study, plumbagin inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human EPCs, without cytotoxic effects. We also found that plumbagin inhibited angiogenesis via the phospholipase C (PLC), Akt, extracellular-signal-regulated kinase (ERK), nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)-1 signaling pathways. In an EPC Matrigel plug assay, plumbagin significantly diminished microvessel formation and EPC-specific marker expression. Our report is the first to reveal that plumbagin reduces EPC-related angiogenesis both in vitro and in vivo. Further evaluations of plumbagin are warranted, to determine its antitumor activity and other angiogenesis-related disorders.
Resveratrol is known to be an effective chemo-preventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this ...study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.
To valorize livestock manure, the present study investigated the production of biochar from cow dung (CD) by microwave pyrolysis. The pore properties and chemical characteristics of CD and CD-based ...biochar products were found to correlate with the process parameters like microwave power (300-1000 W) and residence time (5-20 min). The findings indicated that CD is an excellent biomass based on the richness of lignocellulosic constituents from the results of proximate analysis and thermogravimetric analysis (TGA). Higher calorific values were obtained at mild microwave conditions, giving the maximal enhancement factor 139% in comparison with the calorific value of CD (18.97 MJ/kg). Also, it can be concluded that the biochar product obtained at 800 W for a holding time of 5 min had the maximal BET surface area of 127 m
/g and total pore volume of 0.104 cm
/g, which were microporous and mesoporous in the nitrogen adsorption-desorption adsorption analysis. On the other hand, the CD-based biochar contained oxygen-containing functional groups and inorganic minerals based on the spectroscopic analyses by Fourier-transform infrared spectroscopy (FTIR) and energy-dispersive X-ray spectroscopy (EDS), thus featuring to be prone to hydrophilicity in aqueous solutions.
Imperatorin is a furanocoumarin derivative and an effective ingredient in several Chinese medicinal herbs. It has favorable expectorant, analgesic, and anti-inflammatory effects. In this study, we ...investigated whether imperatorin has protective effects against Dermatophagoides pteronyssinus (Der p)-induced asthma in mice. Lung and bronchial tissues were histopathologically examined through hematoxylin–eosin staining. The concentrations of immunoglobin E (IgE), IgG1, IgG2a in serum and those of T helper 1 (Th1) and two cytokines and eosinophil-activated chemokines in bronchoalveolar lavage fluid (BALF) were detected using an enzyme immunoassay. Histological examination revealed that imperatorin reduced inflammatory cell infiltration, mucus hypersecretion, and endothelial cell hyperplasia. The examination also indicated that imperatorin could reduce the inflammatory cell count in BALF as well as IgE and IgG1 expression in serum, but IgG2a expression was significantly increased. Imperatorin reduced the production of interleukin (IL)-4, IL-5, and IL-13 by Th2, promoted the production of interferon-γ and IL-12 by Th1, and increased the production of IL-10 in bronchoalveolar lavage fluid. These findings suggest that imperatorin has a considerable anti-inflammatory effect on Der p-induced allergic asthma in mice.
Objective To determine the benefit of newborn screening for the long-term prognosis of patients with classic infantile-onset Pompe disease (IOPD). Study design A cohort of patients with classic IOPD ...were diagnosed by newborn screening, treated with recombinant human acid α-glucosidase (rhGAA), and followed prospectively. Outcome measurements included survival, left ventricular mass, serum creatinine kinase, motor function, mental development, and systemic manifestations. Results Ten patients who presented with left ventricular hypertrophy at diagnosis received rhGAA infusions starting at a median age of 16 days (6-34 days). All patients were cross-reactive immunologic material-positive. After a median treatment time of 63 months (range 28-90 months), all could walk independently, and none required mechanical ventilation. All patients had motor capability sufficient for participating in daily activities, but muscle weakness over the pelvic girdle appeared gradually after 2 years of age. Ptosis was present in one-half of the patients, and speech disorders were common. Anti-rhGAA antibody titers were low (median maximal titer value 1:1600, range: undetectable ∼ 1:12 800). Conclusion By studying patients treated since birth who have no significant anti-rhGAA antibody interference, this prospective study demonstrates that the efficacy of rhGAA therapy is high and consistent for the treatment of classic IOPD. This study also exposes limitations of rhGAA treatment. The etiology of the manifestations in these early-treated patients will require further study.
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons. While extracellular Pgk1 (ePgk1) is reported to promote neurite outgrowth, it remains unclear if it can affect ...the survival of dopaminergic cells. To address this, we employed cerebroventricular microinjection (CVMI) to deliver Pgk1 into the brain of larvae and adult zebrafish treated with methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD-like model. The number of dopamine-producing cells in ventral diencephalon clusters of Pgk1-injected, MPTP-treated embryos increased over that of MPTP-treated embryos. Swimming distances of Pgk1-injected, MPTP-treated larvae and adult zebrafish were much longer compared to MPTP-treated samples. The effect of injected Pgk1 on both dopamine-producing cells and locomotion was time- and dose-dependent. Indeed, injected Pgk1 could be detected, located on dopamine neurons. When the glycolytic mutant Pgk1, Pgk1-T378P, was injected into the brain of MPTP-treated zebrafish groups, the protective ability of dopaminergic neurons did not differ from that of normal Pgk1. Therefore, ePgk1 is functionally independent from intracellular Pgk1 serving as an energy supplier. Furthermore, when Pgk1 was added to the culture medium for culturing dopamine-like SH-SY5Y cells, it could reduce the ROS pathway and apoptosis caused by the neurotoxin MPP
. These results show that ePgk1 benefits the survival of dopamine-producing cells and decreases neurotoxin damage.
This study aimed to investigate the relationship of four chronic kidney disease-mineral and bone disorder (CKD-MBD) biomarkers, including intact parathyroid hormone (PTH), fibroblast growth factor 23 ...(FGF23), soluble klotho, and fetuin-A, with aortic stiffness in peritoneal dialysis (PD) patients, comparing those with and without diabetes mellitus (DM). A total of 213 patients (mean age 58 ± 14 years; 81 (38.0%) patients with DM) were enrolled. Their aortic pulse wave velocity (PWV) was measured using pressure applanation tonometry, while serum intact PTH, FGF23, α-klotho, and fetuin-A levels were measured using enzyme-linked immunosorbent assay. Overall, patients with DM had higher aortic PWV than those without (9.9 ± 1.8 vs. 8.6 ± 1.4 m/s, p < 0.001). Among the four CKD-MBD biomarkers, FGF23 levels were significantly lower in DM group (462 127-1790 vs. 1237 251-3120 pg/mL, p = 0.028) and log-FGF23 independently predicted aortic PWV in DM group (β: 0.61, 95% confidence interval: 0.06-1.16, p = 0.029 in DM group; β: 0.10, 95% confidence interval: - 0.24-0.45, p = 0.546 in nonDM group; interaction p = 0.016). In conclusion, the association between FGF23 and aortic PWV was significantly modified by DM status in PD patients.
The recruitment of bone marrow-derived endothelial progenitor cells (EPCs) facilitates physiological and pathological processes involved in new blood vessel synthesis. Glucocerebroside, an extract of ...Cordyceps militaris, inhibits inflammatory cytokine production and monocyte migration, although its anti-angiogenic properties in human EPCs has remained largely unknown up until now. We describe how glucocerebroside reduces migration as well as tube formation induced by vascular endothelial growth factor (VEGF) stimulation in human EPCs, without affecting cell viability. This inhibitory effect was achieved through the focal adhesion kinase (FAK)/c-Src pathways. We also found that glucocerebroside reduced VEGF-promoted upregulation of the transcription factor Runx2 in the EPCs. The in vivo chick embryo chorioallantoic membrane model demonstrated that glucocerebroside reduces new vessel formation. Our investigation is the first to show that glucocerebroside reduces angiogenesis in human EPCs and to describe the underlying mechanisms. Further investigations are needed to examine the effects of glucocerebroside in other angiogenesis-related disorders.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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