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PLoS Neglected Tropical Diseases May 2024Photobiomodulation has exhibited promise in mitigating the local effects induced by Bothrops snakebite envenoming; however, the mechanisms underlying this protection are...
BACKGROUND
Photobiomodulation has exhibited promise in mitigating the local effects induced by Bothrops snakebite envenoming; however, the mechanisms underlying this protection are not yet fully understood. Herein, the effectiveness of photobiomodulation effects on regenerative response of C2C12 myoblast cells following exposure to Bothrops jararacussu venom (BjsuV), as well as the mechanisms involved was investigated.
METHODOLOGY/PRINCIPAL FINDINGS
C2C12 myoblast cells were exposed to BjsuV (12.5 μg/mL) and irradiated once for 10 seconds with laser light of 660 nm (14.08 mW; 0.04 cm2; 352 mW/cm2) or 780 nm (17.6 mW; 0.04 cm2; 440 mW/ cm2) to provide energy densities of 3.52 and 4.4 J/cm2, and total energies of 0.1408 and 0.176 J, respectively. Cell migration was assessed through a wound-healing assay. The expression of MAPK p38-α, NF-Кβ, Myf5, Pax-7, MyoD, and myogenin proteins were assessed by western blotting analysis. In addition, interleukin IL1-β, IL-6, TNF-alfa and IL-10 levels were measured in the supernatant by ELISA. The PBM applied to C2C12 cells exposed to BjsuV promoted cell migration, increase the expression of myogenic factors (Pax7, MyF5, MyoD and myogenin), reduced the levels of proinflammatory cytokines, IL1-β, IL-6, TNF-alfa, and increased the levels of anti-inflammatory cytokine IL-10. In addition, PBM downregulates the expression of NF-kB, and had no effect on p38 MAKP.
CONCLUSION/SIGNIFICANCE
These data demonstrated that protection of the muscle cell by PBM seems to be related to the increase of myogenic factors as well as the modulation of inflammatory mediators. PBM therapy may offer a new therapeutic strategy to address the local effects of snakebite envenoming by promoting muscle regeneration and reducing the inflammatory process.
Topics: Animals; Bothrops; Myoblasts; Mice; Low-Level Light Therapy; Cytokines; Cell Line; Crotalid Venoms; Myogenin; PAX7 Transcription Factor; NF-kappa B; MyoD Protein; Cell Movement; Myogenic Regulatory Factor 5; p38 Mitogen-Activated Protein Kinases; Snake Bites; Venomous Snakes
PubMed: 38814992
DOI: 10.1371/journal.pntd.0012227 -
Cell Death & Disease May 2024The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as...
The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.
Topics: Humans; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; HCT116 Cells; Proteasome Endopeptidase Complex; Apoptosis; Phosphoinositide-3 Kinase Inhibitors; MCF-7 Cells; Proteolysis; A549 Cells; Wortmannin; Senotherapeutics; Class I Phosphatidylinositol 3-Kinases; DNA Damage; Pyrimidines; Quinazolines
PubMed: 38811535
DOI: 10.1038/s41419-024-06755-x -
Pharmacological Research Jul 2024Coronavirus disease 2019 (COVID-19) affected people worldwide, and fever is one of the major symptoms of this disease. Although Acetaminophen (APAP) is a common...
Coronavirus disease 2019 (COVID-19) affected people worldwide, and fever is one of the major symptoms of this disease. Although Acetaminophen (APAP) is a common fever-reducing medication, it can also mediate liver injury. However, the role of PGC-1α in regulating mitochondrial quality control by lactate dehydrogenase B (LDHB), a vital enzyme catalyzing the conversion of lactate to pyruvate, in APAP-induced hepatotoxicity, is unclear. Here, gene expression omnibus data of patients with APAP-induced liver injury were used to explore gene expression profiles. AML12 cells and C57/BL6 mice were used to establish models of APAP-induced acute liver injury. SIRT1 and PGC-1α were overexpressed in vitro via lentiviral transfection to establish stable cell lines. The results showed that APAP treatment decreased SIRT1/PGC-1α/LDHB expression and increased protein lactylation, mitochondrial lactate levels, and pathological damage in liver mitochondria. PGC-1α upregulation or activation ameliorated APAP-induced damage in the cells and liver. Furthermore, PGC-1α overexpression increased LDHB synthesis, reduced lactylation, and induced a switch from lactate to pyruvate production. These results suggest that PGC-1α and LDHB play a role in APAP-induced liver injury by regulating mitochondrial quality control and lactate metabolic reprogramming. Therefore, the PGC-1α/LDHB axis is a potential therapeutic target for APAP-induced liver injury.
Topics: Animals; Acetaminophen; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Chemical and Drug Induced Liver Injury; Mice, Inbred C57BL; Mice; Humans; Male; L-Lactate Dehydrogenase; Lactic Acid; Mitochondrial Proteins; Cell Line; Mitochondria, Liver; Sirtuin 1; Isoenzymes
PubMed: 38810904
DOI: 10.1016/j.phrs.2024.107228 -
Physics and Imaging in Radiation... Apr 2024Dynamic trajectory radiotherapy (DTRT) has been shown to improve healthy tissue sparing compared to volumetric arc therapy (VMAT). This study aimed to assess and compare...
BACKGROUND AND PURPOSE
Dynamic trajectory radiotherapy (DTRT) has been shown to improve healthy tissue sparing compared to volumetric arc therapy (VMAT). This study aimed to assess and compare the robustness of DTRT and VMAT treatment-plans for head and neck (H&N) cancer to patient-setup (PS) and machine-positioning uncertainties.
MATERIALS AND METHODS
The robustness of DTRT and VMAT plans previously created for 46 H&N cases, prescribed 50-70 Gy to 95 % of the planning-target-volume, was assessed. For this purpose, dose distributions were recalculated using Monte Carlo, including uncertainties in PS (translation and rotation) and machine-positioning (gantry-, table-, collimator-rotation and multi-leaf collimator (MLC)). Plan robustness was evaluated by the uncertainties' impact on normal tissue complication probabilities (NTCP) for xerostomia and dysphagia and on dose-volume endpoints. Differences between DTRT and VMAT plan robustness were compared using Wilcoxon matched-pair signed-rank test ( = 5 %).
RESULTS
Average NTCP for moderate-to-severe xerostomia and grade ≥ II dysphagia was lower for DTRT than VMAT in the nominal scenario (0.5 %, p = 0.01; 2.1 %, p < 0.01) and for all investigated uncertainties, except MLC positioning, where the difference was not significant. Average differences compared to the nominal scenario were 3.5 Gy for rotational PS ( 3°) and machine-positioning ( 2°) uncertainties, <7 Gy for translational PS uncertainties ( 5 mm) and < 20 Gy for MLC-positioning uncertainties ( 5 mm).
CONCLUSIONS
DTRT and VMAT plan robustness to the investigated uncertainties depended on uncertainty direction and location of the structure-of-interest to the target. NTCP remained on average lower for DTRT than VMAT even when considering uncertainties.
PubMed: 38808098
DOI: 10.1016/j.phro.2024.100586 -
Frontiers in Public Health 2024Treatments that currently exist in the strategic national stockpile for acute radiation syndrome (ARS) focus on the hematopoietic subsyndrome, with no treatments on...
INTRODUCTION
Treatments that currently exist in the strategic national stockpile for acute radiation syndrome (ARS) focus on the hematopoietic subsyndrome, with no treatments on gastrointestinal (GI)-ARS. While the gut microbiota helps maintain host homeostasis by mediating GI epithelial and mucosal integrity, radiation exposure can alter gut commensal microbiota which may leave the host susceptible to opportunistic pathogens and serious sequelae such as sepsis. To mitigate the effects of hematopoietic ARS irradiation, currently approved treatments exist in the form of colony stimulating factors and antibiotics: however, there are few studies examining how these therapeutics affect GI-ARS and the gut microbiota. The aim of our study was to examine the longitudinal effects of Neulasta and/or ciprofloxacin treatment on the gut microbiota after exposure to 9.5 Gy Co gamma-radiation in mice.
METHODS
The gut microbiota of vehicle and drug-treated mice exposed to sham or gamma-radiation was characterized by shotgun sequencing with alpha diversity, beta diversity, and taxonomy analyzed on days 2, 4, 9, and 15 post-irradiation.
RESULTS
No significant alpha diversity differences were observed following radiation, while beta diversity shifts and taxonomic profiles revealed significant alterations in , , and . Ciprofloxacin generally led to lower Shannon diversity and prevalence with increases in and compared to vehicle treated and irradiated mice. While Neulasta increased Shannon diversity and by day 9 had more similar taxonomic profiles to sham than ciprofloxacin-or vehicle-treated irradiated animals. Combined therapy of Neulasta and ciprofloxacin induced a decrease in Shannon diversity and resulted in unique taxonomic profiles early post-irradiation, returning closer to vehicle-treated levels over time, but persistent increases in and compared to Neulasta alone.
DISCUSSION
This study provides a framework for the identification of microbial elements that may influence radiosensitivity, biodosimetry and the efficacy of potential therapeutics. Moreover, increased survival from H-ARS using these therapeutics may affect the symptoms and appearance of what may have been subclinical GI-ARS.
Topics: Animals; Ciprofloxacin; Gastrointestinal Microbiome; Mice; Anti-Bacterial Agents; Acute Radiation Syndrome; Gamma Rays; Male; Female
PubMed: 38807988
DOI: 10.3389/fpubh.2024.1365161 -
Dental Research Journal 2024The presence of treatment-resistant microorganisms is known as the main cause of pulpectomy failure in the endodontic treatment of deciduous teeth. The usage of lasers...
BACKGROUND
The presence of treatment-resistant microorganisms is known as the main cause of pulpectomy failure in the endodontic treatment of deciduous teeth. The usage of lasers can contribute to reducing these microorganisms. This study aimed to compare the effect of three disinfection methods for deciduous teeth canals using laser diode 810 nm, photodynamic therapy with laser 660 nm and methylene blue, and sodium hypochlorite.
MATERIALS AND METHODS
In this experimental study, 58 single-root deciduous teeth with no root resorption were investigated in four groups, including one control group of 10 and three intervention groups of 16. Preparation of the samples was done using manual files up to three numbers after the initial file. After sterilizing the samples in an autoclave, bacteria were cultured in the canals. In the first group, irrigating with hypochlorite 2.5% was done; in the second group, photodynamic therapy was performed using a laser diode and 0.1 mg/mL methylene solution; and in the third group, high-intensity laser 810 nm direct radiation was done into the canal. Next, samples were taken from all canals. The colony formation unit (CFU) of the bacteria was counted in the blood agar culture medium. The data were analyzed using Kruskal-Wallis and negative binomial regression test (α =0.05).
RESULTS
The mean CFU differed significantly between the four groups. The rate of incidence of colonies showed a reduction in all three intervention groups compared to the negative control. In the high-intensity laser 810 nm group, there was 68.4%; in the photodynamic therapy with diode 660 nm and methylene blue, there was 88%; and in the hypochlorite group, 98.3% reduction was observed compared to the negative control group.
CONCLUSION
Based on the results of this study, to compare three disinfection methods of the deciduous teeth canals without preparation of canals, sodium hypochlorite had greater efficiency. All three groups of laser, photodynamic therapy, and sodium hypochlorite showed reductions of bacterial colony compared to the control group. The reductive effects of CFU were greater in the hypochlorite sodium group, followed by photodynamic and direct laser radiation groups.
PubMed: 38807661
DOI: No ID Found -
Journal of Environmental Radioactivity Jul 2024In recent years, there has been a significant surge in interest in measuring low radon levels in the environment. These measurements are valuable, particularly for...
In recent years, there has been a significant surge in interest in measuring low radon levels in the environment. These measurements are valuable, particularly for identifying radon priority areas as required by the European Council Directive 2013/59/EURATOM and for research related to climate change. Due to the limited sensitivity of existing radon detectors/monitors in addressing these challenges, substantial efforts have been devoted to developing new designs. This report compares the sensitivity of several innovative designs with that of existing passive radon monitors. These novel designs incorporate alpha track detectors, including large area low background detectors, with activated carbon fabric used as an efficient radon adsorber/radiator. Recent innovative solutions to mitigate the impact of temperature and humidity on detectors using adsorbers are also discussed. The background signal of detectors intended for use in these novel designs is examined, and their sensitivity is evaluated. The findings demonstrate that these novel designs have the potential to significantly enhance the sensitivity of long-term radon measurements, surpassing the detectors currently in widespread use by more than an order of magnitude.
Topics: Radon; Radiation Monitoring; Air Pollutants, Radioactive; Air Pollution, Indoor
PubMed: 38805778
DOI: 10.1016/j.jenvrad.2024.107461 -
Lasers in Medical Science May 2024Conventional approaches for enhancing wound healing may not always yield satisfactory results. Instead, we test the effectiveness of a newly developed photodynamic...
PURPOSE
Conventional approaches for enhancing wound healing may not always yield satisfactory results. Instead, we test the effectiveness of a newly developed photodynamic therapy (PDT) that uses methylene blue (MB) loaded with polyethylene glycol (PEG) (MB-PEG) hydrogel to accelerate wound healing process in mice.
METHODS
A dorsal skin incision with 6 mm punch which topically subjected to MB-PEG hydrogel and a low-level laser light of red light to assess the regeneration process of wounded skin. A total of 63 adult male CD1 mice divided into normal group (no treatment) and other wound groups received different treatments of laser (650 ± 5 nm and power intensity of 180 mW/cm), MB-PEG, or PDT (MB-PEG followed by laser). The wound healing parameters were investigated by histological examination of the skin and measuring of proinflammatory cytokines at the early stage (48 h) and a late one on day 21.
RESULTS
at 48 h, the score of tissue granulation, inflammation, and angiogenesis process were markedly improved in wounded groups that received MB + PEG combined with laser compared to the group treated with laser alone. On day 21, a significant improvement of the inflammation was detected in the group treated with MB + PEG plus laser compared to the other groups. At 48 h, the upregulated serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the wound group were significantly (P < 0.001) reduced in the group treated with MB + PEG combined with laser.
CONCLUSION
MB-PEG based hydrogel improves and accelerates wound closure in the context of laser compared to either single treatment.
Topics: Animals; Wound Healing; Mice; Photochemotherapy; Polyethylene Glycols; Methylene Blue; Male; Skin; Hydrogels; Photosensitizing Agents; Cytokines
PubMed: 38801600
DOI: 10.1007/s10103-024-04084-1 -
Neuro-oncology Advances 2024Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in...
BACKGROUND
Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas.
METHODS
Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry.
RESULTS
The MTD of minocycline was 150 mg twice per day ( = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1.
CONCLUSIONS
Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.
PubMed: 38800698
DOI: 10.1093/noajnl/vdae063 -
Journal of Hepatocellular Carcinoma 2024The combination of radiotherapy and monoclonal antibody against programmed cell death 1 (anti-PD1) showed preliminary efficacy in hepatocellular carcinoma (HCC). This...
PURPOSE
The combination of radiotherapy and monoclonal antibody against programmed cell death 1 (anti-PD1) showed preliminary efficacy in hepatocellular carcinoma (HCC). This study aimed to identify the prognostic factors and construct a nomogram to predict the overall survival (OS) of patients with advanced HCC after treatment with intensity-modulated radiotherapy (IMRT) plus anti-PD1.
PATIENTS AND METHODS
The OS and progression-free survival (PFS) of 102 patients with BCLC stage C HCC was analyzed using the Kaplan-Meier method. Potential independent prognostic factors were determined using univariate and multivariate Cox regression analyses. A nomogram was established to predict prognosis whose accuracy and reliability was verified by a calibration curve and area under the receiver operating characteristic curve (AUROC).
RESULTS
The median PFS and OS rates of the 102 patients with advanced HCC were 9.9 months and 14.3 months, respectively. Ninety-three patients were evaluated for efficacy, including five (5.38%) with complete response and 48 (51.61%) with partial response, with an overall response rate of 56.99%. Grade 3 and 4 adverse reactions (AEs) were observed in 32.35% of patients; no grade 5 AEs occurred. Multivariate Cox analysis revealed albumin and alpha-fetoprotein levels, neutrophil counts 3-4 weeks after IMRT initiation, and platelet-to-lymphocyte ratio 3-4 weeks after IMRT initiation to be independent prognostic factors. The nomogram model constructed using these factors had good consistency and accuracy with 1-3 years AUROC of 78.7, 78.6, and 93.5, respectively.
CONCLUSION
IMRT plus anti-PD1 showed promising efficacy and controllable adverse reactions in treating advanced HCC. The nomogram model demonstrated good reliability and clinical applicability.
PubMed: 38799002
DOI: 10.2147/JHC.S459683