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Browsing by Author "Movila, Alexandru"
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Item Age-dependent effects of the recombinant spike protein/SARS-CoV-2 on the M–CSF– and IL-34-differentiated macrophages in vitro(Elsevier, 2021) Duarte, Carolina; Akkaoui, Juliet; Ho, Anny; Garcia, Christopher; Yamada, Chiaki; Movila, Alexandru; Biomedical and Applied Sciences, School of DentistryThe SARS-CoV-2 virus causes elevated production of senescence-associated secretory phenotype (SASP) markers by macrophages. SARS-CoV-2 enters macrophages through its Spike-protein aided by cathepsin (Cat) B and L, which also mediate SASP production. Since M-CSF and IL-34 control macrophage differentiation, we investigated the age-dependent effects of the Spike-protein on SASP-related pro-inflammatory-cytokines and nuclear-senescence-regulatory-factors, and CatB, L and K, in mouse M-CSF- and IL-34-differentiated macrophages. The Spike-protein upregulated SASP expression in young and aged male M-CSF-macrophages. In contrast, only young and aged male IL-34-macrophages demonstrated significantly reduced pro-inflammatory cytokine expression in response to the Spike-protein in vitro. Furthermore, the S-protein elevated CatB expression in young male M-CSF-macrophages and young female IL-34-macrophages, whereas CatL was overexpressed in young male IL-34- and old male M-CSF-macrophages. Surprisingly, the S-protein increased CatK activity in young and aged male M-CSF-macrophages, indicating that CatK may be also involved in the COVID-19 pathology. Altogether, we demonstrated the age- and sex-dependent effects of the Spike-protein on M-CSF and IL-34-macrophages using a novel in vitro mouse model of SARS-CoV-2/COVID-19.Item Bactericidal Efficacy of EdgePRO Er,Cr:YSGG Laser-Activated Irrigation Against a Mature Endodontic Multispecies Biofilm Using an in vitro Infected Tooth Model(2024) Patterson, Samuel B.; Spolnik, Kenneth J.; Gregory, Richard; Ehrlich, Ygal; Movila, AlexandruIntroduction: Treatment goals of non-surgical root canal therapy (nsRCT) include the removal of all organic tissue material, bacterial biofilm and their by-products, and debris materials, in order to disinfect the canal system to a level compatible with healing and to further prevent infection. Standard chemo-mechanical protocols have several well-documented shortcomings and subsequent areas for improvement regarding their disinfection abilities. In recent years, emerging laser technology and its application in root canal therapy has been gaining popularity as a safe and promising tool for advancing endodontic treatment. The newest FDA-approved laser for endodontic application is the EdgePRO Erbium,Chromium-doped:Yttrium-Scandium-Gallium-Garnet (Er,Cr:YSGG) infrared laser operating at a 2780 nm wavelength. Previous in vitro studies using Er,Cr:YSGG lasers have demonstrated their ability to enhanced canal debridement, cleaning, smear layer removal, and bacterial disinfection. Additionally, a few in vivo trails have been completed using this laser type as an adjunct in RCT procedures, which have yielded safe and highly successful results in the clinical setting. However, research specifically using the EdgePro device as well as a standardized protocol for optimal clinical usage of the laser is lacking. Objectives: The aim of this study was to evaluate the bactericidal and biofilm dissolution effects of laser-activated irrigation using the EdgePro laser against a mature multispecies biofilm in an infected tooth model and to assess the potential increased disinfection and cleaning ability compared to a standard needle irrigation protocol. Materials and Methods: Single rooted teeth (n=36) were decoronated to a standardized length of 16mm. The root canals were endodontically prepared using a standard irrigation, hand-filing, and rotary protocol to a final size of ISO 25.06 while maintaining a fully patent apical foramen. An irrigation solution reservoir was created in the coronal 4 mm of the canal space. Sterile specimens were inoculated with multispecies bacterial sample containing E. faecalis. The mixed bacteria was grown anaerobically for 10 days to form a mature biofilm using a previously established protocol. The teeth were divided into a negative control group (saline rinse, n=12), positive control group (standard needle irrigation – SNI, n=12), and an experimental group (laser-assisted treatment protocol, n=12). The positive control and experimental laser groups utilized the same irrigation solutions of 2 mL 17% EDTA followed by 5 mL 3% NaOCl using a standard 27-gauge side-vented irrigation needle placed as far apically as possible without binding. The experimental group underwent additional laser activation using laser tip #2 (350 m diameter) and settings of: 15 mJ, 0.75 W, 50 Hz, 0% air, and 0% water spray (Mid-Root Solutions 1 preset). The laser tip was inserted halfway into the irrigation filled canals (8 mm from orifice and apex) and fired upon withdrawal at a speed of 0.8 mm/sec, which comprised a single lasing cycle of 10 seconds. Three lasing cycles were completed with EDTA first followed by NaOCl, for a total of six lasing cycles with 60 seconds of irradiation time per tooth. A final rinse of sterile saline was used in all tooth samples prior to bacterial sample collection via Versa-brushes and sterile paper points. The samples were transferred to a laboratory setting where they underwent ultrasonic agitation, serial dilution, spiral plating on blood-agar, and two days of anaerobic incubation for assessment of bacterial growth. Colony forming units (CFUs/mL) were counted as a means of quantitative analysis. Results: The negative control group yielded the highest level of bacterial growth with an average of 934,771 CFUs/mL. The positive control group displayed a statistically significant lower amount of bacterial growth with an average of 4,698 CFUs/mL and yielded 1 sample with no bacterial growth. The experimental laser group had statistically significant lower bacterial growth present compared to both the positive and negative control groups and produced all negative bacterial samples with none of the 12 agar plates demonstrating CFU growth and averaged 0 CFUs/mL.. Conclusion: Within the scope of this study, laser-activated irrigation (LAI) using the EdgePro Er,Cr:YSGG laser was capable of producing no detectable bacterial samples in an in vitro infected tooth model. EdgePro LAI displayed statistically significant superior cleaning and disinfection of infected canal space compared to teeth treated with standard needle irrigation alone. The EdgePro laser system indeed shows promise as an adjunctive tool in clinical root canal treatment procedures. Further investigation is warranted using similar protocols in teeth with more complicated anatomy and with supplemental methods for analyzing bactericidal potential.Item Clinical and Radiological Deterioration in a Case of Creutzfeldt–Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration(MDPI, 2021-11-19) Ciolac, Dumitru; Racila, Renata; Duarte, Carolina; Vasilieva, Maria; Manea, Diana; Gorincioi, Nadejda; Condrea, Alexandra; Crivorucica, Igor; Zota, Eremei; Efremova, Daniela; Crivorucica, Veaceslav; Ciocanu, Mihail; Movila, Alexandru; Groppa, Stanislav A.; Biomedical and Applied Sciences, School of DentistrySystemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt-Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD are unknown. In this study, we describe the case of an elderly female patient with sporadic CJD that exhibited clinical deterioration with the emergence of seizures and radiological neurodegenerative progression following an infection with SARS-CoV-2 and severe COVID-19. Despite efforts to control the progression of the disease, a dismal outcome ensued. This report further evidences the age-dependent neurological effects of SARS-CoV-2 infection and proposes a vulnerability to CJD and increased CJD progression following COVID-19.Item Contribution of Porphyromonas gingivalis lipopolysaccharide to experimental periodontitis in relation to aging(Springer, 2021) Akkaoui, Juliet; Yamada, Chiaki; Duarte, Carolina; Ho, Anny; Vardar-Sengul, Saynur; Kawai, Toshihisa; Movila, Alexandru; Biomedical and Applied Sciences, School of DentistryAging is associated with increased prevalence and severity of pathogenic outcomes of periodontal disease, including soft tissue degeneration and bone loss around the teeth. Although lipopolysaccharide (LPS) derived from the key periodontal pathogen Porphyromonas gingivalis (Pg) plays an important role in the promotion of inflammation and osteoclastogenesis via toll-like receptor (TLR)4 signaling, its pathophysiological role in age-associated periodontitis remains unclear. This study investigated the possible effects of Pg-LPS on RANKL-primed osteoclastogenesis and ligature-induced periodontitis in relation to aging using young (2 months old) and aged (24 months old) mice. To the best of our knowledge, our results indicated that expression of TLR4 was significantly diminished on the surface of osteoclast precursors isolated from aged mice compared with that of young mice. Furthermore, our data demonstrated that the TLR4 antagonist (TAK242) dramatically decreased the numbers of tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts differentiated from RANKL-primed young osteoclast precursors (OCPs) compared with those isolated from aged mice in response to Pg-LPS. In addition, using a ligature-induced periodontitis mouse model, we demonstrated that Pg-LPS elevated (1) secretion of senescence-associated secretory phenotype (SASP) markers, including the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, as well as osteoclastogenic RANKL, and (2) the number of OCPs and TRAP+ osteoclasts in the periodontal lesion induced in young mice. In contrast, Pg-LPS had little, or no, effect on the promotion of periodontitis inflammation induced in aged mice. Altogether, these results indicated that periodontal disease in older mice occurs in a manner independent of canonical signaling elicited by the Pg-LPS/TLR4 axis.Item Crosstalk between dihydroceramides produced by Porphyromonas gingivalis and host lysosomal cathepsin B in the promotion of osteoclastogenesis(Wiley, 2022) Duarte, Carolina; Yamada, Chiaki; Garcia, Christopher; Akkaoui, Juliet; Ho, Anny; Nichols, Frank; Movila, Alexandru; Biomedical Sciences and Comprehensive Care, School of DentistryEmerging studies indicate that intracellular eukaryotic ceramide species directly activate cathepsin B (CatB), a lysosomal-cysteine-protease, in the cytoplasm of osteoclast precursors (OCPs) leading to elevated RANKL-mediated osteoclastogenesis and inflammatory osteolysis. However, the possible impact of CatB on osteoclastogenesis elevated by non-eukaryotic ceramides is largely unknown. It was reported that a novel class of phosphoglycerol dihydroceramide (PGDHC), produced by the key periodontal pathogen Porphyromonas gingivalis upregulated RANKL-mediated osteoclastogenesis in vitro and in vivo. Therefore, the aim of this study was to evaluate a crosstalk between host CatB and non-eukaryotic PGDHC on the promotion of osteoclastogenesis. According to a pulldown assay, high affinity between PGDHC and CatB was observed in RANKL-stimulated RAW264.7 cells in vitro. It was also demonstrated that PGDHC promotes enzymatic activity of recombinant CatB protein ex vivo and in RANKL-stimulated osteoclast precursors in vitro. Furthermore, no or little effect of PGDHC on the RANKL-primed osteoclastogenesis was observed in male and female CatB-knock out mice compared with their wild type counterparts. Altogether, these findings demonstrate that bacterial dihydroceramides produced by P. gingivalis elevate RANKL-primed osteoclastogenesis via direct activation of intracellular CatB in OCPs.Item Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels(MDPI, 2023-01-03) Ludwig, Nora; Demaree, Isaac S.; Yamada, Chiaki; Nusbaum, Amilia; Nichols, Frank C.; White, Fletcher A.; Movila, Alexandru; Obukhov, Alexander G.; Anatomy, Cell Biology and Physiology, School of MedicineBacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections.Item Dissecting the Spectrum of Stroke Risk Factors in an Apparently Healthy Population: Paving the Roadmap to Primary Stroke Prevention(MDPI, 2023-01-20) Efremova, Daniela; Ciolac, Dumitru; Zota, Eremei; Glavan, Danu; Ciobanu, Natalia; Aulitzky, Wolfgang; Nics, Anna Maria; Trinka, Eugen; Yamada, Chiaki; Movila, Alexandru; Groppa, Stanislav A.; Biomedical Sciences and Comprehensive Care, School of DentistryWe aimed to investigate, for the first time, the spectrum of stroke risk factors specific to the population of the Republic of Moldova. The subjects were examined according to a pre-established protocol of risk factor estimation. The study involved 300 subjects, including 60% women and 40% men, with a mean age of 49.9 ± 14.5 years. The most common risk factor was abdominal obesity, identified in 75% of subjects; general obesity was detected in 48%, while 32% of subjects were overweight and 20% were normally weighted. Hypertension was observed in 44%; 8% of those examined had atrial fibrillation, and 9% had diabetes mellitus. Left myocardial hypertrophy on ECG was present in 53% of subjects, and acute ischemic changes in 2%. Laboratory observations detected that glycosylated hemoglobin increased by 7%, and >50% had dyslipidemia. Total cholesterol was significantly elevated by 58%, LDL-cholesterol was increased by 32%, and HDL-cholesterol was decreased by 9%. Homocysteine was increased in 55% and high-sensitivity C-reactive protein in 28% of subjects. These results indicate the presence of modifiable risk factors and the necessity to elaborate on the primary prevention strategies aimed at minimizing the burden of stroke in the population of the Republic of Moldova.Item Effectiveness of GentleWave CleanFlow on Multispecies Endodontic Biofilm Removal in Single Rooted Extracted Teeth(2024-06) Beswick, Adam J.; Spolnik, Kenneth J.; Movila, Alexandru; Gregory, Richard L.; Ehrlich, YgalIntroduction: One of the challenges of non-surgical root canal treatment is disinfection. Bacterial biofilms adhere to canal walls and invade the intricate anatomy present within root canal systems. Traditional irrigation methods are unable to deliver irrigation solutions to all parts of the canal system. The GentleWave system is an advanced irrigation method designed to improve irrigation and disinfection, ultimately leading to more successful root canal outcomes. Objective: The aim of this study is to evaluate the GentleWave CleanFlow posterior instrument’s ability to remove a multispecies biofilm from a single canaled extracted tooth compared to traditional irrigation techniques. Materials and Methods: Thirty-six single rooted premolar teeth with single canals were prepared to a uniform size, instrumented to size 25.06 and inoculated with a multispecies bacterial biofilm taken from an adult tooth with pulpal necrosis. Teeth were incubated and biofilm established before teeth were disinfected. Three disinfection groups included: GentleWave irrigation using the Posterior CleanFlow Procedure Instrument on the necrotic tooth cycle, standard needle irrigation with 2.5% NaOCl and 8% EDTA, and needle irrigation with sterile water. Following treatment, canals were swabbed and plated on blood agar plates and incubated for 48 hours when colony forming units were counted. Results: Both GW and standard needle irrigation demonstrated significantly lower CFU/mL than the negative control (p<0.001). However, the GW and positive control groups were not significantly different from one another (p=0.132). Conclusion: The findings of this study suggest that the GentleWave Posterior CleanFlow procedure instrument does not exhibit improved biofilm removal compared to standard needle irrigation. However, based on mixed results when comparing this study to previous GentleWave biofilm removal studies, it is clear that more research is necessary. Future studies should considering using a multispecies biofilm, the GentleWave CleanFlow procedure instrument and multiple techniques to assess biofilm removal.Item Effects of IL-34 and anti-IL-34 neutralizing mAb on alveolar bone loss in a ligature-induced model of periodontitis(Wiley, 2023-10-30) Duarte, Carolina; Yamada, Chiaki; Ngala, Bidii; Garcia, Christopher; Akkaoui, Juliet; Birsa, Maxim; Ho, Anny; Nusbaum, Amilia; AlQallaf, Hawra; John, Vanchit; Movila, Alexandru; Periodontology, School of DentistryMacrophage colony-stimulating factor (M-CSF) and interleukin-34 (IL-34) are ligands for the colony-stimulating factor-1 receptor (CSF-1r) expressed on the surface of monocyte/macrophage lineage cells. The importance of coordinated signaling between M-CSF/receptor activator of the nuclear factor kappa-Β ligand (RANKL) in physiological and pathological bone remodeling and alveolar bone loss in response to oral bacterial colonization is well established. However, our knowledge about the IL-34/RANKL signaling in periodontal bone loss remains limited. Recently published cohort studies have demonstrated that the expression patterns of IL-34 are dramatically elevated in gingival crevicular fluid collected from patients with periodontitis. Therefore, the present study aims to evaluate the effects of IL-34 on osteoclastogenesis in vitro and in experimental ligature-mediated model of periodontitis using male mice. Our initial in vitro study demonstrated increased RANKL-induced osteoclastogenesis of IL-34-primed osteoclast precursors (OCPs) compared to M-CSF-primed OCPs. Using an experimental model of ligature-mediated periodontitis, we further demonstrated elevated expression of IL-34 in periodontal lesions. In contrast, M-CSF levels were dramatically reduced in these periodontal lesions. Furthermore, local injections of mouse recombinant IL-34 protein significantly elevated cathepsin K activity, increased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and promoted alveolar bone loss in periodontitis lesions. In contrast, anti-IL-34 neutralizing monoclonal antibody significantly reduced the level of alveolar bone loss and the number of TRAP-positive osteoclasts in periodontitis lesions. No beneficial effects of locally injected anti-M-CSF neutralizing antibody were observed in periodontal lesions. This study illustrates the role of IL-34 in promoting alveolar bone loss in periodontal lesions and proposes the potential of anti-IL34 monoclonal antibody (mAb)-based therapeutic regimens to suppress alveolar bone loss in periodontitis lesions.Item From the Mind to the Spine: The Intersecting World of Alzheimer's and Osteoporosis(Springer, 2024) Margetts, Tyler J.; Wang, Hannah S.; Karnik, Sonali J.; Plotkin, Lilian I.; Movila, Alexandru; Oblak, Adrian L.; Fehrenbacher, Jill C.; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicinePurpose of review: This comprehensive review delves into the intricate interplay between Alzheimer's disease (AD) and osteoporosis, two prevalent conditions with significant implications for individuals' quality of life. The purpose is to explore their bidirectional association, underpinned by common pathological processes such as aging, genetic factors, inflammation, and estrogen deficiency. Recent findings: Recent advances have shown promise in treating both Alzheimer's disease (AD) and osteoporosis by targeting disease-specific proteins and bone metabolism regulators. Monoclonal antibodies against beta-amyloid and tau for AD, as well as RANKL and sclerostin for osteoporosis, have displayed therapeutic potential. Additionally, ongoing research has identified neuroinflammatory genes shared between AD and osteoporosis, offering insight into the interconnected inflammatory mechanisms. This knowledge opens avenues for innovative dual-purpose therapies that could address both conditions, potentially revolutionizing treatment approaches for AD and osteoporosis simultaneously. This review underscores the potential for groundbreaking advancements in early diagnosis and treatment by unraveling the intricate connection between AD and bone health. It advocates for a holistic, patient-centered approach to medical care that considers both cognitive and bone health, ultimately aiming to enhance the overall well-being of individuals affected by these conditions. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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