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The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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Neural Regeneration Research 2025年第4期20卷 1153-1163页

作者： Susana Mellado María JoséMorillo-Bargues Carla Perpiñá-Clérigues Francisco García-García Victoria Moreno-Manzano Consuelo Guerri María Pascual Department of Physiology School of Medicine and DentistryUniversity of ValenciaValenciaSpain Bioinformatics and Biostatistics Unit Príncipe Felipe Research CenterValenciaSpain Neuronal and Tissue Regeneration Laboratory Príncipe Felipe Research CenterValenciaSpain

Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain *** stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent *** the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge *** demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent *** analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling *** together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

关键词： adolescence binge-like ethanol treatment extracellular vesicles hippocampus mesenchymal stem cells neuroinflammation NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)

Regulation of sleep by astrocytes in the hypothalamic ventrolateral preoptic nucleus

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Neural Regeneration Research 2025年第4期20卷 1098-1100页

作者： Jae-Hong Kim Ruqayya Afridi Il-Sung Jang Maan Gee Lee Kyoungho Suk Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents School of MedicineKyungpook National UniversityDaeguRepublic of Korea Department of Pharmacology School of MedicineKyungpook National UniversityDaeguRepublic of Korea Department of Pharmacology School of DentistryKyungpook National UniversityDaeguRepublic of Korea Brain Science&Engineering Institute Kyungpook National UniversityDaeguRepublic of Korea

Astrocytes are functionally dynamic cells that support neurons in multiple ways throughout an organism’s *** astrocytic regulation of neuronal activity has been increasingly recognized in recent *** are now recognized as playing a more complex role than mere bystanders in the central nervous ***,their role in regulating the sleep neurocircuitry is not well *** this perspective,we highlight the role of astrocytes in sleep modulation,with a particular focus on regulatory mechanisms related to the ventrolateral preoptic nucleus(VLPO)of the *** briefly discuss recent literature reporting the role of VLPO astrocytes in regulating sleep-associated behaviors.

关键词： sleep ventrolateral astrocytes

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu Michael Chopp Michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of Pathology Henry Ford HospitalDetroitMIUSA Division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

Intragingival injection of Porphyromonas gingivalis-derived lipopolysaccharide induces a transient increase in gingival tumour necrosis factor-a, but not interleukin-6,in anaesthetised rats

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International Journal of Oral Science 2015年第3期7卷 155-160页

作者： Hiroko Taguchi Yuri Aono Takayuki Kawato Masatake Asano Noriyoshi Shimizu Tadashi Saigusa Department of Orthodontics Nihon University School of Dentistry Department of Pharmacology Nihon University School of Dentistry at Matsudo Department of Pharmacology Nihon University School of Dentistry Department of Oral Health Sciences Nihon University School of Dentistry Department of Pathology Nihon University School of Dentistry

This study used in vivo microdialysis to examine the effects of intragingival application of lipopolysaccharide（LPS） derived from Porphyromonas gingivalis（Pg-LPS） on gingival tumour necrosis factor（TNF）-a and interleukin（IL）-6 levels in rats. A microdialysis probe with an injection needle attached to the surface of the dialysis membrane was implanted into the gingiva of the upper incisor. For comparison, the effects of LPS derived from Escherichia coli（Ec-LPS） on IL-6 and TNF-a levels were also analysed. Pg-LPS（1 mg/1 m L） or Ec-LPS（1 or 6 mg/1 m L） was applied by microsyringe, with gingival dialysates collected every hour. Enzyme-linked immunosorbent assay（ELISA） revealed that gingival dialysates contained approximately 389 pg？m L21 of IL-6 basally; basal TNF-a levels were lower than the detection limit of the ELISA. Pg-LPS failed to alter IL-6 levels but markedly increased TNF-a levels, which remained elevated for 2 h after treatment. Neither IL-6 nor TNF-a were affected by Ec-LPS. Reverse transcriptase-polymerase chain reaction（RT-PCR） analysis revealed that the gingiva expresses Toll-like receptor（TLR） 2 and TLR4 m RNA. Immunohistochemical examination showed that TLR2 and TLR4 are expressed by gingival epithelial cells. The present study provides in vivo evidence that locally applied Pg-LPS, but not Ec-LPS, into the gingiva transiently increases gingival TNF-a without affecting IL-6. The present results suggest that TLR2 but not TLR4 expressed on gingival epithelial cells may mediate the Pg-LPS-induced increase in gingival TNF-a in rats.

关键词： Porphyromonas gingivalis lipopolysaccharide gingiva tumour necrosis factor-a microdialysis

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

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Neural Regeneration Research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn J.W.So Konstantin Feinberg Marina Manoraj Jenny Cheung Jennifer Zhang Kaveh Mirmoeini JPaul Santerre Tessa Gordon Gregory HBorschel SickKids Research Institute Neuroscience and Mental Health ProgramTorontoONCanada Institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University school of Medicine IndianapolisINUSA Division of Plastic and Reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering Program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic *** its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

关键词： biodegradable local drug delivery nerve injury nerve regeneration nerve wrap tacrolimus

Residual activity of cetrimide and chlorhexidine on Enterococcus faecalis-infected root canals

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International Journal of Oral Science 2014年第1期6卷 46-49页

作者： Carmen María Ferrer-Luque María Teresa Arias-Moliz Matilde Ruíz-Linares María Elena Martínez García Pilar Baca Department of Stomatology School of Dentistry University of Granada Department of Microbiology School of Dentistry University of Granada

Effective final irrigation regimen is an important step in order to achieve better disinfection and ensure residual antimicrobial effects after root canal preparation. The aim of this study was to compare the residual antimicrobial activity of 0.2% cetrimide, and 0.2% and 2% chlorhexidine in root canals infected with Enterococcus faecalis. Biofilms of E. faecalis were grown on uniradicular roots for 4 weeks. After root canal preparation, root canals were irrigated with 17% ethylenediaminetetraacetic acid （EDTA） to remove the smear layer. The roots were randomly divided into three experimental groups （n=26） according to the final irrigating solution： Group I, 5 mL 0.2% cetrimide; Group II, 5 mL 0.2% chlorhexidine; and Group III, 5 mL 2% chlorhexidine. Samples were collected for 50 days to denote the presence of bacterial growth. The proportion of ungrown specimens over 50 days was evaluated using the nonparametric Kaplan-Meier survival analysis. Differences among groups were tested using the log-rank test and the level of statistical significance was set at P〈0.05. The highest survival value was found with 2% chlorhexidine, showing statistically significant differences from the other two groups. At 50 days, E. faecalisgrowth was detected in 69.23% specimens in Groups I and II, and in 34.61% specimens of Group III. There were no significant differences between 0.2% cetrimide and 0.2% chlorhexidine. Final irrigation with 2% chlorhexidine showed greater residual activity than 0.2% chlorhexidine and 0.2% cetrimide in root canals infected with E. faecalis.

关键词： antimicrobial effects biofilms cetrimide chlorhexidine Enterococcus faecalis final irrigation residual activity

Inhibition of matrix metalloproteinases expression in human dental pulp cells by all-trans retinoic acid

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International Journal of Oral Science 2014年第3期6卷 150-153页

作者： Jin Man Kim Sang Wook Kang Su-Mi Shin Duck Su Kim Kyong-Kyu Choi Eun-Cheol Kim Sun-Young Kim Department of Conservative dentistry School of Dentistry Kyung Hee University Department of Maxillofacial Tissue Regeneration School of Dentistry Kyung Hee University

All-trans retinoic acid（ATRA） inhibits matrix metalloproteinase（MMP）-2 and MMP-9 in synovial fibroblasts, skin fibroblasts,bronchoalveolar lavage cells and cancer cells, but activates MMP-9 in neuroblast and leukemia cells. Very little is known regarding whether ATRA can activate or inhibit MMPs in human dental pulp cells（HDPCs）. The purpose of this study was to determine the effects of ATRA on the production and secretion of MMP-2 and-9 in HDPCs. The productions and messenger RNA（mRNA） expressions of MMP-2 and-9 were accessed by gelatin zymography and real-time polymerase chain reaction（PCR）, respectively. ATRA was found to decrease MMP-2 level in a dose-dependent manner. Significant reduction in MMP-2 mRNA expression was also observed in HDPCs treated with 25 mmol？L21ATRA. However, HDPCs treated with ATRA had no effect on the pattern of MMP-9 produced or secreted in either cell extracts or conditioned medium fractions. Taken together, ATRA had an inhibitory effect on MMP-2 expression in HDPCs,which suggests that ATRA could be a candidate as a medicament which could control the inflammation of pulp tissue in vital pulp therapy and regenerative endodontics.

关键词： all-trans retinoic acid human dental pulp cell matrix metalloproteinase zymography

Dopaminergic effects on in vitro osteogenesis

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Bone Research 2015年第3期3卷 130-139页

作者： Dong Joon Lee Henry C Tseng Sing Wai Wong Zhengyan Wang Meng Deng Ching-Chang Ko NC Oral Health Institute School of Dentistry University of North Carolina Duke Eye Center and Department of Ophthalmology Duke University Medical Center Oral Biology Program School of Dentistry University of North Carolina Department of Pediatric dentistry School of Dentistry University of North Carolina Department of Orthodontics School of Dentistry University of North Carolina

Multiple growth factors（e.g., BMP2, TGF-b1, FGF2） and isolated genes have been shown to improve osteoblastic proliferation and mineralization, advancing bone tissue engineering. Among these factors, both polydopamine（PDA） and dopamine（DA） monomer have recently been reported to increase osteoblast proliferation and mineralization in vitro. Although a well-characterized neurotransmitter, DA＇s role in the bone is unknown. We hypothesize that DA can directly act on osteoblasts, and examined whether osteoblasts express DA receptors that respond to exogenous DA. m RNAs and protein cell lysates were obtained from MC3T3-E1 cells during osteogenic differentiation phase. Reverse transcription polymerase chain reaction and western blot analysis were used to examine the expression of DA receptors, D1–D5. Dose-response effect and time course of DA treatment on cell proliferation, mineralization, and osteogenic differentiation were investigated at pre-determined days. Real-time PCR was performed to investigate whether DA affects osteogenic gene expression（ALP, BSP, OC, OSX, RUNX2, and Collagen1a2） with or without receptor antagonists（SCH233390 and GR103691）. Two-way ANOVA was used for statistical analysis. All five DA receptors（D1, D2, D3, D4, and D5） m RNAs and proteins were expressed in MC3T3-E1 cells. DA treatment increased cell proliferation for up to 7 days（P, 0.05）. Osteogenic mineralization was significantly greater in the DA-treated group than control group（P, 0.05）. Finally, expression of all the osteogenic genes was inhibited by DA receptor antagonists for D1, D3, and D5. Our findings suggest that MC3T3-E1 osteoblasts express functional DA receptors that enhance proliferation and mineralization. PDA is not biologically inert and has important implications in orthopedic applications. Furthermore, osteoblast differentiation might be regulated by the nervous system, presumably during bone development, remodeling, or repair.

关键词： osteogenic differentiation cell proliferation polymerase chain reaction bone tissue engineering western blot analysis statistical analysis bone development gene expression nervous system growth factors in vitro

Long-term observation of the mineral trioxide aggregate extrusion into the periapical lesion:a case series

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International Journal of Oral Science 2013年第1期5卷 54-57页

作者： Seok-Woo Chang Tae-Seok Oh WooCheol Lee Gary Shun-Pan Cheung Hyeon-Cheol Kim Department of Conservative dentistry School of DentistryKyung Hee University Department of Conservative dentistry The Institute of Oral Health ScienceSamsung Medical CenterSungkyunkwan University School of Medicine Department of Conservative dentistry School of DentistryDental Research InstituteSeoul National University Area of Endodontics Faculty of Dentistrythe University of Hong Kong Department of Conservative dentistry School of DentistryPusan National UniversityDental Research Institute

One-step apexification using mineral trioxide aggregate(MTA) has been reported as an alternative treatment modality with more benefits than the use of long-term calcium hydroxide for teeth with open ***,orthograde placement of MTA is a challenging procedure in terms of length *** case series describes the sequence of events following apical extrusion of MTA into the periapical area during a one-step apexification procedure for maxillary central incisor with an infected immature *** long-term observation revealed complete resolution of the periapical radiolucent lesion around the extruded *** cases revealed that direct contact with MTA had no negative effects on healing of the periapical ***,intentional MTA overfilling into the periapical lesion is not to be recommended.

关键词： extrusion immature apex mineral trioxide aggregate one-step apexification open apex periapical healing