RESUMO
A thorough comprehension of age-related variances in orthodontic tooth movement (OTM) and bone remodeling response to mechanical force holds significant implications for enhancing orthodontic treatment. Mitophagy plays a crucial role in bone metabolism and various age-related diseases. However, the impact of mitophagy on the bone remodeling process during OTM remains elusive. Using adolescent (6 weeks old) and adult (12 months old) rats, we established OTM models and observed that orthodontic force increased the expression of the mitophagy proteins PTEN-induced putative kinase 1 (PINK1) and Parkin, as well as the number of tartrate-resistant acid phosphatase-positive osteoclasts and osteocalcin-positive osteoblasts. These biological changes were found to be age-related. In vitro, compression force loading promoted PINK1/Parkin-dependent mitophagy in periodontal ligament stem cells (PDLSCs) derived from adolescents (12-16 years old) and adults (25-35 years old). Furthermore, adult PDLSCs exhibited lower levels of mitophagy, impaired mitochondrial function, and a decreased ratio of RANKL/OPG compared to young PDLSCs after compression. Transfection of siRNA confirmed that inhibition of mitophagy in PDLSC resulted in decreased mitochondrial function and reduced RANKL/OPG ratio. Application of mitophagy inducer Urolithin A enhanced bone remodeling and accelerated OTM in rats, while the mitophagy inhibitor Mdivi-1 had the opposite effect. These findings indicate that force-stimulated PDLSC mitophagy contributes to alveolar bone remodeling during OTM, and age-related impairment of mitophagy negatively impacts the PDLSC response to mechanical stimulus. Our findings enhance the understanding of mitochondrial mechanotransduction and offer new targets to tackle current clinical challenges in orthodontic therapy.
Assuntos
Mitocôndrias , Mitofagia , Osteoprotegerina , Ligamento Periodontal , Ligante RANK , Técnicas de Movimentação Dentária , Animais , Mitofagia/fisiologia , Ratos , Ligante RANK/metabolismo , Ligamento Periodontal/metabolismo , Osteoprotegerina/metabolismo , Mitocôndrias/metabolismo , Masculino , Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , Adolescente , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Células-Tronco/metabolismo , Remodelação Óssea/fisiologia , Células CultivadasRESUMO
Melanoma, accounting for a significant proportion of skin cancer-related deaths, has variable survival outcomes based on the stage at diagnosis and treatment efficacy. Traditional treatments, while effective, pose risks of scarring and systemic side effects. Laser therapy offers an emerging non-surgical alternative, with CO2 lasers particularly showing promise in palliative care.A comprehensive search was conducted using PubMed, focusing on laser therapy for melanoma treatment. The search included studies on both stand-alone and adjunct laser therapies, with inclusion criteria requiring peer-reviewed articles detailing treatment outcomes for primary, recurrent, or metastatic melanoma.The literature shows that laser therapy for melanoma falls into four major types when categorized by laser medium: solid-state, diode, pulse-dye, and gas (CO2). Data on solid-state lasers for melanoma are limited and their use remains controversial. However, one study with high-energy pulsed neodymium lasers reported a 5-year survival of 82.9% with minimal adverse effects for primary melanoma. CO2 laser therapy has been effective for palliative treatment, with one study showing 54.8% of patients with recurrent melanoma surviving 5.4 years post-ablation. For metastatic melanoma, numerous studies have shown that CO2 laser therapy can provide symptomatic relief and disease control. Combination therapies using lasers and immune-based therapies have demonstrated enhanced outcomes and immune activation, highlighting the potential of laser therapies in melanoma management.While traditional treatments remain the standard for primary melanoma, laser therapies, particularly CO2 laser ablation, show substantial promise in palliative care for metastatic melanoma. Careful patient selection and assessment are crucial for achieving positive outcomes.
Assuntos
Melanoma , Cuidados Paliativos , Neoplasias Cutâneas , Humanos , Melanoma/terapia , Melanoma/mortalidade , Melanoma/cirurgia , Melanoma/radioterapia , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Cuidados Paliativos/métodos , Resultado do Tratamento , Lasers de Gás/uso terapêutico , Lasers de Gás/efeitos adversos , Terapia a Laser/métodos , Terapia a Laser/efeitos adversos , Terapia Combinada , Lasers de Estado Sólido/uso terapêutico , Lasers de Estado Sólido/efeitos adversos , Recidiva Local de NeoplasiaRESUMO
Rosacea is a common inflammatory skin condition displaying symptoms like flushing, erythema, papules, and pustules. Oral antibiotics, despite long-term adverse effects, are often used due to topical treatment limitations, underscoring the need for cost-effective choices like dietary modifications. Our review investigates the role of vitamins and minerals in rosacea, and provides evidence-based recommendations for supplementation and topical treatment of these nutrients for rosacea. An online search was performed on PubMed, Web of Science, Science Direct, Google Scholar, and ClinicalTrials.gov from 1998 to 2023. Included studies were summarized and assessed for quality and relevance in rosacea management. Varied outcomes emerged concerning the impact of essential vitamins and minerals on rosacea treatment. Vitamin A derivatives, specifically oral isotretinoin, demonstrated significant efficacy, with a 90% reduction in lesions, complete remission in 24% of patients, and marked improvement in 57% of patients. Vitamin B3 derivatives, such as topical 1-methylnicotinamide 0.25% and NADH 1%, improved symptoms in 76.4% (26/34) and 80% of patients, respectively. Outcomes for vitamin D, vitamin C, and zinc supplementation varied across studies. However, zinc sulfate solution 5% significantly reduced acne rosacea severity for patients with 40% and 60% exhibiting a moderate or good response, respectively. Omega-3 fatty acids showed significant improvement in alleviating xerophthalmia in 64% of patients with ocular rosacea. Vitamins and minerals hold potential in managing rosacea symptoms, offering a safe and cost-effective alternative or adjunctive treatment option. Currently, there are no established recommendations regarding their supplementation for rosacea. Studies assessing serum levels of vitamins and minerals in relation to rosacea are warranted, as this avenue holds potential for future advancements in the field.
Assuntos
Suplementos Nutricionais , Rosácea , Vitaminas , Rosácea/tratamento farmacológico , Rosácea/diagnóstico , Humanos , Vitaminas/administração & dosagem , Vitaminas/uso terapêutico , Resultado do Tratamento , Nutrientes/administração & dosagem , Administração CutâneaRESUMO
The Abdominal Re-Approximation Anchor (ABRA®) is a pivotal dynamic wound closure system utilized for achieving primary fascial closure in patients undergoing open abdomen surgeries. However, its efficacy can be hindered in patients with class III obesity due to anatomical complexities and compromised tissue characteristics. Here, we present the unique case of a 25-year-old woman with class III obesity (body mass index (BMI) ≥ 40 kg/m2) who required primary abdominal closure following complications of an ileostomy repair. Traditional placement of the ABRA device was not feasible due to thick subcutaneous tissue layers. Consequently, a modified application of ABRA was decided based on clinical judgment, whereby the ABRA button anchors were strategically placed internally under the subcutaneous tissue instead of externally on the skin surface. The patient completed six intraoperative tightenings of the ABRA device via this novel technique and was treated with washouts over the course of two months until complete resolution was achieved. The presented case demonstrates a successful modification of the ABRA wound closure device to suit an open abdomen patient with class III obesity.
RESUMO
Purpose: The maintenance of stable blood glucose levels in gestational diabetes patients depends on their ability to make scientific decisions. Decision-making ability is influenced by factors such as preferences, knowledge acquisition, and risk perceptions. At present, problems such as irrational dietary structure, difficulties in decision-making, and poor adherence still exist in clinical practice. The key to guiding gestational diabetes patients in developing their scientific decision-making abilities lies in identifying the weak key points that affect their decision-making abilities. There is a lack of validated tools to assess these patients' perceptions of dietary intake. In this study, we aimed to develop and validate the Dietary Intake Perceived Motivation Questionnaire for Patients with Gestational Diabetes Mellitus with the purpose of accurately identifying the obstacles encountered by gestational diabetes mellitus patients in the development of their scientific decision-making abilities. Patients and Methods: In this study, 304 individuals with gestational diabetes were recruited from a public hospital in Wuxi, China. The questionnaire was developed in 3 stages, consisting of questionnaire development, a pilot study, and a formal test, and the validity and reliability of the questionnaire were tested and confirmed. The content validity index and exploratory factor analysis were completed by expert correspondence to indicate the validity of the content and structure. In addition, Cronbach's α was used to evaluate the internal consistency of each item of the questionnaire, and Spearman-Brown analysis was used to analyze the split-half reliability. In addition to the questionnaire, the study participants were asked to complete a general information questionnaire that included items on various demographic factors such as age, week of gestation, and mode of conception. Results: The questionnaire was validated through principal component analysis, resulting in a 31-item questionnaire named the Dietary Intake Perceived Motivation Questionnaire for Patients with Gestational Diabetes Mellitus. This questionnaire explained 86.267% of the variance and demonstrated good internal consistency (Cronbach's α= 0.929). Conclusion: Our study determined that the questionnaire serves as a valuable tool in evaluating the motivation behind dietary intake in gestational diabetes patients.
RESUMO
Sludge reduction is a major challenge in biological wastewater treatment. Hydrolytic enzymes secreted by thermophilic bacteria can lyse sludge and thus achieve sludge reduction, and the indigenous thermophilic community in sludge can lyse sludge more effectively. In this study, the feasibility of combining a sludge lysis reactor based on thermophilic bacteria community (LTBC reactor, 75 °C) with a conventional sequencing batch activated sludge reactor (SBR) for sludge reduction (i.e., LTBC-SBR process) was systematically investigated first time. The effect of lysed sludge returning to the biochemical tank on pollutant removal efficiency, sludge flocculation, sludge settling, and microbial community and function of the LTBC-SBR process was studied. In the LTBC1-SBR process, a sludge growth rate of 0.71 g TSS/day was observed when the lysed sludge reflux ratio (LRR) was 1, and the sludge generation was reduced by 81.5% compared to the conventional SBR reactor. In the LTBC1-SBR process, the removal efficiencies of chemical oxygen demand and total nitrogen were 94.0% and 80.5%, respectively. There was no significant difference in the sludge volume index from the SBR to the LTBC1-SBR stage, however, the effluent suspended solids concentration increased from 35.2 ± 2.1 mg/L to 80.1 ± 5.3 mg/L. This was attributed to the reflux of sludge lysate. In addition, the changes in extracellular polymers content and composition resulted in poor sludge flocculation performance. Heterotrophic bacteria associated with Actinobacteria and Patescibacteria enriched in LTBC1-SBR with relative abundance of 28.51 ± 1.25% and 20.01 ± 1.21%, respectively, which decomposed the macromolecules in the refluxed lysed sludge and contributed to the sludge reduction. Furthermore, due to the inhibition of nitrite-oxidizing bacteria, the nitrite concentration in the effluent of the LTBC1-SBR system reached 4.7 ± 1.1 mg/L, and part of the denitrification process was achieved by short-cut nitrification and simultaneous denitrification. These results indicate that in-situ sludge reduction technology based on lyse sludge lysing by thermophilic community has considerable potential to be widely used in wastewater treatment.
Assuntos
Nitritos , Esgotos , Esgotos/química , Reatores Biológicos/microbiologia , Águas Residuárias , Nitrificação , Bactérias , Nitrogênio , Desnitrificação , Eliminação de Resíduos Líquidos/métodosRESUMO
[This corrects the article DOI: 10.7150/thno.34676.].
RESUMO
BACKGROUND: The biomechanics generated by the clear aligner (CA) material changes continuously during orthodontic tooth movement, but this factor remains unknown during the computer-aid design process and the predictability of molars movement is not as expected. Therefore, the purpose of this study was to propose an iterative finite element method to simulate the long-term biomechanical effects of mandibular molar mesialization (MM) in CA therapy under dual-mechanical systems. METHODS: Three groups including CA alone, CA with a button, and CA with a modified lever arm (MLA) were created. Material properties of CA were obtained by in vitro mechanical experiments. MM was conducted by the rebound force exerted by CA material and the mesial elastic force (2N, 30° to the occlusal plane) applied to the auxiliary devices. Stress intensity and distribution on periodontal ligament (PDL), attachment, button and MLA, and displacement of the second molar (M2) during the iterations were recorded. RESULTS: There was a significant difference between the initial and cumulative long-term displacement. Specifically, compared to the beginning, the maximum stress of PDL decreased by 90% on average in the intermediate and final steps. The aligner was the main mechanical system at first, and then, the additional system exerted by the button and MLA dominated gradually. The stress of attachments and auxiliary devices is mainly concentrated on their interfaces with the tooth. Additionally, MLA provided a distal tipping and extrusive moment, which was the only group that manifested a total mesial displacement of the root. CONCLUSIONS: The innovatively designed MLA was more effective in reducing undesigned mesial tipping and rotation of M2 than the traditional button and CA alone, which provided a therapeutic method for MM. The proposed iterative method simulated tooth movement by considering the mechanical characteristic of CA and its long-term mechanical force changes, which will facilitate better movement prediction and minimize the failure rate.
Assuntos
Aparelhos Ortodônticos Removíveis , Dente , Humanos , Análise de Elementos Finitos , Dente Molar , Ligamento Periodontal , Fenômenos Biomecânicos , Técnicas de Movimentação Dentária , Estresse MecânicoRESUMO
INTRODUCTION: The objectives of this study were to investigate the biomechanical effects of clear aligners (CAs) with various thermoplastic material thicknesses and gingival-margin designs for space closure in extraction treatment and to propose a computer-aided procedure to optimize CA design. METHODS: The radiologic and intraoral scanning technology, in vitro mechanical experiment, viscoelastic modeling, and finite element analysis (FEA) were integrated to establish an orthodontic simulation model. Twelve FEA models of CA were created, comprising combinations of 2 kinds of thicknesses (0.75 and 0.50 mm), 2 forms of gingival-margin shape (scalloped and straight), and 3 types of margin height (-2, 0, and 2 mm). In vitro testing was carried out to determine the actual properties of material thickness. RESULTS: A 0.75-mm-thick aligner resulted in greater periodontal ligament (PDL) stress than 0.50 mm, and there was no clear correlation between the control ability of tooth movement and the thickness. For different margin designs, PDL stress at -2 mm height was significantly lower than those with a higher border. Aligners with straight margins had higher stress than the scalloped aligners, whereas the differences were unnoticeable at 2 mm height. The optimized aligner with differential margin designs was recommended on the basis of biomechanical calculations, which facilitated the efficiency and control of tooth movement for multiple teeth. CONCLUSIONS: The effect of material thickness and margin design of CA on the force and movement differed in different teeth. Preferable CA designs of each tooth during different movement stages should be presented personalized under the guidance of precise biomechanics instead of pure morphologic analysis.
Assuntos
Incisivo , Aparelhos Ortodônticos Removíveis , Humanos , Maxila , Simulação por Computador , Fenômenos Mecânicos , Fenômenos Biomecânicos , Técnicas de Movimentação Dentária , Análise de Elementos Finitos , Desenho de Aparelho OrtodônticoRESUMO
Regeneration of periodontal tissue remains a challenge. Under periodontitis, osteoclasts are overactivated and bone loss occurs. We incorporated sodium alendronate (Alen), a medication commonly used to treat osteoporosis, into a supramolecular hydrogel system in order to create a novel biomaterial that would promote periodontal bone regeneration by inhibiting osteoclast overactivation. The Nap-Gly-Phe-Phe (NapGFF) peptide chain was modified to synthesize the functional Nap-Alen gelator. Afterward, the Nap-Alen/HAP supramolecular hydrogel composite with a suitable hydroxyapatite (HAP) ratio was constructed, which has outstanding mechanical properties and 3D structure. In addition to its good biocompatibility, it can inhibit the proliferation of bone marrow-derived macrophages (BMDMs) and differentiation of osteoclasts. Due to the simultaneous introduction of porous HAP, the hydrogel with a nanofiber structure was formed into a 3D mesh-like sparse porous composite hydrogel. While enhancing the mechanical properties of the gel, the porous structure facilitated the attachment and migration of bone regeneration-related cells. Therefore, it can effectively promote the regeneration of periodontal bone. In the future, by modifying the biophysical properties and loading stem cells or cytokines, this supramolecular hydrogel composite constructed in this study may provide a new strategy for tissue regeneration engineering and provide a preliminary experimental basis for relevant clinical translational studies.
RESUMO
Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5ß1 or αVß3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.
Assuntos
MicroRNAs , Neoplasias Pancreáticas , Receptores Purinérgicos P2 , Humanos , Fibronectinas/genética , Fibronectinas/metabolismo , Neoplasias Pancreáticas/patologia , Matriz Extracelular/metabolismo , Transformação Celular Neoplásica/metabolismo , Receptores Purinérgicos P2/metabolismo , MicroRNAs/genética , Neoplasias PancreáticasRESUMO
Objectives: This study introduced a three-dimensional (3D) surface-to-surface matching technique to evaluate the mandibular symmetry of teenagers and adults with unilateral second molar scissor bite. Methods: The targets came from 73 cone-beam computed tomography (CBCT) images with unilateral second molar scissor bite, including teenagers (n = 30) and adults (n = 43). 73 images without scissor bite and matched in sex and age were selected as controls. The scans were developed into 3D mandible models and seven mandibular functional unit models, including condylar process (Co), coronoid process (Cr), mandibular ramus (Ra), mandibular angle (Ma), alveolar process (Ap), mandibular body (Mb) and chin process (Ch). The surface-to-surface matching technique was introduced. 3D deviation analysis and matching percentages calculation were performed and compared to evaluate the symmetry of the mandible. Results: Comparisons were made between the study samples and control samples. For teenagers, the matching percentages of the entire mandible (55.31 ± 7.24%), Mb (69.04 ± 9.22%) and Co (65.19 ± 10.67%) in the study group were lower than that of the entire mandible (60.87 ± 6.38%) (P <0.01), Mb (75.0 ± 8.71%) (P <0.05) and Co (70.25 ± 8.20%) (P <0.05) in the control group. While Ap, Ra, Ch, Cr and Ma showed no statistically significant differences (P >0.05). For adults, the matching percentages of the entire mandible (48.88 ± 9.77%), Ap (65.83 ± 11.21%), Mb (64.43 ± 12.03%), Ch (79.17 ± 10.29%), Ra (64.11 ± 9.84%) and Co (61.08 ± 11.64%) in the study group were lower than the entire mandible (59.28 ± 5.49%) (P <0.01), Ap (73.65 ± 9.10%) (P <0.01), Mb (71.66 ± 8.40%) (P <0.01), Ch (83.86 ± 5.59%) (P <0.05), Ra (68.54 ± 7.87%) (P <0.05) and Co (66.20 ± 10.62%) (P <0.05) of the control group. Only Cr and Ma showed no statistically significant differences (P >0.05). Conclusion: Mandibular asymmetry was observed in both teenagers and adults with unilateral second molar scissor bite. Moreover, compared with teenagers, more mandibular units of adult patients were affected. Clinical significance: Based on the surface-to-surface matching technique, the symmetric and morphological information of the mandible can be converted into visual color maps and quantitative descriptions. This method can bring convenience to the study of the growth of mandible, orthodontic treatment and orthognathic surgery design.
RESUMO
Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Compostos de Bifenilo , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Interleucina-6/metabolismo , Fígado , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Ratos , Transdução de SinaisRESUMO
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and there is no specific drug to treat it. Recent results showed that 17-beta-hydroxysteroid dehydrogenase type 13 (HSD17B13) is associated with liver diseases, but these conclusions are controversial. Here, we showed that HSD17B13 was more highly expressed in the livers of NAFLD patients, and high expression was induced in the livers of murine NAFLD models and cultural hepatocytes treated using various etiologies. The high HSD17B13 expression in the hepatocytes facilitated the progression of NAFLD by directly stabilizing the intracellular lipid drops and by indirectly activating hepatic stellate cells. When HSD17B13 was overexpressed in the liver, it aggravated liver steatosis and fibrosis in mice fed with a high-fat diet, while down-regulated the high expression of HSD17B13 by short hairpin RNAs produced a therapeutic effect in the NAFLD mice. We concluded that high HSD17B13 expression is a good target for the development of drugs to treat NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Humanos , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl4. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and ß-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion: Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.
RESUMO
Viral entry inhibitors are absent in hepatitis C virus (HCV) treatment regimens although a dozen direct-acting antiviral (DAA) drugs are available now. Based on a previously identified HCV entry inhibitor L0909, chemical space exploration and structure-activity relationship (SAR) studies led to the discovery of a new derived scaffold 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile. Several new scaffold derivatives exhibited higher in vitro anti-HCV activity at low nanomolar concentrations compared to L0909. A biological study indicated that the high potency of active derivatives 3d, 3h, and 3i was primarily driven by the inhibitory effect on the virus entry stage. Moreover, an SPR experiment confirmed that this class of derivatives might target the HCV E1 protein. Pharmacokinetic studies indicated that compounds 3d and 3i are orally available and long-lasting in rat plasma after oral administration to rats by a single dose of 15 mg/kg. In conclusion, this work provided a novel 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile chemotype deserving further investigation into its antiviral therapeutic potential.
Assuntos
Antivirais/síntese química , Hepacivirus/fisiologia , Nitrilas/química , Administração Oral , Animais , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/farmacologia , Linhagem Celular , Desenho de Fármacos , Meia-Vida , Humanos , Nitrilas/metabolismo , Nitrilas/farmacocinética , Nitrilas/farmacologia , Piperazina/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus/efeitos dos fármacosRESUMO
The mixed dentition stage is the period between primary and permanent dentition. The following biological processes are complicated and variable: jaw growth, development of inherited permanent teeth embryo, physiological absorption of primary teeth, restoration of surrounding alveolar bones, and growth and function establishment of soft tissues. For the normal development of the jaw, the establishment of the good occlusion relationship, development, and function of soft tissue is very important, whether or not the primary teeth are normally replaced by the permanent teeth in the mixed dentition stage. The eruption space is linked to the normal replacement of primary and permanent teeth. The presence of a mixed dentition space results in the incidence and progression of malocclusion and impacts the normal growth and development of the occlusion, jaw, and face. Space management in the mixed dentition stage is a crucial means to prevent and reduce malocclusion. The following were discussed and analyzed: the possible space problems, why the size of the space was affected, the content that needs to be assessed, and the methods of space management in the mixed dentition that can be used to unify and standardize the management of mixed dentition. This paper was developed to serve as a guide for regulated space management during the mixed dentition period.
RESUMO
To investigate the effects of two Enterococcus faecalis root canal isolated strains (CA1 and CA2) and of the OG1RF strain on apoptosis, pyroptosis, and necroptosis in macrophages. The virulence factors of E. faecalis CA1 and CA2 pathogenic strains were annotated in the Virulence Factors Database (VFDB). E. faecalis CA1, CA2, and OG1RF strains were used to infect RAW264.7 macrophages (MOI, 100:1). We assessed the viability of intracellular and extracellular bacteria and of macrophages at 2, 6, and 12 h post-infection. We used a live cell imaging analysis system to obtain a dynamic curve of cell death after infection by each of the three E. faecalis strains. At 6 and 12 h post-infection, we quantified the mRNA expression levels of PANoptosis-related genes and proteins by RT-qPCR and western blot, respectively. We identified ultrastructural changes in RAW264.7 cells infected with E. faecalis OG1RF using transmission electron microscopy. We found 145 and 160 virulence factors in the CA1 and CA2 strains, respectively. The extracellular CA1 strains grew faster than the CA2 and OG1RF strains, and the amount of intracellular viable bacteria in the OG1RF group was highest at 6 and 12 h post-infection. The macrophages in the CA1 infection group were the first to reach the maximum PI-positivity in the cell death time point curve. We found the expressions of mRNA expression of caspase-1, GSDMD, caspase-3, MLKL, RIPK3, NLRP3, IL-1ß and IL-18 and of proteins cleaved caspase-1, GSDMD, cleaved caspase-3 and pMIKL in the macrophages of the three infection groups to be upregulated (P<0.05). We detected ultrastructural changes of apoptosis, pyroptosis, and necroptosis in macrophages infected with E. faecalis. The three E. faecalis strains induced varying degrees of apoptosis, pyroptosis, and necroptosis that were probably associated with PANoptosis in macrophages. The E. faecalis CA1 strain exhibited faster growth and a higher real-time MOI, and it induced higher expression levels of some PANoptosis-related genes and proteins in the infected macrophages than the other strains tested.
Assuntos
Necroptose , Piroptose , Apoptose , Cavidade Pulpar , Enterococcus faecalis , MacrófagosRESUMO
Natural killer-like B (NKB) cells, which are newly identified immune subsets, reveal a critical immunoregulatory property in the eradication of microbial infection via the secretion of interleukin (IL)-18. For the first time, this study investigated the role of NKB cells in secreting IL-18 in the pathogenesis of periodontitis. In this study, NKB cells' percentage and IL-18 concentration in peripheral blood and periodontium in periodontitis patients was measured using flow cytometry and ELISA. The role of IL-18 in regulating periodontal inflammation was examined in a Porphyromonas gingivalis (P. gingivalis)-induced periodontitis murine model. Peripheral and periodontal-infiltrating CD3-CD19+NKp46+ NKB cells, which were the main source of IL-18, were elevated and correlated with attachment loss in periodontitis patients. In vitro IL-18 stimulation promoted proinflammatory cytokine production in periodontal ligament cells. P. gingivalis infection induced elevation of IL-18 receptor in periodontium in a periodontitis murine model. IL-18 neutralization not only suppressed P. gingivalis-induced alveolar bone resorption, but also inhibited recruitment of antigen-non-specific inflammatory cells into the periodontium, probably via dampening expressions of cytokines, chemokines, and matrix metalloproteinases. NKB cells secreting IL-18 appeared to be an important mediator in the inflammatory response following intraoral P. gingivalis infection. These findings might be relevant to the development of immunotherapies for periodontitis.