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Background: Polymeric denture materials can be susceptible to colonization by oral microorganisms. Zein-coated magnesium oxide nanoparticles (zMgO NPs) demonstrate antimicrobial activity. The aim of this study was to investigate the antimicrobial effect and adherence of different oral microorganisms on hybrid polymeric denture materials incorporated with zMgO NPs. Methods: Five types of polymeric denture materials were used. A total of 480 disc-shaped specimens were divided by material type (n=96/grp), then subdivided by zMgO NPs concentration: control with no nanoparticles and other groups with zMgO NPs concentrations of 0.3%, 0.5% and 1% by weight. Characterization of the polymeric denture materials incorporating zMgO NPs was done, and the antimicrobial activity of all groups was tested against four types of microorganisms: 1) Streptococcus mutans, 2) Staphylococcus aureus, 3) Enterococcus faecalis and 4) Candida albicans. The samples underwent an adherence test and an agar diffusion test. Experiments were done in triplicates. Results: The characterization of the hybrid samples revealed variation in the molecular composition, as well as a uniform distribution of the zMgO NPs in the polymeric denture materials. All hybrid polymeric denture materials groups induced a statistically significant antimicrobial activity, while the control groups showed the least antimicrobial activity. The agar diffusion test revealed no release of the zMgO NPs from the hybrid samples, indicating the NPs did not seep out of the matrix. Conclusion: The zMgO NPs were effective in reducing the adherence of the tested microorganisms and enhancing the antimicrobial activity of the polymeric denture materials. This antimicrobial effect with the polymeric dentures could aid in resisting microbial issues such as denture stomatitis.

Asunto(s)

Antiinfecciosos , Candida albicans , Staphylococcus aureus , Streptococcus mutans , Zeína , Zeína/química , Zeína/farmacología , Candida albicans/efectos de los fármacos , Streptococcus mutans/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antiinfecciosos/farmacología , Antiinfecciosos/química , Óxido de Magnesio/química , Óxido de Magnesio/farmacología , Nanopartículas/química , Enterococcus faecalis/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Humanos , Materiales Dentales/farmacología , Materiales Dentales/química , Dentaduras/microbiología , Polímeros/química , Polímeros/farmacología

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Background: Cerebrovascular diseases of the brain are usually defined by transient ischemic attacks and strokes. However, they can also cause brain injuries without neurological events. Silent brain infarcts (SBI) and leukoaraiosis are symptoms of both vascular and neurological abnormalities. This study aims to investigate the association between SBI, leukoaraiosis, and middle-aged patients with ischemic stroke. Methods: A single-center retrospective study of 50 middle-aged, ischemic stroke patients were studied from November 2022 and May 2023. The patients were divided into two groups based on the presence or absence of leukoaraiosis. History taking, physical examination, brain CT scan, and MRI were all part of the diagnostic process. Metabolic syndrome (MetS) was also assessed through various factors. The statistical analysis included descriptive statistics, logistic regression analysis, and chi-square test. Results: Out of the cohort comprising 50 patients, characterized by a mean age of 52.26 years (SD 5.29), 32 were male, constituting 64% of the sample. Among these patients, 26 individuals exhibited leukoaraiosis, with 17 of them (65.4%) also presenting with SBI. Moreover, within this cohort, 22 patients were diagnosed with MetS, representing 84.6% of those affected. The Multivariate logistic regression analysis showed a strong and independent association between leukoaraiosis and SBI. Individuals with leukoaraiosis were nearly five times more likely to have SBI compared to those without leukoaraiosis. Conclusion: The study highlights leukoaraiosis as a significant risk factor for SBI, alongside MetS. Advanced imaging techniques have facilitated their detection, revealing a higher prevalence among stroke patients, particularly associated with age and hypertension. Further research is needed to fully understand their complex relationship and develop better management strategies for cerebrovascular diseases, ultimately improving patient outcomes.

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The literature presents insufficient data evaluating the displacement and micromotion effects resulting from the combined use of tooth-implant connections in fixed partial dentures. Analyzing the biomechanical behavior of tooth-implant fixed partial denture (FPD) prothesis is vital for achieving an optimum design and successful clinical implementation. The objective of this study was to determine the relative significance of connector design on the displacement and micromotion of tooth-implant-supported fixed dental prostheses under occlusal vertical loading. A unilateral Kennedy class I mandibular model was created using a 3D reconstruction from CT scan data. Eight simulated designs of tooth-implant fixed partial dentures (FPDs) were split into two groups: Group A with rigid connectors and Group B with non-rigid connectors. The models were subjected to a uniform vertical load of 100 N. Displacement, strain, and stress were computed using finite element analysis. The materials were defined as isotropic, homogeneous, and exhibiting linear elastic properties. This study focused on assessing the maximum displacement in various components, including the bridge, mandible, dentin, cementum, periodontal ligament (PDL), and implant. Displacement values were predominantly higher in Group B (non-rigid) compared to Group A (rigid) in all measured components of the tooth-implant FPDs. Accordingly, a statistically significant difference was observed between the two groups at the FPD bridge (p value = 0.021 *), mandible (p value = 0.021 *), dentin (p value = 0.043 *), cementum (p value = 0.043 *), and PDL (p value = 0.043 *). Meanwhile, there was an insignificant increase in displacement values recorded in the distal implant (p value = 0.083). This study highlighted the importance of connector design in the overall stability and performance of the prosthesis. Notably, the 4.7 mm × 10 mm implant in Group B showed a displacement nearly 92 times higher than its rigid counterpart in Group A. Overall, the 5.7 mm × 10 mm combination of implant length and diameter showcased the best performance in both groups. The findings demonstrate that wider implants with a proportional length offer greater resistance to displacement forces. In addition, the use of rigid connection design provides superior biomechanical performance in tooth-implant fixed partial dentures and reduces the risk of micromotion with its associated complications such as ligament overstretching and implant overload, achieving predictable prognosis and enhancing the stability of the protheses.

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Aberrant activation of the NLRP3 inflammasome is recognized to induce a chronic inflammatory response in the liver, ultimately leading to hepatic fibrosis. HSP90 is suggested to regulate NLRP3 activation and its downstream signaling. This study is the first to explore the potential therapeutic role of pimitespib in mitigating liver fibrosis in rats. The results of the study revealed that pimitespib effectively suppressed hepatic inflammation and fibrogenesis by modulating HSP90's control over the NFκB/NLRP3/caspase-1 axis. In vitro experiments demonstrated that pimitespib reduced LDH levels and increased hepatocyte survival, whereas in vivo, it prolonged the survival of rats with hepatic fibrosis. Additionally, pimitespib exhibited improvements in the function and microscopic characteristics of rat livers. Pimitespib effectively inhibited NFκB, which serves as the priming signal for NLRP3 activation. Pimitespib's inhibitory effect on NLRP3, identified as an HSP90 client protein, plays a central role in the observed anti-fibrotic effect. The simultaneous inhibition of both priming and activation signals of NLRP3 by pimitespib led to a reduction in caspase-1 activity and subsequent suppression of the N-terminal fragment of gasdermin D, ultimately constraining hepatocyte pyroptotic cell death. These diverse effects were associated with a decrease in the transcription of inflammatory mediators IL-1ß, IL-18, and TNF-α, as well as the fibrogenic mediators TGF-ß, TIMP-1, PDGF-BB, and Col1a1. Moreover, pimitespib induced the expression of HSP70, which could further contribute to the repression of fibrosis development. In summary, our findings provide an evolutionary perspective on managing liver fibrosis, positioning pimitespib as a promising candidate for anti-inflammatory and antifibrotic therapy.

Asunto(s)

Caspasa 1 , Proteínas HSP90 de Choque Térmico , Cirrosis Hepática , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/metabolismo , FN-kappa B/metabolismo , Masculino , Caspasa 1/metabolismo , Transducción de Señal , Ratas Sprague-Dawley , Inflamasomas/metabolismo , Sulfonamidas/farmacología , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatocitos/efectos de los fármacos

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Resin cement integrated with zein-incorporated magnesium oxide nanoparticles has previously been found to inhibit oral microbes and decrease bacterial biofilm. However, the bond strength and surface features of this biomaterial have yet to be investigated. The objective of this study was to evaluate the shear bond strength, mode of fracture, and surface roughness of resin cement modified with zein-incorporated magnesium oxide nanoparticles. Characterization of the cement was performed by X-ray diffraction, field emission scanning electron microscopy, and Fourier transform infrared spectroscopy. 126 human teeth were divided into 3 groups and cemented to lithium disilicate ceramic using resin cement with zein-incorporated magnesium oxide nanoparticles at concentrations of 0%, 1%, and 2% (n = 42). 21 samples of each group were subjected to the shear bond strength test, while the other 21 underwent thermocycling for 10,000 cycles before the test, after which all samples were evaluated for the mode of fracture. To assess surface roughness, resin cement disks were analyzed by a profilometer before and after undergoing thermocycling for 10,000 cycles. The shear bond strength of the cement with 1% and 2% nanoparticles was significantly higher than the control before thermocycling. The mode of fracture was found to be mainly adhesive with all groups, with the unmodified cement presenting the highest cohesive failure. There was no significant difference in surface roughness between the groups before or after thermocycling. The addition of zein-incorporated magnesium oxide nanoparticles to resin cement improved or maintained the shear bond strength and surface roughness of the resin cement.

Asunto(s)

Anticoagulantes , Enfermedad Arterial Periférica , Humanos , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/complicaciones , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Administración Oral , Inhibidores del Factor Xa/uso terapéutico

RESUMEN

INTRODUCTION: Zein-incorporated magnesium oxide nanoparticles (zMgO NPs) can influence the mechanical properties of dental materials. However, the effect of this addition on the mechanical properties of resin composite has yet to be investigated. The objective of this study was to add various concentrations of zMgO NPs to conventional, flowable, and bulk-fill composite and assess the effect on the compressive strength, flexural strength, and microhardness. METHODOLOGY: 150 samples each of conventional composite, flowable composite, and bulk-fill composite (n = 450) were enhanced with concentrations of zMgO NPs at 0 %, 0.3 %, 0.5 %, 1 %, and 2 % (n = 30). 10 samples of each group were randomly allotted to the compressive strength, flexural strength, or hardness test. Characterization of the specimens was performed by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and transmission electron microscopy. Two-way ANOVA test was used to compare between groups, and one-way ANOVA followed by Tukey's test was done at p = 0.05 to determine significance. RESULTS: Characterization yielded a uniform distribution of nanoparticles in the matrix and the formation of a new hybrid composite that maintained its properties. Composite of all types enhanced with 0.3 % and 0.5 % zMgO NPs demonstrated a statistically significant increase in compressive strength, flexural strength, and hardness when compared to the control (p < 0.05). The bulk-fill composite with zMgO NPs concentrations of all groups demonstrated a statistically significant increase (p < 0.05) in hardness when compared to the control. CONCLUSION: The modified composites' compressive strength, flexural strength, and hardness improved or remained consistent. CLINICAL SIGNIFICANCE: An improved dental resin composite will enhance the quality of care and patient experience. The augmented strength and hardness of resin composite is desirable in prolonging the durability of the restoration.

Asunto(s)

Resinas Compuestas , Fuerza Compresiva , Materiales Dentales , Resistencia Flexional , Dureza , Óxido de Magnesio , Ensayo de Materiales , Microscopía Electrónica de Rastreo , Nanopartículas , Difracción de Rayos X , Resinas Compuestas/química , Óxido de Magnesio/química , Nanopartículas/química , Materiales Dentales/química , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de Superficie , Espectrometría por Rayos X , Polímeros/química , Metacrilatos/química , Microscopía Electrónica de Transmisión , Humanos , Ácidos Polimetacrílicos/química , Estrés Mecánico

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Microplastics (MPs) have emerged as widespread environmental pollutants, causing significant threats to aquatic ecosystems and organisms. This review examines the toxic effects of MPs on fishes, with a focus on neurobehavioural, physiological, and reproductive impacts, as well as the underlying mechanisms of toxicity. Evidence indicates that MPs induce a range of neurobehavioural abnormalities in fishes, affecting social interactions and cognitive functions. Altered neurotransmitter levels are identified as a key mechanism driving behavioural alterations following MP exposure. Physiological abnormalities in fishes exposed to MPs are also reported, including neurotoxicity, immunotoxicity, and oxidative stress. These physiological disruptions can compromise the individual health of aquatic organisms. Furthermore, reproductive abnormalities linked to MP exposure are discussed, with a particular emphasis on disruptions in endocrine signaling pathways. These disruptions can impair reproductive success in fish species, impacting population numbers. Here we explore the critical role of endocrine disruptions in mediating reproductive effects after exposure to MPs, focusing primarily on the hypothalamic-pituitary-gonadal axis. Our review highlights the urgent need for interdisciplinary research efforts aimed at elucidating the full extent of MP toxicity and its implications for aquatic ecosystems. Lastly, we identify knowledge gaps for future research, including investigations into the transgenerational impacts, if any, of MP exposure and quantifying synergetic/antagonistic effects of MPs with other environmental pollutants. This expanded knowledge regarding the potential risks of MPs to aquatic wildlife is expected to aid policymakers in developing mitigation strategies to protect aquatic species.

Asunto(s)

Peces , Microplásticos , Reproducción , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/toxicidad , Peces/fisiología , Reproducción/efectos de los fármacos , Microplásticos/toxicidad , Disruptores Endocrinos/toxicidad , Conducta Animal/efectos de los fármacos

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Since its identification in the vitreous humour of the eye and laboratory biosynthesis, hyaluronic acid (HA) has been a vital component in several pharmaceutical, nutritional, medicinal, and cosmetic uses. However, little is known about its potential toxicological impacts on aquatic inhabitants. Herein, we investigated the hematological response of Clarias gariepinus to nominal doses of HA. To achieve this objective, 72 adult fish were randomly and evenly distributed into four groups: control, low-dose (0.5 mg/l HA), medium-dose (10 mg/l HA), and high-dose (100 mg/l HA) groups for two weeks each during both the exposure and recovery periods. The findings confirmed presence of anemia, neutrophilia, leucopoenia, lymphopenia, and eosinophilia at the end of exposure to HA. In addition, poikilocytosis and a variety of cytomorphological disturbances were observed. Dose-dependent histological alterations in spleen morphology were observed in the exposed groups. After HA removal from the aquarium for 2 weeks, the groups exposed to the two highest doses still exhibited a notable decline in red blood cell count, hemoglobin concentration, mean corpuscular hemoglobin concentration, and an increase in mean corpuscular volume. Additionally, there was a significant rise in neutrophils, eosinophils, cell alterations, and nuclear abnormalities percentages, along with a decrease in monocytes, coupled with a dose-dependent decrease in lymphocytes. Furthermore, only the highest dose of HA in the recovered groups continued to cause a significant increase in white blood cells. White blood cells remained lower, and the proportion of apoptotic RBCs remained higher in the high-dose group. The persistence of most of the haematological and histological disorders even after recovery period indicates a failure of physiological compensatory mechanisms to overcome the HA-associated problems or insufficient duration of recovery. Thus, these findings encourage the inclusion of this new hazardous agent in the biomonitoring program and provide a specific pattern of hematological profile in HA-challenged fish. Further experiments are highly warranted to explore other toxicological hazards of HA using dose/time window protocols.

Asunto(s)

Bagres , Ácido Hialurónico , Bazo , Animales , Ácido Hialurónico/sangre , Bazo/efectos de los fármacos , Bazo/patología , Relación Dosis-Respuesta a Droga

RESUMEN

INTRODUCTION: Zein-incorporated magnesium oxide nanoparticles (zMgO NPs) were found to be effective against the bacteria S. mutans, S. aureus, E. faecalis and C. albicans, and can impart this antimicrobial effect on the resin composite it is integrated with. However, the effect of different light curing systems on the mechanical properties of this novel biomaterial has yet to be investigated. The objective of this study was to assess the effect of light-emitting diode (LED) and quarts-tungsten halogen (QTH) light curing systems on the compressive strength, flexural strength, and microhardness of bulk-fill resin composite modified with zMgO NPs. METHODOLOGY: A Teflon mold was used to fabricate 180 bulk-fill composite samples with concentrations of zMgO NPs at 0%, 0.3% and 0.5% (n = 60). Samples of each group were allocated to light curing by LED or QTH, after which 10 samples of each group were allotted to a mechanical test. Characterization of the specimens was performed by X-ray diffraction, field emission scanning electron microscopy and Fourier transform infrared spectroscopy. Two-way ANOVA and Tukey's post-hoc test was conducted at P = .05 to determine significance. RESULTS: The characterization revealed a uniform distribution of nanoparticles in the matrix and the formation of a new hybrid composite that maintained its properties. The compressive strength of the 0.3% zMgO composite for the QTH group significantly increased, while the remaining groups underwent no significant change. There was no significant difference among the groups for the flexural strength and microhardness tests. CONCLUSION: The modified composites' compressive strength, flexural strength, and microhardness improved or remained consistent. Long-term clinical studies can further substantiate the enhanced resin composite. CLINICAL RELEVANCE: The modified composite will exhibit similar or improved mechanical properties whether an LED or QTH light cure device is used. The addition of an antimicrobial effect to bulk-fill resin composite will aid in the prevention of secondary caries.

RESUMEN

A transcriptome-wide association study (TWAS) was conducted on genome-wide association study (GWAS) summary statistics of malignant melanoma of skin (UK Biobank dataset) and The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM) gene expression weights to identify melanoma susceptibility genes. The GWAS included 2465 cases and 449,799 controls, while the gene expression testing was conducted on 103 cases. Afterward, a gene enrichment analysis was applied to identify significant TWAS associations. The melanoma's gene-microRNA (miRNA) regulatory network was constructed from the TWAS genes and their corresponding miRNAs. At last, a disease enrichment analysis was conducted on the corresponding miRNAs. The TWAS detected 27 genes associated with melanoma with p-values less than 0.05 (the top three genes are LOC389458 (RBAK), C16orf73 (MEIOB), and EIF3CL). After the joint/conditional test, one gene (AMIGO1) was dropped, resulting in 26 significant genes. The Gene Ontology (GO) biological process associated the extended gene set (76 genes) with protein K11-linked ubiquitination and regulation of cell cycle phase transition. K11-linked ubiquitin chains regulate cell division. Interestingly, the extended gene set was related to different skin cancer subtypes. Moreover, the enriched pathways were nsp1 from SARS-CoV-2 that inhibit translation initiation in the host cell, cell cycle, translation factors, and DNA repair pathways full network. The gene-miRNA regulatory network identified 10 hotspot genes with the top three: TP53, BRCA1, and MDM2; and four hotspot miRNAs: mir-16, mir-15a, mir-125b, and mir-146a. Melanoma was among the top ten diseases associated with the corresponding (106) miRNAs. Our results shed light on melanoma pathogenesis and biologically significant molecular interactions.

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BACKGROUND: Randomized controlled trials (RCTs) examining the outcomes with limus drug-coated balloons (DCBs) vs paclitaxel DCBs were small and underpowered for clinical endpoints. OBJECTIVES: This study sought to compare the angiographic and clinical outcomes with limus DCBs vs paclitaxel DCBs for percutaneous coronary intervention (PCI). METHODS: An electronic search of Medline, EMBASE, and Cochrane databases was performed through January 2024 for RCTs comparing limus DCBs vs paclitaxel DCBs for PCI. The primary endpoint was clinically driven target lesion revascularization (TLR). The secondary endpoints were late angiographic findings. Summary estimates were constructed using a random effects model. RESULTS: Six RCTs with 821 patients were included; 446 patients received a limus DCB, and 375 patients received a paclitaxel DCB. There was no difference between limus DCBs and paclitaxel DCBs in the incidence of TLR at a mean of 13.4 months (10.3% vs 7.8%; risk ratio [RR]: 1.32; 95% CI: 0.84-2.08). Subgroup analysis suggested no significant interaction among studies for de novo coronary lesions vs in-stent restenosis (Pinteraction = 0.58). There were no differences in the risk of major adverse cardiovascular events, cardiac mortality, or target vessel myocardial infarction between groups. However, limus DCBs were associated with a higher risk of binary restenosis (RR: 1.89; 95% CI: 1.14-3.12), late lumen loss (mean difference = 0.16; 95% CI: 0.03-0.28), and a smaller minimum lumen diameter (mean difference = -0.12; 95% CI: -0.22 to -0.02) at late follow-up. In addition, late lumen enlargement occurred more frequently (50% vs 27.5%; RR: 0.59; 95% CI: 0.45-0.77) with paclitaxel DCBs. CONCLUSIONS: Among patients undergoing DCB-only PCI, there were no differences in the risk of clinically driven TLR and other clinical outcomes between limus DCBs and paclitaxel DCBs. However, paclitaxel DCBs were associated with better late angiographic outcomes. These findings support the need for future trials to establish the role of new-generation limus DCBs for PCI.

Asunto(s)

Angioplastia Coronaria con Balón , Catéteres Cardíacos , Fármacos Cardiovasculares , Materiales Biocompatibles Revestidos , Enfermedad de la Arteria Coronaria , Paclitaxel , Intervención Coronaria Percutánea , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/mortalidad , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/efectos adversos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/mortalidad , Reestenosis Coronaria/etiología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento

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Pyrogallol, a botanical hydrolysable tannin, has diverse medical and industrial applications. Its impact on aquatic ecosystems and fish health has been previously studied, revealing histopathological, immunological, biochemical, and haematological alterations in African catfish (Clarias gariepinus). In this study, the neurotoxic potential of pyrogallol was assessed through a 15-day exposure of catfish to concentrations of 1, 5, or 10 mg/L. Enzyme activities such as acetylcholinesterase (AchE), monoamine oxidase (MAO), aldehyde oxidase (AO), and nitric oxide (NO) were measured in serum and brain, along with histopathological examinations in the brain and heart. Pyrogallol exposure led to decreased AchE activity in the brain and serum, increased serum MAO activity, elevated AO in both brain and serum, and suppressed NO levels. Morphological abnormalities and dose-dependent pathological alterations were observed in the brain and heart, including neuropile deformities, shrunken Purkinje cells, cardiomyocyte degeneration, and increased collagen fibers. This suggests that pyrogallol induces adverse effects in fish.

Asunto(s)

Encéfalo , Bagres , Óxido Nítrico , Pirogalol , Contaminantes Químicos del Agua , Animales , Óxido Nítrico/metabolismo , Óxido Nítrico/sangre , Encéfalo/efectos de los fármacos , Encéfalo/patología , Pirogalol/toxicidad , Contaminantes Químicos del Agua/toxicidad , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/sangre , Corazón/efectos de los fármacos , Miocardio/patología , Miocardio/metabolismo , Monoaminooxidasa/metabolismo , Cardiotoxicidad

RESUMEN

The chemicals formed from antipyrines are flexible organic building blocks that are employed in the development of pharmaceuticals. By diazotizing (4-arylazo-3-hydroxy-2-thienyl) 4-antipyrine ketones 1a, 1b and 1c and (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketones (2a, 2b and 2c) further replaced with six other coupling components, a broad spectrum of hybrid molecules have been created. Mass spectra, NMR, FTIR, and elemental analyses have all been used to confirm the structures of the synthesised compounds. The antimicrobial screening was investigated by agar well diffusion and diluting the broth technique against both Gram-negative and positive-tested bacterial strains. (3-methyl-5-(phenylamino)-4-(4-tolylazo)-2-thienyl) 4-antipyrine ketone (2a) was found to be superior to Ciprofloxacin against test strains: Acinetobacter sp (34.33±1.15 mm), Listeria monocytogenes (29.33±1.15 mm) and Streptococcus sp. (19.33±1.15 mm). Also, good to moderate activities were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) which were recorded at 9±1 to 59.67±4.51 µg/mL and 16±4 to >512 µg/mL, respectively, using compounds 2a, 2b, and 2c. MBC/MIC ratio showed, that only, 2a and 2b have a bactericidal effect but other antipyrines with bacteriostatic strength. To conclude, it was suggested that the use of these novel synthesized (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketone derivatives molecules as a new chemical class of antimicrobial agents to perform new drug discovery in pharmaceutical preparations and medicinal research.

Asunto(s)

Antibacterianos , Diseño de Fármacos , Cetonas , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Antipirina/farmacología , Antipirina/química , Antipirina/análogos & derivados , Antipirina/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos

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Liver fibrosis is a disease with a great global health and economic burden. Existing data highlights itraconazole (ITRCZ) as a potentially effective anti-fibrotic therapy. However, ITRCZ effect is hindered by several limitations, such as poor solubility and bioavailability. This study aimed to formulate and optimize chitosan nanoparticles (Cht NPs) loaded with ITRCZ as a new strategy for managing liver fibrosis. ITRCZ-Cht NPs were optimized utilizing a developed 22 full factorial design. The optimized formula (F3) underwent comprehensive in vitro and in vivo characterization. In vitro assessments revealed that F3 exhibited an entrapment efficiency of 89.65% ± 0.57%, a 169.6 ± 1.77 nm particle size, and a zeta potential of +15.93 ± 0.21 mV. Furthermore, in vitro release studies indicated that the release of ITRCZ from F3 adhered closely to the first-order model, demonstrating a significant enhancement (p-value < 0.05) in cumulative release compared to plain ITRCZ suspension. This formula increased primary hepatocyte survival and decreased LDH activity in vitro. The in vivo evaluation of F3 in a rat model of liver fibrosis revealed improved liver function and structure. ITRCZ-Cht NPs displayed potent antifibrotic effects as revealed by the downregulation of TGF-ß, PDGF-BB, and TIMP-1 as well as decreased hydroxyproline content and α-SMA immunoexpression. Anti-inflammatory potential was evident by reduced TNF-α and p65 nuclear translocation. These effects were likely ascribed to the modulation of Hedgehog components SMO, GLI1, and GLI2. These findings theorize ITRCZ-Cht NPs as a promising formulation for treating liver fibrosis. However, further investigations are deemed necessary.

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Deposition of amyloid-ß (Aß) peptides in the brain is a hallmark of Alzheimer's disease. Aßs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aß peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer's pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aß, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate Aß46 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-Aß46 structure reveals an interaction between Aß46 and loop 1PSEN1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Microscopía por Crioelectrón , Proteínas de la Membrana , Presenilina-1 , Humanos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/química , Presenilina-1/metabolismo , Presenilina-1/química , Presenilina-1/genética , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/química , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/química , Endopeptidasas/metabolismo , Endopeptidasas/química , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Unión Proteica , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/química , Enfermedad de Alzheimer/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/química , Péptido Hidrolasas/metabolismo , Péptido Hidrolasas/química , Modelos Moleculares , Proteolisis

RESUMEN

Endocrine disruptors are synthetic or natural chemicals that can agonize/antagonize hormone receptors or can interfere with the production and secretion of hormones, leading to altered tissue histology and physiology. Pyrogallol is a contaminant widely distributed in aquatic environments that presents health risks to both humans and animals. However, the potential for endocrine disruption by pyrogallol, particularly in fish, are lacking. The purpose of this study was to shed light on how pyrogallol may affect hormone signalling, histopathology, and reproductive outcomes in African catfish Clarias gariepinus. To investigate this, African catfish were exposed to one sublethal concentration of pyrogallol at either 0, 1, 5 or 10 mg/L for 15 days. We then assessed the effects of pyrogallol on the thyroid gland as well as the reproductive system by measuring sex hormone, seminal quality, gonadal histopathology, and histochemistry. Thyroid stimulating hormone and thyroxine showed notable decreases in catfish, and triiodothyronine was decreased with 10 mg/L pyrogallol. Unlike luteinizing hormone, follicle-stimulating hormone was significantly reduced in fish following exposure to pyrogallol relative to controls. Testosterone was also decreased in fish following pyrogallol exposure, whereas 17ß-estradiol increased in catfish exposed to pyrogallol. Additionally, in response to pyrogallol toxicity, sperm quality indices, including count, spermatocrit, motility, and sperm viability were adversely affected in a concentration-dependent manner. Pyrogallol exposure also induced several changes in the gonad following exposure to 1, 5, or 10 mg/L. Deformed tubular structures, vacuolation, thickening of the basement membrane, hypertrophy of the seminiferous tubules, intense melanomacrophage localization, spermatozoa loss, and necrosis were all observed in the testes. In the ovary, atretic follicles, deteriorated mature oocytes, degenerated yolk globules, and an increase in perinucleolar oocytes were observed in catfish exposed to pyrogallol. These findings suggest that pyrogallol may act as endocrine disrupting substance in aquatic environments. Further research on the mechanisms by which pyrogallol impairs endocrine systems, particularly in fish, is recommended.

Asunto(s)

Bagres , Disruptores Endocrinos , Pirogalol , Reproducción , Contaminantes Químicos del Agua , Animales , Bagres/fisiología , Disruptores Endocrinos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Reproducción/efectos de los fármacos , Masculino , Pirogalol/toxicidad , Pirogalol/análogos & derivados , Femenino , Glándula Tiroides/efectos de los fármacos

RESUMEN

Hepatotoxicity is the main off-target effect of methotrexate (MTX) limiting its effective clinical use. Besides, MDA-MB231 breast cancer cells show chemoresistance, partly via PI3K/AKT pathway. Therefore, we investigated the ameliorative potentials of the PI3K inhibitor, alpelisib (ALP) on MTX-induced hepatotoxicity (in vivo) and the restraining potentials of ALP on MDA-MB231 chemoresistance to MTX (in vitro). Twenty-eight male BALB/c mice were divided into 4 groups. In treatment groups, mice were administered ALP (2.5 and 5 mg/kg) for 5 days and MTX (20 mg/kg) from day 2 till day 5. The results showed that ALP restored hepatic architecture, reduced immune cell infiltration (F4/80, Ly6G and MPO) and repressed the rise in liver enzymes (AST and ALT) induced by MTX. Additionally, ALP rectified the MTX-induced disruption of cellular oxidant status by boosting antioxidant defense systems (HO-1 and GSH) and repressing lipid peroxidation (MDA and 4-HNE). Finally, ALP curbed MTX-induced hepatocyte apoptosis (NF-κB and BAX) and shifted the cytokine milieu away from inflammation (IL-17, IL-22, IL-6 and IL- 10). The results of the in vitro experiments revealed that ALP alone and in combination with MTX, synergistically, reduced cancer cell viability (MTT assay), migration (wound healing assay) and their capacity to establish colonies (colony formation assay) as compared to MTX alone. RT-PCR revealed the antiproliferative (Bcl-2) and proapoptotic (BAX) potentials of ALP and ALP/MTX combination especially after 24 h. In conclusion, targeting PI3K/AKT pathway is a promising strategy in triple negative breast cancer patients by ameliorating hepatotoxicity and restraining chemoresistance to chemotherapy.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas , Metotrexato , Ratones Endogámicos BALB C , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Mama Triple Negativas , Animales , Metotrexato/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Masculino , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Ratones , Humanos , Línea Celular Tumoral , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Apoptosis/efectos de los fármacos , Sinergismo Farmacológico , Transducción de Señal/efectos de los fármacos , Femenino , Antimetabolitos Antineoplásicos/toxicidad , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo

RESUMEN

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals known for their widespread use and persistence in the environment. Laboratory and epidemiological studies investigating these compounds have signaled their neurotoxic and endocrine-disrupting propensities, prompting further research into their effects on behavioral stress responses and their potential role as risk factors for stress-related disorders such as anxiety and depression. This study elucidates the ramifications of early developmental exposures to individual and combined PFAS on the development and behavioral stress responses of larval zebrafish (Danio rerio), an established model in toxicological research. Wild-type zebrafish embryos were enzymatically dechorionated and exposed to PFOS, PFOA, PFHxS, and PFHxA between 6 and 120 h post-fertilization (hpf). We targeted environmentally relevant concentrations stemming from the USEPA 2016 Hazard Advisory Limit (HAL, 0.07 µg/L) and folds higher (0.35, 0.7, 1.75, and 3.5 µg/L). Evaluations at 120 hpf encompassed mortality, overall development, developmental defects, and larval activity both at baseline stress levels and following exposure to acute stressors (acoustic and visual). Larval exposure to PFOA, PFOS, or PFHxS (0.07 µg/L or higher) elicited significant increases in mortality rates, which capped at 23.1%. Exposure to individual chemicals resulted in limited effects on overall development but increased the prevalence of developmental defects in the body axis, swim bladder, pigmentation, and eyes, as well as the prevalence of yolk sac and pericardial edemas. Larval activity at baseline stress levels and following exposure to acute stimuli was significantly altered. Combined exposure to all four chemicals intensified the breadth of developmental and behavioral alterations, suggesting possible additive or synergistic effects. Our findings shed light on the developmental and neurobehavioral disturbances associated with developmental exposure to PFAS at environmentally relevant concentrations, the added risks of combined exposures to these chemicals, and their possible role as environmental risk factors for stress-related disorders.

Asunto(s)

Conducta Animal , Fluorocarburos , Larva , Contaminantes Químicos del Agua , Pez Cebra , Animales , Fluorocarburos/toxicidad , Larva/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Conducta Animal/efectos de los fármacos , Estrés Fisiológico , Embrión no Mamífero/efectos de los fármacos

RESUMEN

INTRODUCTION: Trials evaluating the role of intravascular imaging in percutaneous coronary intervention (PCI) for complex coronary artery disease have yielded mixed results. This study aimed to compare the outcomes of intravascular imaging specifically intravascular ultrasound (IVUS) with those from conventional coronary angiography in complex PCI. METHODS: Comprehensive electronic search of MEDLINE, EMBASE, and Cochrane databases was performed until March 2023 for randomized clinical trials (RCTs) comparing intravascular imaging with coronary angiography in patients undergoing complex PCI. Complex PCI was defined per each study, and included PCI for American College of Cardiology/American Heart Association (ACC/AHA) type B2/C lesions, unprotected left main coronary artery disease, or multivessel stenting. The primary study outcome was major adverse clinical events (MACE). RESULTS: The meta-analysis included 10 RCTs with a total of 6615 patients (3576 in the intravascular imaging group and 3039 in the coronary angiography group). The weighted mean-follow up was 28.9 months. Compared with coronary angiography, intravascular imaging reduced MACE (8% vs. 13.3%; relative risk [RR] 0.63; 95% confidence interval [CI] 0.54-0.73), cardiac death (RR 0.47; 95% CI 0.31-0.73), definite/probable stent thrombosis (RR 0.48; 95% CI 0.24-0.97), target vessel revascularization (RR 0.62; 95% CI 0.46-0.83), and target lesion revascularization (RR 0.61; 95% CI 0.47-0.79). There was no difference between both groups in all-cause death (RR 0.79; 95% CI 0.53-1.18) and myocardial infarction (RR 0.80; 95% CI 0.61-1.04). CONCLUSION: In patients undergoing complex PCI, intravascular imaging-specifically IVUS-reduced MACE by decreasing the incidence of cardiac death, stent thrombosis, and target vessel and target lesion revascularization.