RESUMEN
As an emerging environmental contaminant, antibiotic resistance genes (ARGs) in tap water have attracted great attention. Although studies have provided ARG profiles in tap water, research on their abundance levels, composition characteristics, and potential threat is still insufficient. Here, 9 household tap water samples were collected from the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) in China. Additionally, 75 sets of environmental sample data (9 types) were downloaded from the public database. Metagenomics was then performed to explore the differences in the abundance and composition of ARGs. 221 ARG subtypes consisting of 17 types were detected in tap water. Although the ARG abundance in tap water was not significantly different from that found in drinking water plants and reservoirs, their composition varied. In tap water samples, the three most abundant classes of resistance genes were multidrug, fosfomycin and MLS (macrolide-lincosamide-streptogramin) ARGs, and their corresponding subtypes ompR, fosX and macB were also the most abundant ARG subtypes. Regarding the potential mobility, vanS had the highest abundance on plasmids and viruses, but the absence of key genes rendered resistance to vancomycin ineffective. Generally, the majority of ARGs present in tap water were those that have not been assessed and are currently not listed as high-threat level ARG families based on the World Health Organization Guideline. Although the current potential threat to human health posed by ARGs in tap water is limited, with persistent transfer and accumulation, especially in pathogens, the potential danger to human health posed by ARGs should not be ignored.
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Agua Potable , Farmacorresistencia Microbiana , Metagenómica , Farmacorresistencia Microbiana/genética , Agua Potable/microbiología , China , Monitoreo del Ambiente , Antibacterianos/farmacología , Microbiología del AguaRESUMEN
Erythromycin fermentation residue (EFR) represents a typical hazardous waste produced by the microbial pharmaceutical industry. Although electrolysis is promising for EFR disposal, its microbial threats remain unclear. Herein, metagenomics was coupled with the random forest technique to decipher the antibiotic resistance patterns of electrochemically treated EFR. Results showed that 95.75% of erythromycin could be removed in 2 hr. Electrolysis temporarily influenced EFR microbiota, where the relative abundances of Proteobacteria and Actinobacteria increased, while those of Fusobacteria, Firmicutes, and Bacteroidetes decreased. A total of 505 antibiotic resistance gene (ARG) subtypes encoding resistance to 21 antibiotic types and 150 mobile genetic elements (MGEs), mainly including plasmid (72) and transposase (52) were assembled in EFR. Significant linear regression models were identified among microbial richness, ARG subtypes, and MGE numbers (r2=0.50-0.81, p< 0.001). Physicochemical factors of EFR (Total nitrogen, total organic carbon, protein, and humus) regulated ARG and MGE assembly (%IncMSE value = 5.14-14.85). The core ARG, MGE, and microbe sets (93.08%-99.85%) successfully explained 89.71%-92.92% of total ARG and MGE abundances. Specifically, gene aph(3')-I, transposase tnpA, and Mycolicibacterium were the primary drivers of the resistance dissemination system. This study also proposes efficient resistance mitigation measures, and provides recommendations for future management of antibiotic fermentation residue.
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Eritromicina , Fermentación , Metagenómica , Antibacterianos/farmacología , Farmacorresistencia Microbiana/genética , Farmacorresistencia Bacteriana/genéticaRESUMEN
OBJECTIVES: The investigation of Candida auris outbreaks is needed to provide insights into its population structure and transmission dynamics. We genotypically and phenotypically characterised a C. auris nosocomial outbreak occurred in Consorcio Hospital General Universitario de Valencia (CHGUV), Spain. METHODS: Data and isolates were collected from CHGUV from September 2017 (first case) until September 2021. Thirty-five isolates, including one from an environmental source, were randomly selected for whole genome sequencing (WGS), and the genomes were analysed along with a database with 335 publicly available genomes, assigning them to one of the five major clades. In order to identify polymorphisms associated with drug resistance, we used the fully susceptible GCA_003014415.1 strain as reference sequence. Known mutations in genes ERG11 and FKS1 conferring resistance to fluconazole and echinocandins, respectively, were investigated. Isolates were classified into aggregating or non-aggregating. RESULTS: All isolates belonged to clade III and were from an outbreak with a single origin. They clustered close to three publicly available genomes from a hospital from where the first patient was transferred, being the probable origin. The mutation VF125AL in the ERG11 gene, conferring resistance to fluconazole, was present in all the isolates and one isolate also carried the mutation S639Y in the FKS1 gene. All the isolates had a non-aggregating phenotype (potentially more virulent). CONCLUSIONS: Isolates are genotypically related and phenotypically identical but one with resistance to echinocandins, which seems to indicate that they all belong to an outbreak originated from a single isolate, remaining largely invariable over the years. This result stresses the importance of implementing infection control practices as soon as the first case is detected or when a patient is transferred from a setting with known cases.
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Antifúngicos , Candida auris , Candidiasis , Infección Hospitalaria , Brotes de Enfermedades , Farmacorresistencia Fúngica , Genotipo , Fenotipo , Secuenciación Completa del Genoma , Humanos , España/epidemiología , Infección Hospitalaria/microbiología , Infección Hospitalaria/epidemiología , Candidiasis/microbiología , Candidiasis/epidemiología , Antifúngicos/farmacología , Candida auris/genética , Candida auris/efectos de los fármacos , Farmacorresistencia Fúngica/genética , Pruebas de Sensibilidad Microbiana , Mutación , Masculino , Fluconazol/farmacología , Femenino , Equinocandinas/farmacología , Persona de Mediana Edad , Candida/genética , Candida/efectos de los fármacos , Candida/clasificación , Candida/aislamiento & purificaciónRESUMEN
BACKGROUND: Vonoprazan, a potassium-competitive acid blocker, is superior to traditional proton pump inhibitor (PPI) in acid suppression and has been approved in the treatment of acid-related disorders. Accumulating evidence suggest associations between PPI use and gut microbiota, yet the effect of vonoprazan on GI microbiota is obscure. METHODS: Transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer (GC) were administered vonoprazan by gavage every other day for 12 weeks. Stomachs were evaluated by histopathology, Ki-67 proliferation index, and inflammatory cytokines. The mucosal and lumen microbiota from stomach, jejunum, ileum, cecum, and feces were detected using 16S rRNA gene sequencing. RESULTS: Higher incidence of intestinal metaplasia and epithelial proliferation were observed in the vonoprazan group than that in the control mice. Vonoprazan also elevated the gastric expression of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6. Each mice comprised a unique microbiota composition that was consistent across different niches. The structure of GI microbiota changed dramatically after vonoprazan treatment with the stomach being the most disturbed segment. Vonoprazan administration shifted the gut microbiota toward the enrichment of pathogenic Streptococcus, Staphylococcus, Bilophila, and the loss of commensal Prevotella, Bifidobacterium, and Faecalibacterium. Interestingly, compared to the controls, microbial interactions were weaker in the stomach while stronger in the jejunum of the vonoprazan group. CONCLUSIONS: Long-term vonoprazan treatment promoted gastric lesions in male INS-GAS mice, with the disequilibrium of GI microbiome. The clinical application of vonoprazan needs to be judicious particularly among those with high risk of GC.
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Microbioma Gastrointestinal , Pirroles , Neoplasias Gástricas , Sulfonamidas , Animales , Pirroles/administración & dosificación , Pirroles/farmacología , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Ratones , Ratones Transgénicos , ARN Ribosómico 16S/genética , Modelos Animales de Enfermedad , Masculino , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/administración & dosificación , Citocinas/metabolismoRESUMEN
In vitro capacitation allows for a greater understanding of the mechanisms underlying fertilization and the development of improved reproductive techniques for improving fertility rates in porcine. Tyrodes albumin lactate pyruvate (TALP) and modified Krebs Ringers Broth (m-KRB) are two medias that are commonly used in research experiments to induce capacitation in boar spermatozoa (Cañón-Beltrán et al., Theriogenology, 198, 2023 and 231; Oberlender et al., Archivos de Medicina Veterinaria, 44, 2012 and 201; Sahoo et al., International Journal of Biological Macromolecules, 241, 2023 and 124502). Moreover, understanding the morphological and functional changes in boar spermatozoa at different hours of capacitation periods might aid in the development of novel techniques for improving sperm quality and increasing the litter size. This study was carried out to investigate the effect of Tyrode albumin lactate pyruvate and modified Krebs Ringers Broth media on in vitro capacitation of HD-K75 boar spermatozoa at three different periods of incubation. A total of 24 ejaculate from four clinically healthy, 10-12 months aged HD-K75 boars, maintained at ICAR-All India Coordinated Research Project (AICRP) on pig were selected. Semen was collected by 'Simple fist' method using a portable dummy. The semen samples having 200 mL volume, 103 × 106 spermatozoa/ml concentration and 70% initial motility were selected and split into two parts and suspended in TALP and m-KRB media, respectively, and incubated for 5 h at 37°C. Seminal parameters viz. sperm viability, plasma membrane integrity and acrosomal integrity were estimated in the samples at 0, 3 and 5 h of incubation. This study revealed that there was significant variation between media in live acrosome-reacted (p < .05) and HOST-reacted (p < .01) spermatozoa, while between capacitation periods significant (p < .01) variation was observed in hyperactivated spermatozoa, live acrosome-reacted spermatozoa, HOST-reacted spermatozoa, FITC-labelled PSA, extracellular protein and sperm cholesterol. Non-significant variation was observed in total phospholipid. TALP showed overall better consequence on sperm viability, plasma membrane and acrosomal integrity of boar spermatozoa. From this study, it could be concluded that both TALP and m-KRB media were virtuous to induce capacitation in HD-K75 boar spermatozoa. TALP media, however, had a better effect on sperm viability, plasma membrane and acrosomal integrity of boar spermatozoa. Out of the three different periods, 3 h capacitation period resulted in significantly (p < .01) higher incidence of sperm viability, plasma membrane and acrosomal integrity in HD-K75 boar spermatozoa.
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Capacitación Espermática , Espermatozoides , Animales , Masculino , Capacitación Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/fisiología , Porcinos , Medios de Cultivo/farmacología , Motilidad Espermática/efectos de los fármacos , Análisis de Semen/veterinariaRESUMEN
Over the past three decades, high-throughput phenotypic cancer cell line screens have revealed unanticipated small-molecule activities and illuminated connections between tumor genotypes and anticancer efficacy. Founded in 1984, the National Cancer Institute's "NCI60" screen laid the conceptual groundwork for the contemporary landscape of phenotypic drug discovery. NCI60 first operated as a primary bioactivity screen, but molecular characterization of the NCI60 cell line panel and development of a small-molecule sensitivity pattern recognition algorithm (called "COMPARE") have enabled subsequent studies into drug mechanisms of action and biomarker identification. In this issue of Cancer Research, Kunkel and colleagues report an updated version of the NCI60 screen, dubbed "HTS384" NCI60, that better aligns with current cell proliferation assay standards and has higher throughput. Changes include the use of a 384-well plate format, automated laboratory equipment, 3 days of compound exposure, and a CellTiter-Glo luminescent endpoint. To confirm that data from the HTS384 and classic NCI60 screen are comparable, the authors tested a library of 1,003 anticancer agents using both protocols and applied COMPARE to analyze patterns of cell line sensitivities. More than three dozen groups of targeted therapies showed high comparability between screens. Modernization of NCI60, and closer integration with other large-scale pharmacogenomic screens and molecular feature sets, will help this public screening service remain pertinent for cancer drug discovery efforts for years to come. See related article by Kunkel et al., p. 2403.
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Antineoplásicos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Descubrimiento de Drogas/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología , National Cancer Institute (U.S.) , Fenotipo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/genética , Estados Unidos , Proliferación Celular/efectos de los fármacosRESUMEN
Fluoride-releasing adhesive tapes have been developed as a new fluoride delivery agent. However, application as caries prevention agents remains underexplored. This study aimed at evaluating the antimicrobial activity of two fluoride-releasing adhesive tapes against S. mutans biofilm. Two polyvinyl alcohol (PVA) tapes were investigated: (i) a fluoride-PVA (F-PVA) tape, (ii) a pullulan incorporated F-PVA (PF-PVA) tape. S. mutan strains were cultured and treated with the tapes. Antimicrobial effects were evaluated using the agar diffusion test, field-emission scanning electron microscopy (FE-SEM), and confocal laser scanning microscopy (CLSM). F-PVA tapes showed higher inhibition-zone diameters than PF-PVA at 48 h and 72 h. However, there were no significant differences (p > 0.05) between the effects of F-PVA and PF-PVA. The bio-volume of S. mutans and extracellular polymeric substances significantly decreased in the F-PVA tapes than in the PF-PVA tapes (p < 0.05). FE-SEM micrographs revealed less S. mutans colonization in F-PVA. F-PVA exhibited better antimicrobial activity against S. mutans than PF-PVA.
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Biopelículas , Fluoruros , Streptococcus mutans , Streptococcus mutans/efectos de los fármacos , Biopelículas/efectos de los fármacos , Fluoruros/farmacología , Fluoruros/química , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacología , Microscopía Confocal , Microscopía Electrónica de Rastreo , Humanos , Cariostáticos/farmacología , Cariostáticos/química , Antiinfecciosos/farmacologíaRESUMEN
Mastitis, a serious threat to the health and milk production function of dairy cows decreases milk quality. Blood from three healthy cows and three mastitis cows were collected in this study and their transcriptome was sequenced using the Illumina HiSeq platform. Differentially expressed genes (DEGs) were screened according to the |log2FoldChange| > 1 and P-value < 0.05 criteria. Pathway enrichment and functional annotation were performed through KEGG and GO analyses. Finally, the mechanism of the AMP-activated protein kinase (AMPK) mediation of (-)-epigallocatechin-3-gallate (EGCG) to promote lipid metabolism in mastitis cows was analyzed in bovine mammary epithelial cells (BMECs). Transcriptome analysis revealed a total of 825 DEGs, with 474 genes showing increased expression and 351 genes showing decreased expression. The KEGG analysis of DEGs revealed that they were mainly linked to tumour necrosis factor, nuclear factor-κB signalling pathway, and lipid metabolism-related signalling pathway, whereas GO functional annotation found that DEGs were enriched in threonine and methionine kinase activity, cellular metabolic processes, and cytoplasm. AMPK expression, which is involved in several lipid metabolism pathways, was downregulated in mastitis cows. The results of in vitro experiments showed that the inhibition of AMPK promoted the expression of lipid synthesis genes in lipopolysaccharide-induced BMECs and that EGCG could promote lipid synthesis by decreasing the expression of AMPK and downregulating the expression of inflammatory factors in inflammatory BMECs. In conclusion, our study demonstrated that AMPK mediated EGCG to inhabit of inflammatory responses and promote of lipid synthesis in inflammatory BMECs.
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Proteínas Quinasas Activadas por AMP , Catequina , Metabolismo de los Lípidos , Glándulas Mamarias Animales , Mastitis Bovina , Animales , Bovinos , Catequina/análogos & derivados , Catequina/farmacología , Femenino , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Mastitis Bovina/genética , Metabolismo de los Lípidos/efectos de los fármacos , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica/veterinaria , Transcriptoma/efectos de los fármacosRESUMEN
In this study, peptides designed using fragments of an antifreeze protein (AFP) from the freeze-tolerant insect Tenebrio molitor, TmAFP, were evaluated as inhibitors of clathrate hydrate formation. It was found that these peptides exhibit inhibitory effects by both direct and indirect mechanisms. The direct mechanism involves the displacement of methane molecules by hydrophobic methyl groups from threonine residues, preventing their diffusion to the hydrate surface. The indirect mechanism is characterized by the formation of cylindrical gas bubbles, the morphology of which reduces the pressure difference at the bubble interface, thereby slowing methane transport. The transfer of methane to the hydrate interface is primarily dominated by gas bubbles in the presence of antifreeze peptides. Spherical bubbles facilitate methane migration and potentially accelerate hydrate formation; conversely, the promotion of a cylindrical bubble morphology by two of the designed systems was found to mitigate this effect, leading to slower methane transport and reduced hydrate growth. These findings provide valuable guidance for the design of effective peptide-based inhibitors of natural-gas hydrate formation with potential applications in the energy and environmental sectors.
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Proteínas Anticongelantes , Metano , Tenebrio , Agua , Proteínas Anticongelantes/química , Cinética , Metano/química , Metano/análogos & derivados , Agua/química , Tenebrio/química , Animales , Gases/química , Péptidos/química , Péptidos/farmacologíaRESUMEN
The Clinical and Laboratory Standards Institute has published epidemiological cut-off values for susceptibility data generated at 22°°C and read after 44-48 h for florfenicol, oxolinic acid and oxytetracycline against Aeromonas salmonicida. The cut-off values for the minimum inhibitory concentration (MIC) and disc diffusion were derived from data obtained by 1 laboratory and 2 laboratories respectively. The present work reports the generation of susceptibility data from additional laboratories and the calculation of provisional cut-off values from aggregations of these data with previously published data. With respect to MIC data, the provisional cut-off values, derived from aggregations of the data from 4 laboratories, were ≤4 µg ml-1 for florfenicol, ≤0.0625 µg ml-1 for oxolinic acid and ≤1 µg ml-1 for oxytetracycline. For disc diffusion data, the provisional cut-off values derived from aggregations of the data from 5 laboratories were ≥30 mm for florfenicol, ≥32 mm for oxolinic acid and ≥25 mm for oxytetracycline. In addition, a cut-off value of ≥29 mm for ampicillin was derived from the aggregation of data from 4 laboratories.
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Aeromonas salmonicida , Antibacterianos , Pruebas de Sensibilidad Microbiana , Aeromonas salmonicida/efectos de los fármacos , Antibacterianos/farmacología , Animales , Enfermedades de los Peces/microbiología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/epidemiología , Farmacorresistencia Bacteriana , Tianfenicol/análogos & derivados , Tianfenicol/farmacologíaRESUMEN
The present study was assumed that Nacetylcysteine (AC) might improve cognitive function in adolescent rats with hypothyroidism through various mechanisms. Sixty adolescent rats were randomly divided into the following groups: Vehicle (received normal saline intraperitoneally (IP)); Propylthiouracil (PTU)induced hypothyroidism (0.05%, dissolved in drinking water); Hypothyroid rats were IP treated with different doses of AC (50, 100, and 150 mg/kg/day) for a period of six weeks; Normal rats treated with the highest doses of AC (150 mg/kg/day). Behavioral and biochemical analyses were studied for all groups. In the Morris water maze test, AC significantly reduced both the time to find the hidden platform and the distance travelled as compared to nontreated hypothyroid rats. In the passive avoidance test, the latency of entering the dark chamber was significantly increased by AC, whereas decreased the time spent in the darkroom of the chamber compared to the hypothyroid rats. In biochemical results, AC reduced both malondialdehyde content and nitrite while increased the thiol content, catalase and superoxide dismutase enzymes activity in both the cortex and the hippocampus, and a notable improvement in brainderived neurotrophic factor (BDNF) levels in hippocampal tissues of the hypothyroid rats, while decreasing the level of interleukin6 in rat hippocampal region. Therefore, based on the results, the beneficial effects of AC on cognitive impairment in adolescent hypothyroid rats are probably related to its antioxidant properties and notable improvement in BDNF levels.
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Acetilcisteína , Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Hipotiroidismo , Estrés Oxidativo , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Hipotiroidismo/metabolismo , Hipotiroidismo/inducido químicamente , Hipotiroidismo/complicaciones , Acetilcisteína/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Trastornos de la Memoria/etiología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Antioxidantes/farmacologíaRESUMEN
The aim of the present study was to evaluate the effect of rosiglitazone (RSG) or pioglitazone (POG) on the synaptic plasticity, neuronal apoptosis, brain-derived neurotrophic factor (BDNF), and nitric oxide (NO) metabolites in the hippocampus of juvenile hypothyroid rats. The animals were divided into four groups: control; propylthiouracil (PTU), 0.05% dose in drinking water for 42 days; PTU-POG; and PTU-RSG. The POG (20 mg/kg) and the RSG (4 mg/kg) were administered by IP injection. We conducted longterm potentiation (LTP) in the cornu ammonis 1 area of the hippocampus using highfrequency stimulation of the Schaffer collateral pathway. Then, the hippocampal tissues were collected to determine BDNF and NO levels and the degree of apoptosis. PTU administration decreased the slope (10-90%) and amplitude of the fEPSPs compared to control. Injection of RSG or POG increased the slope, slope (10-90%), and amplitude of the fEPSP in the PTUPOG or PTURSG groups compared to the PTU group. TUNELpositive neurons and NO metabolites in the hippocampus of the PTU group were higher than those of the control group. RSG or POG increased BDNF content in PTU-POG or PTU-RSG groups. Treatment of the rats with POG or RSG decreased apoptotic neurons and NO metabolites in the hippocampus of PTU-POG or PTU-RSG groups, respectively, compared to the PTU group. This study's results revealed that POG or RSG normalized LTP impairment, neuronal apoptosis, and improved BDNF content in the hippocampal tissue of juvenile hypothyroid rats.
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Apoptosis , Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Hipotiroidismo , Potenciación a Largo Plazo , PPAR gamma , Ratas Wistar , Rosiglitazona , Animales , Apoptosis/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/inducido químicamente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Rosiglitazona/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , PPAR gamma/agonistas , PPAR gamma/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Tiazolidinedionas/farmacología , Pioglitazona/farmacología , Ratas , Propiltiouracilo/farmacología , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Óxido Nítrico/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Cannabinoid and serotonin systems regulate many biological processes. The aim of the present study was to investigate the functional interaction between the cannabinoid and serotonergic systems of the primary somatosensory region (S1) of the brain in epileptiform activity caused by penicillin. The ACEA (an agonist of CB1 receptor), AM251 (an antagonist of CB1 receptor), 8OHDPAT (an agonist of 5HT1A receptor) and WAY100635 (an antagonist of 5HT1A receptor) were administered into the S1 after the same site administration of penicillin in urethaneanesthetized rats. Electrocorticographic recording was done for a 90min period. The spike waves number and amplitude were recorded in 15min intervals. Areas under the curve (AUC) of the abovementioned spike alterations was calculated in 90 min. Spike waves with frequency of 30/min and amplitude of 1.3 mV were appeared after penicillin microinjection. The ACEA (50 ng), 8OHDPAT (500 ng) and ACEA (10 ng) plus 8OHDPAT (100 ng) reduced epileptiform activity. The AM251 (50 ng) and WAY100365 (500 ng) prevented the reducing effects of ACEA (50 ng) and 8OHDPAT (500 ng). The AM251 alone increased spike waves frequency. The AUC results supported the effects of the abovementioned treatments. The results showed that activating CB1 and 5HT1A receptors in the S1 may reduce the epileptiform activity caused by penicillin. Therefore, alone and together activation of central CB1 and 5HT1A receptors might be considered in the management of epilepsy treatment.
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Modelos Animales de Enfermedad , Epilepsia , Penicilinas , Ratas Wistar , Receptor Cannabinoide CB1 , Receptor de Serotonina 5-HT1A , Corteza Somatosensorial , Animales , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Penicilinas/farmacología , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/agonistas , Masculino , Epilepsia/inducido químicamente , Epilepsia/metabolismo , Epilepsia/tratamiento farmacológico , Ratas , Ácidos Araquidónicos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Piridinas/farmacología , Piperazinas/farmacología , Electrocorticografía , Piperidinas/farmacología , Electroencefalografía/métodos , PirazolesRESUMEN
In this study, we evaluated the hepatoprotective effects of astaxanthin, a natural carotenoid, against the cholestatic liver fibrosis induced by bile duct ligation (BDL). Toward this end, male rats were subjected to BDL and treated with astaxanthin for 35 days. Afterwards, their serum and liver biochemical factors were assessed. Also, histopathological and immunohistochemical analyses were performed to determine the fibrosis and the expression levels of alpha-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-ß1) in the liver tissue. Based on the results, BDL caused a significant increase in liver enzyme levels, blood lipids, and bilirubin, while decreasing the activity of superoxide dismutase(SOD), catalase (CAT), and glutathione (GSH) enzymes. Also, in the BDL rats, hepatocyte necrosis, infiltration of inflammatory lymphocytes, and hyperplasia of bile ducts were detected, along with a significant increase in α-SMA and TGF-ß1 expression. Astaxanthin, however, significantly prevented the BDL's detrimental effects. In all, 10 mg/kg of this drug maintained the bilirubin and cholesterol serum levels of BDL rats at normal levels. It also reduced the liver enzymes' activity and serum lipids, while increasing the SOD, CAT, and GSH activity in BDL rats. The expression of α-SMA and TGF-ß1 in the BDL rats treated with 10 mg/kg of astaxanthin was moderate (in 34%-66% of cells) and no considerable cholestatic fibrosis was observed in this group. However, administrating the 20 mg/kg of astaxanthin was not effective in this regard. These findings showed that astaxanthin could considerably protect the liver from cholestatic damage by improving the biochemical features and regulating the expression of related proteins.
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Conductos Biliares , Colestasis , Cirrosis Hepática , Ratas Wistar , Xantófilas , Animales , Xantófilas/farmacología , Xantófilas/uso terapéutico , Masculino , Ratas , Colestasis/patología , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Ligadura , Conductos Biliares/cirugía , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
5-fluorouracil (5-FU) is an inexpensive treatment for colon cancer; however, its efficacy is limited by chemoresistance. This study investigates the combination therapy approach of 5-FU with Sitagliptin (Sita), a diabetic drug with potential cancer-modulating effects. The combination was evaluated in vitro and in silico, focusing on the effects of Sita and 5-FU on colon cancer cells. The results showed that the addition of Sita significantly decreased the IC50 of 5-FU compared to 5-Fu monotherapy. The study also found that Sita and 5-FU interact synergistically, with a combination index below 1. Sita successfully lowered the 5-FU dosage reduction index, decreasing the expression of MDR1 mRNA and p-AKT and NFκB2 subunits p100/p52 protein. Molecular docking analyses confirmed Sita's antagonistic action on MDR1 and thymidylate synthase proteins. The study concludes that sitagliptin can target MDR1, increase apoptosis, and significantly reduce the expression of p-AKT and NFκB2 cell-survival proteins. These effects sensitize colon cancer cells to 5-FU. Repurposing sitagliptin may enhance the anticancer effects of 5-FU at lower dosages.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Neoplasias del Colon , Sinergismo Farmacológico , Fluorouracilo , Proteínas Proto-Oncogénicas c-akt , Fosfato de Sitagliptina , Humanos , Fosfato de Sitagliptina/farmacología , Fluorouracilo/farmacología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Regulación hacia Abajo/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: Melatonin, one of the most versatile hormones in the body, is well appreciated in managing circadian rhythm and for antioxidant properties. Produced in the pineal gland and within mitochondria, melatonin influences many physiologic processes through receptor mediated and direct effects. OBJECTIVE: The present investigation explores the evolving pharmacologic properties of melatonin, as well as current therapeutic uses in areas where mitigating oxidative stress, inflammation, and cellular senescence. This review also delves into novel therapeutic potential of melatonin and how current research is revealing a wide array of therapeutic promise in pain medicine. STUDY DESIGN: A systematic review of randomized controlled trials (RCTs) and observational studies was performed using various search engines focused on melatonin and its role in pain medicine. METHODS: The available literature on melatonin and pain medicine was reviewed. A comprehensive literature search of multiple databases from 1966 to July 2024, including manual searches of the bibliography of known review articles was performed. Quality assessment of the included studies and best evidence synthesis were incorporated into qualitative and quantitative evidence synthesis. OUTCOME MEASURES: The primary outcome measure was the proportion of patients receiving melatonin with significant relief and functional improvement of greater than 50% of at least 3 months. Duration of relief was categorized as short-term (less than 6 months) and long-term (greater than 6 months). RESULTS: Melatonin can affect intervertebral disc (IVD) health through the enhancement of survival and function of nucleus pulposus cells, primarily through activation of the ERK1/2 signaling pathway. Melatonin also influences the biochemical environment of the IVD by modulating inflammation and oxidative stress, crucial factors in the pathogenesis of disc degeneration. Melatonin has been shown to reduce senescence and promote autophagy within disc cells, vital for clearing out damaged cellular components, preserving cellular function and preventing deterioration associated with aging and degenerative diseases. LIMITATIONS: Despite the availability of multiple studies, the paucity of clinical pain related literature is considered as the major drawback. CONCLUSION: Based on the present systematic review, melatonin plays a critical role in sleep, but evolving studies have demonstrated substantive roles in mitigating degenerative conditions in various tissues, including IVD degeneration. Ongoing studies will better clarify the role of melatonin as a potential therapeutic agent, including the targeted delivery to various body regions.
Asunto(s)
Degeneración del Disco Intervertebral , Melatonina , Melatonina/uso terapéutico , Humanos , Degeneración del Disco Intervertebral/tratamiento farmacológico , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Manejo del Dolor/métodosRESUMEN
Due to antimicrobial drug resistance, there is a growing interest in the development of light based alternative antibacterial therapies. This research work is focused on the inactivation of Escherichia coli (E. coli) by exploiting the absorption bands 405, 505, 542, 580 and 631 nm of its indigenously produced Protoporphyrin IX (PpIX) excited by three LEDs with broad emission bands at 418, 522 and 630 nm and two laser diodes with narrow emission bands at 405 and 635 nm. Fluorescence spectroscopy and plate count method have been employed for studying the inactivation rate of E. coli strain in autoclaved water suspension. It has been found that LEDs at 418, 522 and 630 nm produced pronounced antimicrobial photodynamic effect on E. coli strain comparing laser diodes at 405 and 635 nm, which might be attributed to the overlapping of broad emission bands of LEDs with the absorption bands of PpIX than narrow emission bands of laser diodes. Particular effect of LED at 522 nm has been noticed because its broad emission band overlaps three absorption bands 505, 542 and 580 nm of PpIX. The gold standard plate count method strongly correlates with Fluorescence spectroscopy, making it an innovative tool to administer bacterial inactivation. The experimental results suggested the development of a light source that entirely overlap absorption bands of PpIx to produce a pronounced antimicrobial photodynamic effect, which might become an effective modality for in vivo disinfection of antibiotic resistant microbes in wounds and lesions.
Asunto(s)
Escherichia coli , Fotoquimioterapia , Fármacos Fotosensibilizantes , Protoporfirinas , Espectrometría de Fluorescencia , Escherichia coli/efectos de los fármacos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Láseres de Semiconductores/uso terapéutico , HumanosAsunto(s)
Anticoagulantes , Hemofilia A , Proteína C , Animales , Ratones , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Hemofilia A/complicaciones , Proteína C/metabolismo , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Hemartrosis/prevención & control , Hemartrosis/etiología , HumanosRESUMEN
Chronic wounds are susceptible to bacterial infections and at high risk of developing antibiotic-resistant bacterial infections. Silver is an antimicrobial by targeting almost all types of bacteria in chronic wounds to reduce the bacterial load in the infected area and further facilitate the healing process. This study focused on exploring whether silver-based dressings were superior to non-silver dressings in the treatment of chronic wounds. PubMed, Web of Science and Embase were comprehensively searched from inception to March 2024 for randomized clinical trials and observational studies. The endpoints in terms of wound healing rate, complete healing time, reduction on wound surface area and wound infection rate were analysed using Review Manager 5.4 software. A total of 15 studies involving 5046 patients were eventually included. The results showed that compared with patients provided with non-silver dressings, patients provided with silver-based dressings had higher wound healing rate (OR: 1.43, 95% CI: 1.10-1.85, p = 0.008), shorter complete healing time (MD: -0.96, 95% CI: -1.08 ~ -0.85, p < 0.00001) and lower wound infection rate (OR: 0.56, 95% CI: 0.40-0.79, p = 0.001); no significant difference in the reduction on wound surface area (MD: 12.41, 95% CI: -19.59-44.40, p = 0.45) was found. These findings suggested that the silver-based dressings were able to enhance chronic wound healing rate, shorten the complete healing time and reduce wound infection rate, but had no significant improvement in the reduction on wound surface area. Large-scale and rigorous studies are required to confirm the beneficial effects of silver-based dressings on chronic wound healing.
Asunto(s)
Vendajes , Plata , Cicatrización de Heridas , Humanos , Cicatrización de Heridas/efectos de los fármacos , Plata/uso terapéutico , Plata/farmacología , Enfermedad Crónica , Infección de Heridas/tratamiento farmacológico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Adulto , Compuestos de Plata/uso terapéutico , Compuestos de Plata/farmacologíaRESUMEN
Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the kinase conformation (KinCon) reporter system. We first track BRAF kinase activity conformational changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1 kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP kinases in response to TNF pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.