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1.
Microb Cell Fact ; 22(1): 83, 2023 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-37106372

RESUMEN

Various factors contribute to the development of the acute inflammation process, like the pro-inflammatory cytokines, certain enzymes as well as oxidative stress mediators. The anti-inflammatory potential of the endophytic fungus Penicillium brefeldianum was explored in carrageenan-induced inflammation in rats. After isolation of the fungus from Acalypha hispida leaves, it was identified by 18S rRNA gene sequencing. Then, its phytochemical profile was elucidated using LC-ESI-MS/MS technique. There was a remarkable decrease in the edema weight in the endophytic fungi-treated group (200 mg/kg). Also, this group had few inflammatory cells and thickened epidermis with underlying moderate collagenosis when stained with haematoxylin and eosin. Besides, immunostaining with monoclonal antibodies of cyclooxygenase-2 and tumor necrosis factor alpha showed a decrease in the positive immune cells in the endophytic fungi treated group (200 mg/kg) in relation to the positive control. Interestingly, the levels of the inflammatory as well as oxidative stress markers, including prostaglandin E2, nitric oxide, and malondialdehyde, which are hallmarks of the inflammatory process, considerably diminished (p < 0.05) in this group. qRT-PCR was utilised to elucidate the impact of the endophytic fungi treatment on the expression of interleukins (IL-1ß and IL-6) genes, which decreased in comparison with the positive control group. Consequently, we can deduce that P. brefeldianum endophytic fungus has a promising anti-inflammatory potential and should be extensively studied on a broader range in the near future.


Asunto(s)
Penicillium , Espectrometría de Masas en Tándem , Ratas , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Fitoquímicos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico
2.
Int J Mol Sci ; 23(18)2022 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-36142821

RESUMEN

Metabolomics is a potential approach to paving new avenues for clinical diagnosis, molecular medicine, and therapeutic drug monitoring and development. The conventional metabolomics analysis pipeline depends on the data-independent acquisition (DIA) technique. Although powerful, it still suffers from stochastic, non-reproducible ion selection across samples. Despite the presence of different metabolomics workbenches, metabolite identification remains a tedious and time-consuming task. Consequently, sequential windowed acquisition of all theoretical MS (SWATH) acquisition has attracted much attention to overcome this limitation. This article aims to develop a novel SWATH platform for data analysis with a generation of an accurate mass spectral library for metabolite identification using SWATH acquisition. The workflow was validated using inclusion/exclusion compound lists. The false-positive identification was 3.4% from the non-endogenous drugs with 96.6% specificity. The workflow has proven to overcome background noise despite the complexity of the SWATH sample. From the Human Metabolome Database (HMDB), 1282 compounds were tested in various biological samples to demonstrate the feasibility of the workflow. The current study identified 377 compounds in positive and 303 in negative modes with 392 unique non-redundant metabolites. Finally, a free software tool, SASA, was developed to analyze SWATH-acquired samples using the proposed pipeline.


Asunto(s)
Metaboloma , Metabolómica , Bases de Datos Factuales , Humanos , Metabolómica/métodos , Programas Informáticos , Flujo de Trabajo
3.
Molecules ; 26(3)2021 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-33499325

RESUMEN

Zygophyllum coccineum, an edible halophytic plant, is part of the traditional medicine chest in the Mediterranean region for symptomatic relief of diabetes, hypertension, wound healing, burns, infections, and rheumatoid arthritis pain. The current study aimed to characterize Z. coccineum phytoconstituents, and the evaluations of the anti-microbial-biofilm, and anti-cancers bioactivities of the plant's mother liquor, i.e., aqueous-ethanolic extract, and its subsequent fractions. The in silico receptors interaction feasibility of Z. coccineum major constituents with Staph GyraseB, and human topoisomerase-IIß (h-TOP-IIß) were conducted to confirm the plant's anti-microbial and anti-cancer biological activities. Thirty-eight secondary metabolites of flavonoids, stilbene, phenolic acids, alkaloids, and coumarin classes identified by LC-ESI-TOF-MS spectrometric analysis, and tiliroside (kaempferol-3-O-(6''''-p-coumaroyl)-glucoside, 19.8%), zygophyloside-F (12.78%), zygophyloside-G (9.67%), and isorhamnetin-3-O-glucoside (4.75%) were identified as the major constituents. A superior biofilm obliteration activity established the minimum biofilm eradication concentration (MBEC) for the chloroform fraction at 3.9-15.63 µg/mL, as compared to the positive controls (15.63-31.25 µg/mL) against all the microbial strains that produced the biofilm under study, except the Aspergillus fumigatus. The aqueous-ethanolic extract showed cytotoxic effects with IC50 values at 3.47, 3.19, and 2.27 µg/mL against MCF-7, HCT-116, and HepG2 cell-lines, respectively, together with the inhibition of h-TOP-IIß with IC50 value at 45.05 ng/mL in comparison to its standard referral inhibitor (staurosporine, IC50, 135.33 ng/mL). This conclusively established the anti-cancer activity of the aqueous-ethanolic extract that also validated by in silico receptor-binding predicted energy levels and receptor-site docking feasibility of the major constituents of the plant's extract. The study helped to authenticate some of the traditional phytomedicinal properties of the anti-infectious nature of the plant.


Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Zygophyllum/química , Biopelículas/efectos de los fármacos , Simulación por Computador , Girasa de ADN/química , ADN-Topoisomerasas de Tipo II/química , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Cromatografía de Gases y Espectrometría de Masas , Células HCT116 , Células Hep G2 , Humanos , Técnicas In Vitro , Células MCF-7 , Medicina Tradicional , Región Mediterránea , Simulación del Acoplamiento Molecular , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/química , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología
4.
J Ethnopharmacol ; 334: 118566, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-39002823

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Trifolium alexandrinum L. (TA), has traditionally been used in folk medicine for its anti-inflammatory properties against hyperuricemia and gout. However, the specific mechanisms of action of TA have not been thoroughly studied. AIM OF THE WORK: This study aimed to evaluate the protective effects of irradiated (TR25) and non-irradiated (TR0) Trifolium alexandrinum L. aqueous extract (TAAE), along with two isolated compounds, caffeine (CAF) and saponin (SAP), in a rat model of acute gouty arthritis (GA). MATERIALS AND METHODS: The GA model was established by injecting a monosodium urate (MSU) suspension into the knee joint. Synovial tissue pathology was assessed, and levels of TNF-α, IL-6, IL-1ß, NF-κB, mTOR, AKT1, PI3K, NLRP3, and ASC were measured by ELISA. mRNA expression of ERK1, JNK, and p-38 MAPK was detected using qRT-PCR, and Caspase-1 protein expression was assessed by immunohistochemical analysis. Knee swelling, uric acid levels, liver and kidney function, and oxidative stress markers were also evaluated. RESULTS: TAAE analysis identified 170 compounds, with 73 successfully identified using LC-HR-MS/MS, including caffeine citrate and theasapogenol B glycoside as the main constituents. The studied materials demonstrated significant protective effects against GA. TR25 administration significantly mitigated knee joint circumference compared to other treatments. It demonstrated potential in alleviating hyperuricemia, renal and hepatic impairments induced by MSU crystals. TR25 also alleviated oxidative stress and reduced levels of IL1ß, IL-6, TNF-α, and NF-κB. Weak Caspase-1 immune-positive staining was observed in the TR25 group. TR25 decreased NLRP3 and ASC expression, reducing inflammatory cytokine levels in GA. It effectively inhibited the PI3K, AKT, and mTOR signaling pathways, promoting autophagy. Additionally, TR25 suppressed ERK1, JNK, and p-38 MAPK gene expression in synovial tissue. These effects were attributed to various components in TAAE, such as flavonoids, phenolic acids, tannins, alkaloids, and triterpenes. CONCLUSION: Importantly, irradiation (25 KGy) enhanced the antioxidant effects and phtchemical contents of TAAE. Additionally, TR0, TR25, CAF, and SAP exhibited promising protective effects against GA, suggesting their therapeutic potential for managing this condition. These effects were likely mediated through modulation of the NLRP3/ASC/Caspase-1 and ERK/JNK/p-38 MAPK signaling pathways, as well as regulation of the PI3K/AKT/mTOR pathway. Further research is warranted to fully elucidate the underlying mechanisms and optimize their clinical applications.

5.
Metabolites ; 14(6)2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38921451

RESUMEN

The chemical profiles of both Zygophyllum album (Z. album) aerial parts and roots extracts were evaluated with LC-ESI-TOF-MS/MS analysis. Twenty-four compounds were detected. Among them, some are detected in both the aerial parts and the roots extracts, and others were detected in the aerial parts only. The detected compounds were mainly flavonoids, phenolic compounds, triterpenes and other miscellaneous compounds. Such compounds contribute to the diverse pharmacological activities elicited by the Z. album species. This study aimed to elucidate the antiepileptic effect of Z. album aerial parts and roots crude extracts against pentylenetetrazole (PTZ)-induced kindling in mice. Male albino mice were divided into four groups, eight animals each. All groups, except the control group, were kindled with PTZ (35 mg/kg i.p.), once every alternate day for a total of 15 injections. One group was left untreated (PTZ group). The remaining two groups were treated prior to PTZ injection with either Z. album aerial parts or roots crude extract (400 mg/kg, orally). Pretreatment with either extract significantly reduced the seizure scores, partially reversed the histological changes in the cerebral cortex and exerted antioxidant/anti-inflammatory efficacy evinced by elevated hippocampal total antioxidant capacity and SOD and catalase activities, parallel to the decrement in MDA content, iNOS activity and the TXNIB/NLRP3 axis with a subsequent decrease in caspase 1 activation and a release of IL-1ß and IL-18. Moreover, both Z. album extracts suppressed neuronal apoptosis via upregulating Bcl-2 expression and downregulating that of Bax, indicating their neuroprotective and antiepileptic potential. Importantly, the aerial parts extract elicited much more antiepileptic potential than the roots extract did.

6.
Int Immunopharmacol ; 132: 111957, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38554441

RESUMEN

This study investigated the antioxidant, anticancer, antibacterial properties of Dioon rzedowskii extract, which had not been previously explored. We aimed to determine the extract's effect on liver and breast cancer cell lines and on solid Ehrlich carcinoma (SEC) mouse model to investigate the underlying molecular mechanisms. Three female albino mice groups were established: a tumor control group, a group treated with 100 mg/kg of the extract (D100), and a group treated with 200 mg/kg of the extract (D200) for 16 days after tumor development. Results showed that the D. rzedowskii extract inhibited cell growth in both MCF-7 and HepG2 cells in a concentration-dependent manner. This was achieved by suppressing the cell proliferation and inducing apoptosis. The extract also improved liver, heart, and kidney functions compared to the tumor control. Furthermore, oral administration of the extract reduced tumor volume and alleviated oxidative stress in tumor tissue. The anticancer effects were associated with overexpression of p53 and Bax and downregulation of cyclin D1 expression, which was attributed to decreased phosphorylated MAPK kinases. Additionally, D. rzedowskii exhibited antibacterial activity against K. pneumoniae isolated from cancer patients. The extract inhibited bacterial growth and reduced the membrane integrity. The study suggests that D. rzedowskii has promising potential as an adjunctive therapy for cancer treatment. Further investigations are needed to explore its combined anticancer efficacy. These results emphasize the value of natural products in developing compounds with potential anticancer activity and support a paradigm shift in cancer management to improve patients' quality of life.


Asunto(s)
Antibacterianos , Antioxidantes , Apoptosis , Carcinoma de Ehrlich , Proliferación Celular , Extractos Vegetales , Transducción de Señal , Animales , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratones , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Femenino , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/patología , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Células MCF-7 , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
7.
J Chromatogr Sci ; 61(7): 619-624, 2023 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-36097799

RESUMEN

This study uses a liquid chromatography-electrospray ionization-tandem mass spectrometry method to determine ß-Sitosterol and Ferulic acid in Pygeum africanum extract. Chromatographic separation of the two analytes was performed on an ACQUITY UPLC H-Class system coupled with Xevo TQD mass spectrometer and HSS T3 C18 column (2.1 X 50 mm, 1.8 µm). Mobile phase A consisted of an aqueous solution of 0.1% formic acid (v/v), and mobile phase B was 0.1% formic acid (v/v) in methanol pumped through a gradient elution mode. Mass spectrometer parameters were optimized using an electrospray ionization source in the positive and negative ionization modes. The quantification of the two analytes was performed using multiple reaction monitoring transitions. The method was fully validated per (FDA) guidelines regarding linearity, accuracy, precision, carryover and selectivity. The proposed method was applied successfully to determine the two investigated compounds in commercially available pharmaceutical products.


Asunto(s)
Prunus africana , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados
8.
Front Mol Biosci ; 10: 1218518, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37469707

RESUMEN

The tRNA adaptation index (tAI) is a translation efficiency metric that considers weighted values (S ij values) for codon-tRNA wobble interaction efficiencies. The initial implementation of the tAI had significant flaws. For instance, generated S ij weights were optimized based on gene expression in Saccharomyces cerevisiae, which is expected to vary among different species. Consequently, a species-specific approach (stAI) was developed to overcome those limitations. However, the stAI method employed a hill climbing algorithm to optimize the S ij weights, which is not ideal for obtaining the best set of S ij weights because it could struggle to find the global maximum given a complex search space, even after using different starting positions. In addition, it did not perform well in computing the tAI of fungal genomes in comparison with the original implementation. We developed a novel approach named genetic tAI (gtAI) implemented as a Python package (https://github.com/AliYoussef96/gtAI), which employs a genetic algorithm to obtain the best set of S ij weights and follows a new codon usage-based workflow that better computes the tAI of genomes from the three domains of life. The gtAI has significantly improved the correlation with the codon adaptation index (CAI) and the prediction of protein abundance (empirical data) compared to the stAI.

9.
Artif Cells Nanomed Biotechnol ; 51(1): 297-308, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37224186

RESUMEN

Emergent records propose that Aspergillus niger endophytic fungus is a vital source for various bioactive molecules possessing many biological properties. The current study was designed to inspect the antibacterial and anti-Toxoplasma potentials of Ficus retusa-derived endophytic fungi. After isolation and identification (using 18S rRNA gene sequencing) of A. niger endophytic fungus, LC/MS was utilized for identification and authentication of the chemical profile of the A. niger endophyte extract. Then, the fungal extract was assessed for its antibacterial and antibiofilm activities against Klebsiella pneumoniae clinical isolates. Additionally, its efficacy against Toxoplasma gondii was elucidated in vivo. The fungal extract displayed antibacterial activity against K. pneumoniae isolates with minimum inhibitory concentration values of 64-512 µg/mL. It also possessed a membrane potential dissipating effect using flow cytometry. Moreover, it formed distorted cells with rough surfaces and deformed shapes using a scanning electron microscope (SEM). Regarding its antibiofilm activity, it resulted in a dysregulation of the genes encoding biofilm formation (fimH, mrkA and mrkD) using qRT-PCR in nine K. pneumoniae isolates. The in vivo anti-Toxoplasma potential was demonstrated by decreasing the mortality rate of mice and reducing the tachyzoites' count in the peritoneal fluids and liver impression smears of mice. In addition, the deformities of the parasite decreased, as revealed by SEM and the inflammation in tissues diminished. Thus, A. niger endophytic fungi could be a valuable source of antibacterial and anti-Toxoplasma compounds.


Asunto(s)
Asteraceae , Ficus , Toxoplasma , Aspergillus niger , Antibacterianos/farmacología , Extractos Vegetales
10.
Life Sci ; 334: 122237, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37926299

RESUMEN

AIMS: Ewing's Sarcoma is an extremely aggressive tumor in children. The disease is associated with highly metastatic rate, especially at the time of diagnosis, contributing to a lower survival rate and poor prognosis. The study aimed to identify predictive biomarkers for metastatic Ewing's sarcoma through in-depth analysis of the plasma proteome profile of pediatric Ewing's sarcoma patients. MAIN METHODS: Plasma samples from Ewing's sarcoma patients and control individuals were profiled using both shotgun and dimethyl-labeled proteomics analysis. Subsequently, Ewing's sarcoma patients were further stratified according to their metastatic state and chemotherapy response. Western blot was used for validation. Univariate and multivariate analyses were performed to determine proteome metastasis predictors. Receiver operating characteristic (ROC) analysis was done to assess the diagnostic significance of the potential plasma Ewing's sarcoma biomarkers. KEY FINDINGS: Our results revealed a set of proteins significantly associated with the metastatic Ewing's sarcoma disease profile. These proteins include ceruloplasmin and several immunoglobulins. Additionally, our study disclosed significant differentially expressed proteins in pediatric Ewing's sarcoma, including CD5 antigen-like, clusterin, and dermcidin. Stable isotope dimethyl labeling and western blot further confirmed our results, strengthening the impact of such proteins in disease development. Furthermore, an unbiased ROC curve evaluated and confirmed the predictive power of these biomarker candidates. SIGNIFICANCE: This study presented potential empirical predictive circulating biomarkers for determining the disease status of pediatric Ewing's sarcoma, which is vital for early prediction.


Asunto(s)
Neoplasias Óseas , Sarcoma de Ewing , Humanos , Niño , Sarcoma de Ewing/diagnóstico , Neoplasias Óseas/metabolismo , Pronóstico , Proteoma
11.
Sci Rep ; 13(1): 7676, 2023 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-37169776

RESUMEN

This study evaluated the topical effect of Lepidium sativum lyophilized seed extract (LSLE) towards Sustanon-induced alopecia in male adult Wistar albino rats in vivo, compared to minoxidil topical reference standard drug (MRD). LC-MS/MS together with molecular networking was used to profile the metabolites of LSLE. LSLE treated group revealed significant changes in alopecia related biomarkers, perturbation of androgenic markers; decline in testosterone level and elevation in 5α-reductase (5-AR); decline in the cholesterol level. On the other hand, LSLE treated group showed improvement in vascular markers; CTGF, FGF and VEGF. Groups treated topically with minoxidil and LSLE showed significant improvement in hair length. LC-MS/MS profile of LSLE tentatively identified 17 constituents: mainly glucosinolates, flavonoid glycosides, alkaloids and phenolic acids. The results point to the potential role of LSLE in the treatment of alopecia through decreasing 5(alpha)-dihydrotestosterone levels. Molecular docking was attempted to evaluate the probable binding mode of identified compounds to androgen receptor (PDB code: 4K7A).


Asunto(s)
Cabello , Minoxidil , Animales , Inhibidores de 5-alfa-Reductasa/farmacología , Alopecia/tratamiento farmacológico , Cromatografía Liquida , Lepidium sativum , Minoxidil/farmacología , Simulación del Acoplamiento Molecular , Extractos Vegetales/uso terapéutico , Espectrometría de Masas en Tándem , Ratas
12.
Sci Rep ; 13(1): 1802, 2023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36720931

RESUMEN

Three years after the pandemic, we still have an imprecise comprehension of the pathogen landscape and we are left with an urgent need for early detection methods and effective therapy for severe COVID-19 patients. The implications of infection go beyond pulmonary damage since the virus hijacks the host's cellular machinery and consumes its resources. Here, we profiled the plasma proteome and metabolome of a cohort of 57 control and severe COVID-19 cases using high-resolution mass spectrometry. We analyzed their proteome and metabolome profiles with multiple depths and methodologies as conventional single omics analysis and other multi-omics integrative methods to obtain the most comprehensive method that portrays an in-depth molecular landscape of the disease. Our findings revealed that integrating the knowledge-based and statistical-based techniques (knowledge-statistical network) outperformed other methods not only on the pathway detection level but even on the number of features detected within pathways. The versatile usage of this approach could provide us with a better understanding of the molecular mechanisms behind any biological system and provide multi-dimensional therapeutic solutions by simultaneously targeting more than one pathogenic factor.


Asunto(s)
COVID-19 , Humanos , Multiómica , Proteoma , Conocimiento , Bases del Conocimiento
13.
Chem Biol Drug Des ; 99(4): 547-560, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34873844

RESUMEN

Quinoline-based thiazolidinone heterocycles exhibited potent activity in the field of cancer therapy. Hence, ten quinoline-based thiazolidinone derivatives were evaluated for their anticancer activity through cytotoxic activity, epidermal growth factor receptor (EGFR) inhibition pathway, apoptosis investigation through flow cytometric analyses, RT-PCR gene expression, in vivo solid-Ehrlich carcinoma model, and finally in silico approach for highlighting the interaction pose. Results revealed that compound 7 exhibited cytotoxic activity against HCT-116 cells with an IC50 value of 7.43 µM compared to 5-FU (IC50  = 11.36 µM) with moderate cytotoxic activity against the FHC (IC50  = 35.27 µM), and it exhibited remarkable inhibition activity of EGFR with IC50 value of 96.43 nM compared to Erlotinib (IC50  = 78.65 nM). Moreover, it significantly stimulated apoptotic colon cancer cell death with 171.58-fold arresting cell cycle at G2 and S-phases. Additionally, it ameliorated both biochemical and histochemical structures near normal with tumor inhibition ratio of 52.92% compared to 5-FU of 57.16%, with immunohistochemical examinations of EGFR inhibition in the treated group compared to control. Finally, molecular docking study highlighted its good binding affinity through good interactive binding pose inside the EGFR protein. In conclusion, the potent EGFR inhibitory activity of compound 7 was investigated using three integrated approaches in vitro, in vivo, and in silico, so it worth be validated and developed as a chemotherapeutic anticancer agent.


Asunto(s)
Antineoplásicos , Quinolinas , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Fluorouracilo/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Quinolinas/química , Relación Estructura-Actividad
14.
J Fungi (Basel) ; 8(5)2022 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-35628776

RESUMEN

Recently, Candida glabrata has been recognized as one of the most common fungal species that is highly associated with invasive candidiasis. Its spread could be attributed to its increasing resistance to antifungal drugs. Thus, there is a high need for safer and more efficient therapeutic alternatives such as plant extracts. Here, we investigated the antifungal potential of Encephalartos villosus leaves methanol extract (EVME) against C. glabrata clinical isolates. Tentative phytochemical identification of 51 metabolites was conducted in EVME using LC-MS/MS. EVME demonstrated antifungal activity with minimum inhibitory concentrations that ranged from 32 to 256 µg/mL. The mechanism of the antifungal action was studied by investigating the impact of EVME on nucleotide leakage. Additionally, a sorbitol bioassay was performed, and we found that EVME affected the fungal cell wall. In addition, the effect of EVME was elucidated on the efflux activity of C. glabrata isolates using acridine orange assay and quantitative real-time PCR. EVME resulted in downregulation of the expression of the efflux pump genes CDR1, CDR2, and ERG11 in the tested isolates with percentages of 33.33%, 41.67%, and 33.33%, respectively. Moreover, we investigated the in vivo antifungal activity of EVME using a murine model with systemic infection. The fungal burden was determined in the kidney tissues. Histological and immunohistochemical studies were carried out to investigate the effect of EVME. We noticed that EVME reduced the congestion of the glomeruli and tubules of the kidney tissues of the rats infected with C. glabrata. Furthermore, it decreased both the proinflammatory cytokine tumor necrosis factor-alpha and the abnormal collagen fibers. Our results reveal, for the first time, the potential in vitro (by inhibition of the efflux activity) and in vivo (by decreasing the congestion and inflammation of the kidney tissues) antifungal activity of EVME against C. glabrata isolates.

15.
Chem Biol Drug Des ; 97(3): 553-564, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32920942

RESUMEN

Quinoline derivatives are attracting considerable interest due to their biological importance. In this paper, several 2-amino-4-aryl-6-(quinolin-2-ylthio)pyridine-3,5-dicarbonitrile derivatives are synthesized by adopting a one-pot reaction of quinoline-2-thione, aromatic aldehydes, and malononitrile in the presence of sodium hydroxide in absolute ethanol. The structures of these newly synthesized compounds were determined using different spectroscopic techniques, including elemental analyses, IR, 1 H NMR, and MS. The synthesized derivatives were screened for their antimicrobial and cytotoxic activities. Compounds 4a, 4b, 4d, and 4e exhibited promising antimicrobial activity compared to antibacterial and antifungal standard drugs. Additionally, 4f, 4d, and 4g showed potent cytotoxic activity against both MCF-7 and A549 cells with IC50 values (6.39-9.3 µM). Our molecular docking results of compound 4f prove good binding affinity toward the three tested proteins as Jak2/STATA3 inhibition and are in accordance with the RT-PCR mRNA expressions of the compound against MCF-7 cells which downregulated the Jak2 and STAT3 genes, and this may be the proposed mode of action for anti-breast cancer activity.


Asunto(s)
Antiinfecciosos/química , Antineoplásicos/química , Janus Quinasa 2/antagonistas & inhibidores , Piridinas/química , Factor de Transcripción STAT3/antagonistas & inhibidores , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Diseño de Fármacos , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Janus Quinasa 2/metabolismo , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Piridinas/metabolismo , Piridinas/farmacología , Factor de Transcripción STAT3/metabolismo , Relación Estructura-Actividad , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
16.
J Proteomics ; 245: 104302, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34111608

RESUMEN

Metabolomics databases contain crucial information collected from various biological systems and experiments. Developers and scientists performed massive efforts to make the database public and accessible. The diversity of the metabolomics databases arises from the different data types included within the database originating from various sources and experiments can be confusing for biologists and researchers who need further manual investigation for the retrieved data. Xconnector is a software package designed to easily retrieve and visualize metabolomics data from different databases. Xconnector can parse information from Human Metabolome Database (HMDB), Livestock Metabolome Database (LMDB), Yeast Metabolome Database (YMDB), Toxin and Toxin Target Database (T3DB), ReSpect Phytochemicals Database (ReSpectDB), The Blood Exposome Database, Phenol-Explorer Database, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Small Molecule Pathway Database (SMPDB). Using Python language, Xconnector connects the targeted databases, recover requested metabolites from single or different database sources, reformat and repack the data to generate a single Excel CSV file containing all information from the databases, in an application programming interface (API)/ Python dependent manner seamlessly. In addition, Xconnector automatically generates graphical outputs in a time-saving approach ready for publication. SIGNIFICANCE: The powerful ability of Xconnector to summarize metabolomics information from different sources would enable researchers to get a closer glimpse on the nature of potential molecules of interest toward medical diagnostics, better biomarker discovery, and personalized medicine. The software is available as an executable application and as a python package compatible for different operating systems.


Asunto(s)
Metaboloma , Metabolómica , Bases de Datos Factuales , Humanos , Saccharomyces cerevisiae , Programas Informáticos
17.
J Proteomics ; 213: 103613, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31843688

RESUMEN

UniprotR is a software package designed to easily retrieve, cluster and visualize protein data from UniProt knowledgebase (UniProtKB) using R language. The package is implemented mainly to process, parse and illustrate proteomics data in a handy and time-saving approach allowing researchers to summarize all required protein information available at UniProtKB in a readable data frame, Excel CSV file, and/or graphical output. UniprotR generates a set of graphics including gene ontology, chromosomal location, protein scoring and status, protein networking, sequence phylogenetic tree, and physicochemical properties. In addition, the package supports clustering of proteins based on primary gene name or chromosomal location, facilitating additional downstream analysis. SIGNIFICANCE: In this work, we implemented a robust package for retrieving and visualizing information from multiple sources such UniProtKB, SWISS-MODEL, and STRING. UniprotR Contains functions that enable retrieving and cluster data in a handy way and visualize data in publishable graphs to facilitate researcher's work and fulfill their needs. UniprotR will aid in saving time for downstream data analysis instead of manual time consuming data analysis. AVAILABILITY AND IMPLEMENTATION: UniprotR released as free open source code under the license of GPLv3, and available in CRAN (The Comprehensive R Archive Network) and GitHub. (https://cran.r-project.org/web/packages/UniprotR/index.html). (https://github.com/Proteomicslab57357/UniprotR).


Asunto(s)
Secuencia de Aminoácidos , Bases del Conocimiento , Filogenia , Programas Informáticos , Proteínas/genética
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