RESUMEN

Istamycins (ISMs) are 2-deoxyfortamine-containing aminoglycoside antibiotics (AGAs) produced by Streptomyces tenjimariensis ATCC 31603 with broad-spectrum bactericidal activities against most of the clinically relevant pathogens. Therefore, this study aimed to statistically optimize the environmental conditions affecting ISMs production using the central composite design (CCD). Both the effect of culture media composition and incubation time and agitation rate were studied as one factor at the time (OFAT). The results showed that both the aminoglycoside production medium and the protoplast regeneration medium gave the highest specific productivity. Results also showed that 6 days incubation time and 200 rpm agitation were optimum for their production. A CCD quadratic model of 17 runs was employed to test three key variables: initial pH, incubation temperature, and concentration of calcium carbonate. A significant statistical model was obtained including, an initial pH of 6.38, incubation temperature of 30 ˚C, and 5.3% CaCO3 concentration. This model was verified experimentally in the lab and resulted in a 31-fold increase as compared to the unoptimized conditions and a threefold increase to that generated by using the optimized culture media. To our knowledge, this is the first report about studying environmental conditions affecting ISM production as OFAT and through CCD design of the response surface methodology (RSM) employed for statistical optimization. In conclusion, the CCD design is an effective tool for optimizing ISMs at the shake flask level. However, the optimized conditions generated using the CCD model in this study should be scaled up in a fermenter for industrial production of ISMs by S. tenjimariensis ATCC 31603 considering the studied environmental conditions that significantly influence the production proces.

Asunto(s)

Antibacterianos , Medios de Cultivo , Fermentación , Streptomyces , Temperatura , Streptomyces/metabolismo , Streptomyces/crecimiento & desarrollo , Medios de Cultivo/química , Concentración de Iones de Hidrógeno , Antibacterianos/biosíntesis , Antibacterianos/farmacología , Carbonato de Calcio/metabolismo , Aminoglicósidos/farmacología , Microbiología Industrial , Reactores Biológicos/microbiología

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Introduction: Despite years of efforts to develop new antibiotics for eradicating multidrug-resistant (MDR) and multi-virulent Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Staphylococcus aureus (VRSA) infections, treatment failures and poor prognoses in most cases have been common. Therefore, there is an urgent need for new therapeutic approaches targeting virulence arrays. Our aim is to discover new anti-virulence therapies targeting MRSA and VRSA virulence arrays. Methodology: We employed phenotypic, molecular docking, and genetic studies to screen for anti-virulence activities among selected promising compounds: Coumarin, Simvastatin, and Ibuprofen. Results: We found that nearly all detected MRSA and VRSA strains exhibited MDR and multi-virulent profiles. The molecular docking results aligned with the phenotypic and genetic assessments of virulence production. Biofilm and hemolysin productions were inhibited, and all virulence genes were downregulated upon treatment with sub-minimum inhibitory concentration (sub-MIC) of these promising compounds. Ibuprofen was the most active compound, exhibiting the highest inhibition and downregulation of virulence gene products. Moreover, in vivo and histopathological studies confirmed these results. Interestingly, we observed a significant decrease in wound area and improvements in re-epithelialization and tissue organization in the Ibuprofen and antimicrobial treated group compared with the group treated with antimicrobial alone. These findings support the idea that a combination of Ibuprofen and antimicrobial drugs may offer a promising new therapy for MRSA and VRSA infections. Conclusion: We hope that our findings can be implemented in clinical practice to assist physicians in making the most suitable treatment decisions.

Asunto(s)

Antibacterianos , Biopelículas , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Infecciones Estafilocócicas , Staphylococcus aureus Resistente a Vancomicina , Factores de Virulencia , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Staphylococcus aureus Resistente a Meticilina/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Biopelículas/efectos de los fármacos , Factores de Virulencia/genética , Staphylococcus aureus Resistente a Vancomicina/efectos de los fármacos , Animales , Virulencia/efectos de los fármacos , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Humanos , Cumarinas/farmacología , Cumarinas/uso terapéutico , Ratones , Modelos Animales de Enfermedad , Proteínas Hemolisinas/antagonistas & inhibidores , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Farmacorresistencia Bacteriana Múltiple

RESUMEN

Acne is a long-standing skin condition characterized by plugged hair follicles due to the accumulation of dead skin cells, sebum, and Propionibacterium acnes (P. acnes) bacteria, causing inflammation, and the formation of pimples or lesions. Acne was recognized in the ancient times by the ancient Egyptians, Greeks, and Romans. Since ancient times, folk medicine from different cultures have comprised herbal and natural products for the treatment of acne. Current acne medications include antibiotics, keratolytics, corticosteroids, in addition to hormonal therapy for women. However, these conventional drugs can cause some serious side effects. And therefore, seeking new safe treatment options from natural sources is essential. Plants can be a potential source of medicinal phytochemicals which can be pharmacologically active as antibacterial, antioxidant, anti-inflammatory, keratolytic and sebum-reducing. Organic acids, obtained from natural sources, are commonly used as keratolytics in dermatology and cosmetology. Most of the promising phytochemicals in acne treatment belong to terpenes, terpenoids, flavonoids, alkaloids, phenolic compounds, saponins, tannins, and essential oils. These can be extracted from leaves, bark, roots, rhizomes, seeds, and fruits of plants and may be incorporated in different dosage forms to facilitate their penetration through the skin. Additionally, medicinal compounds from marine sources can also contribute to acne treatment. This review will discuss the pathogenesis, types and consequences of acne, side effects of conventional treatment, current possible treatment options from natural sources obtained from research and folk medicine and possible applied dosage forms.

RESUMEN

BACKGROUND: The ineffectiveness of treatments for infections caused by biofilm-producing pathogens and human carcinoma presents considerable challenges for global public health organizations. To tackle this issue, our study focused on exploring the potential of synthesizing new complexes of Co(II), Cu(II), Ni(II), and Zn(II) with sorbic acid to enhance its antibacterial, antibiofilm, and anticancer properties. METHODS: Four novel complexes were synthesized as solid phases by reacting sorbic acid with Co(II), Cu(II), Ni(II), and Zn(II). These complexes were characterized by various technique, including infrared spectra, UV-Visible spectroscopy, proton nuclear magnetic resonance (1H NMR), and thermal analysis techniques, including thermogravimetry (TG). RESULTS: The data acquired from all investigated chemical characterization methods confirmed the chemical structure of the sorbate metal complexes. These complexes exhibited antibacterial and antibiofilm properties against both Gram-positive and Gram-negative bacteria. Furthermore, these complexes enhanced the antibacterial effects of commonly used antibiotics, such as gentamicin and imipenem, with fractional inhibitory concentration (FIC) indices ≤ 0.5. Notably, the Cu(II) complex displayed the most potent antibacterial and antibiofilm activities, with minimum inhibitory concentration (MIC) values of 312.5 µg/mL and 625.0 µg/mL for Bacillus cereus and Escherichia coli, respectively. Additionally, in vitro assays using the methyl thiazolyl tetrazolium (MTT) method showed inhibitory effects on the growth of the human colon carcinoma cell line (HCT-116 cells) following treatment with the investigated metal complexes. The IC50 values for Co(II), Cu(II), Zn(II), and Ni(II) were 3230 µg/mL, 2110 µg/mL, 3730 µg/mL, and 2240 µg/mL, respectively. CONCLUSION: Our findings offer potential for pharmaceutical companies to explore the development of novel combinations involving traditional antibiotics or anticancer drugs with sorbate copper complex.

Asunto(s)

Antibacterianos , Antineoplásicos , Biopelículas , Complejos de Coordinación , Pruebas de Sensibilidad Microbiana , Biopelículas/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ácido Sórbico/farmacología , Ácido Sórbico/química , Bacterias Grampositivas/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos

RESUMEN

BACKGROUND: Antimicrobial-resistant Helicobacter pylori (H. pylori) poses a significant public health concern, especially given the limited therapeutic options for azithromycin-resistant strains. Hence, there is a necessity for new studies to reconsider the use of azithromycin, which has diminished in effectiveness against numerous strains. Thus, we aimed to augment azithromycin's anti-Helicobacter properties by combining it with curcumin in different formulations, including curcumin in clove oil, curcumin nano-gold emulsion, and curcumin nanoemulsion. METHODS: The antimicrobial activities of the investigated compounds, both individually and in combination with other anti-Helicobacter drugs, were evaluated. Their antibiofilm and anti-virulence properties were assessed using both phenotypic and genotypic methods, alongside molecular docking studies. Our findings were further validated through mouse protection assays and histopathological analysis. RESULTS: We observed high anti-Helicobacter activities of curcumin, especially curcumin nanoemulsion. A synergistic effect was detected between curcumin nanoemulsion and azithromycin with fraction inhibitory concentration index (FICI) values <0.5. The curcumin nanoemulsion was the most active anti-biofilm and anti-virulence compound among the examined substances. The biofilm-correlated virulence genes (babA and hopQ) and ureA genes were downregulated (fold change <1) post-treatment with curcumin nanoemulsion. On the protein level, the anti-virulence activities of curcumin nanoemulsion were documented based on molecular docking studies. These findings aligned with histopathological scoring of challenge mice, affirming the superior efficacy of curcumin nanoemulsion/azithromycin combination. CONCLUSION: The anti-Helicobacter activities of all curcumin physical forms pose significant challenges due to their higher  minimum inhibitory concentration (MIC) values exceeding the maximum permissible level. However, using curcumin nanoemulsion at sub-MIC levels could enhance the anti-Helicobacter activity of azithromycin and exhibit anti-virulence properties, thereby improving patient outcomes and addressing resistant pathogens. Therefore, more extensive studies are necessary to assess the safety of incorporating curcumin nanoemulsion into H. pylori treatment.

Asunto(s)

Antibacterianos , Azitromicina , Biopelículas , Curcumina , Infecciones por Helicobacter , Simulación del Acoplamiento Molecular , Azitromicina/farmacología , Azitromicina/química , Animales , Antibacterianos/farmacología , Antibacterianos/química , Ratones , Biopelículas/efectos de los fármacos , Curcumina/farmacología , Curcumina/química , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/genética , Pruebas de Sensibilidad Microbiana , Sinergismo Farmacológico , Productos Biológicos/farmacología , Productos Biológicos/química , Virulencia/efectos de los fármacos , Femenino

RESUMEN

The Cucurbitaceae family includes several edible species that are consumed globally as fruits and vegetables. These species produce high volumes of seeds that are often discarded as waste. In this study, we investigate the chemical composition and biological activity of three seed oils from Cucurbitaceae plants, namely, cantaloupe, honeydew, and zucchini, in comparison to the widely used pumpkin seed oil for their ability to enhance and accelerate wound healing in rats. Our results showed that honeydew seed oil (HSO) was effective in accelerating wound closure and enhancing tissue repair, as indicated by macroscopic, histological, and biochemical analyses, as compared with pumpkin seed oil (PSO). This effect was mediated by down-regulation of the advanced glycation end products (AGE) and its receptor (RAGE) cue, activating the cytoprotective enzymes nuclear factor erythroid 2 (Nrf2) and heme oxygenase-1 (HO-1), suppressing the inflammatory mediators tumor necrosis factor (TNF)-α, nuclear factor kappa B (NF-κB), and nod-like receptor protein 3 (NLRP3), and reducing the levels of the skin integral signaling protein connexin (CX)-43. Furthermore, immunohistochemical staining for epidermal growth factor (EGF) showed the lowest expression in the skin after treatment with HSO, indicating a well-organized and complete healing process. Other seed oils from cantaloupe and zucchini exhibited favorable activity when compared with untreated rats; however, their efficacy was comparatively lower than that of PSO and HSO. Gas chromatographic analysis of the derivatized oils warranted the superior activity of HSO to its high nutraceutical content of linoleic acid, which represented 65.9% of the fatty acid content. This study's findings validate the use of honeydew seeds as a wound-healing fixed oil and encourage further investigation into the potential of Cucurbitaceae seeds as sources of medicinally valuable plant oils.

RESUMEN

Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1ß, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.

Asunto(s)

Lesión Renal Aguda , Anticuerpos Monoclonales Humanizados , Antioxidantes , Receptor 1 de Quimiocinas CX3C , Quimiocina CX3CL1 , Proteína HMGB1 , Hemo Oxigenasa (Desciclizante) , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Wistar , Sepsis , Transducción de Señal , Animales , Masculino , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Proteína HMGB1/metabolismo , Quimiocina CX3CL1/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Hemo Oxigenasa (Desciclizante)/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , FN-kappa B/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Receptor 1 de Quimiocinas CX3C/metabolismo , Transducción de Señal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Modelos Animales de Enfermedad , Lipopolisacáridos , Inhibidores de PCSK9 , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios/farmacología

RESUMEN

BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury is a clinically fundamental phenomenon that occurs through liver resection surgery, trauma, shock, and transplantation. AIMS OF THE REVIEW: This review article affords an expanded and comprehensive overview of various natural herbal ingredients that have demonstrated hepatoprotective effects against I/R injury through preclinical studies in animal models. MATERIALS AND METHODS: For the objective of this investigation, an extensive examination was carried out utilizing diverse scientific databases involving PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate. The investigation was conducted based on specific identifiable terms, such as hepatic ischemia/reperfusion injury, liver resection and transplantation, cytokines, inflammation, NF-kB, interleukins, herbs, plants, natural ingredients, phenolic extract, and aqueous extract. RESULTS: Bioactive ingredients derived from ginseng, curcumin, resveratrol, epigallocatechin gallate, quercetin, lycopene, punicalagin, crocin, celastrol, andrographolide, silymarin, and others and their effects on hepatic IRI were discussed. The specific mechanisms of action, signaling pathways, and clinical relevance for attenuation of liver enzymes, cytokine production, immune cell infiltration, oxidative damage, and cell death signaling in rodent studies are analyzed in depth. Their complex molecular actions involve modulation of pathways like TLR4, NF-κB, Nrf2, Bcl-2 family proteins, and others. CONCLUSION: The natural ingredients have promising values in the protection and treatment of various chronic aggressive clinical conditions, and that need to be evaluated on humans by clinical studies.

Asunto(s)

Hígado , Fitoquímicos , Daño por Reperfusión , Animales , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Humanos , Fitoquímicos/uso terapéutico , Fitoquímicos/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Hepatopatías/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico

RESUMEN

BACKGROUND: Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury. METHODS: Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model. RESULTS: Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio. CONCLUSIONS: Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.

Asunto(s)

Modelos Animales de Enfermedad , Flavanonas , Hemo Oxigenasa (Desciclizante) , MicroARNs , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Pancreatitis , Ratas Sprague-Dawley , Transducción de Señal , Sirtuina 1 , Receptor Toll-Like 4 , Animales , Pancreatitis/inducido químicamente , Pancreatitis/prevención & control , Pancreatitis/metabolismo , Pancreatitis/patología , Pancreatitis/tratamiento farmacológico , Sirtuina 1/metabolismo , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Flavanonas/farmacología , Transducción de Señal/efectos de los fármacos , Ratas , Hemo Oxigenasa (Desciclizante)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Arginina/farmacología , Enfermedad Aguda , Páncreas/efectos de los fármacos , Páncreas/patología , Páncreas/metabolismo , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos

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Purpose: Basic medical sciences are of a solid abstract nature. Pharmacology is a challenging discipline delivered in all healthcare-related curricula with different aims and goals. Memes are one of aiding instructional designs proved to surge students' performance and satisfaction with the educational process. Apart from assessing medical students' and faculty's perception of meme use in pharmacology learning, the current study aimed to explore the criteria of preferences and factors associated with successful memes' adoption in this discipline as one of the most challenging basic medical sciences. Methods: A biphasic study was conducted among second-year undergraduate medical students and faculty members. The study involved assessing the perceptions of staff and students, and thematic content analysis was performed on the narrative responses of the participants to explore factors contributing to the success of learning memes. Additionally, students' performance was also analyzed. Results: The use of memes in pharmacology was well perceived by medical students, with a mean satisfaction rating of 4.5/5 for high-achieving students and 4.33 for low-achieving students. Memes were associated with a performance surge (p = 0.022). Six themes emerged as criteria for a successful learning experience of meme use: previous scientific background on the meme topic, scenario context of the meme, learning concepts tackled by memes, the simplicity of meme's message, the relevance of meme's message to practice, and the modality of meme's use in the topic of education. Regarding the perception of meme use in pharmacology learning, four themes emerged: the mode and engagement of learning experience mode, the feasibility of meme use in pharmacology learning, students' attitudes towards further meme inclusion in their study, and the perceived impact of memes on students' cognitive skills. Conclusion: The use of memes in pharmacology yields positive learning outcomes. A careful selection of memes is required to ensure a successful learning experience.

RESUMEN

Utilizing microwave heating and an aqueous saturated solution of K2CO3 as a catalyst, a rapidone-pot synthesis of oxospiro[chromene-4.3-indoline] derivatives was produced in high yields. The experimental results confirmed that the saturated solution of K2CO3 gives outstanding yield to dangerous metals and strong bases during investigations into high-performance catalysts. The used catalyst is green, affordable, incredibly mild, and widely accessible. However, it generates samples, reduces the amount of byproducts, and is expected to be used in industrial-scale heterocyclic derivatives. New oxospiro[chromene-4.3-indoline] derivatives have been created from various isatin by condensing with various phenols. The biological activities results showed that when compared to erlotinib, the derivatives 3b, 4b, 5b, and 6b were the most effective analogues on A549, MCF-7, HepG-2, and HCT-116 cells, with an IC50 range of 3.32 to 11.88 µM. In A549 cells, compounds 3b, 4b, 5b, and 6b induced apoptosis, as shown by the up-regulation of Bax, the up-regulation of Bcl-2, and the stimulation of caspase-3 and -9. With IC50 value of 0.19 ± 0.09, compound3b was demonstrated to be the most effective against EGFRWT. Compounds 4b and 6b have good antibacterial activity toward Staphylococcus aureus, comparable to ciprofloxacin, and about half as much activity as ampicillin, according to the MIC value. Compound 6b's MIC is about 25% lower than clotrimazole drug. The in silico molecular docking outcomes of compounds 3b, 4b, 5b, and 6b in the EGFR active site depicted their ability to adopt essential binding interactions compared to the reference Erlotinib. Moreover, the investigation of the physicochemical properties of the most promising dual acting antiproliferative and antimicrobial compounds 4b and 6b through the egg-boiled method illustrated acceptable lipophilicity, GIT absorption, and blood-brain barrier penetration characteristics.

RESUMEN

Introduction: In recent years, the world's attention has been drawn to antimicrobial resistance (AMR) because to the frightening prospect of growing death rates. Nanomaterials are being investigated due to their potential in a wide range of technical and biological applications. Methods: The purpose of this study was to biosynthesis zinc oxide nanoparticles (ZnONPs) using Aspergillus sp. SA17 fungal extract, followed by characterization of the produced nanoparticles (NP) using electron microscopy (TEM and SEM), UV-analysis, X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR). Results and Discussion: The HR-TEM revealed spherical nanoparticles with an average size of 7.2 nm, and XRD validated the crystalline nature and crystal structure features of the generated ZnONPs, while the zeta potential was 18.16 mV, indicating that the particles' surfaces are positively charged. The FT-IR was also used to identify the biomolecules involved in the synthesis of ZnONPs. The antibacterial and anticancer properties of both the crude fungal extract and its nano-form against several microbial strains and cancer cell lines were also investigated. Inhibition zone diameters against pathogenic bacteria ranged from 3 to 13 mm, while IC50 values against cancer cell lines ranged from 17.65 to 84.55 M. Additionally, 33 compounds, including flavonoids, phenolic acids, coumarins, organic acids, anthraquinones, and lignans, were discovered through chemical profiling of the extract using UPLC-QTOF-MS/MS. Some molecules, such pomiferin and glabrol, may be useful for antibacterial purposes, according to in silico study, while daidzein 4'-sulfate showed promise as an anti-cancer metabolite.

RESUMEN

BACKGROUND: Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in ß-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic ß-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats. METHODS: Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted. SIGNIFICANCE: QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.

Asunto(s)

Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , MicroARNs , Nanopartículas , Ratas , Masculino , Animales , Quercetina/uso terapéutico , Liposomas/uso terapéutico , MicroARNs/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Labio/metabolismo , Labio/patología , Ratas Wistar , Ratas Sprague-Dawley , Páncreas/metabolismo , Estrés Oxidativo , Insulina/metabolismo , Respuesta de Proteína Desplegada , Estrés del Retículo Endoplásmico , Autofagia

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Dicyandiamide (DCD) reacted with amino acids 1a-f to produce biguanides 2 and 4 and guanidine pyrazolones 3, 5, 6, 7, and 8, according to the reaction. DCD exhibited the following reactions: imidodicarbonimidicdiamide 9, diazocan-2-ylguanidine 10, methyl biguanidylthion 11, N-carbamothioylimidodicarbonimidicdiamide 12, 2-guanidinebenzoimidazole 13a, 2-guanidinylbenzoxazole 13b, and 2-guanidinylbenzothiazol 13c. These reactions were triggered by 6-amino caproic acid, thioacetamide, thiourea, o-aminophenol, o-aminothiophenol, and anthranilic acid, respectively. Compound 2 had the least antimicrobial activity, while compound 13c demonstrated the most antibacterial impact against all bacterial strains. Furthermore, in terms of antiglycation efficacy (AGEs), 12, 11, and 7 were the most effective AGE cross-linking inhibitors. Eight and ten, which showed a considerable inhibition on cross-linking AGEs, come next. Compounds 4 and 6 on the other hand have shown the least suppression of AGE production. The most promising antiglycation scaffolds 8, 11, and 12 in the Human serum albumin (HAS) active site were shown to be able to adopt crucial binding interactions with important amino acids based on the results of in silico molecular docking. The most promising antiglycation compounds 8, 11, and 12 were also shown to have better hydrophilicity, acceptable lipophilicity, gastrointestinal tract absorption (GIT), and blood-brain barrier penetration qualities when their physicochemical properties were examined using the egg-boiled method.

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Onion peels are often discarded, representing an unlimited amount of food by-products; however, they are a valuable source of bioactive phenolics. Thus, we utilized UPLC-MS/MS to analyze the metabolomic profiles of red (RO) and yellow (YO) onion peel extracts. The cytotoxic (SRB assay), anti-inflammatory (Griess assay), and antimicrobial (sensitivity test, MIC, antibiofilm, and SP-SDS tests) properties were assessed in vitro. Additionally, histological analysis, immunohistochemistry, and ELISA tests were conducted to investigate the healing potential in excisional skin wound injury and Candida albicans infection in vivo. RO extract demonstrated antibacterial activity, limited skin infection with C. albicans, and improved the skin's appearance due to the abundance of quercetin and anthocyanin derivatives. Both extracts reduced lipopolysaccharide-induced nitric oxide release in vitro and showed a negligible cytotoxic effect on MCF-7 and HT29 cells. When extracts were tested in vivo for their ability to promote tissue regeneration, it was found that YO peel extract had the greatest impact. Further biochemical analysis revealed that YO extract suppressed NLRP3/caspase-1 signaling and decreased inflammatory cytokines. Furthermore, YO extract decreased Notch-1 levels and boosted VEGF-mediated angiogenesis. Our findings imply that onion peel extract can effectively treat wounds by reducing microbial infection, reducing inflammation, and promoting tissue regeneration.

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Human colostrum (HC) is essential for oral health as it is rich in probiotics that could affect the growth of the cariogenic S. mutans and its biofilm formation; hindering dental caries in advance. In this study, HC was collected from 36 healthy mothers 1-3 days postpartum. The effect of HC on oral health was carried out by assessing the impact of HC and its derived probiotics' cell-free supernatants (CFS) on the growth of S. mutans (using modified well diffusion) and its biofilm formation (using microtiter plate assay). Moreover, the effect of whole HC on L. rhamnosus, a probiotic oral bacterium, was examined. Probiotics were isolated and identified phenotypically by API 50 CH carbohydrate fermentation and genotypically by 16S rRNA amplification. The in vitro study revealed that HC has cariogenic activity and is associated with biofilm formation. Biofilm strength was inversely proportional to HC dilution (p-value < 0.0001). Nevertheless, HC and colostrum-derived probiotics improve oral health by inhibiting the growth of caries-inducing S. mutans with lower inhibition to L. rhamnosus probiotics. The CFS of isolated probiotics reduced the biofilm formation via the cariogenic S. mutans. These results are not only promising for caries eradication, but they also highlight the importance of breastfeeding infants from their first hours to shape healthy oral microbiota, protecting them from various diseases including dental caries.

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The current trend in fighting bacteria is attacking the virulence and quorum-sensing (QS) signals that control bacterial communication and virulence factors, especially biofilm formation. This study reports new Schiff bases and tetracyclic rings based on a pyridine pharmacophore by two methods: a green approach using CAN and a conventional method. The structure of designed derivatives was confirmed using different spectroscopies (IR and 1H/13C NMR) and elemental analysis. The designed derivatives exhibited good to moderate inhibition zones against bacterial and fungal pathogens. In addition, six compounds 2a,b, 3a,b, and 6a,b displayed potency against tested pathogens with eligible MIC and MBC values compared to standard antimicrobial agents. Compound 2a displayed MIC values of 15.6 µg mL-1 compared to Gentamicin (MIC = 250 µg mL-1 against K. pneumoniae), while compound 6b exhibited super-potent activity against P. aeruginosa, and K. pneumoniae with MIC values of 62.5 and 125 µg mL-1, as well as MBC values of 31.25 and 15.6 µg mL-1 compared to Gentamicin (MIC = 250 and 125 µg mL-1 and MBC = 62.5 µg mL-1), respectively. Surprisingly, these six derivatives revealed bactericidal and fungicidal potency and remarkable anti-biofilm activity that could significantly reduce the biofilm formation against MRSA, E. coli, P. aeruginosa, and C. albicans. Furthermore, the most active derivatives reduced the LasR gene's production between 10-40% at 1/8 MICs compared with untreated P. aeruginosa. Besides, they demonstrated promising safety profile on Vero cells (normal cell lines) with IC50 values ranging between (175.17 ± 3.49 to 344.27 ± 3.81 µg mL-1). In addition, the in silico ADMET prediction was carried out and the results revealed that these compounds could be used with oral bioavailability with low toxicity prediction when administered as a candidate drug. Finally, the molecular docking simulation was performed inside LasR and predicted the key binding interactions responsible for the activity that corroborated the biological results.

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Milk contaminated with aflatoxin can lead to liver cancer. Aflatoxin B1 (AFB1), a serious animal feed contaminant, is transformed into Aflatoxin M1 (AFM1) and secreted in milk. In this study, a biological method using probiotic bacteria, Lactobacillus rhamnosus (L. rhamnosus) in combination with Saccharomyces cerevisiae (S. cerevisiae), was used to assess their antiaflatoxigenic effect in animal milk. A Box-Behnken design was used to establish the optimal ratio of L. rhamnosus and S. cerevisiae, incubation time, and temperature for efficient AFM1 detoxification from milk. To achieve this, the primary, interaction, and quadratic effects of the chosen factors were investigated. To investigate the quadratic response surfaces, a second-order polynomial model was built using a three-factor, three-level Box-Behnken design. The quantity of AFM1 was detected by the ELISA technique. The results of these experiments obtained an optimum condition in AFM1 detoxification of the three tested factors in order to maximize their effect on AFM1 detoxification in milk. The model was tested in three highly contaminated milk samples to assure the efficacy of the model. AFM1 detoxification was up to 98.4% in contaminated milk samples. These promising results provide a safe, low-cost, and low-time-consuming solution to get rid of the problem of milk contamination with AFM1.

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Phenytoin-induced liver injury (PHT ILII) is a serious condition that may necessitate discontinuation of the drug. This study investigates the mechanisms of PHT ILII and evaluates the protective effects of Balanites Aegyptiaca (BA) fruit extracts on the liver. We focus on the Nrf2/MAPK/NF-κB/Beclin-1 signaling pathways involved in oxidative stress and inflammation from drug-induced liver injury. Phytochemical analyses of BA fruit extracts (Bu-F and EA-F) are conducted. Molecular docking techniques explore the interaction between phenytoin (PHT) and the Nrf2/MAPK/NF-κB/Beclin-1 pathways. Thirty-six male rats are divided into Control, Bu-F, EA-F, PHT, Bu-F/PHT, and EA-F/PHT groups, and they are observed for 45 days. EA-F extract is rich in phenolics/flavonoids, while Bu-F extract mainly contains saponins.PHT ILII causes histological damage in liver tissues and affects Nrf-2, MAPK, TNF-α, IL-1ß, Mcp-1, Beclin-1, iNOS expression, and liver function markers (ALT, AST, ALP). However, EA-F/Bu-F extracts effectively improve the histological structure and significantly reduce biochemical/immunohistochemical parameters, restoring them to near-normal levels. EA-F extract is particularly effective.In conclusion, the Nrf2/MAPK /Beclin-1 pathways play a critical role in the development of PHT ILII. BA fruit extracts show promise as hepato-protective agents, with the EA-F extract demonstrating superior efficacy. These results lay the groundwork for new treatments for PHT ILII and drug-induced liver injuries.

Asunto(s)

Balanites , Enfermedad Hepática Inducida por Sustancias y Drogas , Ratas , Masculino , Animales , Fenitoína/metabolismo , Fenitoína/farmacología , Extractos Vegetales/química , Factor 2 Relacionado con NF-E2/metabolismo , Balanites/química , Beclina-1/metabolismo , FN-kappa B/metabolismo , Frutas , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Hígado , Sistema de Señalización de MAP Quinasas , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo

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Introduction: Aluminium (Al) is accumulated in the brain causing neurotoxicity and neurodegenerative disease like Alzheimer's disease (AD), multiple sclerosis, autism and epilepsy. Hence, attenuation of Al-induced neurotoxicity has become a "hot topic" in looking for an intervention that slow down the progression of neurodegenerative diseases. Objective: Our study aims to introduce a new strategy for hampering aluminum chloride (AlCl3)-induced neurotoxicity using a combination of sesamol with the probiotic bacteria; Lactobacillus rhamnosus (L. rhamnosus) and also to test their possible ameliorative effects on AlCl3-induced hepatotoxicity. Methods: Sprague-Dawley male rats were randomly divided into five groups (n = 10/group) which are control, AlCl3, AlCl3 + Sesamol, AlCl3 + L. rhamnosus and AlCl3 + Sesamol + L. rhamnosus. We surveilled the behavioral, biochemical, and histopathological alterations centrally in the brain and peripherally in liver. Results: This work revealed that the combined therapy of sesamol and L. rhamnosus produced marked reduction in brain amyloid-ß, p-tau, GSK-3ß, inflammatory and apoptotic biomarkers, along with marked elevation in brain free ß-catenin and Wnt3a, compared to AlCl3-intoxicated rats. Also, the combined therapy exerted pronounced reduction in hepatic expressions of JAK-2/STAT-3, inflammatory (TNF-α, IL-6, NF-κB), fibrotic (MMP-2, TIMP-1, α-SMA) and apoptotic markers, (caspase-3), together with marked elevation in hepatic PPAR-γ expression, compared to AlCl3 -intoxicated rats. Behavioral and histopathological assessments substantiated the efficiency of this combined regimen in halting the effect of neurotoxicity. Discussion: Probiotics can be used as an add-on therapy with sesamol ameliorate AlCl3 -mediated neurotoxicity and hepatotoxicity.