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Introduction: Isoproterenol (ISO) is regarded as an adrenergic non-selective ß agonist. It regulates myocardial contractility and may cause damage to cardiac tissues. Alchemilla vulgaris (AV) is an herbal plant that has garnered considerable attention due to its anti-inflammatory and antioxidant bioactive components. The present investigation assessed the cardioprotective potential of AV towards ISO-induced myocardial damage. Methods: Four groups of mice were utilized: control that received saline, an ISO group (85 mg/kg, S.C.), ISO + AV100, and ISO + AV200 groups (mice received 100 or 200 mg/kg AV orally along with ISO). Results and discussion: ISO induced notable cardiac damage demonstrated by clear histopathological disruption and alterations in biochemical parameters. Intriguingly, AV treatment mitigates ISO provoked oxidative stress elucidated by a substantial enhancement in superoxide dismutase (SOD) and catalase (CAT) activities and reduced glutathione (GSH) content, as well as a considerable reduction in malondialdehyde (MDA) concentrations. In addition, notable downregulation of inflammatory biomarkers (IL-1ß, TNF-α, and RAGE) and the NF-κB/p65 pathway was observed in ISO-exposed animals following AV treatment. Furthermore, the pro-apoptotic marker Bax was downregulated together with autophagy markers Beclin1 and LC3 with in ISO-exposed animals when treated with AV. Pre-treatment with AV significantly alleviated ISO-induced cardiac damage in a dose related manner, possibly due to their antioxidant and anti-inflammatory properties. Interestingly, when AV was given at higher doses, a remarkable restoration of ISO-induced cardiac injury was revealed.
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Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-ß, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.
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Acetaminofén , Compuestos de Bencidrilo , Enfermedad Hepática Inducida por Sustancias y Drogas , Dinaminas , GTP Fosfohidrolasas , Glucósidos , Proteínas de la Membrana , Dinámicas Mitocondriales , Nucleotidiltransferasas , Animales , Masculino , Ratones , Acetaminofén/toxicidad , Acetaminofén/efectos adversos , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Dinaminas/metabolismo , Dinaminas/genética , Glucósidos/farmacología , GTP Fosfohidrolasas/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , FN-kappa B/metabolismo , Nucleotidiltransferasas/metabolismo , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Biosynthetic metals have attracted global attention because of their safety, affordability, and environmental friendliness. As a consequence, the cell-free filtrate (CFF) of Dill leaf-derived endophytic fungus Aspergillus luchuensis was employed for the extracellularly synthesis silver nanoparticles (AgNPs). A reddish-brown color shift confirmed that AgNPs were successfully produced. The obtained AgNPs were characterized by UV-Vis (ultraviolet-visible spectroscopy), Transmission electron microscopy (TEM), FTIR, EDX, and zeta potential. Results demonstrated the creation of crystalline AgNPs with a spherical shape at 427.81 nm in the UV-Vis spectrum, and size ranged from 16 to 18 nm as observed by TEM. Additionally, the biogenic AgNPs had a promising antibacterial activity versus multidrug-resistant bacteria, notably, S. aureus, E. coli, and S. typhi. The highest growth reduction was recorded in the case of E. coli. Furthermore, the biosynthesized AgNPs demonstrated potent antifungal potential versus a variety of harmful fungi. The maximum growth inhibition was evaluated from A. brasinsilles, followed by C. albicans as compared to cell-free extract and AgNO3. In addition, data revealed that AgNPs possess powerful antioxidant activity, and their ability to scavenge radicals increased from 33.0 to 85.1% with an increment in their concentration from 3.9 to 1,000 µg/mL. Furthermore, data showed that AgNPs displayed high catalytic activity of safranin under light irradiation. The maximum decolorization percentage (100%) was observed after 6 h. Besides, the biosynthesized AgNPs showed high insecticidal potential against 3rd larval instar of Culex pipiens. Taken together, data suggested that endophytic fungus, A. luchuensis, is an attractive candidate as an environmentally sustainable and friendly fungal nanofactory.
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Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.
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Productos Biológicos , Nanopartículas del Metal , Neoplasias , Humanos , Ácido Hialurónico/química , Quercetina/farmacología , Nanopartículas del Metal/química , Células CACO-2 , Plata , Polietilenglicoles/química , Agua , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
OBJECTIVE: Diabetes mellitus causes deterioration in the body, including serious damage of the oral cavity related to salivary gland dysfunction, characterised by hyposalivation and xerostomia. Human dental pulp stem cells (hDPSCs) represent a promising therapy source, due to the easy, minimally invasive surgical access to these cells and their high proliferative capacity. It was previously reported that the trophic support mediated by these cells can rescue the functional and structural alterations of damaged salivary glands. However, potential differentiation and paracrine effects of hDPSCs in diabetic-induced parotid gland damage have not been investigated. Our study aimed to investigate the therapeutic effects of intravenous transplantation of hDPSCs on parotid gland injury in a rat model of streptozotocin (STZ)-induced type 1 diabetes. METHODS: Thirty Sprague-Dawley male rats were randomly categorised into three groups: control, diabetic (STZ), and transplanted (STZ + hDPSCs). The hDPSCs or the vehicles were injected into the rats' tail veins, 7 days after STZ injection. Fasting blood glucose levels were monitored weekly. A glucose tolerance test was performed, and the parotid gland weight, salivary flow rate, oxidative stress indices, parotid gland histology, and caspase-3, vascular endothelial growth factor, proliferating cell nuclear antigen, neuronal nitric oxide synthase, endothelial nitric oxide synthase, and tetrahydrobiopterin biosynthetic enzyme expression levels in parotid tissues were assessed 28 days post-transplantation. RESULTS: Transplantation of hDPSCs decreased blood glucose, improved parotid gland weight and salivary flow rate, and reduced oxidative stress. The cells migrated to the STZ-injured parotid gland and differentiated into acinar, ductal, and myoepithelial cells. Moreover, hDPSCs downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and proliferating cell nuclear antigen, likely exerting pro-angiogenic and anti-apoptotic effects and promoting endogenous regeneration. In addition, the transplanted cells enhanced the parotid nitric oxide-tetrahydrobiopterin pathway. CONCLUSIONS: Our results showed that hDPSCs migrated to and survived within the STZ-injured parotid gland, where functional and morphological damage was prevented due to the restoration of normal glucose levels, differentiation into parotid cell populations, and stimulation of paracrine-mediated regeneration. Thus, hDPSCs may have potential in the treatment of diabetes-induced parotid gland injury.
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Glándula Parótida , Factor A de Crecimiento Endotelial Vascular , Animales , Pulpa Dental , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Células Madre/fisiología , Estreptozocina/toxicidadRESUMEN
Oral squamous cell carcinoma (SCC) is one of the most predominant tumors worldwide and the present treatment policies are not enough to provide a specific solution. We aimed to assess the cytotoxic effect of Cu(II)-Mn(II) Schiff base tetradentate complex alone or in combination with cisplatin against squamous cell carcinoma cell line (SCCs) in vitro. Oral-derived gingival mesenchymal stem cells (GMSCs) were used as control. The cell viability was assessed by MTT assay. IC50 values were calculated. Evaluation of apoptosis and DNA damage were performed. In addition, the expression of pro-apoptotic and anti-apoptotic genes and proteins were tested. IC50 values indicated less toxicity of the Schiff base complex on GMSCs compared to cisplatin. Schiff base complex treatment resulted in up-regulation of p53 and Bax genes expression and down-regulation of Bcl2 gene expression in SCCs paralleled with increased protein expression of caspase-3 and Bax and down-regulation of Bcl-2 protein. Annexin V-FITC apoptosis kit showed a higher apoptotic effect induced by a Schiff base complex compared to the cisplatin-treated group. These effects were markedly increased on the combination of Schiff base and cisplatin. The present study established that Cu(II)-Mn(II) Schiff base tetradentate complex might induce a cytotoxic effect on SCCs cells via induction of the apoptotic pathway. Moreover, this Schiff base complex augments the anticancer effect of cisplatin.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Compuestos Organometálicos/química , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Encía/citología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Compuestos Organometálicos/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Bases de Schiff , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic ß-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic ß-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous ß-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost ß-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.
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Pulpa Dental/citología , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Páncreas/fisiología , Trasplante de Células Madre , Células Madre/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Caspasa 3/metabolismo , Diferenciación Celular , Movimiento Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 2/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Factores de Transcripción Paired Box/metabolismo , Páncreas/citología , Páncreas/metabolismo , Ratas , Ratas Sprague-Dawley , Regeneración , EstreptozocinaRESUMEN
Acrylamide, one of the major environmental public health problems, results from its increased accumulation in the process of cooking food materials. This study aimed to demonstrate the light and electron microscopic structural effects of acrylamide on the skeletal muscle fibers of adult male albino rat tongue and to investigate the possible protective effect of vitamin E co-administration. Thirty adult male albino Sprague-Dawley rats were divided into 3 groups, each group included 10 rats. Group I (control), group II which was subdivided into two equal subgroups: subgroup IIa: included 5 rats that received acrylamide orally once daily for 20 days. Subgroup IIb: included 5 rats that received acrylamide orally once daily for 40 days. Group III was also subdivided into two equal subgroups: subgroup IIIa: included 5 rats that received acrylamide and vitamin E orally once daily for 20 days. Subgroup IIIb: included 5 rats that received acrylamide and vitamin E orally once daily for 40 days. At the end of the experiment the tongue was dissected out for histological and electron microscopic studies, another muscle sample was homogenized and processed for biochemical estimation of malondialdehyde (MDA) and total antioxidant capacity (TAC). Light microscopic study of tongue skeletal muscles in acrylamide exposed animals revealed abnormal wavy course and splitting of the muscle fibers with fatty infiltration in between. Moreover, pyknosis and remnants of nuclei were detected. EM revealed marked aggregation of mitochondria of different size and shape with giant cells formation, and partial loss of myofilaments. There were statistically significant increase in MDA and decrease in TAC indicating oxidative stress in acrylamide administrated groups (group II) than the control group which increased by prolonged duration (subgroup IIb versus subgroup IIa, p < 0.0001). This oxidative stress could explain the histological changes in tongue muscles of acrylamide exposed rats. Co-administration of vitamin E with acrylamide ameliorated most of the above mentioned histological changes in the animals used and signs of improvement that became better with prolonged administration of it (subgroup IIIb versus subgroup IIIa, p < 0.0001) were detected. It could be concluded that, chronic exposure to acrylamide might lead to skeletal muscle damage in rat tongue which becomes worth with prolonged duration of exposure. Acrylamide induced oxidative stress is the implicated mechanism of such histological changes. This toxic effect of acrylamide could be minimized when vitamin E is given concomitantly with it by its antioxidant effect.
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[This corrects the article on p. 137 in vol. 3.].