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Genomic interstrand crosslinks (ICLs) are formed by reactive species generated during normal cellular metabolism, produced by the microbiome, and employed in cancer chemotherapy. While there are multiple options for replication dependent and independent ICL repair, the crucial step for each is unhooking one DNA strand from the other. Much of our insight into mechanisms of unhooking comes from powerful model systems based on plasmids with defined ICLs introduced into cells or cell free extracts. Here we describe the properties of exogenous and endogenous ICL forming compounds and provide an historical perspective on early work on ICL repair. We discuss the modes of unhooking elucidated in the model systems, the concordance or lack thereof in drug resistant tumors, and the evolving view of DNA adducts, including ICLs, formed by metabolic aldehydes.
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Adutos de DNA , Reparo do DNA , Humanos , Adutos de DNA/metabolismo , DNA/metabolismo , Dano ao DNA , Animais , Reagentes de Ligações Cruzadas , Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Replicação do DNARESUMO
Diabetic mellitus (DM) is characterized by hyperglycaemia and defective macromolecular metabolism, arising from insulin resistance or lack of insulin production. The present study investigates the potential of artemisinin, a sesquiterpene lactone isolated from Artemisia annua, to exert anti-diabetic and antioxidant effects through modulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Our computational analyses demonstrated a high binding affinity of artemisinin with proteins belonging to the PI3K/AKT signalling cascade. α-Amylase and α-glucosidase studies revealed a notable increase in inhibition percentages with artemisinin treatment across concentrations ranging from 10 to 160 µM. A similar significant (p < 0.05) dose-dependent inhibition of free radicals was observed for the in vitro anti-oxidant assays. Further, toxicological profiling of artemisinin in the in vivo zebrafish embryo-larvae model from 4 to 96 h post-fertilization (hpf) did not exhibit any harmful repercussions. In addition, gene expression investigations confirmed artemisinin's potential mechanism in modulating hyperglycaemia and oxidative stress through the regulation of the PI3K/AKT pathway. Overall, our investigation suggests that artemisinin can be used as a therapeutic intervention for diabetes and oxidative stress, opening up opportunities for future investigation in clinical settings. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04050-2.
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The advanced non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations has put a selective pressure on the discovery and development of newer EGFR inhibitors. Therefore, the present study intends to explore the pharmacological effect of Araguspongine C (Aragus-C) as anticancer agent against lung cancer. The effect of Aragus-C was evaluated on the viability of the A549 and H1975 cells. Further biochemical assays were performed to elaborate the effect of Aragus-C, on the apoptosis, cell-cycle analysis, and mitochondrial membrane potential in A549 cells. Western blot analysis was also conducted to determine the expression of EGFR in A549 cells. Tumor xenograft mice model from A549 cells was established to further elaborate the pharmacological activity of Aragus-C. Results suggest that Aragus C showed significant inhibitory activity against A549 cells as compared to H1975 cells. It has been found that Aragus-C causes the induction of apoptosis and promotes cell-cycle arrest at the G2/M phase of A549 cells. It also showed a reduction in the overexpression of EGFR in A549 cells. In tumor xenograft mice model, it showed a significant reduction of tumor volume in a dose-dependent manner, with maximum inhibitory activity was reported by the 8 mg/kg treated group. It also showed significant anti-inflammatory and antioxidant activity by reducing the level of TNF-α, IL-1ß, IL-6, and MDA, with a simultaneous increase of superoxide dismutase and glutathione peroxidase. We have demonstrated the potent anti-lung cancer activity of Aragus-C, and it may be considered as a potential therapeutic choice for NSCLC treatment.
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Apoptose , Receptores ErbB , Neoplasias Pulmonares , Estresse Oxidativo , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Apoptose/efeitos dos fármacos , Células A549 , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Camundongos Nus , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Camundongos Endogâmicos BALB C , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular TumoralRESUMO
Ischemia-reperfusion (IR) injury remains a pivotal contributor to myocardial damage following acute coronary events and revascularization procedures. Phosphoinositide 3-kinase (PI3K), a key mediator of cell survival signaling, plays a central role in regulating inflammatory responses and cell death mechanisms. Trans-chalcone (Tch), a natural compound known for its anti-inflammatory activities, has shown promise in various disease models. The aim of the current study was to investigate the potential protective effects of Tch against myocardial injury induced by ischemia and reperfusion challenges by targeting the PI3K-inflammasome interaction. Experimental models utilizing male rats subjected to an in vivo model of IR injury and myocardial infarction were employed. Administration of Tch (100 µg/kg, intraperitoneally) significantly reduced myocardial injury, as indicated by limited infarct size and decreased levels of the myocardial enzyme troponin. Mechanistically, Tch upregulated PI3K expression, thereby inhibiting the activity of the NOD-like receptor protein 3 inflammasome followed by the activation of pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. Moreover, it mitigated oxidative stress and suppressed vascular-intercellular adhesion molecules, contributing to its cardioprotective effects. The PI3K/Akt pathway inhibitor LY294002 considerably attenuated the beneficial effects of Tch. These findings highlight the therapeutic potential of Tch in ameliorating myocardial injury associated with IR insults through its modulation of the PI3K/Akt-inflammasome axis. The multifaceted mechanisms underlying its protective effects signify Tch as a promising candidate for further exploration in developing targeted therapies aimed at mitigating ischemic heart injury and improving clinical outcomes in cardiovascular diseases characterized by IR injury.
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Traumatismo por Reperfusão Miocárdica , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fosfatidilinositol 3-Quinases/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Chalcona/farmacologia , Chalcona/análogos & derivados , Chalcona/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that is capable of apoptosis induction selectively in tumor cells. Although TRAIL has been harnessed in numerous clinical trials, resistance to TRAIL-induced apoptosis is a major challenge ahead of this therapy in various cancer models as well as in leukemia. Since histone deacetylases (HDACs) are known to affect drug resistance in malignant cells, the present study aimed to evaluate the potential of fisetin for sensitization of MOLT-4 and K-562 leukemic cells to TRAIL-induced apoptosis. The MOLT-4 and K-562 cells were treated with increasing concentrations of fisetin and its impact on the growth inhibition and apoptosis induction of TRAIL were evaluated by MTT and Annexin V/7-AAD assays. The impact of fisetin on the mRNA and protein expression levels of apoptosis regulatory genes such as BIRC2/c-IAP1, CFLAR/cFLIP, CASP3, CASP7, CASPP9, TNFRSF10A/DR4, TNFRSF10B/DR5, and BID were examined by PCR array, qRT-PCR, and flow cytometry. Pre-treatment of MOLT-4 and K-562 cells with fisetin reduced the IC50 of TRAIL in growth inhibition along with an improvement in apoptosis induction by TRAIL. The expression of the BIRC2 gene encoding antiapoptotic protein c-IAP1 downregulated in the fisetin-treated cells while the expressions of TNFRSF10A and TNFRSF10B encoding TRAIL death receptors increased. Fisetin demonstrated a potential for alleviating the TRAIL resistance by modulating the apoptosis regulatory factors and improving the expressions of TRAIL receptors that could facilitate the application of TRAIL in cancer therapies.
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PURPOSE: Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents into the esophagus. Columbianadin is a coumarin derivative that exhibits anti-inflammatory and antioxidant effects. In this study, we tried to scrutinize the protective effect of Columbianadin against acute reflux esophagitis in rats. METHODS: RAW 264.7 cells were utilized to assess cell viability and measure the production of inflammatory parameters. The rats received anesthesia, and reflux esophagitis was induced via ligation of pylorus and fore stomach and corpus junction. Rats received the oral administration of Columbianadin (25, 50 and 100 mg/kg) and omeprazole (20 mg/kg). The gastric secretion volume, acidity, and pH were measured. Additionally, the levels of oxidative stress parameters, cytokines, and inflammatory markers were determined. At the end of the study, mRNA expression was assessed. RESULTS: Columbianadin remarkably suppressed the cell viability and production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and prostaglandin (PGE2). Columbianadin treatment remarkably suppressed the secretion of gastric volume, total acidity and enhanced the pH level in the stomach. Columbianadin remarkably altered the level of hydrogen peroxidase, free iron, calcium, and plasma scavenging activity, sulfhydryl group; oxidative stress parameters like malonaldehyde, glutathione, superoxide dismutase, catalase, glutathione peroxidase; inflammatory cytokines viz., TNF-α, IL-6, IL-1ß, IL-10, IL-17, and monocyte chemoattractant protein-1; inflammatory parameters including PGE2, iNOS, COX-2, and nuclear kappa B factor (NF-κB). Columbianadin remarkably (P < 0.001) suppressed the mRNA expression TNF-α, IL-6, IL-1ß and plasminogen activator inhibitor-1. CONCLUSIONS: Columbianadin demonstrated a protective effect against acute reflux esophagitis via NF-κB pathway.
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Esofagite Péptica , NF-kappa B , Estresse Oxidativo , Animais , Esofagite Péptica/tratamento farmacológico , NF-kappa B/metabolismo , NF-kappa B/efeitos dos fármacos , Masculino , Ratos , Estresse Oxidativo/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Sobrevivência Celular/efeitos dos fármacos , Doença Aguda , Células RAW 264.7 , Camundongos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
The purpose of this research was to investigate whether or not avicularin (AVL) possesses any anticancer properties when tested against lung cancer. In the beginning, the effect that it had on the cellular viability of A549 cells was investigated, and it was discovered that AVL has a considerable negative impact on cellular viability. Following that, an investigation using flow cytometry was carried out to investigate its function in the process of apoptosis and the cell cycle of A549 cells. It has been discovered that AVL significantly promotes apoptosis and stops the cell cycle at the G2/M phase. The colony-forming capacity of A549 cells was observed to be greatly suppressed as the AVL concentration increased compared to the group that received no treatment. In addition to this, the benzo(a)pyrene in vivo model was established in order to investigate the pharmacological value of AVL. The findings revealed that AVL greatly prevented the formation of pro-inflammatory cytokines, in addition to the reduction in oxidative stress, which was evidenced by a reduction in the concentration of TNF-α, IL-1ß, IL-6, and MDA with an improvement in the concentration of SOD and GPx, respectively. Our results successfully demonstrated the pharmacological benefit of avicularin against lung cancer, and it has been suggested that it showed a multifactorial effect.
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Apoptose , Inflamação , Neoplasias Pulmonares , Estresse Oxidativo , Estresse Oxidativo/efeitos dos fármacos , Humanos , Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Animais , Inflamação/patologia , Inflamação/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , CamundongosRESUMO
Straw mulching incorporation has a wide range of environmental benefits that make it an effective practice for sustainable agro-ecosystem in the semi-arid regions. There is an urgent need to improve the 13C-photosynthates distribution, water use efficiency (WUE) and maize canopy characteristics under the diverse tillage practices with straw mulched management strategies for sustainable intensification of maize production. The field study consists of three diverse tillage systems (RT: rotary tillage; CT, conventional tillage; MT, minimum tillage) with three straws mulching (NS: no straw mulch; SS: straw mulch on the soil surface; SI: straw incorporated into the soil) were assessed under the ridge-furrow rainfall harvesting system. Our results showed that the rotary tillage with straw incorporated into the soil significantly reduces the ET rate (11 %), and leaf rolling index; as a result considerably improves LAI, LEI, 13C-photosynthates distribution, N accumulation, and above ground biomass under various growth stages. The RTSI treatment significantly improved soil water storage, soil organic carbon (52 %, SOC), soil C storage (39 %, SCS), and NPK nutrients uptake (70 %, 62 %, and 69 %) of maize than observed for the rest of all other treatments, respectively. The RTSI treatment improves soil water balance, grain yield (53 %), biomass yield (37 %), WUEg (51 %), WUEb (35 %), nutrients uptake, and mitigating soil water depletion than the MTNS treatment. Although RTSS can achieve optimal soil water storage in the short term, RTSI has a great potential in improving soil carbon stability, canopy characteristics, soil water storage, and WUE, contributing to sustainable and intensive corn production in agricultural ecosystems in semi-arid regions.
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Ischemic stroke is a leading cause of human mortality. Cerebral ischemia-reperfusion injury (CI/RI) is a primary cause of stroke. Ischemia-reperfusion (I/R) resulting in oxidative stress and inflammatory events may lead to severe neuronal impairments. Thus, anti-oxidative and anti-inflammatory mediators that can alleviate post-I/R neuronal injuries are required for the treatment of CI/RI. An alkaloid, voacangine (VCG) is a recognized antioxidant, anti-inflammatory, and anticancer agent. Hence, the current study intended to explore the neuroprotective potential and the principal mechanisms of VCG in CI/RI. The experimental rats were divided into four sets: control, I/R-induced, I/R + VCG (2.5 mg/kg), I/R + VCG (5 mg/kg). CI/RI was induced by implanting a thread into the middle cerebral artery occlusion (MCAO) model. Brain damages were assessed on the basis of brain edema, brain infarct volume, neurological deficit score, histopathology, oxidative stress, and neuroinflammation. Results revealed that VCG inhibited the triggering of NLRP3 inflammasome, pro-inflammatory cytokines, lipid peroxidation, but enhanced the antioxidant status in MCAO rats. Furthermore, VCG treatment averted brain damage by I/R, neuroinflammation, and oxidative stress by suppressing NF-κBp65/MAPK pathways. The results of the study provide pertinent insights pertaining to the role of VCG as a potential neuroprotective agent against ischemic stroke.
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Infarto da Artéria Cerebral Média , Fármacos Neuroprotetores , Estresse Oxidativo , Traumatismo por Reperfusão , Animais , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Masculino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Ratos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Sprague-Dawley , Doenças Neuroinflamatórias/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Fator de Transcrição RelA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacosRESUMO
Owing to the massive importance of dihydropyrimidine (DHPMs) scaffolds in the pharmaceutical industry and other areas, we developed an effective and sustainable one-pot reaction protocol for the synthesis of (R/S)-2-thioxo-DHPM-5-carboxanilides via the Biginelli-type cyclo-condensation reaction of aryl aldehydes, thiourea and various acetoacetanilide derivatives in ethanol at 100 °C. In this protocol, taurine was used as a green and reusable bio-organic catalyst. Twenty-three novel derivatives of (R/S)-TDHPM-5-carboxanilides and their structures were confirmed by various spectroscopy techniques. The aforementioned compounds were synthesized via the formation of one asymmetric centre, one new C-C bond, and two new C-N bonds in the final product. All the newly synthesized compounds were obtained in their racemic form with up to 99% yield. In addition, the separation of the racemic mixture of all the newly synthesized compounds was carried out by chiral HPLC (Prep LC), which provided up to 99.99% purity. The absolute configuration of all the enantiomerically pure isomers was determined using a circular dichroism study and validated by a computational approach. With up to 99% yield of 4d, this one-pot synthetic approach can also be useful for large-scale industrial production. One of the separated isomers (4R)-(+)-4S developed as a single crystal, and it was found that this crystal structure was orthorhombic.
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PURPOSE: To determine the effect of gallic acid or its combination with glibenclamide on some biochemical markers and histology of the cornea of streptozotocin (STZ) induced diabetic rats. METHODS: Following induction of diabetes, 24 male albino rats were divided into four groups of six rats each. Groups 1 and 2 (control and diabetic) received rat pellets and distilled water; group 3 (gallic acid) received rat pellets and gallic acid (10 mg/kg, orally) dissolved in the distilled water; and group 4 (gallic acid + glibenclamide) received rat pellets, gallic acid (10 mg/kg, orally), and glibenclamide (5 mg/kg, orally) dissolved in the distilled water. The treatments were administered for three months after which the rats were sacrificed after an overnight fast. Blood and sera were collected for the determination of biochemical parameters, while their eyes were excised for histology. RESULTS: STZ administration to the rats induced insulin resistance, hyperglycemia, microprotenuria, loss of weight, oxidative stress, inflammation, and alteration of their cornea histology, which was abolished following supplementation with gallic acid or its combination with glibenclamide. CONCLUSIONS: The study showed the potentials of gallic acid and glibenclamide in mitigating systemic complication and histological changes in the cornea of diabetic rats induced with STZ.
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Diabetes Mellitus Experimental , Glibureto , Ratos , Masculino , Animais , Glibureto/efeitos adversos , Hipoglicemiantes/efeitos adversos , Ácido Gálico/efeitos adversos , Estreptozocina/efeitos adversos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Córnea/patologia , Água/efeitos adversos , GlicemiaRESUMO
Osteoarthritis (OA) is characterized by the gradual deterioration and worsening of the knee joint, leading to both pain and deformity. The current research exhibited the anti-osteoarthritis effect of lusianthridin against monosodium iodoacetate (MIA) induced OA in rats. RAW cells were used for the cell viability. The inflammatory cytokines and mediators were estimated in the cell lines after the lipopolysaccharide (LPS) treatment. For the in vivo study, the rats were received the intraperitoneal administration of MIA (3 mg/kg) for the induction of OA. The rats were received the oral administration of lusianthridin (5, 10 and 20 mg/kg) and the body and organ weight estimated. Antioxidant, cytokines, inflammatory and matrix metalloproteinases (MMP) level were also estimated. The mRNA expression of MMP were also estimated. The lusianthridin treatment remarkably suppressed the cell viability. LPS induced RAW cell suppressed the level of nitrate, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), MMP-2 and MMP-9 level. Lusianthridin remarkably altered the level of body weight and organ weight (liver, spleen, renal and heart weight). lusianthridin suppressed the oxidative stress via altered the level of antioxidant parameters. Lusianthridin significantly (p < 0.001) decreased the level of cartilage oligometrix matrix protein (COMP) and c-reactive protein (CRP); cytokines such as TNF-α, IL-1ß, IL-6, IL-10; inflammatory parameters include 5- Lipoxygenase (5-LOX), COX-2, leukotriene B4 (LTB4), PGE2; transforming growth factor beta (TGF-ß); MMP level like MMP-1, 3, 9, 13, respectively. Lusianthridin significantly suppressed the mRNA expression of MMP. Collectively, the result of the study showed that antiosteoarthritis effect of lusianthridin via suppression of inflammatory parameters.
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Osteoartrite , Fator de Necrose Tumoral alfa , Ratos , Animais , Ácido Iodoacético/toxicidade , Antioxidantes/farmacologia , Interleucina-6 , Dinoprostona , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Citocinas/metabolismo , Interleucina-1beta/genética , RNA MensageiroRESUMO
PURPOSE: This study aimed to understand the gender-specific alcohol-induced biochemical changes and TBARS association with the endocrine system. METHODS: Human male and female subjects ranging from 35 ± 10 years old with an 8-10-year drinking history were included in the study. RESULTS: The results demonstrated that testosterone levels were lower in male alcoholics and higher in female alcoholics, as well as higher estrogen and cortisol levels in both genders. In addition, we found lower T3, T4, and thyroid-stimulating hormone (TSH) levels in alcoholics of both sexes. Furthermore, plasma TBARS, protein carbonyls, nitrite, and nitrate levels increased significantly with concomitant decrease in reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in both male and female alcoholics. Furthermore, erythrocyte lysate nitrite and nitrate levels membrane total cholesterol, phospholipid and cholesterol/phospholipid (C/P) ratio with lower total membrane proteins in both genders of alcoholics. SDS-PAGE analysis of erythrocyte membrane proteins revealed increased density of band 3, protein 4.1, 4.2, 4.9 and glycophorins, whereas decreases in spectrin (α and ß) were observed in both genders of alcoholics. Besides, alcoholics of both sexes had a lower ability to resist osmotic hemolysis. Plasma TBARS was negatively correlated with testosterone, TSH, T3 and T4 in male alcoholics, moreover, estradiol and cortisol were positively correlated in males and females respectively. CONCLUSION: Female alcoholics may be more susceptible to osmotic hemolysis due to increased erythrocyte membrane lipid peroxidation with decreased antioxidant status, which results in an altered membrane C/P ratio and membrane protein composition.
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Purpose: To determine the effect of gallic acid or its combination with glibenclamide on some biochemical markers and histology of the cornea of streptozotocin (STZ) induced diabetic rats. Methods: Following induction of diabetes, 24 male albino rats were divided into four groups of six rats each. Groups 1 and 2 (control and diabetic) received rat pellets and distilled water; group 3 (gallic acid) received rat pellets and gallic acid (10 mg/kg, orally) dissolved in the distilled water; and group 4 (gallic acid + glibenclamide) received rat pellets, gallic acid (10 mg/kg, orally), and glibenclamide (5 mg/kg, orally) dissolved in the distilled water. The treatments were administered for three months after which the rats were sacrificed after an overnight fast. Blood and sera were collected for the determination of biochemical parameters, while their eyes were excised for histology. Results: STZ administration to the rats induced insulin resistance, hyperglycemia, microprotenuria, loss of weight, oxidative stress, inflammation, and alteration of their cornea histology, which was abolished following supplementation with gallic acid or its combination with glibenclamide. Conclusions: The study showed the potentials of gallic acid and glibenclamide in mitigating systemic complication and histological changes in the cornea of diabetic rats induced with STZ.
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Animais , Ratos , Glibureto/administração & dosagem , Estreptozocina/administração & dosagem , Córnea/efeitos dos fármacos , Diabetes Mellitus , Ácido Gálico/administração & dosagemRESUMO
Purpose: Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents into the esophagus. Columbianadin is a coumarin derivative that exhibits anti-inflammatory and antioxidant effects. In this study, we tried to scrutinize the protective effect of Columbianadin against acute reflux esophagitis in rats. Methods: RAW 264.7 cells were utilized to assess cell viability and measure the production of inflammatory parameters. The rats received anesthesia, and reflux esophagitis was induced via ligation of pylorus and fore stomach and corpus junction. Rats received the oral administration of Columbianadin (25, 50 and 100 mg/kg) and omeprazole (20 mg/kg). The gastric secretion volume, acidity, and pH were measured. Additionally, the levels of oxidative stress parameters, cytokines, and inflammatory markers were determined. At the end of the study, mRNA expression was assessed. Results: Columbianadin remarkably suppressed the cell viability and production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and prostaglandin (PGE2). Columbianadin treatment remarkably suppressed the secretion of gastric volume, total acidity and enhanced the pH level in the stomach. Columbianadin remarkably altered the level of hydrogen peroxidase, free iron, calcium, and plasma scavenging activity, sulfhydryl group; oxidative stress parameters like malonaldehyde, glutathione, superoxide dismutase, catalase, glutathione peroxidase; inflammatory cytokines viz., TNF-α, IL-6, IL-1ß, IL-10, IL-17, and monocyte chemoattractant protein-1; inflammatory parameters including PGE2, iNOS, COX-2, and nuclear kappa B factor (NF-κB). Columbianadin remarkably (P < 0.001) suppressed the mRNA expression TNF-α, IL-6, IL-1ß and plasminogen activator inhibitor-1. Conclusions: Columbianadin demonstrated a protective effect against acute reflux esophagitis via NF-κB pathway.
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Animais , Ratos , Esofagite Péptica , Refluxo Gastroesofágico , NF-kappa B , Estresse Oxidativo , InflamaçãoRESUMO
PURPOSE: Diabetes mellitus is a serious health problem worldwide, and diabetic nephropathy is the complication. The diabetic nephropathy considerably enhances the oxidative stress, glycation, lipid parameters and inflammatory reaction. Ellipticine has potent free radical scavenging and anti-inflammatory effect. METHODS: In the current study, our objectives were to thoroughly examine the renal protective effects of ellipticine in a rat model of streptozotocin (STZ)-induced diabetic nephropathy (DN) and to elucidate the underlying mechanisms involved. For the induction of diabetic nephropathy, streptozotocin (50 mg/kg) was used, and rats were separated into groups and given varying doses of ellipticine (2.5, 5 and 7.5 mg/kg). The body weight, and renal weight were estimated. The inflammatory cytokines, renal biomarkers, inflammatory antioxidant, and urine parameters were estimated. RESULTS: Result showed that ellipticine considerably enhanced the body weight and reduced the renal tissue weight. Ellipticine treatment significantly (P < 0.001) repressed the level of blood urea nitrogen, serum creatinine, uric acid, blood glucose and altered the lipid parameters. Ellipticine significantly (P < 0.001) repressed the level of malonaldehyde and boosted the glutathione, catalase, superoxide dismutase, and glutathione peroxidase. Ellipticine treatment significantly (P < 0.001) reduced the inflammatory cytokines and inflammatory mediators. CONCLUSIONS: Ellipticine could be a renal protective drug via attenuating the inflammatory reaction, fibrosis and oxidative stress in streptozotocin induced rats.
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Diabetes Mellitus , Nefropatias Diabéticas , Elipticinas , Ratos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/metabolismo , Estreptozocina/metabolismo , Estreptozocina/farmacologia , Estreptozocina/uso terapêutico , Elipticinas/metabolismo , Elipticinas/farmacologia , Elipticinas/uso terapêutico , Rim , Estresse Oxidativo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Peso Corporal , Diabetes Mellitus/metabolismoRESUMO
Duplication of the genome requires the replication apparatus to overcome a variety of impediments, including covalent DNA adducts, the most challenging of which is on the leading template strand. Replisomes consist of two functional units, a helicase to unwind DNA and polymerases to synthesize it. The helicase is a multi-protein complex that encircles the leading template strand and makes the first contact with a leading strand adduct. The size of the channel in the helicase would appear to preclude transit by large adducts such as DNA: protein complexes (DPC). Here we discuss some of the extensively studied pathways that support replication restart after replisome encounters with leading template strand adducts. We also call attention to recent work that highlights the tolerance of the helicase for adducts ostensibly too large to pass through the central channel.
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DNA Helicases , Replicação do DNA , DNA Helicases/metabolismo , DNA/metabolismoRESUMO
Immunofluorescence imaging is a standard experimental tool for monitoring the response of cellular factors to DNA damage. Visualizing the recruitment of DNA Damage Response (DDR) components requires high affinity antibodies, which are generally available. In contrast, reagents for the display of the lesions that induce the response are far more limited. Consequently, DDR factor accumulation often serves as a surrogate for damage, without reporting the actual inducing structure. This limitation has practical implications given the importance of the response to DNA reactive drugs such as those used in cancer therapy. These include interstrand crosslink (ICL) forming compounds which are frequently employed clinically. Among them are the psoralens, natural products that form ICLs upon photoactivation and applied therapeutically since antiquity. However, despite multiple attempts, antibodies against psoralen ICLs have not been developed. To overcome this limitation, we developed a psoralen tagged with an antigen for which there are commercial antibodies. In this report we describe our application of the tagged psoralen in imaging experiments, and the unexpected discoveries they revealed.
Assuntos
Reparo do DNA , Ficusina , Ficusina/farmacologia , Reagentes de Ligações Cruzadas/farmacologia , Dano ao DNA , DNARESUMO
Acute Lung Injury (ALI) is a critical medical condition that induces the injury into the lung tissue, resulting in decreased the oxygen levels in the circulation and finally causes the respiratory failure. In this study, we try to made effort for scrutinized the preventive effect of gossypin against lipopolysaccharide (LPS) induced lung inflammation and explore the underlying mechanism. LPS (7.5 mg/kg) was used for induction the lung inflammation in the rats and rats were received the oral administration of gossypin (5, 10 and 15 mg/kg). The wet to dry weight lung ratio and lung index were estimated. The bronchoalveolar lavage fluid (BALF) were collected to determination the inflammatory cells, total protein, macrophages and neutrophils. ELISA kits were used for the estimation of antioxidant, inflammatory cytokines, inflammatory parameters, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) parameters. Finally, we used the lung tissue for scrutinize the alteration in the lung histopathology. Gossypin treatment significantly (p < .001) reduced the W/D ratio of lung tissue and lung index. Gossypin significantly (p < .001) decreased the total cells, neutrophils, macrophages and total protein in BALF. It is also altered the level of inflammatory cytokines, antioxidant and inflammatory parameters, respectively. Gossypin improved the level of Nrf2 and HO-1 at dose dependent manner. Gossypin treatment remarkably enhance the ALI severity via balancing the structural integrity of lung tissue, decrease the thickness of the alveolar wall, decline the pulmonary interstitial edema, and number of inflammatory cells in the lung tissue. Gossypin is a promising agent for the treatment of LPS induced lung inflammation via altering Nrf2/HO-1 and NF-κB.
Assuntos
Lesão Pulmonar Aguda , Pneumonia , Ratos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/metabolismo , Transdução de Sinais , Pulmão , Lesão Pulmonar Aguda/metabolismo , Pneumonia/patologia , Citocinas/metabolismo , Inflamação/metabolismoRESUMO
Railroads are a critical part of the United States' transportation sector. Over 40 percent (by weight) of the nation's freight is transported by rail, and according to the Bureau of Transportation statistics, railroads moved $186.5 billion of freight in 2021. A vital part of the freight network is railroad bridges, with a good number being low-clearance bridges that are prone to impacts from over-height vehicles; such impacts can cause damage to the bridge and lead to unwanted interruption in its usage. Therefore, the detection of impacts from over-height vehicles is critical for the safe operation and maintenance of railroad bridges. While some previous studies have been published regarding bridge impact detection, most approaches utilize more expensive wired sensors, as well as relying on simple threshold-based detection. The challenge is that the use of vibration thresholds may not accurately distinguish between impacts and other events, such as a common train crossing. In this paper, a machine learning approach is developed for accurate impact detection using event-triggered wireless sensors. The neural network is trained with key features which are extracted from event responses collected from two instrumented railroad bridges. The trained model classifies events as impacts, train crossings, or other events. An average classification accuracy of 98.67% is obtained from cross-validation, while the false positive rate is minimal. Finally, a framework for edge classification of events is also proposed and demonstrated using an edge device.