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A new series of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was designed and synthesized using readily available starting materials, specifically, ß-enaminoester. Their cytotoxicity was screened against three cancer cell lines, namely, MCF-7, HCT-116, and PC-3. 2-(4-bromophenyl)triazole 10b and 2-(anthracen-9-yl)triazole 10e afforded excellent potency against MCF-7 cell lines (IC50 = 19.4 ± 0.22 and 14.5 ± 0.30 µM, respectively) compared with doxorubicin (IC50 = 40.0 ± 3.9 µM). The latter derivatives 10b and 10e were further subjected to in silico ADME and docking simulation studies against EGFR and PI3K and could serve as ideal leads for additional modification in the field of anticancer research.
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Antineoplásicos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Linhagem Celular Tumoral , Desenho de FármacosRESUMO
A growing body of studies suggests that Ca2+ signaling controls a variety of biological processes in brain elements. Activation of L-type voltage-operated Ca2+ channels (VOCCs) plays a role in the development of oligodendrocyte (OL) lineage loss, and indicates that the blocking of these channels may be an effective way to inhibit OL lineage cell loss. For this study, 10.5-day-old male Sprague-Dawley rats were used to generate cerebellar tissue slices. The slice tissues were cultured and randomly allocated to one of four groups (six each) and treated as follows: Group I, (sham control); Group II, 0.1% dimethyl sulfoxide (DMSO) only (vehicle control); Group III, injury (INJ); Group IV, (INJ and treatment with NIF). The injury was simulated by exposing the slice tissues to 20 min of oxygen-glucose deprivation (OGD). At 3 days post-treatment, the survival, apoptosis, and proliferation of the OL lineages were measured and compared. Results: In the INJ group, there was a decrease in mature myelin basic protein+ OLs (MBP+ OLs) and their precursors, NG2+ OPCs (Nerve-glia antigen 2+ oligodendrocyte precursor cell), compared with controls. A significant elevation was observed in the NG2+ OPCs and apoptotic MBP+ OLs as confirmed by a TUNEL assay. However, the cell proliferation rate was decreased in NG2+ OPCs. NIF increased OL survival as measured by apoptosis rate in both OL lineages and preserved the rate of proliferation in the NG2+ OPCs. Conclusions: Activation of L-type VOCCs may contribute to OL pathology in association with reduced mitosis of OPCs following brain injury as a strategy to treat demyelinating diseases.
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Since ancient times, plants have been used as green bioresources to ensure a healthier life by recovering from different diseases. Kattosh (Lasia spinosa L. Thwaites) is a local plant with various traditional uses, especially for arthritis, constipation and coughs. This research investigated the effect of Kattosh stem extract (LSES) on streptozotocin-induced damage to the pancreas, kidney, and liver using in vitro, in vivo and in silico methods. In vitro phytochemical, antioxidative and anti-inflammatory effects of LSES were accomplished by established methods followed by antidiabetic actions in in vivo randomized controlled intervention in STZ-induced animal models for four weeks. In an in silico study, LSES phytocompounds interacted with antidiabetic receptors of peroxisome proliferator-activated receptor-gamma (PPAR, PDB ID: 3G9E), AMP-activated protein kinase (AMPK, PDB ID: 4CFH) and α-amylase enzyme (PDB ID: 1PPI) to verify the in vivo results. In addition, LSES showed promising in vitro antioxidative and anti-inflammatory effects. In contrast, it showed a decrease in weekly blood glucose level, normalized lipid profile, ameliorated liver and cardiac markers, managed serum AST and ALT levels, and increased glucose tolerance ability in the animal model study. Restoration of pancreatic and kidney damage was reflected by improving histopathological images. In ligand-receptor interaction, ethyl α-d-glucopyranoside of Kattosh showed the highest affinity for the α-amylase enzyme, PPAR, and AMPK receptors. Results demonstrate that the affinity of Kattosh phytocompounds potentially attenuates pancreatic and kidney lesions and could be approached as an alternative antidiabetic source with further clarification.
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PPAR gama , Extratos Vegetais , Proteínas Quinases Ativadas por AMP , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Rim/patologia , PPAR gama/metabolismo , Pâncreas/patologia , Extratos Vegetais/farmacologia , Estreptozocina/toxicidade , alfa-Amilases/farmacologiaRESUMO
BACKGROUND: Deregulated microRNAs (miRs) significantly impact cancer development and progression. Our in silico analysis revealed that miR-497 and its target gene B-cell lymphoma-2 (BCL2) could be related to poor cancer outcomes. PURPOSE: To investigate the BCL2/miRNA-497 expression ratio in colorectal cancer (CRC) and explore its association with the clinicopathological characteristics and CRC prognosis. METHODS: Archived samples from 106 CRC patients were enrolled. MiR-497 and BCL2 gene expressions were detected by Taq-Man Real-Time quantitative polymerase chain reaction in propensity-matched metastatic and nonmetastatic cohorts after elimination of confounder bias. RESULTS: B-cell lymphoma-2 gene was upregulated in metastatic samples (median = 1.16, 95%CI = 1.09-1.60) compared to nonmetastatic (median = 1.02, 95%CI = 0.89-1.25, p < 0.001). In contrast, lower levels of miR-495 were detected in specimens with distant metastasis (median = 0.05, 95%CI = 0.04-0.20) than nonmetastatic samples (median = 0.54, 95%CI = 0.47-0.58, p < 0.001). Estimated BCL2/miR-497 ratio yielded a significant differential expression between the two cohort groups. Higher scores were observed in metastasis group (median = 1.39, 95%CI = 0.9-1.51) than nonmetastatic patients (median = 0.29, 95%CI = 0.19-0.39, p < 0.001). Receiver operating characteristic curve analysis showed BCL2/miR-497 ratio score to have the highest predictive accuracy for metastasis at presentation. The area under the curve was 0.90 (95%CI = 0.839-0.964, p < 0.001) at cut-off of >0.525, with high sensitivity 81.1% (95%CI = 68.6%-89.4%) and specificity 92.5% (95%CI = 82.1%-97.0%). Also, the ratio score was negatively correlated with disease-free survival (r = -0.676, p < 0.001) and overall survival times (r = -0.650, p < 0.001). Kaplan-Meier curves showed lower survival rates in cohorts with high-score compared to low-score patients. CONCLUSION: The BCL2/miR497 expression ratio is associated with poor CRC prognosis in terms of metastasis and short survival.
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Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Expressão Gênica , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Curva ROC , Estudos RetrospectivosRESUMO
In the present study, naphthyl acetohydrazide (HL) ligand was prepared and used for the synthesis of new six amorphous transition metal (Co(II), Ni(II), Cu(II), Zn(II), Pb(II), Cd(II)) complexes. All the compounds were characterized by elemental analysis, UV-vis, FT-IR, 1H- and 13C-NMR, and Matrix-Assisted Laser Desorption Ionization (MALDI). The solubilization study was carried out by estimating the interaction between the metal complexes with surfactants viz. sodium stearate (SS) and Cetyltrimethylammonium bromide (CTAB). UV-Visible spectroscopy was employed to determine partitioning and binding parameters, whereas electrical conductivity measurements were employed to estimate critical micellar concentration (CMC), the extent of dissociation, and free energy of micellization. The CT-DNA interaction of synthesized compounds with DNA represents the major groove binding. The synthesized ligand and metal complexes were also tested against bacterial and fungal strains and it has been observed that Cu(II) complex is active against all the strains except Candida albicans, while Cd(II) complex is active against all bacterial and fungal strains except Pseudomonas. Among all compounds, only the Pd(II) complex shows reasonable activity against cervical cancer HeLa cell lines, representing 97% inhibition.
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Anti-Infecciosos/farmacologia , Complexos de Coordenação/síntese química , DNA/metabolismo , Hidrazonas/síntese química , Hidrazonas/farmacologia , Metais/química , Micelas , Neoplasias/patologia , Bactérias/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Sobrevivência Celular/efeitos dos fármacos , Condutividade Elétrica , Células HeLa , Humanos , Hidrazonas/química , Ligantes , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/químicaRESUMO
The microbial resistance to current antibiotics is increasing day by day, which in turn accelerating the development of new effective drugs. Several studies have proved the high antimicrobial potential of the interaction of several organic ligands with a variety of metal ions. In the present study, a conventional method has been adopted in the synthesis of twelve new heteroleptic complexes of cobalt (II), nickel (II), copper (II) and zinc (II) using three aldimines, namely, (HL1 ((E)-2-((4-chloro-2-hydroxybenzylidene)amino)-3,4-dimethyl-5-phenylcyclopent-2-en-1-one), HL2 ((Z)-3-((4-chlorobenzylidene)amino)-4-hydroxy-5-nitrobenzenesulfonic acid) HL3 (2,2'-((1,2-phenylenebis(azaneylylidene))bis(methaneylylidene))diphenol)) as primary ligands, while phenyl glycine was the secondary ligand. The synthesized compounds were characterized by UV-vis, IR and multinuclear (1H and 13C) NMR spectroscopy, elemental analysis, and electrical conductance. The IR study revealed the coordination of the aldimine derivatives with the -OH and N atom of imine moiety. In contrary to this, the phenyl glycine coordinated to the metal ions via oxygen of carboxylate and nitrogen of the amino group. The spectroscopic analysis unveiled the tetrahedral geometry of the synthesized metal (II) complexes, except for ligand HL3 which exhibited octahedral geometry. The synthesized compounds generally showed antibacterial activity for all microbes, except Ni (II) complexes lacking sensitivity. Furthermore, to access the bioavailability, the synthesized complexes were screened for their solubilization in the micellar media of sodium lauryl sulphate. The metal complex-surfactant interaction was revealed by UV-vis spectroscopy and electrical conductivity measurements.
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Anti-Infecciosos/química , Complexos de Coordenação/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Cobalto/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Condutividade Elétrica , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Níquel/química , Dodecilsulfato de Sódio/química , Solubilidade , Espectrofotometria Infravermelho , Zinco/químicaRESUMO
Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150 000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long-term prognosis. Thus, there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down-regulation of E-cadherin expression concomitant with a suppression of cell:cell junctions, and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell:cell junctions and the level of PAK5 expression. Interestingly, exogenous PAK5 has recently been described to be associated with cell:cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that, in both our own patient samples and a commercially available dataset, PAK5mRNA levels are reduced in human bladder cancer compared with normal controls. Taken together, the present study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression.
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Caderinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Junções Intercelulares/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Bexiga Urinária/metabolismo , Quinases Ativadas por p21/metabolismo , Antígenos CD , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/química , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Adesão Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Junções Intercelulares/enzimologia , Junções Intercelulares/patologia , Gradação de Tumores , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Interferência de RNA , Proteínas Recombinantes de Fusão/metabolismo , Bexiga Urinária/enzimologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/metabolismo , Urotélio/patologia , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/química , Quinases Ativadas por p21/genéticaRESUMO
Breast cancer is a heterogeneous disease that remains the most common malignancy among women worldwide. During genomic analysis of breast tumours, mRNA levels of IQGAP3 were found to be upregulated in triple negative tumours. IQGAP3 was subsequently found to be expressed across a panel of triple negative breast cancer (TNBC) cell lines. Depleting expression levels of IQGAP3 delivered elongated cells, disrupted cell migration, and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. The morphological changes induced by IQGAP3 depletion were found to be dependent on RhoA. Indeed, reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. Interestingly, IQGAP3 was also found to interact with p-21 activated kinase 6 (PAK6); a protein already associated with the regulation of cell morphology. Moreover, PAK6 depletion phenocopied IQGAP3 depletion in these cells. Whereas PAK6 overexpression rescued the IQGAP3 depletion phenotype. Our work points to an important PAK6-IQGAP3-RhoA pathway that drives the cellular contractility of breast cancer cells promoting both cell migration and adhesive invasion of these cells. As this phenotype is relevant to the process of metastasis and re-seeding of metastasis, the pharmacological targeting of PAK6 could lead to clinical benefit in TNBC patients.
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Movimento Celular , Neoplasias de Mama Triplo Negativas , Quinases Ativadas por p21 , Proteína rhoA de Ligação ao GTP , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Proteína rhoA de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Feminino , Podossomos/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Adesão Celular , Regulação Neoplásica da Expressão Gênica , Proteínas Ativadoras de GTPaseRESUMO
Introduction: Any disruption in renal function can have cascading effects on overall health. Understanding how a heat-born toxicant like acrylamide (ACR) affects kidney tissue is vital for realizing its broader implications for systemic health. Methods: This study investigated the ACR-induced renal damage mechanisms, particularly focusing on the regulating role of miR-21a-5p/fibrotic and miR-122-5p/inflammatory signaling pathways via targeting Timp-3 and TP53 proteins in an In silico preliminary study. Besides, renal function assessment, oxidative status, protein profile, and the expression of renal biomarkers (Timp-1, Keap-1, Kim-1, P53, TNF-α, Bax, and Caspase3) were assessed in a 60-day experiment. The examination was additionally extended to explore the potential protective effects of green-synthesized zinc oxide nanoparticles (ZNO-MONPs). A four-group experiment including control, ZNO-MONPs (10 mg/kg b.wt.), ACR (20 mg/kg b.wt.), and ZNO-MONPs + ACR was established encompassing biochemical, histological, and molecular levels. The study further investigated the protein-binding ability of ZNO and MONPs to inactivate caspase-3, Keap-1, Kim-1, and TNFRS-1A. Results: ZNO-MONPs significantly reduced ACR-induced renal tissue damage as evidenced by increased serum creatinine, uric acid, albumin, and oxidative stress markers. ACR-induced oxidative stress, apoptosis, and inflammationare revealed by biochemical tests, gene expression, and the presence of apoptotic nuclei microscopically. Also, molecular docking revealed binding affinity between ACR-BCL-2 and glutathione-synthetase, elucidating the potential mechanisms through which ACR induces renal damage. Notably, ZNO-MONPs revealed a protective potential against ACR-induced damage. Zn levels in the renal tissues of ACR-exposed rats were significantly restored in those treated with ACR + ZNO-MONPs. In conclusion, this study establishes the efficacy of ZNO-MONPs in mitigating ACR-induced disturbances in renal tissue functions, oxidative stress, inflammation, and apoptosis. The findings shed light on the potential renoprotective activity of green-synthesized nanomaterials, offering insights into novel therapeutic approaches for countering ACR-induced renal damage.
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BACKGROUND: Several factors can contribute to the development of postpartum depression (PPD) and negatively affect mothers' mental and physical well-being. The objective of this study was to determine the relationship between fatigue, sleep quality, resilience, and the risk of PPD development. METHODS: A cross-sectional study was conducted using an online questionnaire distributed to mothers during their postpartum period. The risk of PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS), postpartum fatigue (PPF) was assessed using the Fatigue Severity Scale (FSS), sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and resilience was assessed using the Brief Resilience Scale (BRS). The Pearson correlation coefficient was calculated to determine the relationship between the study variables. Simple and multiple linear regression analyses were performed to explain the contributions of PPF, sleep quality, and resilience as independent predictors of PPD development. RESULTS: A total of 1409 postpartum women were included in the analysis, with 75% of the participants reporting a risk of PPD, 61% reporting PPF, 97% reporting having sleep problems, and 36% being in the "low resilience level" category. In terms of correlations, the scores of FSS and the PSQI showed moderate positive relationships with the EPDS scores (r = 0.344 and r = 0.447, respectively, p = .000). The BRS scores were negatively associated with the EPDS scores (r = -0.530, p = 0.000). Fatigue, sleep quality, and resilience were predictors of depressive symptoms (ß = 0.127, ß = 0.262, and ß = -0.393, respectively, R2 = 0.37, p = 0.000). The association remained significant in the regression model after adjusting for mother's age, mother's BMI, child's age, smoking status, full-term pregnancy, having a chronic disease, and taking anti-depressant. CONCLUSIONS: Mothers with higher levels of fatigue, poor sleep quality, and low resilience levels were at high risk of developing PPD. Healthcare providers should identify these factors and thus set better rehabilitation goals to improve overall maternal health.
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Depressão Pós-Parto , Gravidez , Criança , Feminino , Humanos , Depressão Pós-Parto/psicologia , Saúde Mental , Qualidade do Sono , Estudos Transversais , Saúde Materna , Período Pós-Parto , Mães/psicologia , Fadiga , Fatores de RiscoRESUMO
Bisphenol A (BPA), a ubiquitous plasticizer, is capable of producing oxidative splenic injury, and ultimately led to spleen pathology. Further, a link between VitD levels and oxidative stress was reported. Hence the role of VitD in BPA-induced oxidative splenic injury was investigated in this study. Sixty male and female Swiss albino mice (3.5 weeks old) were randomly divided into control and treated groups 12 mice in each (six males and six females). The control groups were further divided into sham (no treatment) and vehicle (sterile corn oil), whereas the treatment group was divided into VitD (2,195 IU/kg), BPA (50 µg/kg), and BPA+VitD (50 µg/kg + 2,195 IU/kg) groups. For six weeks, the animals were dosed intraperitoneally (i.p). One week later, at 10.5 weeks old, mice were sacrificed for biochemical and histological analyses. Findings showed BPA triggered neurobehavioral abnormalities and spleen injury with increased apoptotic indices (e.g. DNA fragmentation) in both sexes. A significant increase was found in lipid peroxidation marker, MDA in splenic tissue, and leukocytosis. Conversely, VitD treatment altered this scenario into motor performance preservation, reducing oxidative splenic injury with a decrease in the percent apoptotic index. This protection was significantly correlated with preserving leukocyte counts and reduced MDA levels in both genders. It can be concluded from the above findings that VitD treatment has an ameliorative effect on oxidative splenic injury induced by BPA, highlighting the continuous crosstalk between oxidative stress and the VitD signaling pathway.
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Baço , Vitamina D , Animais , Feminino , Masculino , Camundongos , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Estresse Oxidativo , Vitamina D/farmacologia , Vitaminas/farmacologiaRESUMO
Sixteen fuberidazole derivatives as potential new anticancer bioreductive prodrugs were prepared and characterized. The in vitro anticancer potential was examined to explore their cytotoxic properties by employing apoptosis, DNA damage, and proliferation tests on chosen hypoxic cancer cells. Eight substances (Compound 5a, 5c, 5d, 5e, 5g, 5h, 5i, and 5m) showed promising cytotoxicity values compared to the standard control. The potential of compounds was also examined through in silico studies (against human serum albumin), including chem-informatics, to understand the structure-activity relationship (SAR), pharmacochemical strength, and the mode of interactions responsible for their action. The DFT calculations revealed that only the 5b compound showed the lowest ΔET (2.29 eV) while 5i showed relatively highest ßtot (69.89 x 10-31 esu), highest αave (3.18 x 10-23 esu), and dipole moment (6.49 Debye). This study presents a novel class of fuberidazole derivatives with selectivity toward hypoxic cancer cells.
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Antineoplásicos , Neoplasias , Humanos , Simulação de Acoplamento Molecular , Flúor , Relação Estrutura-Atividade , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Estrutura Molecular , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
BACKGROUND & AIM: Significant evidence indicates that endocrine disrupted bisphenol A (BPA) seriously endangers human health. In males, BPA affects testis architecture and sperm quality, and ultimately reduces fertility. This study explored the therapeutic potential of Nigella sativa (NS) seed extract on testis and sperm abnormalities in BPA-exposed mice and characterized the underlying mechanism. METHODS: Forty male Swiss albino mice (5.5 weeks old, N = 8 per group) were randomly divided into five groups: Group I, normal control, Group II, vehicle control (sterile corn oil); Group III, NS-exposed (oral 200 mg/kg); Group IV, BPA-exposed (oral 400 µg/kg body weight); Group V, BPA + NS-exposed mice. Animals were treated for 6 weeks and sacrificed for biochemical and histological examination. RESULTS: The results indicated that BPA exposure results in significant testis and sperm abnormalities. Specifically, BPA promoted a marked reduction in the body and testis compared with the control group. Histopathological findings showed that BPA caused a widespread degeneration of spermatogenic cells of the seminiferous epithelium, decreased sperm counts and motility, and augmented sperm abnormalities, and whereas little alteration to sperm DNA was observed. In addition, BPA increased the levels of the lipid peroxidation marker, malondialdehyde (MDA), and reduced the levels of the antioxidant marker, reducing glutathione (GSH). Treatment with NS oil extract during BPA exposure significantly alleviated testis and sperm abnormalities, reduced MDA levels, and enhanced GSH levels. CONCLUSION: The results demonstrate that NS oil protects mice against BPA-induced sperm and testis abnormalities, likely by suppressing levels of the oxidative stress marker, MDA, and enhancing the levels of the antioxidant marker, GSH.
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Antioxidantes , Testículo , Humanos , Masculino , Camundongos , Animais , Testículo/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo , Espermatozoides/patologia , Oxirredução , Glutationa/metabolismoRESUMO
COVID-19 is considered as the most challenging in the current situation but lung cancer is also the leading cause of death in the global population. These two malignancies are among the leading human diseases and are highly complex in terms of diagnostic and therapeutic approaches as well as the most frequent and highly complex and heterogeneous in nature. Based on the latest update, it is known that the patients suffering from lung cancer, are considered to be significantly at higher risk of COVID-19 infection in terms of survival and there are a number of evidences which support the hypothesis that these diseases may share the same functions and functional components. Multi-level unwanted alterations such as (epi-)genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major sources which promote a number of complex diseases and such heterogeneous level of complexities are considered as the major barrier in the development of therapeutics. With so many challenges, it is critical to understand the relationships and the common shared aberrations between them which is difficult to unravel and understand. A simple approach has been applied for this study where differential gene expression analysis, pathway enrichment, and network level understanding are carried out. Since, gene expression changes and genomic alterations are related to the COVID-19 and lung cancer but their pattern varies significantly. Based on the recent studies, it appears that the patients suffering from lung cancer and and simultaneously infected with COVID-19, then survival chance is lessened. So, we have designed our goal to understand the genes commonly overexpressed and commonly enriched pathways in case of COVID-19 and lung cancer. For this purpose, we have presented the summarized review of the previous works where the pathogenesis of lung cancer and COVID-19 infection have been focused and we have also presented the new finding of our analysis. So, this work not only presents the review work but also the research work. This review and research study leads to the conclusion that growth promoting pathways (EGFR, Ras, and PI3K), growth inhibitory pathways (p53 and STK11), apoptotic pathways (Bcl- 2/Bax/Fas), and DDR pathways and genes are commonly and dominantly altered in both the cases COVID-19 and lung cancer.
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COVID-19 , Neoplasias Pulmonares , Humanos , COVID-19/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/genética , MutaçãoRESUMO
Antipsychotics (APs) are widely used medications with reported diabetogenic side effects. This study investigated the effect of commonly used APs, namely chlorpromazine (CPZ), haloperidol (HAL) and clozapine, on the bioenergetics of male CD1 mice isolated pancreatic beta cells as an underlying mechanism of their diabetogenic effects. The effect of APs on Alamar blue reduction, adenosine triphosphate (ATP) production and glucose-stimulated insulin secretion (GSIS) of isolated beta cells was evaluated. Then, the effects of APs on the activities of mitochondrial complexes and their common coding genes expression, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and lactate production were investigated. The effects of APs on the mitochondrial membrane fluidity (MMF) and mitochondrial membrane fatty acid composition were also examined. Results showed that the tested APs significantly decreased cellular ATP production and GSIS of the beta cells. The APs significantly inhibited the activities of mitochondrial complexes and their coding gene expression, MMP and OCR of the treated cells, with a parallel increase in lactate production to different extents with the different APs. CPZ and HAL showed increased MMF and mitochondrial membrane polyunsaturated fatty acid content. In conclusion, the tested APs-induced mitochondrial disruption can play a role in their diabetogenic side effect.
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Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Clozapina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Haloperidol/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismoRESUMO
BACKGROUND: Hatikana is a traditional medicinal plant used to treat inflammation, urolithiasis, goiter, cancer, wounds and sores, gastrointestinal, tumor, tetanus, arthritis, hepatic damage, neurodegeneration, and other ailments. The goal of this study is to investigate the antidiabetic properties of Hatikana extract (HKEx) and to construct the effects of its natural constituents on the genes and biochemical indices that are connected with them. METHODS: HKEx was evaluated using GC-MS and undertaken for a three-week intervention in fructose-fed STZ-induced Wistar albino rats at the doses of HKEx50, HKEx100, and HKEx200 mg/kg bw. Following intervention, blood serum was examined for biochemical markers, and liver tissue was investigated for the mRNA expression of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD1) by RTPCR analysis. Most abundant compounds (oleanolic acid, 7α, 28-olean diol, and stigmasterol) from GC-MS were chosen for the network pharmacological assay to verify function-specific gene-compound interactions using STITCH, STRING, GSEA, and Cytoscape plugin cytoHubba. RESULTS: In vivo results showed a significant (P < 0.05) decrease of blood sugar, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine kinase (CK-MB), and lactate dehydrogenase (LDH) and increase of liver glycogen, glucose load, and serum insulin. Out of three antioxidative genes, catalase (CAT) and superoxide dismutase (SOD1) were found to be few fold increased. Oleanolic acid and stigmasterol were noticed to strongly interact with 27 target proteins. Oleanolic acid interacted with the proteins AKR1B10, CASP3, CASP8, CYP1A2, CYP1A2, HMGB1, NAMPT, NFE2L2, NQO1, PPARA, PTGIR, TOP1, TOP2A, UGT2B10, and UGT2B11 and stigmasterol with ABCA1, ABCG5, ABCG8, CTSE, HMGCR, IL10, CXCL8, NR1H2, NR1H3, SLCO1B1, SREBF2, and TNF. Protein-protein interaction (PPI) analysis revealed the involvement of 25 target proteins out of twenty seven. Cytoscape plugin cytoHubba identified TNF, CXCL8, CASP3, PPARA, SREBF2, and IL10 as top hub genes. Pathway analysis identified 31 KEGG metabolic, signaling, and immunogenic pathways associated with diabetes. Notable degree of PPI enrichment showed that SOD1 and CAT are responsible for controlling signaling networks and enriched pathways. CONCLUSION: The findings show that antioxidative genes have regulatory potential, allowing the HKEx to be employed as a possible antidiabetic source pending further validation.
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Diabetes Mellitus Experimental/tratamento farmacológico , Vitaceae/química , Vitaceae/metabolismo , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Glutationa Peroxidase/metabolismo , Hipoglicemiantes/farmacologia , Fígado/patologia , Masculino , Medicina Tradicional/métodos , Farmacologia em Rede/métodos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Cellular elements of maturing brain are vulnerable to insults, which lead to neurodevelopmental defects. There are no established treatments at present. Here we examined the efficacy of selective adenosine A2A receptor inhibitor SCH58261 to combat brain injury, particularly oligodendrocyte (OL) lineage cells, in young rats. Wistar rats (n = 24, 6.5 days old) were randomly divided into equal groups of four. The sham (SHAM) group received no treatment, the vehicle (VEHICLE) group received 0.1% dimethylsufoxide, the injury (INJ) group was exposed to oxygen-glucose deprivation insult, and the injury+SCH58261 (INJ+SCH58261) group was exposed to the insult and received 1 µM SCH58261. Immunocytochemical experiments revealed that there was a significant reduction in the populations of mature OL (MBP+ OLs) and immature OL precursors (NG2+ OPCs) in the INJ group compared to SHAM group. Furthermore, there was also a significant increase in the percent of apoptotic MBP+ OL and NG2+ OPC populations as evidenced by TUNEL assay. In addition, there was a significant reduction in the proliferation rate among NG2+ OPCs, which was confirmed by BrdU immunostaining. On the other hand, treatment with SCH58261 significantly enhanced survival, evidenced by the reduction in apoptotic indices for both cell types, and it is preserved the NG2+ OPC proliferation. Activation of adenosine A2A receptors may contribute to OL lineage cell loss in association with decreased mitotic behavior of OPCs in neonatal brains upon injury. Future investigations assessing ability of SCH58261 to regenerate myelin will provide insights into its wider clinical relevance.
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Bisphenol A (BPA), an endocrine and metabolic disruptor, is widely used to manufacture polycarbonate plastics and epoxy resins. Accumulating evidence suggests that paternal BPA exposure adversely affects male germlines and results in atypical reproductive phenotypes that might persist for generations to come. Our study investigated this exposure on testicular architecture and sperm quality in mouse offspring, and characterised underlying molecular mechanism(s). A total of 18 immature male Swiss albino mice (3.5 weeks old) were randomly divided into three groups and treated as follows: Group I, no treatment (sham control); Group II, sterile corn oil only (vehicle control); Group III, BPA (400 µg/kg) in sterile corn oil. At 9.5 weeks old, F0 males were mated with unexposed females. F0 offspring (F1 generation) were monitored for postnatal development for 10 weeks. At 11.5 weeks old, the animals were sacrificed to examine testicular architecture, sperm parameters, including DNA integrity, and oxidative stress biomarkers. Results showed that BPA significantly induced changes in the body and testis weights of the F0 and F1 generation BPA lineages compared to F0 and F1 generation control lineages. A decrease in sperm count and motility with further, increased sperm abnormalities, no or few sperm DNA alterations and elevated levels of MDA, PC and NO were recorded. Similar effects were found in BPA exposed F0 males, but were more pronounced in the F0 offspring. In addition, BPA caused alterations in the testicular architecture. These pathological changes extended transgenerationally to F1 generation males' mice, but the pathological changes were more pronounced in the F1 generation. Our findings demonstrate that the biological and health BPA impacts do not end in paternal adults, but are passed on to offspring generations. Hence, linking observed testis and sperm abnormalities in the F1 generation to BPA exposure of their parental line was evident in this work. The findings also illustrate that oxidative stress appears to be a molecular component of the testis and sperm pathologies.
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The purpose of this study was to look into the effects of green coconut mesocarp juice extract (CMJE) on diabetes-related problems in streptozotocin- (STZ-) induced type 2 diabetes, as well as the antioxidative functions of its natural compounds in regulating the associated genes and biochemical markers. CMJE's antioxidative properties were evaluated by the standard antioxidant assays of 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide radical, nitric oxide, and ferrous ions along with the total phenolic and flavonoids content. The α-amylase inhibitory effect was measured by an established method. The antidiabetic effect of CMJE was assayed by fructose-fed STZ-induced diabetic models in albino rats. The obtained results were verified by bioinformatics-based network pharmacological tools: STITCH, STRING, GSEA, and Cytoscape plugin cytoHubba bioinformatics tools. The results showed that GC-MS-characterized compounds from CMJE displayed a very promising antioxidative potential. In an animal model study, CMJE significantly (P < 0.05) decreased blood glucose, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, uric acid, and lipid levels and increased glucose tolerance as well as glucose homeostasis (HOMA-IR and HOMA-b scores). The animal's body weights and relative organ weights were found to be partially restored. Tissue architectures of the pancreas and the kidney were remarkably improved by low doses of CMJE. Compound-protein interactions showed that thymine, catechol, and 5-hydroxymethylfurfural of CMJE interacted with 84 target proteins. Of the top 15 proteins found by Cytoscape 3.6.1, 8, CAT and OGG1 (downregulated) and CASP3, COMT, CYP1B1, DPYD, NQO1, and PTGS1 (upregulated), were dysregulated in diabetes-related kidney disease. The data demonstrate the highly prospective use of CMJE in the regulation of tubulointerstitial tissues of patients with diabetic nephropathy.
Assuntos
Antioxidantes/farmacologia , Cocos/química , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Glicemia/análise , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , alfa-Amilases/antagonistas & inibidoresRESUMO
OBJECTIVE: MicroRNAs are large family clusters of small noncoding RNAs that implicated in genetic and epigenetic regulation of several immunological processes and pathways. As an epigenetic modifier, the microRNA 17-92 cluster host gene (MIR17HG) has been shown to regulate the expression of genes involved in systemic lupus erythematosus (SLE) pathway. This study aimed to explore the association of MIR17HG (rs4284505; A>G) variant with SLE development and phenotype in a sample of the Eastern Mediterranean population. METHODS: A total of 326 participants (163 patients with SLE and 163 healthy controls) were enrolled in this study. The different genotypes of the MIR17HG (rs4284505) variant were characterized using the TaqMan real-time polymerase chain reaction technique. Association with the available clinical and laboratory data, including the systemic lupus erythematosus disease activity index (SLEDAI), was also executed. RESULTS: The MIR17HG (rs4284505) variant showed a protective effect against developing SLE under heterozygote (A/G vs A/A; odds ratio [OR] = 0.10, 95% confidence interval [CI] = 0.05-0.20, P < 0.001) and dominant (A/G+G/G vs A/A; OR = 0.39, 95% CI = 0.25-0.61, P < .001) models. This association was consistent even after SLE stratified by lupus nephritis. In contrast, rs4284505 (G/G) genotype conferred increased susceptibility to SLE (G/G vs A/A+A/G; OR = 2.15, 95% CI = 1.31-3.53, P = .002). Moreover, the rs4284505 variant showed a statistically significant association with mucocutaneous lesions and SLEDAI scores (all P < .05). CONCLUSION: This study is the first one to explore that the MIR17HG rs4284505 is associated with SLE risk; (A/G) genotype conferred a protective effect, while the (G/G) genotype showed increased susceptibility to SLE and association with the disease severity in the study population.