Molecular dynamics exploration of Lupenone: therapeutic implications for glioblastoma multiforme and alzheimer's amyloid beta pathogenesis.

Neuro-oncological and neurodegenerative disorders, represented paradigmatically by glioblastoma and Alzheimer's disease, respectively, persist as formidable challenges in the biomedical realm. The interconnected molecular underpinnings of these conditions necessitate rigorous and novel therapeutic examinations. This comprehensive research was anchored on the premise of unveiling the therapeutic potential and specificity of Lupenone, a potent phytoconstituent, in targeting the molecular pathways underpinning both glioblastoma and Alzheimer's amyloid beta pathology. This was gauged through its interactions with key protein structures, 5H08 and 2ZHV. An integrative approach was adopted, marrying advanced proteomics and modern computer-aided drug design techniques. Molecular docking of Lupenone with 5H08 and 2ZHV was meticulously executed, with subsequent molecular dynamics simulations providing insights into the stability, viability, and intricacies of these interactions. Lupenone demonstrated profound binding affinities, evidenced by robust docking scores of -9.54 kcal/mol for 5H08 and -10.59 kcal/mol for 2ZHV. These interactions underscored Lupenone's eminent therapeutic potential in mitigating glioblastoma and modulating the amyloid beta pathology inherent to Alzheimer's. The introduction of Proteolysis Targeting Chimeras (PROTACs) further magnified the therapeutic prospects, accentuating Lupenone's efficacy. The findings of this study not only underscore the therapeutic acumen of Lupenone in addressing the challenges posed by glioblastoma and Alzheimer's but also lay a strong foundation for its consideration as a leading candidate in future neuro-oncological and neurodegenerative research endeavors. Given the compelling in-silico data, a clarion call is made for its empirical validation in holistic in-vivo settings, potentially pioneering a new therapeutic epoch in both glioblastoma and Alzheimer's interventions.

Dominance of Pro-Inflammatory Cytokines Over Anti-Inflammatory Ones in Placental Bed of Creta Cases.

Objective: The objective of the study is to investigate changes occurring in key inflammatory cytokines at molecular level (including genetic and protein) in placental bed of placenta creta compared to that of normal placenta and their correlation to interstitial extravillous trophoblasts (EVT) number. Subjects and Methods: Case-control study including placentas of patients with invasive placentation (creta placentas, n = 19) compared with those of normal placentation (n = 19). Besides routine histology and immunocytochemistry detection (cytokeratin-7 [CK-7]), addition to biochemical evaluation of expression of various cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), IL6, IL-1RA, IL-8, IL-10, and IL-13 was carried out. Results: Routine histological examination of placentas of creta cases revealed CK-7+ extravillous trophoblasts (EVT) penetrating deeply the myometrium with various histopathological arrangements and trophoblastic vascular invasion of the deep myometrial blood vessels. A significant increase (P < 0.05) in the mRNA expression of TNF-α, IL-1 ß, and IL6 with an insignificant decrease in placental bed IL-1RA, IL-8, IL-10, and IL-13 was observed in creta cases compared to the control ones. A corresponding significant increase was detected in the protein levels of TNF-α, IL-1 ß, and IL-6 as well as an insignificant decrease in placental bed IL-1RA, IL-8, IL-10, and IL-13 in creta cases compared to the normal ones. Moreover, we displayed a significant positive correlation (P < 0.05) between interstitial EVT number and mRNA expression of almost all pro-inflammatory cytokines with negative but insignificant correlation with anti-inflammatory cytokines in creta cases. Conclusion: The upregulated pro-inflammatory cytokines and the correlation of their expression with the increased interstitial EVT provide a supporting evidence of their potentially more relevant role in the development of placenta creta than the anti-inflammatory ones.

Co-application of titanium nanoparticles and melatonin effectively lowered chromium toxicity in lemon balm (Melissa officinalis L.) through modifying biochemical characteristics.

Chromium (Cr) toxicity can negatively affect plant growth and development, impacting agricultural productivity and posing risks to human health. Metallic nanoparticles (MNPs) such as titanium dioxide (TiO2) and natural growth regulators such as melatonin (MT) become a promising technology to manage heavy metal-contaminated soils and promote safe food production. The present work was conducted to find the effect of foliar application of TiO2 NPs (15 mg L-1) and MT (100 µM) on growth, biochemical attributes, and Cr accumulation in plant tissues of Melissa officinalis L. under Cr toxicity (50 and 100 mg Cr kg-1 soil). The results showed that Cr toxicity led to decreased plant performance, where 100 mg Cr kg-1 soil led to notable decreases in shoot weight (28%), root weight (27%), essential oil (EO) yield (34%), chlorophyll (Chl) a + b (33%), while increased malondialdehyde (MDA, 30%), superoxide dismutase (SOD) activity (51%), and catalase (CAT) activity (122%). The use of TiO2 NPs and MT, particularly their co-application, remarkably reduced Cr toxicity by enhancing plant weight, Chl content, and lowered MDA and antioxidant activity. Total phenolic content (TPC), total flavonoid content (TFC), EO percentage, and rosmarinic acid in plants treated with Cr at 50 mg Cr kg-1 soil and co-application of TiO2 NPs and MT were relatively higher than in other treatments. Under 100 mg Cr kg-1 soil, the synergic effect of TiO2 NPs and MT-enhanced rosmarinic acid content (22%) but lowered Cr accumulation in roots (51%) and shoots (72%). Heat map analysis showed that CAT, SOD, MDA, and EO yield had the maximum variability under Cr, TiO2 NPs, and MT. Exogenous TiO2 NPs and MT can be recommended to modulate Cr toxicity in lemon balm under soil Cr toxicity.

Potassium silica nanostructure improved growth and nutrient uptake of sorghum plants subjected to drought stress.

Introduction: Recent advancements in nanotechnology present promising opportunities for enhancing crop resilience in adverse environmental conditions. Methods: In this study, we conducted a factorial experiment to investigate the influence of potassium nanosilicate (PNS) on sorghum plants exposed to varying degrees of drought stress A randomized complete block design with three replications was employed to subject the sorghum plants to different drought conditions. The three levels of stress were designated as non-stress (NS at -0.03 MPa), moderate stress (MD at -0.6 MPa), and severe stress (SD at -1.2 MPa). The plants were administered PNS at concentrations of 0 mM (control), 3.6 mM Si, and 7.2 mM Si. Results and discussion: As drought stress intensified, we observed significant reductions in multiple plant parameters, including height, fresh weight, dry weight, leaf number, stem diameter, cluster length, seed weight, and nutrient uptake, with the most pronounced effects observed under SD conditions. Interestingly, nitrogen (N) and potassium (K) levels exhibited an increase under drought stress and PNS application, peaking at MD, alongside Si concentrations. Notably, PNS application facilitated enhanced nutrient uptake, particularly evident in the significant increase in nitrogen concentration observed at 3.6 mM PNS. Furthermore, the application of PNS significantly enhanced the fresh weight and nutrient concentrations (notably K and Si) in sorghum seeds under drought stress, despite varying statistical significance for other nutrients. These findings shed light on the mechanisms through which PNS exerts beneficial effects on plant performance under drought stress. By elucidating the complex interactions between PNS application, drought stress, and plant physiology, this study contributes significantly to the development of sustainable agricultural practices aimed at bolstering crop resilience and productivity in water-limited environments.

Chemotherapeutic potential of betanin/capecitabine combination targeting colon cancer: experimental and bioinformatic studies exploring NFκB and cyclin D1 interplay.

Introduction: Betanin (C24H26N2O13) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approach was designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-α (4.58-fold), NFκB (5.33-fold), IL-1ß (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) and immunostaining for NFκB (2.94-fold) were high while periodic-acid Schiff staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients.

Investigating the potential neuroprotective benefits of taurine and Dihydrotestosterone and Hydroxyprogesterone levels in SH-SY5Y cells.

Background: Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type of dementia, which becomes more prevalent as people age. This experiment aimed to assess the neuroprotective effects of taurine on SH-SY5Y cells by examining its impact on Dihydrotestosterone (DHT), Dihydroprogesterone (DHP), as well as the expression of miRNA-21 and miRNA-181. Methods: The effects of various taurine concentrations (0.25, and 0.75 mg/mL), and LPS (0.1, and 12 mg/mL) on the SH-SY5Y cell line were assessed using the MTT assay. The levels of DHT and DHP were quantified using an ELISA kit. Additionally, the expression levels of miRNA-181 and miRNA-21 genes were examined through Real-Time PCR analysis. Results: The results of the MTT assay showed that treatment with taurine at concentrations of 0.25, and 0.75 mg/mL reduces the toxicity of LPS in SH-SY5Y cells. ELISA results indicated that taurine at a concentration of 0.25, and 0.75 mg/mL significantly elevated DHT and DHP hormones in the SH-SY5Y cell line compared to the untreated group (p < 0.01). The expression levels of IL-1ß and IL-6 were decreased under the influence of LPS in SH-SY5Y cells after taurine treatment (p < 0.01). Gene expression analysis revealed that increasing taurine concentration resulted in heightened expression of miRNA-181 and miRNA-21, with the most significant increase observed at a concentration of 0.75 mg/mL (p < 0.001). Conclusion: Our study findings revealed that the expression of miRNA-181 and miRNA-21 can be enhanced by taurine. Consequently, exploring the targeting of taurine, miRNA-181, and miRNA-21 or considering hormone therapy may offer potential therapeutic approaches for treating AD or alleviating severe symptoms. Nonetheless, in order to fully comprehend the precise mechanisms involved, additional research is required.

Gadd45A-mediated autophagy regulation and its impact on Alzheimer's disease pathogenesis: Deciphering the molecular Nexus.

BACKGROUND: The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD). METHODS: Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology. RESULTS: Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A-/-) mice revealed that Gadd45A-/- mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A-/- mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A-/- mice, likely contributing to the observed cognitive deficits. CONCLUSIONS: These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD.

Enhancement of Vitamin C's Protective Effect against Thimerosal-Induced Neurotoxicity in the Cerebral Cortex of Wistar Albino Rats: An In Vivo and Computational Study.

Vitamin C was examined to ameliorate the neurotoxicity of thimerosal (THIM) in an animal model (Wistar albino rats). In our work, oxidative and antioxidative biomarkers such as SOD, LPO, and GSH were investigated at various doses of THIM with or without concurrent vitamin C administration. Furthermore, the adverse effects of THIM on hepatic tissue and cerebral cortex morphology were examined in the absence or presence of associated vitamin C administration. Also, we studied the effect of vitamin C on the metallothionein isoforms (MT-1, MT-2, and MT-3) in silico and in vivo using the RT-PCR assay. The results showed that the antioxidant biomarker was reduced as the THIM dose was raised and vice versa. THIM-associated vitamin C reduced the adverse effects of the THIM dose. The computation studies demonstrated that vitamin C has a lower ΔG of -4.9 kcal/mol compared to -4.1 kcal/mol for THIM to bind to the MT-2 protein, which demonstrated that vitamin C has a greater ability to bind with MT-2 than THIM. This is due to multiple hydrogen bonds that exist between vitamin C and MT-2 residues Lys31, Gln23, Cys24, and Cys29, and the sodium ion represents key stabilizing interactions. Hydrogen bonds involve electrostatic interactions between hydrogen atom donors (e.g., hydroxyl groups) and acceptors (e.g., carbonyl oxygens). The distances between heavy atoms are typically 2.5-3.5 Å. H-bonds provide directed, high-affinity interactions to anchor the ligand to the binding site. The five H-bonds formed by vitamin C allow it to form a stable complex with MT, while THIM can form two H-bonds with Gln23 and Cys24. This provides less stabilization in the binding pocket, contributing to the lower affinity compared to vitamin C. The histopathological morphologies in hepatic tissue displayed an expansion in the portal tract and the hepatocytes surrounding the portal tract, including apoptosis, binucleation, and karyomegaly. The histopathological morphologies in the brain tissue revealed a significant decrease in the number of Purkinje cells due to THIM toxicity. Interestingly, THIM toxicity was associated with hemorrhage and astrogliosis. Both intracellular and vasogenic edema appeared as the concentrations of THIM rose. Finally, vitamin C ameliorated the adverse effect on the cerebral cortex in Wistar albino rats.

Relation of pharmacopenile duplex ultrasonography parameters and glycated hemoglobin (HbA1c) in diabetic patients with erectile dysfunction / Relación de los parámetros de la ecografía dúplex fármaco-penile y el nivel de hemoglobina glicosilada (HbA1c) en los pacientes diabéticos con disfunción eréctil

Introduction and objectives: Erectile dysfunction (ED) is one of the main threats in diabetic patients. This research aimed to assess the relationship between glycated hemoglobin (HbA1c) level and pharmacopenile duplex ultrasonography (PPDU) indices in diabetic patients with ED.Materials and methods: A total of 130 males with ED were recruited (100 had diabetes mellitus (DM) and 30 did not as control). The International Index of Erectile Function (IIEF) was used to evaluate patients for ED. Measurement of HbA1c, lipid profile and assessment of erectile function using PPDU were performed. All participants were assessed to take the medical history.Results: The mean age±SD was 53.8±8.9 and 53.6±2.8 years for patients and controls, respectively. Patients had variable grades of ED: mild in 20%, mild to moderate in 32.3%, moderate in 35.3%, and severe in 12.3%. A significant association was found between the existence of DM and a deprived response to intracorporeal injection (ICI), rising end-diastolic velocity (EDV), and reducing resistance index (RI) values. Comparing all diabetic groups according to HbA1c with controls, a significant relationship was found in; severity of IIEF-5 score, poor response to ICI, decreased peak systolic velocity (PSV) at 10min, increased EDV at 10, 20min and decreased RI at 10, 20min. A significant relationship was found between smoking, dyslipidaemia, and decreased PSV at 10, 20min and decreased increment ratio. However, a non-significant relationship was observed between age, type of DM and PPDU parameters.Conclusion: Poor glycaemic control of DM is associated with an increase in EDV and decrease in RI, and PSV of PPDU. (AU)

Introducción y objetivos: La disfunción eréctil (DE) es una de las principales amenazas en los pacientes diabéticos. El objetivo de este estudio fue evaluar la relación entre el nivel de hemoglobina glicosilada (HbA1c) y los índices de la ecografía dúplex fármaco-penile (PPDU) en los pacientes diabéticos con DE.Materiales y métodos: Se reunió a un total de 130 varones con DE (100 con diabetes mellitus [DM] y 30 no diabéticos como control). Se utilizó el Índice Internacional de Función Eréctil (IIEF) para evaluar la DE en los pacientes. Se midieron los valores de HbA1c, perfil lipídico y evaluación de la función eréctil utilizando PPDU. Se evaluó a todos los participantes para realizar la historia médica.Resultados: La edad±DE fue de 53,8±8,9 y 53,6±2,8 años para los pacientes y controles, respectivamente. Los pacientes tenían grados variables de DE: leve en el 20% de los casos, de leve a moderado en el 32,3%, moderado en el 35,3% y grave en el 12,3%. Se encontró una asociación significativa entre la existencia de DM y la ausencia de respuesta a la inyección intracorpórea (ICI), incremento de la velocidad diastólica final (VDF) y reducción de los valores del índice de resistencia (IR). Con arreglo a la HbA1c, la comparación entre todos los grupos diabéticos y los controles arrojó una relación significativa en cuanto a: gravedad de la puntuación IIEF-5, mala respuesta a la ICI, reducción de la velocidad sistólica pico (VSP) a los 10min, incremento de VDF a los 10 y 20min y reducción de IR a los 10 y 20min. Se encontró una relación significativa entre tabaquismo, dislipidemia y reducción de VSP a los 10 y 20min y reducción del ratio de incremento. Sin embargo, se observó una relación no significativa entre la edad, tipo de DM y parámetros PPDU.Conclusión: Un mal control glucémico en la DM está asociado al incremento de VDF y a la reducción del IR y de la VSP de PPDU. (AU)