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Future Medicinal Chemistry Jul 2024We aim to develop new anti-leishmanial agents against and . A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for activity...
We aim to develop new anti-leishmanial agents against and . A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for activity against promastigotes of and . The -benzoyl analogue was found potent (IC = 12.7 μM) against and non toxic to normal cells. The docking studies, indicates that these inhibitors may target folate and glycolytic pathways of the parasite. The -hexyl compound was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound , with a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against , but was cytotoxic in nature. Compound was thus identified as a hit for further studies.
PubMed: 38953461
DOI: 10.1080/17568919.2024.2359362 -
Journal of Cellular and Molecular... Jul 2024In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown...
In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti-inflammatory agents, alpinetin has shown promising anti-inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti-inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF-KB family) and p300 (a type of co-activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti-inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti-inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2's anti-inflammatory assistance. In conclusion, Mecp2 may augment the anti-inflammatory effects of alpinetin through epigenetic 'crosstalk', highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti-inflammatory intervention.
Topics: Methyl-CpG-Binding Protein 2; Animals; Flavanones; Epigenesis, Genetic; Mice; Anti-Inflammatory Agents; Promoter Regions, Genetic; RAW 264.7 Cells; DNA Methylation; Lipopolysaccharides; Transcription Factor RelA; Sepsis; Macrophages; Inflammation; DNA Methyltransferase 3A; Male; E1A-Associated p300 Protein; Disease Models, Animal; Mice, Inbred C57BL; DNA (Cytosine-5-)-Methyltransferases
PubMed: 38953409
DOI: 10.1111/jcmm.18510 -
Langmuir : the ACS Journal of Surfaces... Jul 2024The effect of embedded graphitic carbon nitride (g-CN) nanosheets on hydration and thermal response behavior of cross-linked thermoresponsive poly(di(ethylene glycol)...
The effect of embedded graphitic carbon nitride (g-CN) nanosheets on hydration and thermal response behavior of cross-linked thermoresponsive poly(di(ethylene glycol) methyl ether methacrylate--oligo(ethylene glycol) methyl ether methacrylate), abbreviated as P(MA--MA), thin films is probed by white light interferometry. Compared with that of the cross-linked pure P(MA--MA) films, the surface roughness of the cross-linked hybrid films is slightly increased, which is caused by the minor aggregation of g-CN nanosheets during the spin-coating process. After exposure to a water vapor atmosphere, both cross-linked pure and hybrid films can absorb water and swell. However, the introduction of g-CN not only induces a larger hydration extent but also triggers a nonlinear transition behavior upon heating. This prominent difference might be related to the residual hydrophilic groups (-NH and N-H) on the surface of g-CN nanosheets, which enhance the interaction and absorption capability for water molecules in the hybrid films. Upon further increasing the amount of embedded g-CN nanosheets in films, more hydrogen bonds are formed and a larger hydration extent of films is observed. To break all of the hydrogen bonds in films, a higher transition temperature (TT) is required. The observed hydration and transition behaviors of hybrid films can be used to design hydrogel-based films for hydrogen evolution or wastewater treatment.
PubMed: 38953342
DOI: 10.1021/acs.langmuir.4c01630 -
Molecular Ecology Jul 2024When facing challenges, vertebrates activate a hormonal stress response that can dramatically alter behaviour and physiology. Although this response can be costly,...
When facing challenges, vertebrates activate a hormonal stress response that can dramatically alter behaviour and physiology. Although this response can be costly, conceptual models suggest that it can also recalibrate the stress response system, priming more effective responses to future challenges. Little is known about whether this process occurs in wild animals, particularly in adulthood, and if so, how information about prior experience with stressors is encoded. One potential mechanism is hormonally mediated changes in DNA methylation. We simulated the spikes in corticosterone that accompany a stress response using non-invasive dosing in tree swallows (Tachycineta bicolor) and monitored the phenotypic effects 1 year later. In a subset of individuals, we characterized DNA methylation using reduced representation bisulfite sequencing shortly after treatment and a year later. The year after treatment, experimental females had stronger negative feedback and initiated breeding earlier-traits that are associated with stress resilience and reproductive performance in our population-and higher baseline corticosterone. We also found that natural variation in corticosterone predicted patterns of DNA methylation. Finally, corticosterone treatment influenced methylation on short (1-2 weeks) and long (1 year) time scales; however, these changes did not have clear links to functional regulation of the stress response. Taken together, our results are consistent with corticosterone-induced priming of future stress resilience and support DNA methylation as a potential mechanism, but more work is needed to demonstrate functional consequences. Uncovering the mechanisms linking experience with the response to future challenges has implications for understanding the drivers of stress resilience.
PubMed: 38953311
DOI: 10.1111/mec.17456 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were...
Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.
Topics: Humans; Female; Paired Box Transcription Factors; DNA Methylation; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; SOXB1 Transcription Factors; Adult; Middle Aged; Sensitivity and Specificity; Young Adult
PubMed: 38953256
DOI: 10.3881/j.issn.1000-503X.15734 -
Frontiers in Pharmacology 2024Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and...
BACKGROUND
Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis.
METHODS
We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism.
RESULTS
In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3.
CONCLUSION
This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.
PubMed: 38953111
DOI: 10.3389/fphar.2024.1406493 -
RSC Advances Jun 2024This study investigates the potential and applicability of a novel solid magnetic catalyst constructed by incorporating molybdenum oxide (MoO) into zinc ferrite (ZnFeO)...
This study investigates the potential and applicability of a novel solid magnetic catalyst constructed by incorporating molybdenum oxide (MoO) into zinc ferrite (ZnFeO) to biodiesel production using Waste Frying Oil (WFO) as the residual raw material. The molybdenum amounts (5, 15, 25, 35 and 45%) present in the catalyst were studied and the catalyst demonstrated great characteristics and high acid properties, as well as superior magnetic and catalytic attributes. The one variable at time (OVAT) optimization method revealed that the application of the MoO/ZnFeO catalyst resulted in obtaining a biodiesel with 97.6% ± 0.727 conversion to fatty acid methyl esters (FAME) under the following optimized reaction conditions: temperature of 165 °C, methanol : WFO molar ratio of 40 : 1, catalyst amount of 6 wt% and reaction time of 3 h. In addition, the catalyst showed high reusability after six reaction cycles, with conversion to esters above 90%. Besides, the activation energy ( ) calculated in the kinetic study was 25.3 kJ mol. Moreover, the properties of the synthesized biodiesel met the standards set by the ASTM D6751 and EN 14214, which indicates the high MoO/ZnFeO potential for industrial application with low energy consumption as well as minimal negative environmental impact.
PubMed: 38952943
DOI: 10.1039/d4ra03580a -
RSC Advances Jun 2024PEGylated gold nanoparticles (PEG-AuNPs) are widely used in drug delivery, imaging and diagnostics, therapeutics, and biosensing. However, the effect of PEG dispersity...
PEGylated gold nanoparticles (PEG-AuNPs) are widely used in drug delivery, imaging and diagnostics, therapeutics, and biosensing. However, the effect of PEG dispersity on the molecular weight ( ) distribution of PEG grafted onto AuNP surfaces has been rarely reported. This study investigates the effect of PEG dispersity on the distribution of PEG grafted onto AuNP surfaces and its subsequent impact on protein adsorption and pharmacokinetics, by modifying AuNPs with monodisperse PEG methyl ether thiols (mPEG -HS, = 36, 45) and traditional polydisperse mPEG2k-SH ( = 1900). Polydisperse PEG-AuNPs favor the enrichment of lower PEG fractions on their surface due to the steric hindrance effect, which leads to increased protein adsorption. In contrast, monodisperse PEG-AuNPs have a uniform length of PEG outlayer, exhibiting markedly lower yet constant protein adsorption. Pharmacokinetics analysis in tumor-bearing mice demonstrated that monodisperse PEG-AuNPs possess a significantly prolonged blood circulation half-life and enhanced tumor accumulation compared with their polydisperse counterpart. These findings underscore the critical, yet often underestimated, impacts of PEG dispersity on the and behavior of PEG-AuNPs, highlighting the role of monodisperse PEG in enhancing therapeutic nanoparticle performance.
PubMed: 38952930
DOI: 10.1039/d4ra03153a -
Vavilovskii Zhurnal Genetiki I Selektsii Jun 2024The diversity of pathogenetic mechanisms underlying arterial hypertension leads to the necessity to devise a personalized approach to the diagnosis and treatment of the...
The diversity of pathogenetic mechanisms underlying arterial hypertension leads to the necessity to devise a personalized approach to the diagnosis and treatment of the disease. Metabolomics is one of the promising methods for personalized medicine, as it provides a comprehensive understanding of the physiological processes occurring in the body. The metabolome is a set of low-molecular substances available for detection in a sample and representing intermediate and final products of cell metabolism. Changes in the content and ratio of metabolites in the sample mark the corresponding pathogenetic mechanisms by highlighting them, which is especially important for such a multifactorial disease as arterial hypertension. To identify metabolomic markers for hypertensive conditions of different origins, three forms of arterial hypertension (AH) were studied: rats with hereditary AH (ISIAH rat strain); rats with AH induced by L-NAME administration (a model of endothelial dysfunction with impaired NO production); rats with AH caused by the administration of deoxycorticosterone in combination with salt loading (hormone-dependent form - DOCA-salt AH). WAG rats were used as normotensive controls. 24-hour urine samples were collected from all animals and analyzed by quantitative NMR spectroscopy for metabolic profiling. Then, potential metabolomic markers for the studied forms of hypertensive conditions were identified using multivariate statistics. Analysis of the data obtained showed that hereditary stress-induced arterial hypertension in ISIAH rats was characterized by a decrease in the following urine metabolites: nicotinamide and 1-methylnicotinamide (markers of inflammatory processes), N- acetylglutamate (nitric oxide cycle), isobutyrate and methyl acetoacetate (gut microbiota). Pharmacologically induced forms of hypertension (the L-NAME and DOCA+NaCl groups) do not share metabolomic markers with hereditary AH. They are differentiated by N,N-dimethylglycine (both groups), choline (the L-NAME group) and 1-methylnicotinamide (the group of rats with DOCA-salt hypertension).
PubMed: 38952704
DOI: 10.18699/vjgb-24-34 -
Cureus Jun 2024Background Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease characterized by inflammation and dysfunction of the thyroid gland, resulting in hypothyroidism,...
Background Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease characterized by inflammation and dysfunction of the thyroid gland, resulting in hypothyroidism, it results in impaired thyroid hormone generation and mimics hypothyroidism. The disease involves complex interactions among genetic, environmental, and epigenetic factors, particularly affecting the regulation of T regulatory (Treg) cells, including CD4 + + T cells. Treg cells, defined as CD4 + T cells, rely on the expression of the transcription factor, which is crucial for their development and differentiation. Disruptions in this regulation can lead to immune dysregulation and potential proinflammatory responses. The study focuses on investigating the impact of dietary patterns on the epigenetic changes in the gene, a key player in the development of HT. The primary aim was to evaluate how eliminating gluten and casein proteins from dietary regimens may influence the methylation levels of the gene, considering the potential link between these dietary components and the triggering of autoimmune diseases. Methods An epigenetic analysis of the gene in HT patients who were strictly following a dietary plan compared with the control group. For the epigenetic study, a methylation analysis experiment was conducted. Results Our findings revealed a notable reduction in gene methylation levels among HT patients who adhered to a diet excluding casein and gluten. The control maintained normal dietary guidelines and showed no significant alterations in methylation levels. Discussion The laboratory values showed a decrease in methylation levels of the gene, with statistical significance indicated as *p<0.005, **p<0.001, ***p<0.0001, suggesting a potential enhancement in its expression which could have profound implications for immune system regulation. Disruptions in the pathway are crucial in the development of autoimmune disorders, where altered activity hinders the regulation of T cell (Treg) development, ultimately contributing to conditions like HT disease. These findings imply that nutritional interventions, especially for individuals with HT, could potentially be a strategy for mitigating autoimmunity through epigenetic mechanisms.
PubMed: 38952602
DOI: 10.7759/cureus.63208