Summary: Genes associated with the same disease frequently engage in mutual biological interactions, e.g., perturbation within a specific neighborhood in the molecular interactome, often referred to as the disease module. This has propelled the advancement of network-based approaches toward elucidating the molecular bases of human diseases. Although many computational methods have been developed to integrate the molecular interactome and omics profiles to extract such context-dependent disease modules, approaches that leverage multi-omics for disease-module detection are still lacking. Here, we developed a statistical physics approach based on the random-field O(n) model (RFOnM) to fill this gap. We applied the RFOnM approach to integrate gene-expression data and genome-wide association studies or mRNA data and DNA methylation for several complex diseases with the human interactome. We found that the RFOnM approach outperforms existing single omics methods in most of the complex diseases considered in this study. Motivation: Disease-module detection can help to uncover new mechanistic knowledge of complex diseases, reveal disease-disease relationships, discover therapeutic targets, and stratify biomarkers. However, computational methods for disease-module detection that integrate multi-omics are still lacking. To fill this gap, we developed a method based on the random-field O(n) model (RFOnM) to integrate multiple data types for several complex diseases with the human interactome for disease-module detection.
Cellulose nanofibers (CNFs), known for their high aspect ratio and abundant surface groups, have emerged as support materials for metal nanoparticles. Although numerous studies have reported the loading of spherical metal nanoparticles onto CNFs, achieving controlled loading of platelet-shaped metal nanoparticles remains a challenge. We developed a new method to achieve controlled loading of hexagonal silver nanoplates (h-AgNPs) onto CNFs. This process resulted in the formation of ball-like agglomerates with a diameter of ∼2 μm. These agglomerates, composed of Mille-Feuille-like sheets that intersect each other and form a spherical contour (silver Mille-Feuille ball (SMFB)), were prepared by adding CNFs into a colloidal solution of h-AgNPs. It was indicated that the self-assembly of the h-AgNPs was mediated by CNFs, leading to the formation of SMFBs. The high aspect ratio of the platelet shape and monodisperse size distribution of h-AgNPs contributed to the formation of SMFBs. Furthermore, the morphology of the agglomerates was successfully modified by varying the CNF-to-h-AgNP ratio. SMFBs exhibited superior catalytic activities as a rate constant of 0.901 min-1 for 4-nitrophenol reduction and an oxygen reduction reaction onset potential of 0.91V vs. RHE. These results highlight the potential of SMFBs for catalytic applications.
Dorianne Sant’Angelo, Géraldine Descamps, Valentin Lecomte
et al.
The emergence of nanotechnology in medicine, particularly using iron oxide nanoparticles (IONPs), may impact cancer treatment strategies. IONPs exhibit unique properties, such as superparamagnetism, biocompatibility, and ease of surface modification, making them ideal candidates for imaging, and therapeutic interventions. Their application in targeted drug delivery, especially with traditional chemotherapeutic agents like cisplatin, has shown potential in overcoming limitations such as low bioavailability and systemic toxicity of chemotherapies. Moreover, IONPs, by releasing iron ions, can induce ferroptosis, a form of iron-dependent cell death, which offers a promising pathway to reverse radio- and chemoresistance in cancer therapy. In particular, IONPs demonstrate significant potential as radiosensitisers, enhancing the effects of radiotherapy by promoting reactive oxygen species (ROS) generation, lipid peroxidation, and modulating the tumour microenvironment to stimulate antitumour immune responses. This review explores the multifunctional roles of IONPs in radiosensitisation through ferroptosis induction, highlighting their promise in advancing treatment for head and neck cancers. Additional research is crucial to fully addressing their potential in clinical settings, offering a novel approach to personalised cancer treatment.
PURPOSE The aim of this study was to compare the traditional stationary stand type (T-wall) test and the newly developed mobile seated type (Touch pods) test for visual-motor coordination assessment, and to propose a new method for the evaluation of coordination in the National Fitness 100 for adolescents. METHODS A total of 99 adolescents, with an average age of 12.8 years, participated in this study. They were assessed for visual-motor coordination using two types of test tools (T-wall, Touch pods). The correlations between the two tools were examined to verify their reliability. An estimation formula, which applied test equivalency, was derived to apply the results of the Touch pods test to the evaluation standards of the National Fitness 100. RESULTS A significant correlation was observed between the two test tools (r=0.527). When the estimation formula that applies test equivalency was used to apply the results of the two tests to the evaluation standards of the National Fitness 100, the age-grade classification and annual grade ratio appeared to be similar. CONCLUSIONS These results suggest that the newly developed mobile seated test can be considered a reliable tool for measuring visual-motor coordination compared to the traditional stationary stand-type test, as well as a valid tool that can be applied to National Fitness 100 evaluation. However, further research is required to determine their general application.
Group 14 metalloles have attracted much attention as core structures of conjugated functional materials. In this work, we prepared dithieno[3,2-<i>b</i>:4,5-<i>c</i>’]germole as a new unsymmetrically condensed dithienogermole and benzo[4,5]thieno[2,3-c]germole as the benzene-condensed analog. The electronic states and properties of these unsymmetrically condensed germoles are discussed on the basis of the results of optical and electrochemical measurements with the help of quantum chemistry calculations on the simplified model compounds. The Stille cross-coupling reactions of bromodithieno[3,2-<i>b</i>:4,5-<i>c</i>’]germole with di(stannylthienyl)- and di(stannylthiazolyl)benzothiadiazole provided conjugated donor–acceptor compounds that exhibited clear solvatochromic behavior in the photoluminescence spectra, indicating the potential application of the dithieno[3,2-<i>b</i>:4,5-<i>c</i>’]germole unit as an electron donor in donor–acceptor systems.
Sarai Rojas-Jiménez, María Guadalupe Valladares-Cisneros, David Osvaldo Salinas-Sánchez
et al.
<i>Euphorbia</i> is a large genus of the Euphorbiaceae family. Around 250 species of the <i>Euphorbia</i> genus have been studied chemically and pharmacologically; different compounds have been isolated from these species, especially diterpenes and triterpenes. Several reports show that several species have anti-inflammatory activity, which can be attributed to the presence of diterpenes, such as abietanes, ingenanes, and lathyranes. In addition, it was found that some diterpenes isolated from different <i>Euphorbia</i> species have anti-cancer activity. In this review, we included compounds isolated from species of the <i>Euphorbia</i> genus with anti-inflammatory or cytotoxic effects published from 2018 to September 2023. The databases used for this review were Science Direct, Scopus, PubMed, Springer, and Google Scholar, using the keywords <i>Euphorbia</i> with anti-inflammatory or cytotoxic activity. In this review, 68 studies were collected and analyzed regarding the anti-inflammatory and anti-cancer activities of 264 compounds obtained from 36 species of the <i>Euphorbia</i> genus. The compounds included in this review are terpenes (95%), of which 68% are diterpenes, especially of the types ingenanes, abietanes, and triterpenes (approximately 15%).
Objective: the study was to find a suitable treatment for acute drug-induced liver injury. The use of nanocarriers can improve the therapeutic effect of natural drugs by targeting hepatocytes and higher loads. Methods: firstly, uniformly dispersed three-dimensional dendritic mesoporous silica nanospheres (MSNs) were synthesized. Glycyrrhetinic acid (GA) was covalently modified on MSN surfaces through amide bond and then loaded with COSM to form drug-loaded nanoparticles (COSM@MSN-NH<sub>2</sub>-GA). The constructed drug-loaded nano-delivery system was determined by characterization analysis. Finally, the effect of nano-drug particles on cell viability was evaluated and the cell uptake in vitro was observed. Results: GA was successfully modified to obtain the spherical nano-carrier MSN-NH<sub>2</sub>-GA (≤200 nm). The neutral surface charge improves its biocompatibility. MSN-NH<sub>2</sub>-GA has high drug loading (28.36% ± 1.00) because of its suitable specific surface area and pore volume. In vitro cell experiments showed that COSM@MSN-NH<sub>2</sub>-GA significantly enhanced the uptake of liver cells (LO2) and decreased the AST and ALT indexes. Conclusion: this study demonstrated for the first time that formulation and delivery schemes using natural drug COSM and nanocarrier MSN have a protective effect on APAP-induced hepatocyte injury. This result provides a potential nano-delivery scheme for the targeted therapy of acute drug-induced liver injury.
Abstract Background Gene editing has emerged as an exciting therapeutic development platform for numerous genetic and nongenetic diseases. Targeting lipid-modulating genes such as angiopoietin-related protein 3 (ANGPTL3) with gene editing offers hope for a permanent solution to lower cardiovascular disease risks associated with hypercholesterolemia. Results In this study, we developed a hepatocyte-specific base editing therapeutic approach delivered by dual adeno-associated virus (AAV) to enable hepatocyte-specific targeting of Angptl3 to lower blood lipid levels. Systemic AAV9-mediated delivery of AncBE4max, a cytosine base editor (CBE), targeting mouse Angptl3 resulted in the installation of a premature stop codon in Angptl3 with an average efficiency of 63.3 ± 2.3% in the bulk liver tissue. A near-complete knockout of the ANGPTL3 protein in the circulation were observed within 2–4 weeks following AAV administration. Furthermore, the serum levels of triglyceride (TG) and total cholesterol (TC) were decreased by approximately 58% and 61%, respectively, at 4 weeks after treatment. Conclusions These results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.
The quality of Radix Bupleuri is greatly affected by its growing environment. In this study, Radix Bupleuri samples that were harvested from seven different regions across northwest China were examined by high-performance liquid chromatography (HPLC) and gas chromatography (GC) coupled with mass spectrometry (MS) to reveal significant differences in quality contributed by the cultivation region. An HPLC-MS method was firstly established and used in the multiple reaction monitoring mode for the quantitative analysis of five saikosaponins in Radix Bupleuri so as to evaluate the difference in the absolute content of saikosaponins attributable to the cultivation region. The effect on the components of Radix Bupleuri was further investigated based on the profiles of the representative saponins and volatile compounds, which were extracted from the Radix Bupleuri samples and analyzed by HPLC-MS and GC-MS. Multivariate statistical analysis was employed to differentiate the Radix Bupleuri samples cultivated in different regions and to discover the differential compositions. The developed quantitative method was validated to be accurate, stable, sensitive, and repeatable for the determination of five saikosaponins. Further statistical tests revealed that the collected Radix Bupleuri samples were distinctly different from each other in terms of both saponins and volatile compounds, based on the provinces where they were grown. In addition, twenty-eight saponins and fifty-eight volatile compounds were identified as the differentially accumulated compositions that contributed to the discrimination of the Radix Bupleuri samples. The Radix Bupleuri samples grown in Shouyang county showed the highest content of saikosaponins. All of the results indicated that the cultivation region significantly affected the accumulation and diversity of the main chemical components of Radix Bupleuri. The findings of this research provide insights into the effect of the cultivation region on the quality of Radix Bupleuri and the differentiation of Radix Bupleuri cultivated in different regions based on the use of HPLC-MS and GC-MS combined with multivariate statistical analysis.
Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the <i>N</i>′-methylene position of indoles’ Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives <b>9a</b>–<b>9w</b> were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and <i>N</i>-dimethylformamide dimethylacetal. All compounds were characterized by <sup>1</sup>H-NMR, <sup>13</sup>C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, <b>9h</b> exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound <b>9h</b> inhibited cell growth and arrested the cell cycle. Additionally, <b>9h</b> leads to the cleavage of PARP. We initially explored the mechanism of <b>9h</b>-induced apoptosis and found that compound <b>9h</b> can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that <b>9h</b> may be a promising anti-tumor leading compound for the further research.
Kamila Rybczyńska-Tkaczyk, Teresa Korniłłowicz-Kowalska, Konrad A. Szychowski
The aim of this study was to evaluate the bioremoval mechanism of anthracycline antibiotics by the white-rot fungus <i>B. adusta</i> CCBAS 930. The activity of oxidoreductases and levels of phenolic compounds and free radicals were determined during the biotransformation of anthraquinone antibiotics: daunomycin (DNR) and doxorubicin (DOX) by <i>B. adusta</i> strain CCBAS 930. Moreover, phytotoxicity (<i>Lepidium sativum</i> L.), ecotoxicity (<i>Vibrio fischeri</i>), genotoxicity and cytotoxicity of anthraquinone dyes were evaluated before and after biological treatment. More than 80% and 90% of DNR and DOX were removed by biodegradation (decolorization). Initial solutions of DNR and DOX were characterized by eco-, phyto-, geno- and cytotoxicity. Despite efficient decolorization, secondary metabolites, toxic to bacteria, formed during biotransformation of anthracycline antibiotics in <i>B. adusta</i> CCBAS 930 cultures. DNR and DOX metabolites did not increase reactive oxygen species (ROS) production in human fibroblasts and resazurin reduction. DNR metabolites did not change caspase-3 activity.
Angelika A. Adamus-Grabicka, Magdalena Markowicz-Piasecka, Marcin Cieślak
et al.
A series of 3-benzylidenechrmanones <b>1</b>, <b>3</b>, <b>5</b>, <b>7</b>, <b>9</b> and their spiropyrazoline analogues <b>2</b>, <b>4</b>, <b>6</b>, <b>8</b>, <b>10</b> were synthesized. X-ray analysis confirms that compounds <b>2</b> and <b>8</b> crystallize in a monoclinic system in P2<sub>1</sub>/n space groups with one and three molecules in each asymmetric unit. The crystal lattice of the analyzed compounds is enhanced by hydrogen bonds. The primary aim of the study was to evaluate the anti-proliferative potential of 3-benzylidenechromanones and their spiropyrazoline analogues towards four cancer cell lines. Our results indicate that parent compounds <b>1</b> and <b>9</b> with a phenyl ring at C2 have lower cytotoxic activity against cancer cell lines than their spiropyrazolines analogues. Analysis of IC<sub>50</sub> values showed that the compounds <b>3</b> and <b>7</b> exhibited higher cytotoxic activity against cancer cells, being more active than the reference compound (4-chromanone or quercetin). The results of this study indicate that the incorporation of a pyrazoline ring into the 3-arylideneflavanone results in an improvement of the compounds’ activity and therefore it may be of use in the search of new anticancer agents. Further analysis allowed us to demonstrate the compounds to have a strong inhibitory effect on the cell cycle. For instance, compounds <b>2</b>, <b>10</b> induced 60% of HL-60 cells to be arrested in G2/M phase. Using a DNA-cleavage protection assay we also demonstrated that tested compounds interact with DNA. All compounds at the concentrations corresponding to cytotoxic properties are not toxic towards red blood cells, and do not contribute to hemolysis of RBCs.
Daniel García Velázquez, Rafael Luque, Ángel Gutiérrez Ravelo
A novel family of water-soluble π-conjugated hexaazatrinaphthylenes-based dendritic architectures constructed by hexaketocyclohexane and 1,2,4,5-benzenetetramine units is developed in a microwave-assisted organic synthesis (MAOS) approach. The structures and purity of these compounds are verified by <sup>1</sup>H and <sup>13</sup>C-NMR, MALDI-TOF MS, UV-vis, elemental analysis, DSC, AFM, STM and cyclic voltammetry.
Blair Armistead, Pilar Herrero-Foncubierta, Michelle Coleman
et al.
Granadaene, produced by Group B Streptococcus (GBS), is a long polyene lipid involved in cellular toxicity and hemolytic activity. Here, the authors synthesize and characterize granadaene-like compounds and show that a non-toxic analog diminishes GBS infection in mice when incorporated into a vaccine formulation.
Catarina I. V. Ramos, Susana P. Almeida, Leandro M. O. Lourenço
et al.
The stabilization of G-Quadruplex DNA structures by ligands is a promising strategy for telomerase inhibition in cancer therapy since this enzyme is responsible for the unlimited proliferation of cancer cells. To assess the potential of a compound as a telomerase inhibitor, selectivity for quadruplex over duplex DNA is a fundamental attribute, as the drug must be able to recognize quadruplex DNA in the presence of a large amount of duplex DNA, in the cellular nucleus. By using different spectroscopic techniques, such as ultraviolet-visible, fluorescence and circular dichroism, this work evaluates the potential of a series of multicharged phthalocyanines, bearing four or eight positive charges, as G-Quadruplex stabilizing ligands. This work led us to conclude that the existence of a balance between the number and position of the positive charges in the phthalocyanine structure is a fundamental attribute for its selectivity for G-Quadruplex structures over duplex DNA structures. Two of the studied phthalocyanines, one with four peripheral positive charges (ZnPc1) and the other with less exposed eight positive charges (ZnPc4) showed high selectivity and affinity for G-Quadruplex over duplex DNA structures and were able to accumulate in the nucleus of UM-UC-3 bladder cancer cells.
Over 11 million people in the United States alone have some form of age-related macular degeneration (AMD). Oxidative stress, cell death, and the degeneration of retinal pigment epithelial (RPE) cells contribute to AMD pathology. Recent evidence suggests that ceramide (Cer), a cellular sphingolipid mediator that acts as a second messenger to induce apoptosis, might play a role in RPE cell death. The lysosomal breakdown of Cer by acid ceramidase [N-acylsphingosine amidohydrolase (ASAH)1] into sphingosine (Sph) is the major source for Sph 1-phosphate production, which has an opposing role to Cer and provides cytoprotection. Here, we investigated the role of Cer in human RPE-derived ARPE19 cells under hydrogen peroxide-induced oxidative stress, and show that Cer and hexosyl-Cer levels increase in the oxidatively stressed ARPE19 cells, which can be prevented by overexpression of lysosomal ASAH1. This study demonstrates that oxidative stress generates sphingolipid death mediators in retinal cells and that induction of ASAH1 could rescue retinal cells from oxidative stress by hydrolyzing excess Cers.
Jaime Franco, Florencia Sardi, László Szilágyi
et al.
With the aim to develop compounds able to target multiple metabolic pathways and, thus, to lower the chances of drug resistance, we investigated the anti-trypanosomal activity and selectivity of a series of symmetric diglycosyl diselenides and disulfides. Of 18 compounds tested the fully acetylated forms of di-β-D-glucopyranosyl and di-β-D-galactopyranosyl diselenides (13 and 15, respectively) displayed strong growth inhibition against the bloodstream stage of African trypanosomes (EC50 0.54 μM for 13 and 1.49 μM for 15) although with rather low selectivity (SI < 10 assayed with murine macrophages). Nonacetylated versions of the same sugar diselenides proved to be, however, much less efficient or completely inactive to suppress trypanosome growth. Significantly, the galactosyl (15), and to a minor extent the glucosyl (13), derivative inhibited glucose catabolism but not its uptake. Both compounds induced redox unbalance in the pathogen. In vitro NMR analysis indicated that diglycosyl diselenides react with glutathione, under physiological conditions, via formation of selenenylsulfide bonds. Our results suggest that non-specific cellular targets as well as actors of the glucose and the redox metabolism of the parasite may be affected. These molecules are therefore promising leads for the development of novel multitarget antitrypanosomal agents. Keywords: Glutathione, Redox biosensor, Selenosugar, Trypanosome inhibition, Selenium NMR
Marcin Baranowski, Agnieszka Blachnio-Zabielska, Tomasz Hirnle
et al.
Data from animal experiments strongly suggest that ceramide is an important mediator of lipotoxicity in the heart and that accumulation of ceramide contributes to cardiomyocyte apoptosis associated with type 2 diabetes and obesity. However, it remains unknown whether a similar relationship is present also in the human heart. Therefore, we aimed to examine whether myocardial apoptosis in obese and type 2 diabetic patients is associated with elevated ceramide level. The study included 11 lean and 26 overweight or moderately obese subjects without (n = 11, OWT) or with (n = 15, T2D-OWT) a history of type 2 diabetes. Samples of the right atrial appendage were obtained from patients at the time of coronary bypass surgery. Compared with lean subjects, the extent of DNA fragmentation (a marker of apoptosis) was significantly higher in the myocardium of OWT patients and increased further in T2D-OWT subjects. However, the content of ceramide and sphingoid bases remained stable. Interestingly, the mRNA level of enzymes involved in synthesis and degradation of ceramide including serine palmitoyltransferase, sphingosine kinase 1, neutral sphingomyelinase, and ceramidases was markedly higher in the myocardium of OWT and T2D-OWT patients compared with lean subjects. Our results indicate that in the human heart, or at least in the atrium, ceramide is not a major factor in cardiomyocyte apoptosis associated with obesity and type 2 diabetes.
African green monkeys were fed diets containing either 11% (by weight) fish oil or lard for 2.5 yr. To test the hypothesis that fish oil decreases hepatic secretion of triglyceride (TG) and apoB, livers from these animals were perfused with a fatty acid mixture [85% (w/w) oleate containing [14C]oleate and 15% n-3 containing [3H]eicosapentaenoic acid (EPA)] at a rate of 0.1 mumol fatty acid/min per g liver. Liver perfusate was sampled every 30 min during 4 h of recirculating perfusion. The concentration of triglyceride was similar for livers of animals of both groups and there was no difference between groups in the extent of incorporation of [3H]EPA or [14C]oleate into hepatic TG. While the secretion rate for the mass of TG was less in the fish oil-fed group (8.3 +/- 2.5 vs 18.3 +/- 4.4 mg/h per 100 g liver, P less than 0.05), the apoB secretion rate was similar (0.92 +/- 0.15 vs 1.01 +/- 0.13 mg/h per 100 g liver). Significantly less [3H]EPA was incorporated into secreted TG in the fish oil group (0.4 +/- 0.1 vs 1.0 +/- 0.1% infused dose/h; P less than 0.01). The rate of secretion of [14C]TG was similar for both groups (1.3 +/- 0.3 vs 1.4 +/- 0.1% infused dose/h for fish oil and lard groups, respectively). No significant diet-related differences in [3H]TG or [14C]TG fatty acid specific activity were observed for perfusate TG or hepatic TG. After perfusion, livers from fish oil-fed monkeys contained significantly more [3H]EPA in hepatic phospholipid than livers from lard-fed monkeys (19.5 +/- 1.8 vs 11.4 +/- 1.7% infused dose; P less than 0.01) although hepatic phospholipid mass concentrations were similar. The liver phospholipids of the fish oil group were enriched in n-3 fatty acid mass and were relatively depleted of oleate and linoleate. We conclude that although apoB secretion was unaffected, dietary fish oil significantly decreased hepatic TG secretion through relatively poor utilization of EPA for the synthesis of TG destined for secretion in VLDL; at the same time, increased incorporation of [3H]EPA into hepatic phospholipid accompanied the decreased incorporation into secreted TG and these events may be coupled.(ABSTRACT TRUNCATED AT 400 WORDS)