Initial Mechanistic Insight Research Articles

Elucidating the role of exogenous melatonin in mitigating alkaline stress in soybeans across different growth stages: a transcriptomic and metabolomic approach

BackgroundSoybean (Glycine max), a vital grain and oilseed crop, serves as a primary source of plant protein and oil. Soil salinization poses a significant threat to soybean planting, highlighting the urgency to improve soybean resilience and adaptability to saline stress. Melatonin, recently identified as a key plant growth regulator, plays crucial roles in plant growth, development, and responses to environmental stress. However, the potential of melatonin to mitigate alkali stress in soybeans and the underlying mechanisms remain unclear.ResultsThis study investigated the effects of exogenous melatonin on the soybean cultivar Zhonghuang 13 under alkaline stress. We employed physiological, biochemical, transcriptomic, and metabolomic analyses throughout both vegetative and pod-filling growth stages. Our findings demonstrate that melatonin significantly counteracts the detrimental effects of alkaline stress on soybean plants, promoting plant growth, photosynthesis, and antioxidant capacity. Transcriptomic analysis during both growth stages under alkaline stress, with and without melatonin treatment, identified 2,834 and 549 differentially expressed genes, respectively. These genes may play a vital role in regulating plant adaptation to abiotic stress. Notably, analysis of phytohormone biosynthesis pathways revealed altered expression of key genes, particularly in the ARF (auxin response factor), AUX/IAA (auxin/indole-3-acetic acid), and GH3 (Gretchen Hagen 3) families, during the early stress response. Metabolomic analysis during the pod-filling stage identified highly expressed metabolites responding to melatonin application, such as uteolin-7-O-(2''-O-rhamnosyl)rutinoside and Hederagenin-3-O-glucuronide-28-O-glucosyl(1,2)glucoside, which helped alleviate the damage caused by alkali stress. Furthermore, we identified 183 differentially expressed transcription factors, potentially playing a critical role in regulating plant adaptation to abiotic stress. Among these, the gene SoyZH13_04G073701 is particularly noteworthy as it regulates the key differentially expressed metabolite, the terpene metabolite Hederagenin-3-O-glucuronide-28-O-glucosyl(1,2)glucoside. WGCNA analysis identified this gene (SoyZH13_04G073701) as a hub gene, positively regulating the crucial differentially expressed metabolite of terpenoids, Hederagenin-3-O-glucuronide-28-O-glucosyl(1,2)glucoside. Our findings provide novel insights into how exogenous melatonin alleviates alkali stress in soybeans at different reproductive stages.ConclusionsIntegrating transcriptomic and metabolomic approaches, our study elucidates the mechanisms by which exogenous melatonin ameliorates the inhibitory effects of alkaline stress on soybean growth and development. This occurs through modulation of biosynthesis pathways for key compounds, including terpenes, flavonoids, and phenolics. Our findings provide initial mechanistic insights into how melatonin mitigates alkaline stress in soybeans, offering a foundation for molecular breeding strategies to enhance salt-alkali tolerance in this crop.

Abstract LB355: Cryo-immune vaccination (CIV) by SYNC-T therapy: Preclinical modeling of a novel device-multidrug immunotherapeutic approach to eradicate advanced metastatic cancers

Abstract A major challenge to further development of immune checkpoint therapies (ICT) for advanced cancer is the inherent toxicity of higher-order multidrug combinations likely needed to eradicate metastatic disease. Recently, early clinical studies have investigated a new general approach to address this challenge, termed cryo-immune vaccination (CIV). The CIV approach by SYNC-T therapy involves cycles of local cryolysis of a solid tumor followed by infusion of the same lesion with a low-dose multi-API formulation. CIV has never been explored methodically in preclinical or clinical settings, so the basis for systemic responses that have been observed in early clinical testing are not fully understood. Accordingly, as trials of the safety and efficacy of CIV proceed, there is now a need of preclinical model systems to help illuminate the mechanistic foundations of the approach, investigate safety and efficacy, and learn where and how it might be best leveraged. To develop the conceptual framework of CIV, we adapted the orthotopic metastatic 4T1 breast cancer model used extensively in our laboratory as a foundation to study CIV antitumor responses and mechanisms of action. Briefly, breast tumors were initiated in naïve murine subjects by orthotopic injection of 1x104 cells into the mammary fad pads of immunocompetent BALB/c hosts. When tumors reached ~5-7 mm, a time when occult pulmonary metastases have seeded, primary tumors were exposed surgically on skin flaps and contacted directly with a liquid nitrogen-cooled pointed steel rod for 15-30 sec. The rod was then withdrawn and tumor tissue allowed to thaw fully before injection into the cryolysed tumor of a selected ICT multidrug cocktail (or negative control murine IgG) in 25-50 µl total volume. The selected multidrug cocktail was modeled on SYNC-T combination therapy currently under study in a Phase 1 clinical trial (Syncromune, Inc.) Briefly, the ICT drug cocktails were variably composed of murine-reactive antibodies against CTLA4, PD-1 or OX40 (agonist), CD40L (agonist) and CpG oligonucleotide. As a starting point, allometric scaling was used to model dosing analogous to the proprietary ICT drug formulations SV-101 and SV-102 in clinical testing (Syncromune, Inc.). For exploratory toxicology, a standard panel of blood-borne liver and kidney toxicity biomarkers was assessed. For exploratory pharmacology, a ‘super mouse’ design was employed with ELISA-based determinations to measure antibody distribution in blood serum. To gain initial mechanistic insights, responses will be compared in host mice that are genetically deficient in selected components of the adaptive or innate immune systems. Progress in methodological and mechanistic studies will be presented. Citation Format: James B. DuHadaway, Alexander J. Muller, Lisa D. Laury-Kleintop, U. Margaretha Wallon, Susan K. Gilmour, Marie Webster, Jason R. Williams, Gabriela R. Rossi, Mario R. Mautino, Jonathan Lewis, Charles J. Link, George C. Prendergast. Cryo-immune vaccination (CIV) by SYNC-T therapy: Preclinical modeling of a novel device-multidrug immunotherapeutic approach to eradicate advanced metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB355.

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors

Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

Perfectly Isotactic Polypropylene upon In Situ Activation of Ultrarigid meso Hafnocenes.

For more than 40 years, the synthesis of C2 -symmetric indenyl-based racemic metallocenes for the isoselective polymerization of propylene relied on a tedious separation of the produced rac and meso isomers. Status quo, latter are considered wasteful as they produce atactic polypropylene (aPP) rather than isotactic polypropylene (iPP) if activated with methylaluminoxane (MAO). Unexpectedly, the in situ activation of meso hafnocene I yielded perfectly isotactic polypropylene. We verified an isomerization of the meso compound to the corresponding racemic one upon triisobutylaluminum (TIBA) addition via nuclear magnetic resonance (NMR) spectroscopy and established an easy and convenient polymerization protocol, enabling productivities comparable to pure rac-I if applied to pure meso-I or a mixture of both isomers. With this established isomerization protocol, the potential yield of iPP was enhanced by more than 400 %. This protocol was also shown to be applicable to other meso hafnocenes and some initial mechanistic insights were received.

A cis-regulatory element promoting increased transcription at low temperature in cultured ectothermic Drosophila cells

BackgroundTemperature change affects the myriad of concurrent cellular processes in a non-uniform, disruptive manner. While endothermic organisms minimize the challenge of ambient temperature variation by keeping the core body temperature constant, cells of many ectothermic species maintain homeostatic function within a considerable temperature range. The cellular mechanisms enabling temperature acclimation in ectotherms are still poorly understood. At the transcriptional level, the heat shock response has been analyzed extensively. The opposite, the response to sub-optimal temperature, has received lesser attention in particular in animal species. The tissue specificity of transcriptional responses to cool temperature has not been addressed and it is not clear whether a prominent general response occurs. Cis-regulatory elements (CREs), which mediate increased transcription at cool temperature, and responsible transcription factors are largely unknown.ResultsThe ectotherm Drosophila melanogaster with a presumed temperature optimum around 25 °C was used for transcriptomic analyses of effects of temperatures at the lower end of the readily tolerated range (14–29 °C). Comparative analyses with adult flies and cell culture lines indicated a striking degree of cell-type specificity in the transcriptional response to cool. To identify potential cis-regulatory elements (CREs) for transcriptional upregulation at cool temperature, we analyzed temperature effects on DNA accessibility in chromatin of S2R+ cells. Candidate cis-regulatory elements (CREs) were evaluated with a novel reporter assay for accurate assessment of their temperature-dependency. Robust transcriptional upregulation at low temperature could be demonstrated for a fragment from the pastrel gene, which expresses more transcript and protein at reduced temperatures. This CRE is controlled by the JAK/STAT signaling pathway and antagonizing activities of the transcription factors Pointed and Ets97D.ConclusionBeyond a rich data resource for future analyses of transcriptional control within the readily tolerated range of an ectothermic animal, a novel reporter assay permitting quantitative characterization of CRE temperature dependence was developed. Our identification and functional dissection of the pst_E1 enhancer demonstrate the utility of resources and assay. The functional characterization of this CoolUp enhancer provides initial mechanistic insights into transcriptional upregulation induced by a shift to temperatures at the lower end of the readily tolerated range.

An Organogold Compound as Potential Antimicrobial Agent against Drug-Resistant Bacteria: Initial Mechanistic Insights.

The rise of antimicrobial resistance has necessitated novel strategies to efficiently combat pathogenic bacteria. Metal‐based compounds have been proven as a possible alternative to classical organic drugs. Here, we have assessed the antibacterial activity of seven gold complexes of different families. One compound, a cyclometalated Au(III) C^N complex, showed activity against Gram‐positive bacteria, including multi‐drug resistant clinical strains. The mechanism of action of this compound was studied in Bacillus subtilis. Overall, the studies point towards a complex mode of antibacterial action, which does not include induction of oxidative stress or cell membrane damage. A number of genes related to metal transport and homeostasis were upregulated upon short treatment of the cells with gold compound. Toxicity tests conducted on precision‐cut mouse tissue slices ex vivo revealed that the organogold compound is poorly toxic to mouse liver and kidney tissues, and may thus, be treated as an antibacterial drug candidate.

Brain proteomic changes by histone deacetylase inhibition after traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a leading cause of morbidity and mortality. There are currently no cytoprotective treatments for TBI. There is growing evidence that the histone deacetylase inhibitor valproic...

Cellular requirements for PIN polar cargo clustering in Arabidopsis thaliana.

Summary Cell and tissue polarization is fundamental for plant growth and morphogenesis. The polar, cellular localization of Arabidopsis PIN‐FORMED (PIN) proteins is crucial for their function in directional auxin transport. The clustering of PIN polar cargoes within the plasma membrane has been proposed to be important for the maintenance of their polar distribution. However, the more detailed features of PIN clusters and the cellular requirements of cargo clustering remain unclear.Here, we characterized PIN clusters in detail by means of multiple advanced microscopy and quantification methods, such as 3D quantitative imaging or freeze‐fracture replica labeling. The size and aggregation types of PIN clusters were determined by electron microscopy at the nanometer level at different polar domains and at different developmental stages, revealing a strong preference for clustering at the polar domains.Pharmacological and genetic studies revealed that PIN clusters depend on phosphoinositol pathways, cytoskeletal structures and specific cell‐wall components as well as connections between the cell wall and the plasma membrane.This study identifies the role of different cellular processes and structures in polar cargo clustering and provides initial mechanistic insight into the maintenance of polarity in plants and other systems.

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33–driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

Peripheral microvascular serotoninergic signaling is dysregulated in young adults with major depressive disorder.

Dysfunction of the brain serotonergic system is implicated in the pathogenesis of major depressive disorder (MDD). Serotonin is also a vasoactive signaling molecule, the effects of which are modulated by both nitric oxide (NO) and the serotonin transporter [the primary target of selective serotonin reuptake inhibitors (SSRIs)]. Despite its role in the neurobiology of depression, serotoninergic signaling mechanisms in the microvasculature of adults with MDD are unknown. We hypothesized that 1) cutaneous microvascular responsiveness to serotonin would be attenuated in MDD and mediated by reductions in both 2) NO-dependent and 3) serotonin reuptake-dependent mechanisms. In 12 adults with MDD (nonmedicated) and 12 nondepressed adults, red cell flux (laser-Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of 1) serotonin (10-10 to 10-1 mol/L) alone and in combination with a nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 15 mmol/L) and the SSRI paroxetine (10 μmol/L); and 2) paroxetine (n = 6; 10-9 to 10-2 M) alone and in combination with l-NAME. Serotonin-induced vasodilation was preserved in MDD. The NO-dependent component of serotonin-induced vasodilation was not different between groups. Paroxetine augmented vasodilatory responsiveness to serotonin via NO-dependent mechanisms in both groups; however, the magnitude was blunted in MDD. The NO contribution to direct paroxetine-induced vasodilation was also reduced in adults with MDD. Collectively, these preliminary data suggest that cutaneous microvascular serotoninergic signaling is dysregulated in adults with MDD and mediated by NO-dependent and serotonin reuptake-dependent mechanisms, providing initial mechanistic insight to the purported vasculoprotective effect of chronic SSRI treatment.NEW & NOTEWORTHY Cutaneous microvascular vasodilatory responsiveness to serotonin was preserved in adults with major depressive disorder (MDD). However, the contribution of serotonin reuptake-dependent mechanisms to serotonin-induced dilation was reduced in MDD. Direct perfusion of the selective serotonin reuptake inhibitor (SSRI) paroxetine elicited vasodilation that is partially mediated by nitric oxide (NO)-dependent mechanisms, but these responses were blunted in MDD, reflective of a diminished contribution of NO to the direct effects of a SSRI on the cutaneous microvasculature.

Elevated temperature increases meiotic crossover frequency via the interfering (Type I) pathway in Arabidopsis thaliana.

For most eukaryotes, sexual reproduction is a fundamental process that requires meiosis. In turn, meiosis typically depends on a reciprocal exchange of DNA between each pair of homologous chromosomes, known as a crossover (CO), to ensure proper chromosome segregation. The frequency and distribution of COs are regulated by intrinsic and extrinsic environmental factors, but much more is known about the molecular mechanisms governing the former compared to the latter. Here we show that elevated temperature induces meiotic hyper-recombination in Arabidopsis thaliana and we use genetic analysis with mutants in different recombination pathways to demonstrate that the extra COs are derived from the major Type I interference sensitive pathway. We also show that heat-induced COs are not the result of an increase in DNA double-strand breaks and that the hyper-recombinant phenotype is likely specific to thermal stress rather than a more generalized stress response. Taken together, these findings provide initial mechanistic insight into how environmental cues modulate plant meiotic recombination and may also offer practical applications.

Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2

ObjectiveThe canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na+-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. MethodsTo this aim, we used PiT2 KO and DMP1Cre; PiT1lox/lox fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. ResultsIn vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. ConclusionsOur data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease.

Cyclotron Phase-Coherent Ion Spatial Dispersion in a Non-Quadratic Trapping Potential is Responsible for FT-ICR MS at the Cyclotron Frequency.

Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) at the cyclotron frequency instead of the reduced cyclotron frequency has been experimentally demonstrated using narrow aperture detection electrode (NADEL) ICR cells. Here, based on the results of SIMION simulations, we provide the initial mechanistic insights into the cyclotron frequency regime generation in FT-ICR MS. The reason for cyclotron frequency regime is found to be a new type of a collective motion of ions with a certain dispersion in the initial characteristics, such as pre-excitation ion velocities, in a highly non-quadratic trapping potential as realized in NADEL ICR cells. During ion detection, ions of the same m/z move in phase for cyclotron ion motion but out of phase for magnetron (drift) ion motion destroying signals at the fundamental and high order harmonics that comprise reduced cyclotron frequency components. After an initial magnetron motion period, ion clouds distribute into a novel type of structures - ion slabs, elliptical cylinders, or star-like structures. These structures rotate at the Larmor (half-cyclotron) frequency on a plane orthogonal to the magnetic field, inducing signals at the true cyclotron frequency on each of the narrow aperture detection electrodes. To eliminate the reduced cyclotron frequency peak upon dipolar ion detection, a number of slabs or elliptical cylinders organizing a star-like configuration are formed. In a NADEL ICR cell with quadrupolar ion detection, a single slab or an elliptical cylinder is sufficient to minimize the intensity of the reduced cyclotron frequency components, particularly the second harmonic. Graphical Abstract ᅟ.

Exploring the C^N^C theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes

A family of cyclometalated Au(III) complexes featuring a tridentate C^N^C scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(C^N^C)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules.

Potentiodynamic Chromium Deposition from Trivalent and Hexavalent Systems on Glassy Carbon Electrodes: Initial Stages and Mechanistic Insights

AbstractDeveloping a functional Cr(III) electrolyte to replace carcinogenic and toxic Cr(VI) electroplating requires a deeper understanding of the deposition mechanisms. Hence, this study investigates and compares the growth of chromium on inert glassy carbon (GC) electrodes from low‐concentration Cr(III) and Cr(VI) electrolytes, using a novel potentiodynamic deposition scheme. This allows the initial stages of deposition to be probed, which are crucial for determining the overall deposition mechanism. Scanning electron microscopy shows that, for both systems, micrometer‐sized hexagonal chromium hydride crystals could be deposited on GC, thus serving to be the first reporting of such structures. In addition, by increasing the deposition time, the changes in a particle structure for both systems were tracked; therefore, possible areas of similarity as well as key differences could be identified, which, when addressed may provide a more viable, environmentally friendly trivalent electrolyte for chromium electroplating.

Structural and functional insights into asymmetric enzymatic dehydration of alkenols.

The asymmetric dehydration of alcohols is an important process for the direct synthesis of alkenes. We report the structure and substrate specificity of the bifunctional linalool dehydratase isomerase (LinD) from the bacterium Castellaniella defragrans that catalyzes in nature the hydration of β-myrcene to linalool and the subsequent isomerization to geraniol. Enzymatic kinetic resolutions of truncated and elongated aromatic and aliphatic tertiary alcohols (C5-C15) that contain a specific signature motif demonstrate the broad substrate specificity of LinD. The three-dimensional structure of LinD from Castellaniella defragrans revealed a pentamer with active sites at the protomer interfaces. Furthermore, the structure of LinD in complex with the product geraniol provides initial mechanistic insights into this bifunctional enzyme. Site-directed mutagenesis confirmed active site amino acid residues essential for its dehydration and isomerization activity. These structural and mechanistic insights facilitate the development of hydrating catalysts, enriching the toolbox for novel bond-forming biocatalysis.

Iridium(I) Compounds as Prospective Anticancer Agents: Solution Chemistry, Antiproliferative Profiles and Protein Interactions for a Series of Iridium(I) N-Heterocyclic Carbene Complexes.

A series of structurally related mono- and bis-NHC-iridium(I) (NHC: N-heterocyclic carbene) complexes have been investigated for their suitability as potential anticancer drugs. Their spectral behaviour in aqueous buffers under physiological-like conditions and their cytotoxicity against the cancer cell lines MCF-7 and HT-29 are reported. Notably, almost all complexes exhibit significant cytotoxic effects towards both cancer cell lines. In general, the cationic bis-carbene complexes show higher stability and greater anticancer activity than their neutral mono-carbene analogues with IC50 values in the high nanomolar range. Furthermore, to gain initial mechanistic insight, the interactions of these iridium(I)-NHC complexes with two model proteins, namely lysozyme and cytochrome c, were explored by HR-ESI-MS analyses. The different protein metalation patterns of the complexes can be roughly classified into two distinct groups. Those interactions give us a first idea about the possible mechanism of action of this class of compounds. Overall, our findings show that iridium(I)-NHC complexes represent very interesting candidates for further development as new metal-based anticancer drugs.

ChemInform Abstract: Unstrained C—C Bond Activation and Directed Fluorination Through Photocatalytically‐Generated Radical Cations.

Expanding the repertoire of controlled radical fluorination techniques, we present a photosensitized unstrained C–C bond activation/directed monofluorination method using Selectfluor and 9-fluorenone. The reaction is amenable to the opening of multiple 1-acetal-2-aryl substituted rings to yield ω-fluoro carboxylic acids, esters, alcohols, and ketones with relative ease. Initial mechanistic insight suggests radical ion intermediates.

Unstrained C-C bond activation and directed fluorination through photocatalytically-generated radical cations.

Expanding the repertoire of controlled radical fluorination techniques, we present a photosensitized unstrained C-C bond activation/directed monofluorination method using Selectfluor and 9-fluorenone. The reaction is amenable to the opening of multiple 1-acetal-2-aryl substituted rings to yield ω-fluoro carboxylic acids, esters, alcohols, and ketones with relative ease. Initial mechanistic insight suggests radical ion intermediates.

Maternal diabetes mellitus and the origin of non-communicable diseases in offspring: the role of epigenetics.

Offspring of diabetic mothers are susceptible to the onset of metabolic syndromes, such as type 2 diabetes and obesity at adulthood, and this trend can be inherited between generations. Genetics cannot fully explain how the noncommunicable disease in offspring of diabetic mothers is caused and inherited by the next generations. Many studies have confirmed that epigenetics may be crucial for the detrimental effects on offspring exposed to the hyperglycemic environment. Although the adverse effects on epigenetics in offspring of diabetic mothers may be the result of the poor intrauterine environment, epigenetic modifications in oocytes of diabetic mothers are also affected. Therefore, the present review is focused on the epigenetic alterations in oocytes and embryos of diabetic mothers. Furthermore, we also discuss initial mechanistic insight on maternal diabetes mellitus causing alterations of epigenetic modifications.