Palladium‐Catalyzed Decarbonylative Dehydration of Fatty Acids for the Production of Linear Alpha Olefins

A highly efficient palladium‐catalyzed decarbonylative dehydration reaction of carboxylic acids is reported. This method transforms abundant and renewable even‐numbered natural fatty acids into valuable and expensive odd‐numbered alpha olefins. Additionally, the chemistry displays a high functional group tolerance. The process employs a low loading of palladium catalyst and proceeds under solvent‐free and relatively mild conditions.

     

Gold nanorods with a hematoporphyrin-loaded silica shell for dual-modality photodynamic and photothermal treatment of tumors in vivo

Nanocomposites （NCs） consisting of a gold nanorod core and a mesoporous silica shell doped with hematoporphyrin （HP） have been fabricated in order to improve the efficiency of cancer treatment by combining photothermal and photodynamic therapies （PDT ＋ PTT） in vivo. In addition to the long-wavelength plasmon resonance near 810-830 nm, the fabricated NCs exhibited a 400-nm absorbance peak corresponding to bound HP, generated singlet oxygen under 633-nm excitation near the 632.5-nm Q-band, and produced heat under a 808-nm near-infrared （NIR） laser irradiation. These modalities were used for a combined PDT ＋ PTT treatment of large （about 3 cm3） solid tumors in vivo with a xenorafted tumor rat model. NCs were directly injected into tumors and irradiated simultaneously with 633-nm and 808-nm lasers to stimulate the combined photodynamic and photothermal activities of NCs. The efficiency of the combined therapy was evaluated by optical coherence tomography, histological analysis, and by measurements of the tumor volume growth during a 21-day period. The NC-mediated PDT led to weak changes in tissue histology and to a moderate 20% decrease in the tumor volume. In contrast, the combined PDT ＋ PTT treatment resulted in the large-area tumor necrosis and led to dramatic decrease in the tumor volume.     

4‐Cyanoresorcinol‐Based Bent‐Core Mesogens with Azobenzene Wings: Emergence of Sterically Stabilized Polar Order in Liquid Crystalline Phases

A new series of azobenzene containing bent‐core molecules incorporating 4‐cyanoresorcinol as the central core unit exhibiting cybotactic nematic, rectangular, columnar, and different types of tilted smectic (SmC) phases are synthesized. The mesophase behavior and phase structures are characterized in bulk and freely suspended films using a variety of experimental techniques. Depending on the chain length and temperature a series of different mesophases is observed in these compounds, ranging from cybotactic nematic via paraelectric SmC phases, polarization randomized SmC_sP_R phases to ferroelectric and antiferroelectric SmC phases, associated with increasing size and correlation length of the polar domains. Spontaneous formation of chiral domains is observed in the paraelectric SmC and the SmC_sP_R phases and discussed in relation with superstructural chirality, bend elastic constants, and surface effects.     

Probing Red Blood Cell Membrane Microviscosity Using Fluorescence Anisotropy Decay Curves of the Lipophilic Dye PKH26

Red blood cell (RBC) aggregation and deformation are governed by the molecular processes occurring on the membrane. Since several social important diseases are accompanied by alterations in RBC aggregation and deformability, it is important to develop a diagnostic parameter of RBC membrane structural integrity and stability. In this work, we propose membrane microviscosity assessed by time-resolved fluorescence anisotropy of the lipophilic PKH26 fluorescent probe as a diagnostic parameter. We measured the fluorescence decay curves of the PKH26 probe in the RBC membrane to establish the optimal parameters of the developed fluorescence assay. We observed a complex biphasic profile of the fluorescence anisotropy decay characterized by two correlation times corresponding to the rotational diffusion of free PKH26, and membrane-bounded molecules of the probe. The developed assay allowed us to estimate membrane microviscosity ηm in the range of 100–500 cP depending on the temperature, which paves the way for assessing RBC membrane properties in clinical applications as predictors of blood microrheological abnormalities.     

Specific S100 Proteins Bind Tumor Necrosis Factor and Inhibit Its Activity

Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here, we report that among eighteen representatives of the multifunctional S100 protein family, only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (K_d) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent K_d values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1–0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatics analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect the efficacy of anti-TNF treatment in various diseases.     

The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca²⁺ stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation.     

Isolating Linum usitatissimum L. Nuclear DNA Enabled Assembling High-Quality Genome

High-quality genome sequences help to elucidate the genetic basis of numerous biological processes and track species evolution. For flax (Linum usitatissimum L.)—a multifunctional crop, high-quality assemblies from Oxford Nanopore Technologies (ONT) data were unavailable, largely due to the difficulty of isolating pure high-molecular-weight DNA. This article proposes a scheme for gaining a contiguous L. usitatissimum assembly using Nanopore data. We developed a protocol for flax nuclei isolation with subsequent DNA extraction, which allows obtaining about 5 μg of pure high-molecular-weight DNA from 0.5 g of leaves. Such an amount of material can be collected even from a single plant and yields more than 30 Gb of ONT data in two MinION runs. We performed a comparative analysis of different genome assemblers and polishers on the gained data and obtained the final 447.1-Mb assembly of L. usitatissimum line 3896 genome using the Canu—Racon (two iterations)—Medaka combination. The genome comprised 1695 contigs and had an N50 of 6.2 Mb and a completeness of 93.8% of BUSCOs from eudicots_odb10. Our study highlights the impact of the chosen genome construction strategy on the resulting assembly parameters and its eligibility for future genomic studies.     

Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease

The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects.     

Regulation of the Key Epithelial Cancer Suppressor miR-124 Function by Competing Endogenous RNAs

A decrease in the miR-124 expression was observed in various epithelial cancers. Like a classical suppressor, miR-124 can inhibit the translation of multiple oncogenic proteins. Epigenetic mechanisms play a significant role in the regulation of miR-124 expression and involve hypermethylation of the MIR-124-1/-2/-3 genes and the effects of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) according to the model of competing endogenous RNAs (ceRNAs). More than 40 interactomes (lncRNA/miR-124/mRNA) based on competition between lncRNAs and mRNAs for miR-124 binding have been identified in various epithelial cancers. LncRNAs MALAT1, NEAT1, HOXA11-AS, and XIST are the most represented in these axes. Fourteen axes (e.g., SND1-IT1/miR-124/COL4A1) are involved in EMT and/or metastasis. Moreover, eight axes (e.g., OIP5-AS1/miR-124-5p/IDH2) are involved in key pathways, such as Wnt/b-catenin, E2F1, TGF-β, SMAD, ERK/MAPK, HIF-1α, Notch, PI3K/Akt signaling, and cancer cell stemness. Additionally, 15 axes impaired patient survival and three axes reduced chemo- or radiosensitivity. To date, 14 cases of miR-124 regulation by circRNAs have been identified. Half of them involve circHIPK3, which belongs to the exonic ecircRNAs and stimulates cell proliferation, EMT, autophagy, angiogenesis, and multidrug resistance. Thus, miR-124 and its interacting partners may be considered promising targets for cancer therapy.     

Photoprocesses in Derivatives of 1,4- and 1,3-Diazadistyryldibenzenes

Photoprocesses in 1,4-diazadistyrylbenzene (1) and 1,3-diazadistyrylbenzene derivative (2) diperchlorates in MeCN were studied by absorption, luminescence, and kinetic laser spectroscopies. For compound 1, trans-cis-photoisomerization and intersystem crossing to a triplet state are observed. For compound 2, photoelectrocyclization is suggested. Quantum chemical calculations of diazadistyrylbenzene structures in the ground and excited states were carried out. The schemes for photoreactions were proposed.