Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-κB p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED.Subject terms: Biological therapy, Cytokines, Recombinant protein therapy, Extracellular signalling molecules     

Ultrasensitive Detection of Cu(II) and Pb(II) Using a Water-Soluble Perylene Probe

The selective detection of metal ions in water, using sustainable detection systems, is of crescent importance for monitoring water environments and drinking water safety. One of the key elements of future chemical sciences is the use of sustainable approaches in the design of new materials. In this study, we design and synthesize a low-cost, water-soluble potassium salt of 3,4,9,10-perylene tetracarboxylic acid (PTAS), which shows a selective optical response on the addition of Cu²⁺ and Pb²⁺ ions in aqueous solutions. By using a water-soluble chromophore, the interactions with the metal ions are definitely more intimate and efficient, with respect to standard methods employing cosolvents. The detection limits of PTAS for both Cu²⁺ and Pb²⁺ are found to be 2 µM by using a simple absorbance mode, and even lower (1 μM) with NMR experiments, indicating that this analyte–probe system is sensitive enough for the detection of copper ions in drinking water and lead ions in waste water. The complexation of PTAS with both ions is supported with NMR studies, which reveal the formation of new species between PTAS and analytes. By combining a low-cost water-soluble chromophore with efficient analyte–probe interactions due to the use of aqueous solutions, the results here obtained provide a basis for designing sustainable sensing systems.     

Effect of Culture Conditions on Fatty Acid Profiles of Bacteria and Lipopolysaccharides of the Genus Pseudomonas—GC-MS Analysis on Ionic Liquid-Based Column

The profiling of bacterial fatty acids is a well-established technique in identifying and classifying bacteria. Cultivation conditions may affect the biosynthesis, thereby, changing the fatty acid profile in bacteria. The effect of the culture conditions on the fatty acid components of Pseudomonas aeruginosa PAO1, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa polyresistant and Pseudomonas putida all are aligned to the genus Pseudomonas. The fatty acids in the lipopolysaccharides of Pseudomonas aeruginosa PAO1 were also examined. The effects of the cultivation conditions were followed by using agar and blood agar media at the characteristic temperatures, 25 °C, 37 °C and 42 °C, respectively, and an analysis was made during the 1st, 3rd and 5th day following inoculation. In addition to quantitative differences, we also experienced qualitative differences in the fatty acid profiles which detect newly appearing fatty acids, due to changes in environmental factors. The application of ionic liquid-based column unveils new possibilities for the analyses of fatty acids in GC-MS experiments for bacterial fatty acid profiling. The validation results (response linearity, limit of detection, limit of quantification, system suitability, intraday and interday repeatability and accuracy) show the high separation efficiency of the ionic liquid-based column in the analyses.     

Global Analysis of Plasmodium falciparum Dihydropteroate Synthase Variants Associated with Sulfadoxine Resistance Reveals Variant Distribution and Mechanisms of Resistance: A Computational-Based Study

The continual rise in sulfadoxine (SDX) resistance affects the therapeutic efficacy of sulfadoxine-pyrimethamine; therefore, careful monitoring will help guide its prolonged usage. Mutations in Plasmodium falciparum dihydropteroate synthase (Pfdhps) are being surveilled, based on their link with SDX resistance. However, there is a lack of continuous analyses and data on the potential effect of molecular markers on the Pfdhps structure and function. This study explored single-nucleotide polymorphisms (SNPs) in Pfdhps that were isolated in Africa and other countries, highlighting the regional distribution and its link with structure. In total, 6336 genomic sequences from 13 countries were subjected to SNPs, haplotypes, and structure-based analyses. The SNP analysis revealed that the key SDX resistance marker, A437G, was nearing fixation in all countries, peaking in Malawi. The mutation A613S was rare except in isolates from the Democratic Republic of Congo and Malawi. Molecular docking revealed a general loss of interactions when comparing mutant proteins to the wild-type protein. During MD simulations, SDX was released from the active site in mutants A581G and A613S before the end of run-time, whereas an unstable binding of SDX to mutant A613S and haplotype A437A/A581G/A613S was observed. Conformational changes in mutant A581G and the haplotypes A581G/A613S, A437G/A581G, and A437G/A581G/A613S were seen. The radius of gyration revealed an unfolding behavior for the A613S, K540E/A581G, and A437G/A581G systems. Overall, tracking such mutations by the continuous analysis of Pfdhps SNPs is encouraged. SNPs on the Pfdhps structure may cause protein–drug function loss, which could affect the applicability of SDX in preventing malaria in pregnant women and children.     

Decrypting the Potential of Nanotechnology-Based Approaches as Cutting-Edge for Management of Hyperpigmentation Disorder

The abundant synthesis and accretion of melanin inside skin can be caused by activation of melanogenic enzymes or increase in number of melanocytes. Melasma is defined as hyperpigmented bright or dark brown spots which are symmetrically distributed and have serrated and irregular borders. The three general categories of pigmentation pattern include centro facial pattern, malar pattern, and mandibular pattern. Exposure to UV rays, heat, use of cosmetics and photosensitizing drugs, female sex hormonal therapies, aberrant production of melanocyte stimulating hormone, and increasing aesthetic demands are factors which cause the development of melasma disease. This review gives a brief overview regarding the Fitzpatrick skin phototype classification system, life cycle of melanin, mechanism of action of anti-hyperpigmenting drugs, and existing pharmacotherapy strategies for the treatment of melasma. The objectives of this review are focused on role of cutting-edge nanotechnology-based strategies, such as lipid-based nanocarriers, i.e., lipid nanoparticles, microemulsions, nanoemulsions, liposomes, ethosomes, niosomes, transfersomes, aspasomes, invasomes penetration-enhancing vesicles; inorganic nanocarriers, i.e., gold nanoparticles and fullerenes; and polymer-based nanocarriers i.e., polymeric nanoparticles, polymerosomes, and polymeric micelles for the management of hyperpigmentation.     

Synthesis,Structure and Cytotoxic Properties of Copper(II) Complexes of 2-Iminocoumarins Bearing a 1,3,5-Triazine or Benzoxazole/Benzothiazole Moiety

A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC₅₀ values ranging from 0.04 μM to 15.66 μM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7′ of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7′ of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.     

Fluorescent Imidazo[1,2-a]pyrimidine Compounds as Biocompatible Organic Photosensitizers that Generate Singlet Oxygen: A Potential Tool for Phototheranostics

Photodynamic therapy has been used to treat a variety of diseases, however, there is continuing search for new biocompatible photosensitizers. Herein, we demonstrate for the first time that imidazo[1,2-a]pyrimidine compounds are able to generate singlet oxygen species and can act as photosensitizers in the intracellular environment. Our results show that this class of compounds absorb and emit in the 400–500 nm region, present low cytotoxicity in the dark, are efficiently uptaken by cells, are fluorescent in intracellular medium, and generate singlet oxygen upon irradiation, killing cancer cells within 2 h at low concentration (2.0 μm ). The imidazo[1,2-a]pyrimidine compounds are a potential new tool for phototheranostics, because they can be simultaneously used for fluorescence imaging and photodynamic therapy.     

Aroma Profile and Chemical Composition of Reverse Osmosis and Nanofiltration Concentrates of Red Wine Cabernet Sauvignon

Wine aroma represents one of the main properties that determines the consumer acceptance of the wine. It is different for each wine variety and depends on a large number of various chemical compounds. The aim of this study was to prepare red wine concentrates with enriched aroma compounds and chemical composition. For that purpose, Cabernet Sauvignon red wine variety was concentrated by reverse osmosis (RO) and nanofiltration (NF) processes under different operating conditions. Different pressures (2.5, 3.5, 4.5 and 5.5 MPa) and temperature regimes (with and without cooling) were applied on Alfa Laval LabUnit M20 equipped with six composite polyamide RO98pHt M20 or NF M20 membranes. Higher pressure increased the retention of sugars, SO₂, total and volatile acids and ethanol, but the temperature increment had opposite effect. Both membranes were permeable for water, ethanol, acetic acid, 4-ethylphenol and 4-ethylguaiacol and their concentration decreased after wine filtration. RO98pHt membranes retained higher concentrations of total aroma compounds than NF membranes, but both processes, reverse osmosis and nanofiltration, resulted in retentates with different aroma profiles comparing to the initial wine. The retention of individual compounds depended on several factors (chemical structure, stability, polarity, applied processing parameters, etc.).     

Metabolomic Study of Heterotrophically Grown Chlorella sp. Isolated from Wastewater in Northern Sweden

There are numerous strains of Chlorella with a corresponding variety of metabolic pathways. A strain we previously isolated from wastewater in northern Sweden can grow heterotrophically as well as autotrophically in light and has higher lipid contents under heterotrophic growth conditions. The aims of the present study were to characterize metabolic changes associated with the higher lipid contents in order to enhance our understanding of lipid production in microalgae and potentially identify new compounds with utility in sustainable development. Inter alia, the amino acids glutamine and lysine were 7-fold more abundant under heterotrophic conditions, the key metabolic intermediate alpha-ketoglutarate was more abundant under heterotrophic conditions with glucose, and maltose was more abundant under heterotrophic conditions with glycerol than under autotrophic conditions. The metabolite 3-hydroxy-butyric acid, the direct precursor of the biodegradable plastic PHB (poly-3-hydroxy-butyric acid), was also more abundant under heterotrophic conditions. Our metabolomic analysis has provided new insights into the alga’s lipid production pathways and identified metabolites with potential use in sustainable development, such as the production of renewable, biodegradable plastics, cosmetics, and nutraceuticals, with reduced pollution and improvements in both ecological and human health.     

Revealing the Origin of Transition-Metal Migration in Layered Sodium-Ion Battery Cathodes: Random Na Extraction and Na-Free Layer Formation

Cation migration often occurs in layered oxide cathodes of lithium-ion batteries due to the similar ion radius of Li and transition metals (TMs). Although Na and TM show a big difference of ion radius, TMs in layered cathodes of sodium-ion batteries (SIBs) can still migrate to Na layer, leading to serious electrochemical degeneration. To elucidate the origin of TM migration in layered SIB cathodes, we choose NaCrO₂, a typical layered cathode suffering from serious TM migration, as a model material and find that the TM migration is derived from the random desodiation and subsequent formation of Na-free layer at high charge potential. A Ru/Ti co-doping strategy is developed to address the issue, where the doped active Ru is first oxidized to create a selective desodiation and the doped inactive Ti can function as a pillar to avoid complete desodiation in Ru-contained TM layers, leading to the suppression of the Na-free layer formation and subsequent enhanced electrochemical performance.