Brachio-cervical inflammatory myopathy associated with systemic sclerosis. Case series and review of literature.

This study was aimed at describing a case series of brachio-cervical inflammatory myopathy (BCIM) associated with systemic sclerosis (SSc), due to its rarity and limited coverage in published data. Another aim was to provide a literature review. We reported four cases of BCIM-SSc from our tertiary center. In addition, we researched the literature and found six articles featuring 17 patients who fit this phenotype. We pooled all cases and reported their features. Most patients were female and had limited SSc, and the median time of BCIM presentation was three years after SSc diagnosis. Asymmetric muscle involvement, scapular winging, dropped head, axial weakness, camptocormia, dysphagia, and dermatomyositis stigmas were common features. All patients had esophageal involvement. Most had positive antinuclear antibody results, a scleroderma pattern in their capillaroscopy images, elevated serum creatine phosphokinase, myopathic electrophysiology, and muscle involvement in magnetic resonance imaging. Muscle histopathological findings varied widely, but in general all showed the presence of lymphoid infiltrates, muscle atrophy, increased MHC-I expression, MAC deposits, vasculopathy, and muscle fiber necrosis. The response to immunosuppressive therapy was highly irregular. BCIM-SSc is a rare disorder that shares many similar phenotypes among the described cases, but has a highly heterogeneous response to treatment. At present, more data on the physiopathology, clinical features, and treatment is still needed.

A 1000-year-old mystery solved: Unlocking the molecular structure for the medieval blue from Chrozophora tinctoria, also known as folium.

The molecular structure of the medieval watercolor known as folium has finally been solved in the 21st century. The interdisciplinary approach taken was the key to producing extracts that had been prepared following medieval instructions, and shows the blue/purple chromophore as the major dye in Chrozophora tinctoria fruits (shell). A multi-analytical characterization of its structure was made using HPLC-DAD-MS, GC-MS, NMR (1H, 13C, COSY, HSQC, HMBC, INADEQUATE), and computational studies. The results demonstrate that the blue compound corresponds to 6'-hydroxy-4,4'-dimethoxy-1,1'-dimethyl-5'-{[3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-[3,3'-bipyridine]-2,2',5,6(1H,1'H)-tetraone, a hermidin derivative, which we named chrozophoridin. Experimental data and computational modeling studies show that this mono-glycosylated dimer is represented by two stable isomers (atropisomers). This is an indispensable piece of knowledge for the characterization of this medieval dye in works of art such as medieval manuscript illuminations and for testing its stability and contributes to the preservation of our cultural heritage.

Photosensitisation by voriconazole-N-oxide results from a sequence of solvent and pH-dependent photochemical and thermal reactions.

The phototoxicity of voriconazole (VN) prescribed in the treatment of severe fungal infections is frequently reported. Its major metabolite, a N-oxide derivative (VNO), was suspected to be the photosensitizer because it shows a maximum absorbance at ~310 nm in aqueous solutions. It was reported that the VNO photoproduct (VNOP) was phototoxic to human keratinocytes. Steady state and laser flash photolyses were performed to shed light on the phototoxic properties of VNO and VNOP. The quantum yield of the VNOP production by UVB-UVA light in buffered or alcoholic solutions is 0.6. VNOP has been identified as (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-7-oxa-1,3-diazabicyclo[4.1.0]hepta-2,4-dien-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. VNOP undergoes a marked thermal degradation and an efficient UVA photolysis with well differentiated kinetics and end-products. The temperature-dependent VNOP dark degradation produces a single product VNOPD identified as 6-[(2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-5-fluoropyrimidin-4-ol with absorbance maximum at 308 nm and ε = 2700 M-1 cm-1. Under UVB-UVA irradiation, VNOPD, the stable end-product, is a remarkable photodynamic photosensitizer towards Trp and His. The Trp photo-oxidation (Φox(Trp) = 0.13) mainly involves type I radical reactions whereas His is oxidized by 1O2 (Φox(His) = 0.012). These results force us to question the validity of the in vitro photosensitization of human keratinocytes by VNO and VNOP previously reported.

Endogenous Factors in the Recovery of Reproductive Function After Testicular Injury and Cancer.

The testes are one of the most delicate organs in the male body and highly susceptible to the exogenous influences capable of inducing cell damage. Cancer therapies are well known to negatively affect the male reproductive tract with a severe impairment of spermatogenesis and infertility. The present work aimed to systematically review the available information about the different endogenous factors (hormonal and nonhormonal) that may have protective or advantageous properties on the recovery of male reproductive function after gonadal injury. Furthermore, the perspective that these endogenous molecules could act as cryoprotectants to improve the quality of cryopreserved semen samples was also discussed. The knowledge reviewed herein allowed to identify promising factors able to mitigate the male fertility problems arising either from oncological treatments or other gonadal damage, and opened new possibilities to ameliorate the recovery of spermatogenesis or to preserve fertility.

A molecular insight into the phototoxic reactions observed with vemurafenib, a first-line drug against metastatic melanoma.

The electronic properties of vemurafenib (VB) provide a rational basis for understanding its strong UVA-induced phototoxicity. Thus, solvation of hydrophobic VB by hydrogen bonding solvents controls its photophysical, photochemical and photosensitizing properties. Addition of phosphate buffered saline (PBS) to methanol (MeOH) induces a bathochromic shift of the VB absorbance spectrum and a fluorescence emission (λmax = 450 nm, quantum yield (Φ) = 0.011). Phosphorescence (λmax = 461 nm) is observed at 77 K in MeOH. 308 nm laser flash spectroscopy demonstrates that the lifetimes (τ) and quantum yields of the VB triplet state ((3)T(*)(1)) in deaerated MeOH (τMeOH = 0.41 µs, λmax ∼ 380 nm), MeOH-PBS and HSA solutions markedly depend on the microenvironment. A long-lived radical (half-life >200 µs) is also formed. The state (3)T(*)(1) is quenched by O2 and electron donors (Cys and 2'-deoxyguanosine) at a rate constant >1 × 10(9) M(-1) s(-1). UVA-irradiation of VB in air-saturated MeOH or MeOH-PBS solutions produces a UVA-absorbing photoproduct (Φ âˆ¼ 5 × 10(-4)). VB photosensitizes Trp destruction by type I (radical formation) and type II (singlet oxygen ((1)O2) formation) photodynamic reactions (Φ = 0.005). Singlet oxygen production is further demonstrated by the VB-photosensitized His oxidation (ΦMeOH = 0.006).

Facile synthesis of oxo-/thioxopyrimidines and tetrazoles C-C linked to sugars as novel non-toxic antioxidant acetylcholinesterase inhibitors.

Microwave-assisted synthesis of oxo-/thioxopyrimidines and tetrazoles linked to furanoses with D-xylo and D-ribo configuration, and to a D-galacto pyranose is reported and compared to conventional methods. Reaction of dialdofuranoses and dialdopyranoses with a ß-keto ester and urea or thiourea under microwave irradiation at 300 W gave in 10 min the target molecules containing the 2-oxo- or 2-thioxo-pyrimidine ring in high yield. The tetrazole-derived compounds were obtained in two steps by reaction of the formyl group with hydroxylamine hydrochloride, copper sulfate, triethylamine and dicyclohexylcarbodiimide to give an intermediate nitrile, which was then treated with sodium azide. The use of microwave irradiation in the latter step also resulted in a considerably shorter reaction time (10 min) compared to hours under conventional heating to obtain a complete starting materials conversion. Acetylcholinesterase inhibition ranged from 20% to 80% for compounds concentration of 100 µg/mL, demonstrating the potential of this family of compounds for the control of Alzheimer's disease symptoms. Most of the compounds showed antioxidant activity in the ß-carotene/linoleic acid assay, some of them exhibiting IC(50) values in the same order of magnitude as those of gallic acid. The bioactive compounds did not show cytotoxic effects to human lymphocytes using the MTT method adapted for non-adherent cells, nor genotoxicity determined by the short-term in vitro chromosomal aberration assay.

The chemical composition of hexane extract from bark of Juniperus brevifolia.

The phytochemical analysis of the bark of Juniperus brevifolia was undertaken for the first time. The GC-MS analysis of the hexane extract from bark of "cedro-do-mato" (J. brevifolia) allowed to identify three rare compounds for the first time in Juniperus genus: 6,7-dehydroferrugin-12-methyl ether, 11-hydroxy-6,7-dehydroferruginol and 6,7-dehydrohinokiol. The results also showed that the chemical composition of the extract were essentially abietane-type diterpenoids with alcohol function (44.9%) and with carbonyl function (8.6%). Fatty acids such palmitic, oleic, stearic and docosanoic acids were the second most abundant family of identified compounds (9.5%) and its value increased (12.7%) after alkaline hydrolysis, mainly due to docosanoic and tetradocosanoic acids. Sterols like sitosterol and stigmast-4-en-3-one, were also present (6.6%), along with esters of sterols (8.4%). Significant quantities of the long-chain aliphatic alcohols (ca 3.7%) were identified in the hexane extract only after alkaline hydrolysis.

Structure elucidation of xanthone derivatives: studies of nuclear magnetic resonance spectroscopy.

1H and 13C NMR spectra remain the first tool used by chemists to perform the structure elucidation of their products on a routine basis. It is common to provide NMR data on both proton and carbon spectra based on one-dimensional experiments, but often only proton resonances are assigned. The increasing complexity of natural compounds and their synthetic related derivatives imply the use of some more recent 1D and 2D NMR techniques. The purpose of this review is to describe the main NMR features of the most common and important classes of xanthones and also to discuss the application of several 1D and 2D NMR techniques in the structure elucidation of these compounds. A brief discussion of these NMR techniques from the point of view of structure elucidation of organic compounds will also be considered. The calculated NMR chemical shifts in the structure elucidation of xanthones and the use of NMR to study their mode of action in biological activities will be also described.

Study of the behaviour of amino acids in aqueous solution by time-domain NMR and high-resolution NMR.

The study of protein hydration by time-domain NMR is complicated by the great number of interactions involved, resulting from the presence of several amino acids and the possible modifications produced by the various structures. Moreover, a good comprehension of the molecular interactions of the simple amino acids in solution is essential to elucidate the mechanism of the biological functions of proteins. Measurements of transverse relaxation rates of the protons of water (R(2) = 1/T(2)) in aqueous solutions of amino acids such as L-glycine, L-asparagine, L-arginine and L-tryptophan were carried out in order to study the effects of chemical exchange and molecular diffusion on the amplitude of R(2). The values of R(2) measured by the Carr-Purcell-Meiboom-Gill (CPMG) sequence were studied while varying the solution pH and the parameters of the CPMG sequence. The dependence of R(2) on pH and tau (inter-pulse delay between the first and the second pulses of the CPMG sequence) is interpreted in terms of chemical exchange between the protons of water and those of the labile amino acid groups. This interpretation was confirmed by the analysis of the proton spectra acquired using a 300 MHz NMR spectrometer.

Electrochemical and spectroscopic studies of the oxidation mechanism of the herbicide propanil.

Electrochemical oxidation of propanil in deuterated solutions was studied by cyclic, differential pulse, and square wave voltammetry using a glassy carbon microelectrode. The oxidation of propanil in deuterated acid solutions occurs at the nitrogen atom of the amide at a potential of +1.15 V vs Ag/AgCl. It was also found that, under the experimental conditions used, protonation at the oxygen atom of propanil occurs, leading to the appearance of another species in solution which oxidizes at +0.60 V. The anodic peak found at +0.79 V vs Ag/AgCl in deuterated basic solutions is related to the presence of an anionic species in which a negative charge is on the nitrogen atom. The electrochemical data were confirmed by the identification of all the species formed in acidic and basic deuterated solutions by means of NMR spectroscopy. The results are supported by electrochemical and spectroscopic studies of acetanilide in deuterated solutions.