Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the ...treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration-dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ranaviruses in amphibians and fish are considered emerging pathogens and several isolates have been extensively characterized in different studies. Ranaviruses have also been detected in reptiles ...with increasing frequency, but the role of reptilian hosts is still unclear and only limited sequence data has been provided. In this study, we characterized a number of ranaviruses detected in wild and captive animals in Europe based on sequence data from six genomic regions (major capsid protein (MCP), DNA polymerase (DNApol), ribonucleoside diphosphate reductase alpha and beta subunit-like proteins (RNR-α and -β), viral homolog of the alpha subunit of eukaryotic initiation factor 2, eIF-2α (vIF-2α) genes and microsatellite region). A total of ten different isolates from reptiles (tortoises, lizards, and a snake) and four ranaviruses from amphibians (anurans, urodeles) were included in the study. Furthermore, the complete genome sequences of three reptilian isolates were determined and a new PCR for rapid classification of the different variants of the genomic arrangement was developed. All ranaviruses showed slight variations on the partial nucleotide sequences from the different genomic regions (92.6-100%). Some very similar isolates could be distinguished by the size of the band from the microsatellite region. Three of the lizard isolates had a truncated vIF-2α gene; the other ranaviruses had full-length genes. In the phylogenetic analyses of concatenated sequences from different genes (3223 nt/10287 aa), the reptilian ranaviruses were often more closely related to amphibian ranaviruses than to each other, and most clustered together with previously detected ranaviruses from the same geographic region of origin. Comparative analyses show that among the closely related amphibian-like ranaviruses (ALRVs) described to date, three recently split and independently evolving distinct genetic groups can be distinguished. These findings underline the wide host range of ranaviruses and the emergence of pathogen pollution via animal trade of ectothermic vertebrates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sporotrichosis is a globally distributed subcutaneous fungal infection caused by dimorphic fungi belonging to the
species complex that affects the skin of limbs predominantly, but not exclusively. A ...rare case of ocular sporotrichosis in an immunocompetent Brazilian patient from the countryside of Rio de Janeiro State is reported. A 68-year-old woman presented with a subconjunctival infiltrative lesion in the right eye with pre-auricular lymphadenopathy of onset 4 months ago that evolved to suppurative nodular lesions on the eyelids. Conjunctival secretion was evaluated by histopathological examination and inoculated on Sabouraud Dextrose Agar (SDA). Histopathology showed oval bodies within giant cells and other mononucleated histiocytes. Fungus grown on SDA was identified as
sp. by morphological observations. The isolated strain was finally identified by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) associated with an in-house database enriched with reference
complex spectra. The strain presented a MALDI spectrum with the ion peaks of the molecular mass profile of
. The patient was adequately treated with amphotericin B subsequently replaced by itraconazole. Due to scars left by the suppurative process, the patient presented poor final visual acuity. The present work presents an overview of ocular sporotrichosis and discusses the diagnostic difficulty that can lead to visual sequelae in these cases.
Nineteen 3,5‐disubstituted‐isoxazole analogs were synthesized based on nitrofuran scaffolds, by a 3 + 2 cycloaddition reaction between terminal acetylenes and 5‐nitrofuran chloro‐oxime. The compounds ...were obtained in moderate to very good yields (45–91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p–r were active on both the promastigote and amastigote forms, with emphasis on compound 14p, which showed strong activity against the amastigote form (IC50 = 0.6 μM and selectivity index SI = 5.2). In the alkyl series, compound 14o stands out with an IC50 = 8.5 μM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron‐donor groups, such as trimethoxy isoxazole 14g (IC50 = 1.2 μM and SI = 20.2); compound 14h, with IC50 = 7.0 μM and SI = 6.1; and compound 14j containing the 4‐SCH3 group, with IC50 = 5.7 μM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration MIC = 3.4 μM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 μM for C. glabrata, lower than that of the fluconazole used as the reference drug.
Nineteen 3,5‐disubstituted isoxazole analogs were synthesized based on 5‐nitrofuran scaffolds and evaluated against the promastigote and amastigote forms of Leishmania amazonensis and against Candida species. Alkylchlorinated compounds 14p–r were active on both promastigotes and amastigotes and 11 isoxazole derivatives showed activity against C. parapsilosis.
Dimethyl fumarate (DMF) is indicated for the treatment of relapsing multiple sclerosis and may exert therapeutic effects via activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) ...pathway. Following oral DMF administration, central nervous system (CNS) tissue is predominantly exposed to monomethyl fumarate (MMF), the bioactive metabolite of DMF, which can stabilize NRF2 and induce antioxidant gene expression; however, the detailed NRF2-dependent mechanisms modulated by MMF that lead to cytoprotection are unknown. Our data identify a mechanism for MMF-mediated cytoprotection in human astrocytes that functions in an OSGIN1-dependent manner, specifically via upregulation of the OSGIN1-61 kDa isoform. NRF2-dependent OSGIN1 expression induced P53 nuclear translocation following MMF administration, leading to cell-cycle inhibition and cell protection against oxidative challenge. This study provides mechanistic insight into MMF-mediated cytoprotection via NRF2, OSGIN1, and P53 in human CNS-derived cells and contributes to our understanding of how DMF may act clinically to ameliorate pathological processes in neurodegenerative disease.
Sympathetic hyperactivation and baroreflex dysfunction are hallmarks of heart failure with reduced ejection fraction (HFrEF). However, it is unknown whether the progressive loss of phasic activity of ...sympathetic nerve bursts is associated with baroreflex dysfunction in HFrEF patients. Therefore, we investigated the association between the oscillatory pattern of muscle sympathetic nerve activity (LF
MSNA
/HF
MSNA
) and the gain and coupling of the sympathetic baroreflex function in HFrEF patients. In a sample of 139 HFrEF patients, two groups were selected according to the level of LF
MSNA
/HF
MSNA
index: (1) Lower LF
MSNA
/HF
MSNA
(lower terciles,
n
= 46, aged 53 ± 1 y) and (2) Higher LF
MSNA
/HF
MSNA
(upper terciles,
n
= 47, aged 52 ± 2 y). Heart rate (ECG), arterial pressure (oscillometric method), and muscle sympathetic nerve activity (microneurography) were recorded for 10 min in patients while resting. Spectral analysis of muscle sympathetic nerve activity was conducted to assess the LF
MSNA
/HF
MSNA
, and cross-spectral analysis between diastolic arterial pressure, and muscle sympathetic nerve activity was conducted to assess the sympathetic baroreflex function. HFrEF patients with lower LF
MSNA
/HF
MSNA
had reduced left ventricular ejection fraction (26 ± 1 vs. 29 ± 1%,
P
= 0.03), gain (0.15 ± 0.03 vs. 0.30 ± 0.04 a.u./mmHg,
P
< 0.001) and coupling of sympathetic baroreflex function (0.26 ± 0.03 vs. 0.56 ± 0.04%,
P
< 0.001) and increased muscle sympathetic nerve activity (48 ± 2 vs. 41 ± 2 bursts/min,
P
< 0.01) and heart rate (71 ± 2 vs. 61 ± 2 bpm,
P
< 0.001) compared with HFrEF patients with higher LF
MSNA
/HF
MSNA
. Further analysis showed an association between the LF
MSNA
/HF
MSNA
with coupling of sympathetic baroreflex function (
R
= 0.56,
P
< 0.001) and left ventricular ejection fraction (
R
= 0.23,
P
= 0.02). In conclusion, there is a direct association between LF
MSNA
/HF
MSNA
and sympathetic baroreflex function and muscle sympathetic nerve activity in HFrEF patients. This finding has clinical implications, because left ventricular ejection fraction is less in the HFrEF patients with lower LF
MSNA
/HF
MSNA
.
Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis ...intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.
In all synapses, Ca2+ triggers neurotransmitter release to initiate signal transmission. Ca2+ presumably acts by activating synaptic Ca2+ sensors, but the nature of these sensors--which are the ...gatekeepers to neurotransmission--remains unclear. One of the candidate Ca2+ sensors in release is the synaptic Ca2+-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca2+ affinity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca2+ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Organosulfur compounds show cytotoxic potential towards many tumor cell lines. Disulfides and thiosulfonates act through apoptotic processes, inducing proteins associated with apoptosis, endoplasmic ...reticulum stress, and the unfolded protein response. Three p‐substituted symmetric diaryl disulfides and three diaryl thiosulfonates were synthesized and analyzed for inhibition of tubulin polymerization and for human cancer cell cytotoxic activity against seven tumor cell lines and a non‐tumor cell line. S‐(4‐methoxyphenyl)‐4‐methoxybenzenesulfonothioate (6) exhibited inhibition of tubulin polymerization and showed the best antiproliferative potential, especially against the 786‐0 cell line, being six times more selective as compared with the non‐tumor cell line. In addition, compound 6 was able to activate caspase‐3 after 24 and 48 h treatments of the 786‐0 cell line and induced cell‐cycle arrest in the G2/M stage at the highest concentration evaluated at 24 and 48 h. Compound 6 was able to cause complete inhibition of proliferation, inducing the death of 786‐0 cells, by increasing the number of cells at G2/M and greater activation of caspase‐3.
Repurposing a diaryl thiosulfonate: S‐(4‐methoxyphenyl)‐4‐methoxybenzenesulfonothioate (6) exhibited antitubulin activity. Compound 6 showed antiproliferative activity against the 786‐0 cell line, induces morphological alterations and death in 786‐0 cells, activates caspase‐3, and induces G2/M phase cell‐cycle arrest in 786‐0 cells.
Cytotoxic Orbitide from the Latex of Croton urucurana Cândido-Bacani, Priscila de M; Figueiredo, Patrícia de O; Matos, Maria de F. C ...
Journal of natural products (Washington, D.C.),
11/2015, Letnik:
78, Številka:
11
Journal Article
Recenzirano
The bioactive ethyl acetate phase obtained from the latex of Croton urucurana Baillon afforded a novel orbitide (1), 1–9-NαC-crourorb A1, that proved active against NCI-ADR/RES (ovary, ...multidrug-resistance phenotype) cells with the same potency as doxorubicin (positive control) and inactive up to the highest concentration tested against nontumor NIH/3T3 cells. The structure elucidation was based on 1D and 2D NMR spectroscopy, further supported by HRESIMS data and by application of Marfey’s method for determination of the absolute configuration of its amino acid residues. This is the first orbitide obtained from C. urucurana.
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