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1.
J Anim Physiol Anim Nutr (Berl) ; 108(4): 1152-1163, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38602249

RESUMO

As sturgeon breeding has proliferated, there has been a heightened demand for growth stimulators in their diets. This study aimed to determine the impact of dietary chitosan on growth performance, whole-body proximate composition, growth-related gene expression, and intestinal histology in juvenile Acipenser stellatus. A total of 180 A. stellatus juveniles with an average weight of 31.90 ± 0.73 g were fed with diets containing 0 (control), 1.5, 3.0, 4.5, and 6.0 g chitosan.kg-1 basic diet for eight weeks. The findings revealed a significant enhancement in growth performance with rising chitosan concentrations. Furthermore, chitosan supplementation upregulated the expression of the growth hormone gene in both brain and liver tissues. In liver samples, the most pronounced expression of the insulin-like growth factor-1 gene was noted at 6.0 g chitosan.kg-1, while in brain samples, peak expressions were observed in both the 4.5 and 6.0 g chitosan.kg-1 treatments. While the whole-body proximate composition remained relatively stable, there was a notable decrease in whole-body lipids with the escalation of chitosan dosage. Intestinal villi dimensions, both height and width, were amplified in the chitosan-supplemented groups compared to controls. In summation, chitosan supplementation showed promise in bolstering growth performance, refining intestinal morphology, and enhancing growth-related gene expression. Analysis of the polynomial regression of weight gain and specific growth rate revealed that the optimum dietary chitosan requirements in A. stellatus were 5.32 and 5.21 g chitosan.kg-1, respectively.


Assuntos
Ração Animal , Quitosana , Dieta , Peixes , Regulação da Expressão Gênica , Intestinos , Animais , Quitosana/farmacologia , Quitosana/administração & dosagem , Ração Animal/análise , Peixes/crescimento & desenvolvimento , Dieta/veterinária , Intestinos/efeitos dos fármacos , Intestinos/anatomia & histologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal , Suplementos Nutricionais
2.
Cancer Invest ; : 1-8, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36601856

RESUMO

OBJECTIVE: To evaluate the diagnostic mismatch (discrepancy) of pathology reports in consulted specimens referred for second opinion. MATERIALS AND METHODS: This cross-sectional study was conducted at a major cancer center, Omid Hospital. In this study, 350 primary pathology reports and 350 reviewed pathology reports were extracted from the archives of Omid Hospital from 2011 to 2020 and assessed in terms of the extent of discrepancy, by two pathologists and one oncologist. The required data for each sample were entered into a checklist and then statistically analyzed. Cases with the same diagnosis on both reports were assigned to the matched group and the rest were assigned to the minor or major mismatch (discrepancy) group. Minor mismatches included changes in diagnosis that did not lead to changes in treatment (may lead to changes in prognosis or provide additional information to the oncologist) and major mismatches included changes in diagnosis leading to changes in treatment or remedies. RESULTS: Two hundred seven cases (59.1%) out of three hundred fifty cases had concordant results between the diagnosis of the first pathologist and the reviewing pathologist. In one hundred forty-three cases (40.9%) mismatch (discrepancy) was observed, including eighty- two cases (23.4%) with minor mismatches (discrepancy) and sixty-one cases (17.4%) with major mismatches (discrepancy). In the major mismatch group, fifteen cases (4.3%) changed from malignant to benign, eighteen cases (5.1%) changed from benign to malignant, two cases (0.6%) changed from one stage to another stage of Disease and twenty-six cases (7.4%) had changes in the type of malignancy. In this study, it was found that there was no significant relationship between anatomical areas of sampling and diagnostic mismatch (p = 0.254). The study also found that the rate of diagnostic mismatch in specimens obtained by resection or excisional biopsy was greater than that of small biopsies (eighty cases (22.8%) and sixty-two cases (17.7%, respectively)). There was no significant relationship in this regard (p = 0.077). CONCLUSION: Compared to most similar studies, the present study reported the highest discrepancy between the diagnosis of the first pathologist and the reviewing pathologist (40.9%).

3.
Bioorg Med Chem ; 49: 116397, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34619406

RESUMO

Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Linezolida/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Linezolida/síntese química , Linezolida/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
4.
Phytother Res ; 35(6): 3365-3376, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33624311

RESUMO

Morus nigra is a rich source of anthocyanins, phytochemicals that have anticancer effects. This study aimed to investigate the effects of M. nigra extract (MNE) on diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC). Male Sprague-Dawley rats were assigned into four groups (n = 10): control, DEN, and DEN +100 or 400 mg/kg of MNE. After 4 months, the DEN group showed a significant mortality rate, hepatic lipid peroxidation, dysplastic nodules in the cirrhotic liver, and an increase of blood bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Also, the body weight gain, blood albumin and glucose, liver antioxidant capacity (thiol groups), and some hematological parameters (RBC, hematocrit, hemoglobin, and platelet) were significantly decreased in the DEN group. MNE significantly increased survival, reduced the size of HCC nodules, improved liver oxidant/antioxidant status, and prevented the above-mentioned changes in the blood (except ALP, glucose, and platelet). Quantitative real-time PCR showed that MNE decreased the expression of Wnt4 and ß-catenin, while had no significant effect on PI3K, Akt, and PTEN expression. The MNE did not exhibit antiproliferative activity against HepG2 liver cancer cells. In conclusion, MNE exhibits a hepatoprotective effect through inhibiting oxidative stress and Wnt4/ß-catenin pathway and therefore prolongs the survival of rats with HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Morus/química , Extratos Vegetais/farmacologia , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/efeitos adversos , Células Hep G2 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
5.
Drug Chem Toxicol ; 44(1): 75-83, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33319629

RESUMO

Oxidative stress is related to increased fat deposition in the liver, known as hepatic steatosis. The present study is an evaluation of the anti-oxidative and antihyperlipidemic effects of the hydroalcoholic extract of Rhus coriaria L. (HARE) in rats on a high-fat diet (HFD). Twenty male Wistar rats were divided into four groups: control, HFD, HFD + HARE 50 mg/kg/day, and HFD + HARE 250 mg/kg/day for 12 weeks. Animals were weighed weekly and treated with the HARE extract for 12 weeks by gavage. Subsequently, the histopathological changes, oxidative markers, and lipid profile were evaluated. Statistical analysis was performed using the one-way analysis of variance (ANOVA) for multiple comparisons. First, the active ingredients of the extract were determined by HPLC. Then, the levels in the serum lipid profile (TG, cholesterol, HDL, and LDL) in rats fed with the HFD + HARE were analyzed where a significant reduction was observed. The HFD proved to increase the activity of the liver enzymes, the serum lipid levels, and the malondialdehyde (MDA) level. The ferric-reducing antioxidant activity power (FRAP), catalase (CAT), and superoxide dismutase (SOD) catalytic activity were reduced in the liver homogenate of HFD rats compared to the controls. Additionally, the aforementioned liver enzymes activities were reduced in response to HARE. Evaluation of oxidative stress determined a reduction in the MDA level while a raised FRAP was confirmed. In accordance with the present results, histopathological observations have also demonstrated that HARE ameliorated grade-1 hepatic steatosis induced by HFD. Taken together, the findings of this study introduce HARE as a future potential therapeutic agent in treating hepatic steatosis and reducing oxidative damages of an HFD in the liver.


Assuntos
Antioxidantes/farmacologia , Dislipidemias/prevenção & controle , Hipolipemiantes/farmacologia , Lipídeos/sangue , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rhus , Animais , Antioxidantes/isolamento & purificação , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/etiologia , Hipolipemiantes/isolamento & purificação , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Rhus/química
6.
J Struct Biol ; 210(3): 107496, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32224091

RESUMO

An alpha/ beta hydrolase annotated as a putative salicylate esterase within the genome of a species of Paenibacillus previously identified from differential and selective growth on Kraft lignin was structurally and functionally characterised. Feruloyl esterases are key to the degradation of lignin in several bacterial species and although this activity was investigated, no such activity was observed. The crystal structure of the Paenibacillus esterase, here denoted as PnbE, was determined at 1.32 Å resolution, showing high similarity to Nicotiana tabacum salicylic acid binding protein 2 from the protein database. Structural similarities between these two structures across the core domains and key catalytic residues were observed, with superposition of catalytic residues giving an RMSD of 0.5 Å across equivalent Cα atoms. Conversely, the cap domains of PnbE and Nicotiana tabacum SABP2 showed greater divergence with decreased flexibility in the PnbE cap structure. Activity of PnbE as a putative methyl salicylate esterase was supported with binding studies showing affinity for salicylic acid and functional studies showing methyl salicylate esterase activity. We hypothesise that this activity could enrich Paenibacillus sp. within the rhizosphere by increasing salicylic acid concentrations within the soil.


Assuntos
Hidrolases/metabolismo , Nicotiana/enzimologia , Nicotiana/metabolismo , Paenibacillus/enzimologia , Paenibacillus/metabolismo , Hidrolases/genética , Paenibacillus/genética , Rizosfera , Ácido Salicílico/metabolismo , Nicotiana/genética
7.
Malays J Med Sci ; 27(1): 57-69, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32158345

RESUMO

INTRODUCTION: The aim of the current study is to evaluate the antihyperlipidemic and anti-oxidative effects of hydro-alcoholic extract of marjoram (HAEM) in rats fed with a high-fat diet (HFD). METHODS: In the experimental study, the rats were randomly divided into four groups of five rats in each and fed with high-fat diet for 12 weeks as follows: One group (normal diet group) was fed with a standard diet, one group was fed with HFD, and two groups were fed with HFD and orally fed with 150 and 450 mg/kg/day HAEM. The serum samples and liver tissues were used for measuring the biochemical and oxidative parameters and histopathological studies. HFD induced hepatosteatosis in rats as evidenced by the altered liver enzymes activity, serum lipid profile and oxidative status. RESULTS: Serum lipid profile (triglyceride, cholesterol and low-density lipoprotein) in rats fed with HFD + HAEM (150 and 450 mg/kg/day) was significantly decreased. Furthermore, the evaluation of oxidative stress showed a reduction of the malondialdehyde (MDA) level and an increase in ferric-reducing anti-oxidant power. Meanwhile, liver enzyme activities declined in response to HAEM. CONCLUSION: Using the HAEM could be a future therapeutic agent in treating hepatosteatosis and reducing oxidative damages of HFD in the liver.

8.
J Nat Prod ; 81(2): 236-242, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29397715

RESUMO

Two new cis-clerodane-type furanoditerpenes, crispenes F and G (1 and 2), together with seven known compounds, were isolated from the stems of Tinospora crispa. Crispenes F and G (1 and 2) inhibited STAT3 dimerization in a cell-free fluorescent polarization assay and were found to have significant cytotoxicity against a STAT3-dependent MDA-MB 231 breast cancer cell line, while being inactive in a STAT3-null A4 cell line. These two compounds share structural similarities with a previously reported STAT3 inhibitor, crispene E, isolated from the same plant. Molecular docking studies suggested that the molecules inhibit STAT3 by interacting with its SH2 domain.


Assuntos
Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Terpenos/química , Terpenos/farmacologia , Tinospora/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dimerização , Humanos , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia
9.
J Bioenerg Biomembr ; 49(2): 139-147, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28275929

RESUMO

Hexokinase (HK) is the first enzyme of glycolysis pathway. In brain, most dominant form of HK, HK-I, binds reversibly to the outer mitochondria membrane. Those metabolites that affect binding or releasing of the enzyme from the mitochondria have regulatory effect on glucose consumption of the cell. In this study destructive effect of phenylalanine and its metabolites in relation to glucose metabolism in brain have been studied. The results show that phenylpyruvic acid decreases the activity of enzyme in the presence and absence of glucose-6-phosphate (G6P) and increases the release of the enzyme from mitochondria, whereas phenylalanine and phenyllactic acid have no such effects. Obtained Interactions and elicited binding energies of docking and MD simulations also showed more affinity for phenylpyruvic acid compared with the other potent inhibitors for hexokinase after the natural product of G6P. It is possible that phenylpyruvic acid is the cause of the reduction of glucose consumption by decreasing hexokinase activity and the higher inhibitory function. Therefore, production of ATP declines in brain cells.


Assuntos
Encéfalo/metabolismo , Hexoquinase/metabolismo , Fenilalanina/metabolismo , Animais , Glucose/metabolismo , Glicólise , Hexoquinase/antagonistas & inibidores , Mitocôndrias , Simulação de Acoplamento Molecular , Ácidos Fenilpirúvicos , Ligação Proteica , Ratos
10.
Mol Pharm ; 14(8): 2660-2669, 2017 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-28648081

RESUMO

The aim of the study was to use in silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir, and dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyze the identified drug-transporter interaction more mechanistically. The transport of tenofovir, darunavir, and dapivirine was investigated in the Caco-2 cell models and colorectal tissue, and their apparent permeability coefficient (Papp), efflux ratio (ER), and the effect of transporter inhibitors were evaluated. In silico, dapivirine and darunavir showed strong affinity for P-gp with similar free energy of binding; dapivirine exhibiting a ΔGPB value -38.24 kcal/mol, darunavir a ΔGPB value -36.84 kcal/mol. The rank order of permeability of the compounds in vitro was tenofovir < darunavir < dapivirine. The Papp for tenofovir in Caco-2 cell monolayers was 0.10 ± 0.02 × 10-6 cm/s, ER = 1. For dapivirine, Papp was 32.2 ± 3.7 × 10-6 cm/s, but the ER = 1.3 was lower than anticipated based on the in silico findings. Neither tenofovir nor dapivirine transport was influenced by P-gp inhibitors. The absorptive permeability of darunavir (Papp = 6.4 ± 0.9 × 10-6 cm/s) was concentration dependent with ER = 6.3, which was reduced by verapamil to 1.2. Administration of the drugs in combination did not alter their permeability compared to administration as single agents. In conclusion, in silico modeling, cell culture, and tissue-based assays showed that tenofovir does not interact with P-gp and is poorly permeable, consistent with a paracellular transport mechanism. In silico modeling predicted that darunavir and dapivirine were P-gp substrates, but only darunavir showed P-gp-dependent permeability in the biological models, illustrating that in silico modeling requires experimental validation. When administered in combination, the disposition of the proposed triple-therapy antiretroviral drugs in the colorectal mucosa will depend on their distinctly different permeability, but was not interdependent.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Darunavir/química , Pirimidinas/química , Tenofovir/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Células CACO-2 , Doenças do Colo/prevenção & controle , Doenças do Colo/virologia , Darunavir/uso terapêutico , Infecções por HIV/prevenção & controle , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/uso terapêutico , Tenofovir/uso terapêutico
11.
J Nat Prod ; 80(4): 1173-1177, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28257197

RESUMO

Bioactivity-guided fractionation of the ethyl acetate extract obtained from the culture of the endophytic fungus Fusarium solani resulted in the isolation of one new naphthoquinone, 9-desmethylherbarine (1), and two azaanthraquinone derivatives, 7-desmethylscorpinone (2) and 7-desmethyl-6-methylbostrycoidin (3), along with four known compounds. Their structures were elucidated by spectral analysis, as well as a direct comparison of spectral data with those of known compounds. Azaanthraquinones 2 and 3 showed cytotoxic activity against four human tumor cell lines, MDA MB 231, MIA PaCa2, HeLa, and NCI H1975. A molecular docking study suggested DNA interactions as the mode of action of these naphthoquinones and azaanthraquinones.


Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Compostos Aza/isolamento & purificação , Compostos Aza/farmacologia , Fusarium/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Acetatos , Antraquinonas/química , Antineoplásicos/química , Compostos Aza/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/química , Ressonância Magnética Nuclear Biomolecular
12.
Arch Biochem Biophys ; 594: 54-60, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26901432

RESUMO

A Dyp-type peroxidase enzyme from thermophilic cellulose degrader Thermobifida fusca (TfuDyP) was investigated for catalytic ability towards lignin oxidation. TfuDyP was characterised kinetically against a range of phenolic substrates, and a compound I reaction intermediate was observed via pre-steady state kinetic analysis at λmax 404 nm. TfuDyP showed reactivity towards Kraft lignin, and was found to oxidise a ß-aryl ether lignin model compound, forming an oxidised dimer. A crystal structure of TfuDyP was determined, to 1.8 Å resolution, which was found to contain a diatomic oxygen ligand bound to the heme centre, positioned close to active site residues Asp-203 and Arg-315. The structure contains two channels providing access to the heme cofactor for organic substrates and hydrogen peroxide. Site-directed mutant D203A showed no activity towards phenolic substrates, but reduced activity towards ABTS, while mutant R315Q showed no activity towards phenolic substrates, nor ABTS.


Assuntos
Actinobacteria/enzimologia , Lignina/metabolismo , Peroxidase/química , Peroxidase/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Oxirredução , Peroxidase/genética
13.
Bioorg Med Chem ; 24(24): 6340-6347, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27021004

RESUMO

This review covers recent developments in the inhibition of translocase MraY and related phospho-GlcNAc transferases WecA and TagO, and insight into the inhibition and catalytic mechanism of this class of integral membrane proteins from the structure of Aquifex aeolicus MraY. Recent studies have also identified a protein-protein interaction site in Escherichia coli MraY, that is targeted by bacteriophage ϕX174 lysis protein E, and also by cationic antimicrobial peptides containing Arg-Trp close to their N- or C-termini.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Transferases/antagonistas & inibidores , Proteínas Virais/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Proteínas de Bactérias/metabolismo , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Nucleosídeos/química , Nucleosídeos/farmacologia , Transferases/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)
14.
Iran J Med Sci ; 41(2): 157-60, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26989289

RESUMO

A uterocutaneous fistula is a rare clinical presentation that occurs following Cesarean section and other pelvic operations. There are only a few reports discussing the treatments. We describe a patient with successful surgical management and review the literature. A 25-year-old woman referred to our department 13 months after her first Cesarean section. She had a history of an abdominal mass and collection 2 months after surgery and some fistula opening with discharge from her previous incision. She had a previous surgical operation and antibiotic therapy without complete response. We performed fistulography to evaluate the tracts. In the operation - she had fistula tracts, one of which was between the uterus and skin. We debrided the necrotic tissue in the uterus, excised the fistula tracts, and drained the uterine cavity. At 8 months' postoperative follow-up, she had no recurrence. A uterocutaneous fistula is a rare condition with many causes and needs proper investigation and timely medical and surgical management.

15.
Bioorg Med Chem ; 22(17): 4566-71, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25127465

RESUMO

The National Cancer Institute (NCI) Diversity Set was screened for potential inhibitors of phospho-MurNAc-pentapeptide translocase MraY from Escherichia coli using a primary fluorescence enhancement assay, followed by a secondary radiochemical assay. One new MraY inhibitor was identified from this screen, a naphthylisoquinoline alkaloid michellamine B, which inhibited E. coli MraY (IC50 456µM) and Bacillus subtilis MraY (IC50 386µM), and which showed antimicrobial activity against B. subtilis (MIC 16µg/mL). Following an earlier report of halogenated fluoresceins identified from a combined MraY/MurG screen, three halogenated fluoresceins were tested as inhibitors of E. coli MraY and E. coli MurG, and phloxine B was identified as an inhibitor of E. coli MraY (IC50 32µM). Molecular docking of inhibitor structures against the structure of Aquifex aeolicus MraY indicates that phloxine B appears to bind to the Mg(2+) cofactor in the enzyme active site, while michellamine B binds to a hydrophobic groove formed between transmembrane helices 5 and 9.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Azul de Eosina I/farmacologia , Isoquinolinas/farmacologia , Naftalenos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Transferases/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/enzimologia , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Azul de Eosina I/síntese química , Azul de Eosina I/química , Escherichia coli/enzimologia , Isoquinolinas/síntese química , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Transferases/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)
16.
Elife ; 132024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39240985

RESUMO

Mass cytometry is a cutting-edge high-dimensional technology for profiling marker expression at the single-cell level, advancing clinical research in immune monitoring. Nevertheless, the vast data generated by cytometry by time-of-flight (CyTOF) poses a significant analytical challenge. To address this, we describe ImmCellTyper (https://github.com/JingAnyaSun/ImmCellTyper), a novel toolkit for CyTOF data analysis. This framework incorporates BinaryClust, an in-house developed semi-supervised clustering tool that automatically identifies main cell types. BinaryClust outperforms existing clustering tools in accuracy and speed, as shown in benchmarks with two datasets of approximately 4 million cells, matching the precision of manual gating by human experts. Furthermore, ImmCellTyper offers various visualisation and analytical tools, spanning from quality control to differential analysis, tailored to users' specific needs for a comprehensive CyTOF data analysis solution. The workflow includes five key steps: (1) batch effect evaluation and correction, (2) data quality control and pre-processing, (3) main cell lineage characterisation and quantification, (4) in-depth investigation of specific cell types; and (5) differential analysis of cell abundance and functional marker expression across study groups. Overall, ImmCellTyper combines expert biological knowledge in a semi-supervised approach to accurately deconvolute well-defined main cell lineages, while maintaining the potential of unsupervised methods to discover novel cell subsets, thus facilitating high-dimensional immune profiling.


Assuntos
Análise de Dados , Citometria de Fluxo , Análise de Célula Única , Humanos , Citometria de Fluxo/métodos , Análise de Célula Única/métodos , Software , Análise por Conglomerados
17.
Dermatol Reports ; 16(2): 9833, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38979521

RESUMO

Worldwide, squamous cell carcinoma (SCC) incidence is rising. The literature debates the human papillomavirus (HPV)'s role in cutaneous SCC development. We examined HPV histopathology in SCC samples in this study. Retrospective study at tertiary referral skin center in 2020. Histopathological features of HPV, including koilocytosis, hyperkeratosis, acanthosis, hypergranulosis, parakeratosis, solar elastosis, papillomatosis, and tumor grade, were examined in SCC specimens. Two dermatopathologists independently reevaluated all samples. We examined 331 SCC cases (male:female ratio = 3.9:1). The mean age was 68.1, with 15.1 standard deviation. Lesions were most common on the face (40.5%), scalp (22.7%), and extremities (20.8%). Koilocytes were found in 50 (15.1%) lesions. Nail (38.1%, p=0.007), oral cavity (36.8%, p=0.014), and genitalia (60.0%, p=0.026) lesions had higher koilocytosis rates. SCCs were found in 6.6% of specimens, but in situ tumors had the highest koilocytosis (64.7%), significantly higher than other grades (p<0.001). SCC pathology often shows HPV and specific koilocyte histopathology. Well-differentiated SCC has a stronger association with nail, oral, and genital lesions.

18.
Iran J Otorhinolaryngol ; 35(129): 227-230, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37497157

RESUMO

Introduction: Multifocal Langerhans' cell histocytosis is a rare condition that can affect multiple organs and manifest in various scenarios. While the condition is more commonly found in children, it can also occur in adults. Case Report: A 43-year-old female presented with refractory otorrhea and had a rubbery neck mass in the left mid-cervical area, as well as an itchy eczematoid lesion in the left parietal area. The otic lesion was eventually resected, and histopathologic examination confirmed the diagnosis of Langerhans histiocytosis. Conclusions: Although rare in adults, Langerhans histiocytosis should be considered as one of the differential diagnoses for ear canal polyps. If diagnosed, medical treatment should be pursued.

19.
Toxicol Rep ; 11: 452-459, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38045604

RESUMO

Background: The possible toxicity of natural products must be tested before being used in the market. The present work aimed to evaluate acute, subacute, and subchronic toxicity of an herbal formulation containing Anethum graveolens, Cynara scolymus, Citrus aurantium, Portulaca oleracea, and Silybum marianum. Material and methods: Acute toxicity (2000 mg/kg, single dose) and sub-acute toxicity (600 and 1200 mg/kg/day, 4 weeks) tests were performed on female and male rats according to OECD 423 and OECD 407 guidelines, respectively. In the subchronic study (12 weeks), the animals were divided into three groups (6 females and 6 males per group): control, low-dose group (food supplemented with 300 mg/kg of the herbal product), and high-dose group (600 mg/kg). Results: The herbal product at a single dose of 2000 mg/kg did not induce mortality for 14 days. In the sub-acute study, administration of the product for 28 days at 1200 mg/kg/day had no effect on survival, appetite (water and food consumption), body weight, serum biochemical parameters (BUN, creatinine, AST, ALT, ALP, bilirubin, albumin), histology of vital organs (liver, kidney, heart, brain), and hematological markers related to erythrocyte, platelet, and leukocyte. Similarly, in the subchronic study, the product did not induce mortality, change in histology of the vital organs, or alteration in hematological or biochemical parameters (except for an increase in ALP in female rats received 600 mg/kg). Conclusion: The formulated product shows no signs of toxicity in rats up to 2000 mg/kg, 1200 mg/kg, and 600 mg/kg in acute, subacute, and subchronic phases, respectively. It is suggested to monitor ALP levels in females in case of long-term use of the product.

20.
RSC Chem Biol ; 4(1): 94-100, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36685252

RESUMO

A number of Gram-negative bacteria such as Pseudomonas aeruginosa are becoming resistant to front-line antibiotics. Consequently, there is a pressing need to find alternative bio-molecular targets for the development of new drugs. Since non-canonical DNA structures such as guanine-quadruplexes (G4s) have been implicated in regulating transcription, we were interested in determining whether there are putative quadruplex-forming sequences (PQS) in the genome of Pseudomonas aeruginosa. Using bioinformatic tools, we screened 36 genes potentially relevant to drug resistance for the presence of PQS and 10 of these were selected for biophysical characterisation (i.e. circular dichroism and thermal difference UV/Vis spectroscopy). These studies showed that three of these G-rich sequences (linked to murE, ftsB and mexC genes) form stable guanine-quadruplexes which were studied by NMR spectroscopy; detailed analysis of one of the sequences (mexC) confirmed that it adopts a two-quartet antiparallel quadruplex structure in the presence of K+ ions. We also show by FRET melting assays that small molecules can stabilise these three new G4 DNA structures under physiological conditions. These initial results could be of future interest in the development of new antibiotics with alternative bio-molecular targets which in turn would help tackle antimicrobial resistance.

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