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Molecules (Basel, Switzerland) Jan 2018Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of... (Review)
Review
Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.
Topics: Animals; Anti-HIV Agents; Anti-Inflammatory Agents; Anti-Obesity Agents; Antidepressive Agents; Antipsychotic Agents; Chemistry, Pharmaceutical; Drug Design; Humans; Pyrazoles
PubMed: 29329257
DOI: 10.3390/molecules23010134 -
Toxics Nov 2022As one of the most prevalent estrogenic mycotoxins in cereals and animal feed, zearalenone (ZEN) can cause serious reproductive disorders. ZEN control in food and feed...
As one of the most prevalent estrogenic mycotoxins in cereals and animal feed, zearalenone (ZEN) can cause serious reproductive disorders. ZEN control in food and feed commodities has been an imperative area of research. In this study, 87 lactic acid bacteria (LAB) were isolated from pickles and their ZEN (5 mg/L) removal abilities ranged from 0% to 68.4%. Then, five strains with potent ZEN removal ability (>50%) were identified: Lactobacillus plantarum 22, L. plantarum 37, L. plantarum 47, L. paracasei 85, and L. buchneri 93. Under optimization conditions (48 h, pH 4.0, 37 °C, and 5 mg/L), the highest ZEN removal abilities of L. paracasei 85 and L. buchneri 93 reached 77.7% and 72.8%, respectively. Moreover, the two lactic acid bacteria decreased the toxicity of ZEN, because the levels of β-zearalenol (β-ZOL) transformed from ZEN were more than two-fold higher than α-zearalenol (α-ZOL). Additionally, cell free supernatant and pellet biotransformation of ZEN to α-ZOL and β-ZOL in LAB were detected for the first time. Furthermore, chemical and enzymatical treatments combined with Fourier-transform infrared spectroscopy analysis indicated that exopolysaccharides, proteins, and lipids on the cell wall could bond to ZEN through hydrophobic interactions. Scanning electron microscopy indicated that cell structure damage occurred during the ZEN clearance to L. buchneri 93, but it did not with L. paracasei 85. In addition, various organic acids, alcohols, and esters of the two LAB participated in ZEN removal. Hence, L. paracasei 85 and L. buchneri 93 can be considered as potential detoxification agents for ZEN removal for food and feedstuff.
PubMed: 36355971
DOI: 10.3390/toxics10110680 -
Gut Feb 1974Basal, as well as betazole-stimulated gastric acid secretion in man is reduced after the intravenous administration of bromazepam. In subjects staying awake, this...
Basal, as well as betazole-stimulated gastric acid secretion in man is reduced after the intravenous administration of bromazepam. In subjects staying awake, this reduction is limited to the first two 15-minute periods. The reduction is highly significant in subjects who fall asleep after receiving the drug. Natural sleep causes the same depression. The low level of acid secretion is maintained until the subjects are awakened when there is a sharp and highly significant rise. Acid secretion in subjects who fall asleep after the simultaneous administration of betazole and bromazepam is significantly higher than after the administration of bromazepam alone. Sleep causes a much greater depression of basal and betazole-stimulated acid secretion than does the benzodiazepine itself. Acid secretion was measured by continuous intragastric titration and a pH-sensitive endoradiosonde.
Topics: Adult; Benzodiazepinones; Ethylamines; Female; Gastric Juice; Gastrointestinal Motility; Humans; Hydrogen-Ion Concentration; Injections, Intravenous; Injections, Subcutaneous; Male; Pyrazoles; Pyridines; Sleep; Telemetry
PubMed: 4820635
DOI: 10.1136/gut.15.2.116 -
Toxins Nov 2022Zearalenone (ZON), zearalanone (ZAN) and their phase I metabolites: α-zearalenol (α-ZOL), β-zearalenol (β-ZOL), α-zearalalanol (α-ZAL) and β-zearalalanol (β-ZAL)...
Zearalenone (ZON), zearalanone (ZAN) and their phase I metabolites: α-zearalenol (α-ZOL), β-zearalenol (β-ZOL), α-zearalalanol (α-ZAL) and β-zearalalanol (β-ZAL) are compounds with estrogenic activity that are metabolized and distributed by the circulatory system in animals and can access the food chain through meat products from livestock. Furthermore, biomonitoring of zearalenones in biological matrices can provide useful information to directly assess mycotoxin exposure; therefore, their metabolites may be suitable biomarkers. The aim of this study was to determine the presence of ZON, ZAN and their metabolites in alternative biological matrices, such as liver, from three different animals: chicken, pig and lamb, in order to evaluate their exposure. A solid-liquid extraction procedure coupled to a GC-MS/MS analysis was performed. The results showed that 69% of the samples were contaminated with at least one mycotoxin or metabolite at varying levels. The highest value (max. 152.62 ng/g of β-ZOL) observed, and the most contaminated livers (42%), were the chicken liver samples. However, pig liver samples presented a high incidence of ZAN (33%) and lamb liver samples presented a high incidence of α-ZOL (40%). The values indicate that there is exposure to these mycotoxins and, although the values are low (ranged to 0.11-152.6 ng/g for α-ZOL and β-ZOL, respectively), analysis and continuous monitoring are necessary to avoid exceeding the regulatory limits and to control the presence of these mycotoxins in order to protect animal and human health.
Topics: Humans; Swine; Sheep; Animals; Zearalenone; Chickens; Tandem Mass Spectrometry; Mycotoxins; Liver
PubMed: 36422956
DOI: 10.3390/toxins14110782 -
Toxins Nov 2021The purpose of this research was to investigate the toxicity of zearalenone (ZEN) on the growth performance, genital organs, serum hormones, biomarkers, and...
The purpose of this research was to investigate the toxicity of zearalenone (ZEN) on the growth performance, genital organs, serum hormones, biomarkers, and histopathological changes of female gilts and to evaluate the efficacy of ZJ-2019-1 in alleviating ZEN toxicosis in gilts. Twenty-four female gilts were randomly allocated to four groups with six replicates per group and one gilt per replicate, fed on four feeds prepared previously, which were basic diet (control group, C group), ZEN diet (Z group), Zlb diet (Zlb group) containing B. subtilis ZJ-2019-1 in liquid form, and Zdb diet (Zdb group) containing ZJ-2019-1 in dehydrated form. The results showed that the vulva size and relative weight of reproductive organs had no significant difference in the control group, Zlb group, and Zdb group, but were significantly lower than in the Z group ( < 0.05); the relative weight of the liver was lower in the C group, Zlb group, and Zbd group than in the Z group (0.05 < < 0.1). The concentration of serum glutamate dehydrogenase (GLDH) was lower, but follicle-stimulating hormone (FSH) was higher in the Z group, Zlb group, and Zdb group than in the Z group (0.05 < < 0.1). Additionally, serum luteinizing hormone (LH) concentration had no significant difference in the C group, Zlb group, and Zdb group but was significantly lower than in the Z group ( < 0.05); estradiol (E2) was significantly lower in the Zlb group and Zdb group than that in C group, but significantly higher than that in Z group ( < 0.05); PRL was significantly higher in the Zlb group and Zdb group than in the C group, but was significantly lower than in Z group ( < 0.05). ZEN and its reduced metabolites were measured in biological samples after enzymatic hydrolysis of the conjugated forms. The concentration of serum ZEN and its metabolite, α-zeralenol (α-ZOL), had no significant difference in Zlb, Zdb, and control groups but was significantly lower than in the Z group ( < 0.05); urine ZEN and its metabolites, α-ZOL and β-zeralenol (β-ZOL), had no significant difference in Zlb, Zdb, and control groups but was significantly lower than in the Z group ( < 0.05). Cell damages were observed in the liver, uterus, and ovary of gilts in the Z group and alleviated in Zlb and Zdb groups, but the loss of oocytes was irreversible in the ovary. The ZEN-contaminated diet caused serious changes in female hormones and brought harm to the livers and reproductive organs, but ZJ-2019-1 could naturally remove the ZEN significantly, which ameliorated the reproductive impairment in gilts caused by ZEN. The addition of ZJ-2019-1 to ZEN-contaminated feeds could ameliorate the toxic effects effectively, regardless of liquid or dry culture. Therefore, the ZJ-2019-1 strain has great potential industrial applications.
Topics: Animals; Bacillus subtilis; Estrogens, Non-Steroidal; Female; Mycotoxins; Sus scrofa; Zearalenone
PubMed: 34822572
DOI: 10.3390/toxins13110788 -
Molecules (Basel, Switzerland) Nov 2022This study evaluated the ability of selected strains of , . , and . to inhibit mycelium growth and the biosynthesis of mycotoxins deoxynivalenol (DON), nivalenol (NIV),...
This study evaluated the ability of selected strains of , . , and . to inhibit mycelium growth and the biosynthesis of mycotoxins deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEN), α-(α-ZOL) and β-zearalenol (β-ZOL) by selected strains of and . . For this purpose, an in vitro experiment was carried out on solid substrates (PDA and rice). After 5 days of co-culture, it was found that all strains used in the experiment significantly inhibited the growth of mycelium. Qualitative assessment of pathogen-antagonist interactions showed that colonized 75% to 100% of the medium surface (depending on the species and strain of the antagonist and the pathogen) and was also able to grow over the mycelium of the pathogen and sporulate. The rate of inhibition of mycelium growth by ranged from approximately 24% to 66%. When and were co-cultured on rice, strains were found to inhibit DON biosynthesis by about 73% to 98%, NIV by about 87% to 100%, and ZEN by about 12% to 100%, depending on the pathogen and antagonist strain. A glycosylated form of DON was detected in the co-culture of . and whereas it was absent in cultures of the pathogen alone, thus suggesting that is able to glycosylate DON. The results also suggest that a strain of . is able to convert ZEN into its hydroxylated derivative, β-ZOL.
Topics: Fusarium; Trichoderma; Trichothecenes; Mycotoxins; Zearalenone; Oryza
PubMed: 36500242
DOI: 10.3390/molecules27238146 -
Theranostics 2023Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug...
Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model. We used reduced linked green fluorescent protein (GFP) reporter gene expression as a read-out for reduced inflammation in a screen of 1081 compounds in larval zebrafish. Hit drugs were tested in a moderate contusion model in mice for cytokine regulation, and improved tissue preservation and locomotor recovery. Three compounds robustly reduced expression in zebrafish. Cimetidine, an over-the-counter H2 receptor antagonist, also reduced the number of pro-inflammatory neutrophils and rescued recovery after injury in a zebrafish mutant with prolonged inflammation. Cimetidine action on expression levels was abolished by somatic mutation of H2 receptor , suggesting specific action. In mice, systemic treatment with Cimetidine led to significantly improved recovery of locomotor behavior as compared to controls, accompanied by decreased neuronal tissue loss and a shift towards a pro-regenerative profile of cytokine gene expression. Our screen revealed H2 receptor signaling as a promising target for future therapeutic interventions in spinal cord injury. This work highlights the usefulness of the zebrafish model for rapid screening of drug libraries to identify therapeutics to treat mammalian spinal cord injury.
Topics: Mice; Animals; Zebrafish; Cimetidine; Larva; Drug Evaluation, Preclinical; Spinal Cord Injuries; Inflammation; Cytokines; Mammals
PubMed: 37215570
DOI: 10.7150/thno.81332 -
Foods (Basel, Switzerland) Sep 2022Zearalenone (ZEN) and its derivatives pose a serious threat to global food quality and animal health. The use of enzymes to degrade mycotoxins has become a popular...
Zearalenone (ZEN) and its derivatives pose a serious threat to global food quality and animal health. The use of enzymes to degrade mycotoxins has become a popular method to counter this threat. In this study, Aspergillus niger ZEN-S-FS10 extracellular enzyme solution with ZEN-degrading effect was separated and purified to prepare the biological enzyme, FSZ, that can degrade ZEN. The degradation rate of FSZ to ZEN was 75−80% (pH = 7.0, 28 °C). FSZ can function in a temperature range of 28−38 °C and pH range of 2.0−7.0 and can also degrade ZEN derivatives (α-ZAL, β-ZOL, and ZAN). According to the enzyme kinetics fitting, ZEN has a high degradation rate. FSZ can degrade ZEN in real samples of corn flour. FSZ can be obtained stably and repeatedly from the original strain. One ZEN degradation product was isolated: FSZ−P(C18H26O4), with a relative molecular weight of 306.18 g/mol. Amino-acid-sequencing analysis revealed that FSZ is a novel enzyme (homology < 10%). According to the results of molecular docking, ZEN and ZAN can utilize their end-terminal carbonyl groups to bind FSZ residues PHE307, THR55, and GLU129 for a high-degradation rate. However, α-ZAL and β-ZOL instead contain hydroxyl groups that would prevent binding to GLU129; thus, the degradation rate is low for these derivatives.
PubMed: 36141036
DOI: 10.3390/foods11182908 -
Toxicology Reports 2015Zearalenone (ZEA) is a secondary fungal metabolite produced mainly by a . To clarify the toxicokinetics, and residues of ZEA and its major metabolites α-zearalenol...
Zearalenone (ZEA) is a secondary fungal metabolite produced mainly by a . To clarify the toxicokinetics, and residues of ZEA and its major metabolites α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL) in chickens, ZEA was then administered intravenously (iv) or orally (po) to broiler chickens at a dosage of 1.2 mg/kg body weight. The concentrations of ZEA, α-ZOL and β-ZOL in the plasma and various tissues were quantified using LC-MS/MS. The plasma concentrations of ZEA were measurable up to 2 h after iv and po administration, and the concentrations of α-ZOL and β-ZOL were detected up to 4 h after both types of administration. A two-compartment model was developed to describe the toxicokinetic of ZEA in broilers. The values of and were 1.36 ± 0.29 h and 6.40 ± 0.89 l/kg, respectively. The absolute oral bioavailability was 29.66 ± 5.6%. ZEA, α-ZOL and β-ZOL were measurable in the vital organs after po administration. These results suggest that ZEA is absorbed from the gastrointestinal tract and it has ability to penetrate into the various tissues of broiler chickens.
PubMed: 28962368
DOI: 10.1016/j.toxrep.2014.12.011 -
Green Chemistry : An International... May 2021As an alternative to classical synthetic approaches for the production of betazole drug, a one-pot biocatalytic system for this pharmaceutical molecule from its alcohol...
As an alternative to classical synthetic approaches for the production of betazole drug, a one-pot biocatalytic system for this pharmaceutical molecule from its alcohol precursor has been developed. An ω-transaminase, an alcohol dehydrogenase and a water-forming NADH oxidase for cofactor recycling have been combined to catalyse this reaction, yielding 75% molar conversion in batch reactions with soluble enzymes. This multienzyme system was then co-immobilised through a newly established protocol for sequential functionalization of a methacrylate-based porous carrier to enable tailored immobilisation chemistries for each enzyme. This pluri-catalytic system has been set up in a continuous flow packed-bed reactor, generating a space-time yield of up to 2.59 g L h with 15 min residence and a constant supply of oxygen for cofactor recycling through a segmented air-liquid flow. The addition of an in-line catch-and-release column afforded >80% product recovery.
PubMed: 34220333
DOI: 10.1039/d1gc01095f