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Tetrasubstituted 2-acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6–8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, 1H-13C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn’t guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics.

Decreasing the dietary intake of methionine exerts robust anti‐adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti‐adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine‐ and cysteine‐titrated diets, we demonstrate that the anti‐adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non‐glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck‐M. In mice, the magnitude of SAAR‐induced changes in molecular markers depended on dietary fat concentration (60% fat >10% fat), sex (males > females), and age‐at‐onset (young > adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross‐sectional epidemiological study. Controlled feeding of low‐SAA, high‐polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia. The proposed mechanism of CR‐specific effects of SAAR on adipose metabolism. (1) Due to the lack of Cys in SAAR diets, it imposes both MR and CR. CR specifically results in decreased biosynthesis of the tripeptide glutathione. (2) Lower hepatic glutathione increases the abundance of the transcription factor Nrf2, which translocates to the nucleus and induces the transcription of Phgdh. (3) Increase in the transcription and translation of Phgdh and Pck‐2 results in higher hepatic serinogenesis (Ser biosynthesis from substrates other than glucose, that is, from oxaloacetic acid). (4) Higher serinogenesis competes with glyceroneogenesis as both pathways use the same set of substrates, which results in lower fatty acid re‐esterification. Note: broken arrows represent the presence of other biochemical intermediates not shown in the figure. Up and down arrows adjacent to the metabolic intermediates represent an increase and decrease, respectively. 3PG, 3‐phosphoglycerate; OAA, oxaloacetic acid; DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate; FA, fatty acids.

Several new pyrazole, pyridine, [1,2,4]triazolo[1,5-α]pyrimidine, benzimidazo[1,2-a]pyrimidine and 1,2,4-triazolo[3,4-c][1,2,4]triazine derivatives incorporating a thiophene moiety were synthesized from (E)-ethyl 5-(3-(dimethylamino)acryloyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate (1). The structures of the newly synthesized compounds were confirmed by IR, 1H-, 13C-NMR, mass spectral data and elemental analysis. The antibacterial and antifungal activities of all the synthesized compounds were evaluated. The results indicated that compounds 9, 12, and 19 were found to be more potent than the standard drug Amphotericin B against Aspergillus fumigates. Additionally, compound 12 exhibited higher activity than the standard drug Amphotericin B against Syncephalastrum racemosum.

Background Dietary restriction of methionine and cysteine is a well-described model that improves metabolic health in rodents. To investigate the translational potential in humans, we evaluated the effects of dietary methionine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double-blind randomized controlled pilot study. Methods Twenty women with overweight or obesity were allocated to a diet low (Met/Cys -low, n = 7), medium (Met/Cys -medium, n = 7) or high (Met/Cys -high, n = 6) in methionine and cysteine for 7 days. The diets differed only by methionine and cysteine content. Blood and urine were collected at day 0, 1, 3 and 7 and subcutaneous adipose tissue biopsies were taken at day 0 and 7. Results Plasma methionine and cystathionine and urinary total cysteine decreased, whereas FGF21 increased in the Met/Cys -low vs. Met/Cys -high group. The Met/Cys -low group had increased mRNA expression of lipogenic genes in adipose tissue including DGAT1 . When we excluded one participant with high fasting insulin at baseline, the Met/Cys -low group showed increased expression of ACAC, DGAT1, and tendencies for increased expression of FASN and SCD1 compared to the Met/Cys -high group. The participants reported satisfactory compliance and that the diets were moderately easy to follow. Conclusions Our data suggest that dietary methionine and cysteine restriction may have beneficial effects on circulating biomarkers, including FGF21, and influence subcutaneous adipose tissue gene expression. These results will aid in the design and implementation of future large-scale dietary interventions with methionine and cysteine restriction. Trial registration ClinicalTrials.gov Identifier: NCT03629392, registration date: 14/08/2018 https://clinicaltrials.gov/ct2/show/NCT03629392 .

Quality control and non-destructive monitoring are of notable interest of food and pharmaceutical industries. It relies on the ability of non-invasive inspection which can be employed for manufacturing process control. We hereby apply terahertz (THz) time-domain spectroscopy as non-destructive technique to monitor pure and degraded oils as well as hydrocarbon chemicals. Significant differences in the spectra of refractive index (RI) and absorption coefficient arising from the presence of ester linkages in the edible and technical oils were obtained. Explicit increase from 1.38 to 1.5 of the RI in all THz spectrum range was observed in hydrocarbons and mono-functional esters with the increase of molar mass. This fact is in contrast of RI dependence on molar mass in multi-functional esters, such as Adipate or vegetable oils, where it is around 1.54. Degradation products, Oleic Acid (OA) and water in particular, lead only to some changes in absorption coefficient and RI spectra of vegetable oils. We demonstrate that complex colloidal and supramolecular processes, such as dynamics of inverse micelles and oil hydrolysis, take part during oil degradation and are responsible for non-uniform dependence of optical properties on extent of degradation.

In this study, the chemical compositions of the ethanolic and aqueous extracts of the leaves of Origanum syriacum and Salvia lanigera were identified based on GC-MS spectrometric analyses. The in vitro anti-inflammatory potential of the different extracts was evaluated by determining the membrane stabilization of human red blood cells and the percent inhibition of the COX1/2, 5LOX, and sPLA 2 -V enzymes. Both ethanolic extracts showed maximum membrane stabilization (≤ 91%, at 100 μg/mL) compared to the aqueous extracts (≤ 45%) and the reference drug diclofenac sodium (90.75%). The membrane-stabilizing effects of the ethanolic extracts could be directly correlated to their anti-inflammatory activity. While both ethanolic fractions strongly inhibited the 5LOX and COX-1 enzymes at 100 μg/mL, only the O. syriacum ethanolic extract selectively inhibited sPLA 2 -V (99.35%, at 50 μg/mL). The differences in the pharmacological efficiencies of the different extracts could be attributed to the variation in their chemical compositions particularly the content of oxygenated monoterpenoids. Additionally, none of the ethanolic extracts demonstrated cytotoxicity to human colorectal cancer cell lines (HCT-116 and Lovo), even at the highest concentration tested (200 μg/mL). The safe profiles of these extracts towards the tested cell lines may be due to the absence of the toxic phthalic acid ester substances. Collectively, these findings clearly suggest that the studied ethanolic extracts of O. syriacum and S. lanigera can be considered interesting candidates for the treatment of human inflammatory diseases related to oxidative stress and microbial infections.

Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6–7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown.

Introduction Whether retinoids and carotenoids impact on graft‐versus‐host disease (GVHD) following allogeneic stem cell transplantation (ASCT) is unknown. Methods We conducted a 1:1 randomized controlled trial with extracorporeal photopheresis for GVHD‐prophylaxis as the intervention. The plasma levels of retinoids and carotenoids were determined at randomization and 3 months after ASCT. Results We found no significant difference in GVHD occurrence and levels of retinoids between the intervention and control groups at either of the two time points. Conclusion Whether routine vitamin A supplementation is warranted for GVHD prevention, needs further study. Our exploratory study highlights the complex role of retinoid homeostasis in immune function during ASCT. Trial Registration ClinicalTrials.gov identifier: NCT03204721

BackgroundHuman milk vitamin B12 (B12) concentrations depend on maternal status and intake; only few data are available in high-income countries.ObjectiveWe assessed human milk B12 concentrations during the first 6 months postpartum in Norwegian women and its association with maternal dietary B12 intake and maternal urinary methylmalonic acid (MMA) concentration.MethodsIn this cross-sectional study, 175 mothers, exclusively (80%) or partially (20%) breastfeeding, were included. Milk B12 was measured by IMMULITE®/IMMULITE® 1000 B12 competitive protein binding assay and urinary MMA relative to creatinine (MMA/Cr) by liquid chromatography–tandem-mass spectrometry. Maternal habitual B12 intake and supplement use were estimated using a food frequency questionnaire.ResultsMean human milk B12 concentration was 327 pmol/L (range 140–1089), with 402 pmol/L at 1 month (n = 21), 333 pmol/L at four months (n = 32), and 299 pmol/L at 6 months (n = 21). Maternal B12 intake was 5 µg/d, 89% met the Estimated Average Requirement, and supplement use did not affect milk B12 concentrations. MMA/Cr was low in all women compared with published data. In exclusively breastfeeding women, MMA/Cr (beta (95% CI) −42.5 (−82.5, −2.5) and time since birth (−4.9 (−9.6, −0.3)) were significant predictors of human milk B12 concentrations. There was no association between total B12 intake and milk B12 concentration or between total B12 intake and MMA/Cr.ConclusionsMaternal B12 status and human milk B12 concentrations are likely sufficient, based on adequate maternal B12 dietary intake combined with low urinary MMA concentrations. Nevertheless, milk B12 concentration fell during 6 months postpartum while maternal B12 status did not change.