Oleuropein, glycosylated secoiridoid present in olive leaves is known to be an important antioxidant phenolic compound. We studied the antioxidant effect of low doses of oleuropein aglycone (3,4-DHPEA-EA) and oleuropein aglycone peracetylated (3,4-DHPEA-EA(P)) in murine C2C12 myocytes treated with hydrogen peroxide (H2O2). Both compounds were used at a concentration of 10 μM and were able to inhibit cell death induced by the H2O2 treatment, with 3,4-DHPEA-EA(P) being more. Under our experimental conditions, H2O2 efficiently induced the phosphorylated-active form of JNK and of its downstream target c-Jun. We demonstrated, by Western blot analysis, that 3,4-DHPEA-EA(P) was efficient in inhibiting the phospho-active form of JNK. This data suggests that the growth arrest and cell death of C2C12 proceeds via the JNK/c-Jun pathway. Moreover, we demonstrated that 3,4-DHPEA-EA(P) affects the myogenesis of C2C12 cells; because MyoD mRNA levels and the differentiation process are restored with 3,4-DHPEA-EA(P) after treatment. Overall, the results indicate that 3,4-DHPEA-EA(P) prevents ROS-mediated degenerative process in a genomic and epigenomic manner by functioning as an efficient antioxidant.

Oleuropein, glycosylated secoiridoid present in olive leaves is known to be an important antioxidant phenolic compound. We studied the antioxidant effect of low doses of oleuropein aglycone (3,4-DHPEA-EA) and oleuropein aglycone peracetylated (3,4-DHPEA-EA(P)) in murine C2C12 myocytes treated with hydrogen peroxide (H2O2). Both compounds were used at a concentration of 10 μM and were able to inhibit cell death induced by the H2O2 treatment, with 3,4-DHPEA-EA(P) being more. Under our experimental conditions, H2O2 efficiently induced the phosphorylated-active form of JNK and of its downstream target c-Jun. We demonstrated, by Western blot analysis, that 3,4-DHPEA-EA(P) was efficient in inhibiting the phospho-active form of JNK. This data suggests that the growth arrest and cell death of C2C12 proceeds via the JNK/c-Jun pathway. Moreover, we demonstrated that 3,4-DHPEA-EA(P) affects the myogenesis of C2C12 cells; because MyoD mRNA levels and the differentiation process are restored with 3,4-DHPEA-EA(P) after treatment. Overall, the results indicate that 3,4-DHPEA-EA(P) prevents ROS-mediated degenerative process in a genomic and epigenomic manner by functioning as an efficient antioxidant.

Oleuropein, glycosylated secoiridoid present in the olive leaves, is known as an important antioxidant phenolic compound. We studied the antioxidant effect of low dose of oleuropein aglycone (3,4-DHPEA-EA) and oleuropein aglycone peracetylated (3,4-DHPEA-EA(P)) in murine C2C12 myocytes treated with hydrogen peroxide (H2O2). Both compounds were used at a concentration of 10 μM and were able to inhibit cell death induced by H2O2 treatment, with 3,4-DHPEA-EA(P) being more. Under our experimental conditions H2O2 efficiently induced the phosphorylated-active form of JNK and of its downstream target c-Jun. We demonstrated, by Western blot analysis, that 3,4-DHPEA-EA(P) was efficient in inhibiting the phospho-active form of JNK. This data suggest that growth arrest and cell dead of C2C12 proceeds via the JNK/c-Jun pathway. Moreover, we demonstrated that 3,4-DHPEA-EA(P) affects myogenesis of C2C12 cells; because the MyoD mRNA levels and the differentiation process are restored after treatment with 3,4-DHPEA-EA(P). Overall, the results indicate that 3,4-DHPEA-EA(P) prevents ROS-mediated degenerative process by functioning as an efficient antioxidant.

The combined influence of the North Atlantic Oscillation (NAO) and the East Atlantic (EA) patterns on the covariability of temperatures and precipitation in 35 stations of the Iberian Peninsula during the period 1950-2019 is analysed in this work. Four EA-NAO composites were defined from teleconnection patterns positive and negative phases: EA+NAO+, EA+NAO-, EA-NAO+, and EA-NAO-. Daily data of maximum and minimum temperature were used to obtain seasonal means (TX, and TN, respectively), and the covariability of these variables with accumulated seasonal rainfall (R) was studied comparing results obtained for different NAO and EA composites. Main results indicate slight differences in the spatial coverage of correlation coefficients between R and temperature variables, except in spring when the generalized negative relationship between R and TX under EA+NAO+ and EA-NAO- disappears under EA-NAO+ and EA+NAO- composites. This result may be useful to interpret and discuss historical reconstructions of Iberian climate.

Objective: We aimed to clarify the differences in the association between re-admission for heart failure (HF) and left atrial (LA) overload indices by sex in heart failure and a preserved ejection fraction (HFpEF). Methods: We analysed 898 HFpEF patients hospitalized for acute decompensated HF. Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for HF during the first year. Results: The ratio of diastolic elastance to arterial elastance (p=0.014), a relative index of LA pressure overload, in men and LA volume index (LAVI, p=0.020) in women were significant for re-admission for HF during the first year in the multivariable Fine-Gray analysis. Stroke volume (SV)/LA volume (LAV), another index for LAV overload, was not a significant prognostic factor of re-admission for HF during this time. Conclusion: LA overload was an important prognostic factor for HF re-readmission during the first year after enrolment in patients with HFpEF, but the indices relating to LA overload differed by sex.

The authors developed a wealth curve (bell curve) that can predict a group of individuals’ wealth based on the composite intelligence score which is calculated based on the sum of the intelligence quotient and emotional awareness score. The intelligence quotient was defined as one's ability to perform, comprehend and learn, and emotional awareness was defined as the emotional ability to recognize and make sense of emotions. To move towards the right on the X-axis of the Kabir wealth curve (e.g., accumulate more wealth), individuals must improve emotional awareness and choose a professional career path that lands higher income, calculated risk-taking, and being connected with individuals that can lead to financial deals. Similarly, those facing social injustice can accumulate more wealth by improving emotional awareness, which will help them navigate challenging environments.

A new synthetic approach to polyfunctional hexahydropyrrolo[3,4-b]pyrroles was developed based on cyclization of N-arylbromomaleimides with aminocrotonic acid esters. A highly chemo- and stereoselective reaction is a Hantzsch-type domino process, involving the steps of initial nucleophilic C-addition or substitution and subsequent intramolecular nucleophilic addition without recyclyzation of imide cycle.

Isoamyl (E)-3-(3,4-dimethoxyphenyl)acrylate (1) was obtained 95% yield by 2-methyl-6-nitrobenzoic anhydride (MNBA)/4-dimethylaminopyridine (DMAP)-catalyzed reaction at room temperature for 190 minutes in dichloromethane. The structure of isoamyl (E)-3-(3,4-dimethoxyphenyl)acrylate (1) was established by NMR, FTIR, and the high resolution of mass spectroscopies. In vitro sun protection factor evaluation exhibited value of 37.10 ± 0.03 which indicates that isoamyl (E)-3-(3,4-dimethoxyphenyl)acrylate (1) as a sunscreen agent with high protection.

A derivative series of 3,4-dimethoxy-β-nitrostyrene were synthesized and identified including new compound 6. The effect of antimicrobial activity of 3,4-alkyloxy modification of β-nitrostyrene was investigated. A molecular docking was also performed to obtain information about their interactions with Protein Tyrosine Phosphatase 1B (PTP1B). PTP1B containing cysteine 215 and arginine 221 as essential active residues plays a key role in signaling pathways that regulate various cell functions of microorganisms, which also act as negative regulator in signaling pathways of insulin that are involved in type 2 diabetes and other metabolic diseases. Compound 5 and 6 were the most potent as fragment of PTP1B inhibitor based on molecular docking, but compound 5 was more effective against Candida albicans. These compounds interact with serine 216 and arginine 221 residues. However, further research is needed to investigate their potential medicinal use.

3,4-Dihydro-2(1H)-pyridones (3,4-DHPo) and their derivatives are privileged structures present in natural products, which has been increased its relevance due to its biological activity in front of a broad range of targets, but especially for its importance as synthetic precursors of a variety of compounds with marked biological activity. Taking into account the large number of contributions published over the years regarding this kind of heterocycle, here we presented a current view of 3,4-dihydro-2(1H)-pyridones (3,4-DHPo), which include general aspects such as those related to nomenclature, synthesis, and biological activity; but also highlighting the importance of DHPo as building blocks of other relevance structures.

Abstract: An efficient and environmentally Pumice as a new catalyst for designing of 3,4- dihydropyrimidin-2(1H) ones / thiones via one-pot multi component condensation of aromatic aldehydes, urea/ thiourea and ethyl acetoacetate or acetyl acetone in excellent yields (96-99 %). The advantages using of this new catalyst is very cheap, available, non-toxic, stable under thermal conditions, easy work-up, improved yields, the product of reaction is very pure without using chromatographic methods and solvent free conditions.

The three-component reaction of enaminones, benzaldehyde and hydrazine-HCl or four-component reaction of enaminones, benzaldehyde, hydrazine–HCl and ethyl cyanoacetate in water in the presence of catalytic amount of ammonium acetate has been devised as a straightforward , sustainable approach for the synthesis of 1-H-pyrazole, N-aminopyridine and pyrazol[3,4-b]pyridine derivatives . The key benefits of this approach is simple experimental procedure associated with cost effective and environmentally friendly techniques.

3,4-Dihydroquinolin-2(1H)-ones represent a class of valuable bioactive compounds with six-membered nitrogen-containing heterocyclic structures. The development of simple, mild and efficient synthetic methods has been widely concerned by synthetic chemists. In this review, we have summarized a series of different synthetic strategies for the synthesis of dihydroquinoline-2(1H)-ones via catalytic annulation of α,β-unsaturated N-arylamides in the past decade, including covering electrophilic cyclization, radical initiated cyclization and photochemical cyclization reactions. Besides, the substrate scope and mechanistic details are also discussed. This paper will provide a useful reference for the development of diverse synthesis methodologies of 3,4-dihydroquinolin-2(1H)-ones.

Antimicrobial resistance is on the rise, and there aren't enough new treatments to combat it. This might send the modern world back to the pre-antibiotic age. The molecular hybrids of pyrazolo[3,4-b]pyridine and triazole have been designed, synthesized, and analyzed for their drug-like molecule nature and in vitro analyses for their inhibition potentials against S. Aureus and K. Pneumoniae. The compounds CY-R2-25 and CY-R2-28 have been identified as the high potential molecules in this series based on in vitro experiments. CY-R2-25 has zone of inhibition values of 15 0.82 and 14 0.7, whilst CY-R2-28 has the zone of inhibition values of 18 0.95 and 16 0.82 against S. Aureus and K. Pneumoniae, respectively. MIC and MIB values for CY-R2-25 and CY-R2-28 against S. Aureus and K. Pneumoniae are 0.25 and 0.5, respectively.

We prepared poly(3,4-ethylenedioxythiophene) (PEDOT)-coated sulfonated polystyrene copolymer particles as efficient heat-shielding agents, which showed strong near-infrared (NIR) absorption, with high solid contents and good solution stability. The poly(styrene sulfonate -co-styrene) (P(SS-co-St)) copolymers were successfully synthesized via radical solution polymerization, and PEDOT-coated P(SS-co-St) (PEDOT:P(SS-co-St)) was synthesized via Fe⁺-catalyzed oxidative polymerization. PEDOT:P(SS-co-St) was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopies. The particle size and morphology of PEDOT:P(SS-co-St) were examined using transmission electron microscopy, dynamic light scattering, and zeta potential measurements. The maximum NIR-shielding efficiency of the film was 92.0% with 40% transmittance. The high solution stability of PEDOT:P(SS-co-St) make it an ideal candidate for heat-insulating materials that find application in semi-transparent heat-insulator-coated windows.

Abstract: Breast cancer is one of the leading causes of death in the female population due to the re-sistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubil-ity and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxy curcumin magnesium complex with cyclodex-trin (DiMeOC-Mg-BCD, 5) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media (PBS) was improved by a factor of 6x over the free metal complex (DiMeOC-Mg). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the MMP-2 and MMP-9, IL-6, and STAT3 expression levels on MDA MB 231 cell lines. Results of an antitumor assay in an in-ovo model showed up to 30% inhi-bition of tumour growth for breast cancer (MDA-MB-231) when using 5 (0.650 mg/Kg dose), and 17.29 % inhibition with the free homoleptic metal complex (1.5 mg/Kg dose, DiMeOC-Mg). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new DiMeOC-Mg-BCD exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butylhydroperoxide(TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM+10% FBS for 24 hours and pretreated with different concentrations of MDHB or N-acetyl-L-cysteine (NAC) for 4 hours prior to the addition of 40 μM TBHP for 24 hours. Cell viability was analyzed using the methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rate. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells

In Nitrate Vulnerable Zones (NVZ) site-specific techniques are needed to match N availability with durum wheat (Triticum turgidum subsp. durum Desf.) requirements. Enhanced-efficiency fertilizers (EEF) can improve efficient N supply and reduce leaching, thus contributing to sustainable agriculture. To study the effects of rates, sources and timings of nitrogen application, two-year field experiments were carried out at two Mediterranean NVZs of Central Italy (Pisa and Arezzo). The trial compared: i) two N rates: one based on the crop N requirements (NO), the other on the Action Programmes’ prescriptions of the two NVZ (NAP); ii) three N sources (urea, methylene urea (MU), and nitrification inhibitor (NI) 3,4-Dimethylpyrazole phosphate (DMPP); and two top-dressing timings (1st tiller visible and 1st node detectable). Grain yield and yield components were determined, together with N uptake. Results showed that: i) grain and biomass production were reduced with NAP at both locations; ii) urea performed better than slow-release fertilizers; iii) the best application time varied depending on N source and location: at Pisa enhanced-efficiency fertilizers achieved higher yields when applied earliest, while for urea the contrary was true; at Arezzo different N fertilizers showed similar performances between the two application timings. Different behaviors of top-dressing fertilizers at the two localities could be related to the diverse patterns of temperatures and rainfall. Therefore, optimal fertilization strategies vary according to environmental conditions.

By using the method of high-temperature solid-phase reaction, the new piezoceramic SrBi2Nb2-2xWxSnxO9 was obtained, in which partial substitution of niobium (Nb) atoms with Sn4+ and W6+ atoms in the compound SrBi2Nb2O9 took place in the octahedra of the perovskite layer (B-position). X-ray diffraction studies have shown that these compounds are single-phase SrBi2Nb2-2xWxSnxO9 (x = 0.1, 0.2) and two-phase SrBi2Nb2-2xWxSnxO9 (x = 0.3, 0.4), but they all had the structure of Aurivillius – Smolensky phases (ASPs) with similar parameters of orthorhombic elementary cells, corresponding to the spatial group A21am. The dependences on temperature of the relative permittivity ε/ε0 and the tangent of the loss angle tan d at different frequencies were measured.

Epoxy asphalt (EA) concrete is widely used in constructing long-span steel bridge pavements (SBDPs). This study aims to derive a fatigue damage evolution law, conducting an experimental investigation of SBDP. First, a general theoretical form of the fatigue damage evolution law of materials is established based on the thermal motion of atoms. Then, fatigue experiments demonstrate that this evolution law well represents the known damage–life relationships of SBDP. Taking into account the experimental relationships between damage and fatigue life under symmetrical cyclic loadings with different overload amplitudes and temperature variations, a detailed damage evolution law is deduced. Finally, the role of damage accumulation is discussed on the basis of the proposed damage evolution law for the extreme situation of heavy overload and severe environments. The results show that both heavy loading and falling temperatures increase the fatigue damage of SBDP considerably; therefore, SBDP should avoid heavy loading combined with winter temperatures. EA shows a fatigue life two to three times longer than that of modified matrix asphalt (SMA) or guss asphalt (GA). For the same thickness, EA pavement is demonstrated to be more suitable for an anti-fatigue design of large-span SBDP under high traffic flows and low temperatures.

Rhes is one of the most interesting proteins regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. It is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, several data showed that lack of Rhes enhanced cocaine and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson’s disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.

Modern organic synthesis is majorly focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-Mass spectroscopy. Major highlights of the reported work include: atom economical process, extremely milder reaction conditions, operational simplicity, high isolated yields, and excellent catalyst turnover number. The molecular docking studies suggest that the compound 4n has the hydrogen bonding, hydrophobic and π-pair interactions with the active site of active sites of CXT M 15 receptor.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or by a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalon- dianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichlorophenyl)- 7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was con-firmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computa-tional scheme. The results revealed that the rate limiting step is a cyclization process leading to the closure of 1,4-dihydropyridine ring with an activation barrier of 28.8 kcal/mol. Some of dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D . Additional-ly, ADMET parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Cattle occasionally develop brassica-associated liver disease (BALD) and photosensitisation when grazing turnip or swede (Brassica spp.) forage crops. The liver toxin in these brassica varieties has yet to be discovered. Progoitrin is the dominant glucosinolate in incriminated crops. Apart from goitrin, progoitrin hydrolysis yields the nitrile, 1-cyano-2-hydroxy-3-butene (CHB), and the epithionitrile, 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB). The two compounds were custom-synthesised. In a small pilot trial, New Zealand White rabbits were given either CHB or CHEB by gavage. Single doses of 0.75 mmol/kg of CHB or 0.25 mmol/kg of CHEB were subtoxic and elicited subclinical effects. Higher doses were severely hepatotoxic causing periportal to massive hepatic necrosis associated with markedly elevated serum liver biomarkers often resulting in severe illness or death within 24 h. The possibility that one or both of these hepatotoxic nitriles causes BALD in cattle requires further investigation.

Looking for effective synthetic methods for 1H-pyrazolo[3,4-b]quinolines preparation, we came across a procedure where in a three component reaction catalyzed by L-proline, 4-aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines are formed. These compounds can be easily oxidized to a fully aromatic system, which gave hope for a synthetic method that could replace e.g. Friedländer condensation, often used for this purpose, although severely limited by the availability of suitable substrates. However, after careful repetition of the procedures described in the publication, it turned out that the compounds described therein do not form at all. The actual compounds turned out to be 4,4-(phenylmethylene)-bis-(3-methyl-1-phenylpyrazol-5-oles). 4-Aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines were prepared by another method and used as standards to compare the products formed in the original procedure.

There is a lot of pressures from organizations to continually redesign the business processes and the technology infrastructure to support the organization, but to also help organizations manage competing stakeholder needs, changing objectives and behaviour, and so on. A key part of this is making sure that all their activities in the different components of the business are interconnected and that they are moving in the same direction. Enterprise Architecture (EA) is an effective way of dealing with the challenge of designing business activities and supporting IT. This paper will summarize the organization of EA and look more closely at some major components of EA: governance architecture, business architecture, information architecture and technical architecture and consider the overlap and constructive interaction involved. Enterprise Architecture can be best understood through business process redesign. So, it is useful to briefly review the leading frameworks for business process redesign, including COBIT from ISACA, LEAN from the Toyota Group, TOGAF from the Object-Management Group, and the Capgemini Integrated Architecture Framework (IAF). All these frameworks allow us to more successful transformation, to return to the central idea of this paper.