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Primary hyperoxalurias (PHs) represent rare diseases associated with disruptions in glyoxylate metabolism within hepatocytes. Impaired glyoxylate detoxification in PH patients results in its accumulation and subsequent conversion into oxalate, a process catalyzed by the hepatic lactate dehydrogenase A enzyme ( h LDHA). Targeting this enzyme selectively in the liver using small organic molecules emerges as a potential therapeutic strategy for PH. However, achieving selective hepatic inhibition of h LDHA poses challenges, requiring precise delivery of potential inhibitors into hepatocytes to mitigate adverse effects in other tissues. Our recent efforts focused on the design of polymeric micelle nanocarriers tailored for the selective transport and release of h LDHA inhibitors into liver tissues. In this study, we synthesized and assessed the internalization and disaggregation dynamics of chitosan-based polymeric micelles in both hepatic and nonhepatic cell models using live-cell imaging. Our findings indicate that lactonolactone residues confer internalization capacity to the micelles upon exposure to cells. Moreover, we demonstrated the intracellular disaggregation capacity of these nanocarriers facilitated by the cystamine redox-sensitive linker attached to the polymer. Importantly, no cytotoxic effects were observed throughout the experimental time frame. Finally, our results underscore the higher selectivity of these nanocarriers for hepatic HepG2 cells compared to other nonhepatic cell models., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives ( 13 - 18 )( a - d ) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds ( 7 - 12 ), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines ( VIII ( a - d )) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC 50 values lower than 5 μM, and for four of them ( 16a , 18b , 18c and 18d ), IC 50 ≈ 1 μM. Additionally, all compounds with IC 50 < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them ( 15c , 15d and 16d ) being selective to the A isoform, with their hLDHB IC 50 > 100 μM, and the other thirteen behaving as double inhibitors.

The Japanese plum tree ( Prunus salicina Lindl.) is mainly cultivated in temperate areas of China and some European countries. Certain amounts of wood (from pruning works) are generated every year from this crop of worldwide commercial significance. The main objective of this work was to value this agricultural woody residue, for which the chemical composition of pruning wood extracts from six Japanese plum cultivars was investigated, and the antiproliferative activity of extracts and pure phenolics present in those extracts was measured. For the chemical characterization, total phenolic content and DPPH radical-scavenging assays and HPLC‒DAD/ESI‒MS analyses were performed, with the procyanidin (-)-ent-epicatechin-(2α→ O →7,4α→8)-epicatechin ( 5 ) and the propelargonidin (+)-epiafzelechin-(2β→ O →7,4β→8)-epicatechin ( 7 ) being the major components of the wood extracts. Some quantitative differences were found among plum cultivars, and the content of proanthocyanidins ranged from 1.50 (cv. 'Fortune') to 4.44 (cv. 'Showtime') mg/g of dry wood. Regarding the antitumoral activity, eight wood extracts and four phenolic compounds were evaluated in MCF-7 cells after 48 h of induction, showing the wood extract from cv. 'Songold' and (‒)-annphenone ( 3 ), the best antiproliferative activity (IC 50 : 424 μg/mL and 405 μg/mL, respectively).

A description of new antimicrobial agents suitable for food industries has become necessary, and natural compounds are being considered as promising sources of new active derivatives to be used with the aim of improving food safety. We have previously described desirable antimicrobial and antibiofilm activities against foodborne bacteria by analogs to A-type proanthocyanidins (PACs) with a nitro (NO 2 ) group at carbon 6 of the A-ring. We report herein the synthesis of eight additional analogs with chloro and bromo atoms at the A-ring and the systematic study of their antimicrobial and antioxidant activities in order to evaluate their possible application as biocides or food preservatives, as well as to elucidate new structure-activity relationships. The results from this study show that halogenated analogs to natural A-type proanthocyanidins rise above the nitro derivatives previously reported in their antimicrobial activities. Gram-positive bacteria are the most sensitive to all the analogs and combinations assayed, showing MICs from 10 to 50 μg/mL in most cases, as well as reductions in biofilm formation and the disruption of preformed biofilms of at least 75%. Some structure-activity relationships previously described have also been corroborated. Analogs with just one OH group at the B-ring show better antimicrobial activities than those with two OH groups, and those analogs with two or three OH groups in the whole structure are more active than those with four OH groups. In addition, the analogs with two OH groups at the B-ring and chloro at the A-ring are the most effective when antibiofilm activities are studied, especially at low concentrations.

We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For this study we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect against sphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell line tested, with GI 50 below 5 µM, being (5) the most promising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study about the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ricardo Daniel Enriz reports financial support was provided by National University of San Luis. Justo Cobo reports financial support was provided by University of Jaen. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Giardiasis is a parasitosis caused by Giardia lamblia with significant epidemiological and clinical importance due to its high prevalence and pathogenicity. The lack of optimal therapies for treating this parasite makes the development of new effective chemical entities an urgent need. In the search for new inhibitors of the adenylyl cyclase gNC1 obtained from G. lamblia , 14 extracts from Argentinian native plants were screened. Lepechinia floribunda and L. meyenii extracts exhibited the highest gNC1 inhibitory activity, with IC 50 values of 9 and 31 µg/mL, respectively. In silico studies showed rosmarinic acid, a hydroxycinnamic acid present in both mentioned species, to be a promising anti-gNC1 compound. This result was confirmed experimentally, with rosmarinic acid showing an IC 50 value of 10.1 µM. Theoretical and experimental findings elucidate the molecular-level mechanism of rosmarinic acid, pinpointing the key interactions stabilizing the compound-enzyme complex and the binding site. These results strongly support that rosmarinic acid is a promising scaffold for developing novel compounds with inhibitory activity against gNC1, which could serve as potential therapeutic agents to treat giardiasis.

The first chiral methodology enabling the separation of indacaterol enantiomers was developed in this work by cyclodextrin-electrokinetic chromatography. Indacaterol (IND) is a chiral drug marketed as a pure enantiomer. Then, the separation and quantification of each enantiomer is of great importance for the quality control of pharmaceutical formulations. After selecting the most suitable chiral selector and background electrolyte, two Box-Behnken designs were achieved to optimize the electrophoretic conditions using two different approaches to shorten analysis times: i) decreasing the capillary length, or ii) performing a short-end injection. Indacaterol enantiomers were separated in less than 5 min with a resolution value of 3.6 under the optimal separation conditions: 0.7% (m/v) carboxymethyl-α-cyclodextrin in 50 mM sodium formate buffer (pH 4.0) and using a short-end injection. Then, the analytical characteristics of the method were evaluated and LODs of 0.05 mg/L for S-IND and 0.04 mg/L for R-IND were achieved. Also, the method allowed the detection of a 0.1% enantiomeric impurity (S-IND) in the R-IND-based pharmaceutical formulations. The developed method was applied to the analysis of two pharmaceutical formulations. Percentages of 97 ± 3% and 103 ± 6% of R-IND with respect to the labeled amounts were found., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Glutamine is the most abundant free proteinogenic α-amino acid. It is naturally produced in the organism and acts as a precursor for the synthesis of different biologically important molecules (such as proteins or nucleotides). However, under stressful conditions, the organism is unable to produce it in enough amounts to function properly. Thus, glutamine (Gln)-based supplements have become increasingly popular over the last decade. Since legal regulations establish that amino acid-based dietary supplements must contain only the L-enantiomer and not the racemate, adequate chiral methodologies are required to achieve their quality control. In this work, an analytical methodology based on the use of micellar electrokinetic chromatography is proposed for the rapid enantiomeric determination of DL-Gln in dietary supplements. Using (+)-1-(9-fluorenyl)-ethyl chloroformate as a derivatizing agent and ammonium perfluorooctanoate as separation medium, the Gln diastereoisomers formed under optimal conditions were separated in 8 min with a resolution of 2.8. The analytical characteristics of the method were evaluated in terms of linearity, precision, accuracy, and limits of detection/quantitation, and they were found appropriate for the analysis of L-Gln-based dietary supplements., (© 2024 The Authors. Journal of Separation Science published by Wiley-VCH GmbH.)

Olacein (OLA), one of the main secoiridoids derived from extra virgin olive oil (EVOO), has been shown to modulate oxidative and inflammatory responses in various pathological conditions; however, its potential benefit in joint disorders such as rheumatoid arthritis (RA) is unknown. Therefore, this study was designed to evaluate the preventive role of the effects of an OLA-supplemented diet in the murine model of collagen-induced arthritis (CIA), delving into the possible mechanisms and signaling pathways involved. Animals were fed an OLA-enriched preventive diet for 6 weeks prior to CIA induction and until the end of the experimental time course. On day 43 after the first immunization, mice were sacrificed: blood was collected, and paws were histologically and biochemically processed. Dietary OLA prevented collagen-induced rheumatic bone, joint and cartilage conditions. Circulating matrix metalloproteinase (MMP)-3 and proinflammatory cytokine (IL-6, IL-1β, TNF-α, IL-17) levels were significantly decreased in the joint, as well as MMP-9 and cathepsin-K (CatK) expression in secoiridoid-fed animals. In addition, dietary OLA was able to decrease COX-2, mPGES-1 and iNOS protein expressions and, also, PGE 2 levels. The mechanisms possibly involved in these protective effects could be related to the activation of the Nrf-2/HO-1 axis and the inhibition of proinflammatory signaling pathways, including JAK-STAT, MAPKs and NF-κB, involved in the production of inflammatory and oxidative mediators. These results support the interest of OLA, as a nutraceutical intervention, in the management of RA.

Phenolic compounds play a key role in the health benefits of Extra Virgin Olive Oil (EVOO). Among these molecules, the focus has been recently put on (-)-oleocanthal and (-)-oleacein, for which anti-cancer and angiogenesis-related findings have been reported. Here, we explored the modulatory action of (-)-oleocanthal and (-)-oleacein on angiogenesis, the process by which new vessels are created from pre-existent ones, which is directly linked to tumor progression and other pathological conditions. Two in vivo models strongly sustained by angiogenesis, and an in vitro model of endothelial cells to study different steps of angiogenesis, were used. In vivo evidence pointed to the anti-angiogenic effects of both compounds in vivo. In vitro, (-)-oleacein and (-)-oleocanthal inhibited the proliferation, invasion, and tube formation of endothelial cells, and (-)-oleacein significantly repressed migration and induced apoptosis in these cells. Mechanistically, the compounds modulated signaling pathways related to survival and proliferation, all at concentrations of physiological relevance for humans. We propose (-)-oleacein and (-)-oleocanthal as good candidates for angioprevention and for further studies as modulators of angiogenesis in clinical interventions, and as interesting functional claims for the food industry. Chemical compounds studied in this article: Oleocanthal (PubChem CID: 11652416); Oleacein (PubChem CID: 18684078)., Competing Interests: Declaration of Competing Interest There are none., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The nano-LC technique is increasingly used for both fast studies on enantiomeric analysis and test beds of novel stationary phases due to the small volumes involved and the short conditioning and analysis times. In this study, the enantioseparation of 10 drugs from different families was carried out by nano-LC, utilizing silica with immobilized amylose tris(3-chloro-5-methylphenylcarbamate) column. The effect on chiral separation caused by the addition of different salts to the mobile phase was evaluated. To simultaneously separate as many enantiomers as possible, the effect of buffer concentration in the mobile phase was studied, and, to increase the sensitivity, a liquid-liquid microextraction based on the use of isoamyl acetate as sustainable extraction solvent was applied to pre-concentrate four chiral drugs from tap and environmental waters, achieving satisfactory recoveries (>70%)., (© 2023 Wiley-VCH GmbH.)

Developing new types of effective antimicrobial compounds derived from natural products is of interest for the food industry. Some analogs to A-type proanthocyanidins have shown promising antimicrobial and antibiofilm activities against foodborne bacteria. We report herein the synthesis of seven additional analogs with NO 2 group at A-ring and their abilities for inhibiting the growth and the biofilm formation by twenty-one foodborne bacteria. Among them, analog 4 (one OH at B-ring; two OHs at D-ring) showed the highest antimicrobial activity. The best results with these new analogs were obtained in terms of their antibiofilm activities: analog 1 (two OHs at B-ring; one OH at D-ring) inhibited at least 75% of biofilm formation by six strains at all of the concentrations tested, analog 2 (two OHs at B-ring; two OHs at D-ring; one CH 3 at C-ring) also showed antibiofilm activity on thirteen of the bacteria tested, and analog 5 (one OH at B-ring; one OH at D-ring) was able to disrupt preformed biofilms in eleven strains. The description of new and more active analogs of natural compounds and the elucidation of their structure-activity relationships may contribute to the active development of new food packaging for preventing biofilm formation and lengthening the food shelf life.

Human lactate dehydrogenase ( h LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, h LDHA and h LDHB are the predominant ones. In the last few years, h LDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. h LDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new h LDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives ( 42 - 70 ) by reaction between flavylium salts ( 27 - 35 ) and several nucleophiles ( 36 - 41 ). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC 50 values lower than 10 µM against h LDHA and better activity than our previously reported compound 2 . In order to know the selectivity of the synthesized compounds against h LDHA, their h LDHB inhibitory activities were also measured. In particular, compounds 58 , 62a , 65b , and 68a have shown the lowest IC 50 values against h LDHA (3.6-12.0 µM) and the highest selectivity rate (>25). Structure-activity relationships have been deduced. Kinetic studies using a Lineweaver-Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on h LDHA enzyme.

European plum tree (Prunus domestica L.) is cultivated in many countries for its delicious and nutritive fruit and, accordingly, certain amounts of wood (from pruning works) are generated every year. The main objective of this work was to value this agricultural woody residue, for which the chemical composition of pruning wood extracts from four European plum cultivars was investigated, and the human lactate dehydrogenase A (hLDHA) inhibitory activity of plum wood extracts and pure proanthocyanidins present in those extracts was measured. For the chemical characterization, total phenolic content and DPPH radical-scavenging assays and HPLC-DAD/ESI-MS analyses were performed, the procyanidin (-)-ent-epicatechin-(2α→O→7,4α→8)-catechin (4), the phenolic glucoside (-)-annphenone (3) and the flavan-3-ol catechin (1) being the major components of the wood extracts. Some quantitative and qualitative differences were found among plum cultivars, and the content of proanthocyanidins ranged from 1.51 (cv. 'Claudia de Tolosa') to 8.51 (cv. 'De la Rosa') mg g -1 of dry wood. For the hLDHA inhibitory activity, six wood extracts and six proanthocyanidins were evaluated by a UV spectrophotometric assay, compound 4 showing the highest inhibitory activity (IC 50 3.2 μM) of this enzyme involved on the excessive production of oxalate in the liver of patients affected by the rare disease Primary Hyperoxaluria., (© 2023 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

Purpose: To describe the eTEP approach for treating lateral primary and incisional hernia and show its results in a prospective series of cases., Methods: A descriptive prospective study with patients treated surgically for lateral hernias using eTEP approach. Every patient was operated by the same surgeon from November 2018 to December 2021. Inclusion criteria were primary and incisional hernia, lateral and W1 and W2 sized using the EHS classification. Exclusion criteria were W3 hernia, loss of domain, need to remove previous mesh, dystrophic or ulcerative skin, history of previous complex surgery. Details of the surgical technique are described., Results: 34 patients were operated. Median age was 65 years old and BMI, 29.9 (22.1-47.1). There were several locations being the most frequent L3 in 18 patients. The median length was 41 mm (10-129) and width, 44 mm (10-97). The median of defect-mesh ratio was 5.05 (0.9-447.64). TAR was practised in 21 patients (61.8%). Only one patient suffered a clinically relevant complication, being a hematoma (Dindo-Clavien II). 50% of patients were operated in ambulatory surgery. After a median follow-up of 13.5 months, only one recurrence has been reported (2.9%)., Conclusion: eTEP to treat lateral hernias is feasible and reproducible showing good results in terms of hernia recurrence and complications. A further prospective randomized clinical trial is needed to support these results., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Human lactate dehydrogenase A (hLDHA) is one of the main enzymes involved in the pathway of oxalate synthesis in human liver and seems to contribute to the pathogenesis of disorders with endogenous oxalate overproduction, such as primary hyperoxaluria (PH), a rare life-threatening genetic disease. Recent published results on the knockdown of LDHA gene expression as a safe strategy to ameliorate oxalate build-up in PH patients are encouraging for an approach of hLDHA inhibition by small molecules as a potential pharmacological treatment. Thus, we now report on the synthesis and hLDHA inhibitory activity of a new family of compounds with 2,8-dioxabicyclo[3.3.1]nonane core (23-42), a series of twenty analogues to A-type proanthocyanidin natural products. Nine of them (25-27, 29-34) have shown IC 50 values in the range of 8.7-26.7 µM, based on a UV spectrophotometric assay, where the hLDHA inhibition is measured according to the decrease in absorbance of the cofactor β-NADH (340 nm). Compounds 25, 29, and 31 were the most active hLDHA inhibitors. In addition, the inhibitory activities of those nine compounds against the hLDHB isoform were also evaluated, finding that all of them were more selective inhibitors of hLDHA versus hLDHB. Among them, compounds 32 and 34 showed the highest selectivity. Moreover, the most active hLDHA inhibitors (25, 29, 31) were evaluated for their ability to decrease the oxalate production by hyperoxaluric mouse hepatocytes (PH1, PH2 and PH3) in vitro, and the relative oxalate output at 24 h was 16% and 19 % for compounds 25 and 31, respectively, in Hoga1 -/- mouse primary hepatocyte cells (a model for PH3). These values improve those of the reference compound used (stiripentol). Compounds 25 and 31 have in common the presence of two hydroxyl groups at rings B and D and an electron-withdrawing group (NO 2 or Br) at ring A, pointing to the structural features to be taken into account in future structural optimization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Obesity is a risk factor for developing abdominal wall hernias and is associated with major postoperative complications, such as surgical site infection, delayed wound healing and recurrent hernia. Therefore, treating incisional hernia in this patient subgroup is a challenge., Methods: We conducted a comparative, prospective study on patients who underwent primary ventral hernia surgery or incisional hernia surgery through the extended totally extraperitoneal pathway, with body mass indices (BMIs) ≤ 30 (no obesity) and BMI > 30 (with obesity). We collected demographic data, preoperative and intraoperative variables, complication and recurrence rate, hospital stay and follow-up as postoperative data., Results: From May 2018 to December 2020, 74 patients underwent this surgery, 38 patients without obesity and 36 with obesity. The median area of the hernia defect measured by CT was 57 cm 2 and 93 cm 2 in patients without and with obesity, respectively (p = 0.012). The median follow-up was 16 months. One patient without obesity experienced some postoperative complication compared with four patients with obesity (p > 0.05). No patient without obesity had recurrent hernia compared with two patients with obesity (p > 0.05)., Conclusions: There were statistically significant differences between patients with and without obesity in the size of the hernia defect. However, there were no significant differences in terms of complications, hospital stay, postoperative pain or relapses. Therefore, the minimally invasive completely extraperitoneal approach for patients with obesity appears to be a safe procedure despite our study limitations. Studies with longer follow-ups and a greater number of patients are needed., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism that result in an excess of oxalate production by the oxidation of glyoxylate by the human lactate dehydrogenase A enzyme (hLDHA). The selective liver inhibition of this enzyme is one of the therapeutic strategies followed in the treatment of this disease. Even though several efforts have been recently performed using gene silencing by the RNA interference approach, small-molecule inhibitors that selectively reach hepatocytes are preferred since they present the advantages of a lower production cost and better pharmacological properties. In that sense, the design, synthesis, and physicochemical characterization by NMR, FTIR, DLS and TEM of two nanocarriers based on chitosan conjugates (1, non-redox-sensitive; 2, redox-sensitive) have been performed to (i) achieve the selective transport of hLDHA inhibitors into hepatocytes and (ii) their disruption once they reach the hepatocytes cytosol. Polymer 2 self-assembled into micelles in water and showed high drug loadings (19.8-24.5 %) and encapsulation efficiencies (31.9-40.8%) for the hLDHA inhibitors (I-III) tested. The non-redox-sensitive micelle 1 remained stable under different glutathione (GSH) concentrations (10 μM and 10 mM), and just a residual release of the inhibitor encapsulated was observed (less than 10 %). On the other hand, micelle 2 was sufficiently stable under in vitro physiological conditions (10 μM, GSH) but it quickly disassembled under the simulated reducing conditions present inside hepatocytes (10 mM GSH), achieving a 60 % release of the hLDHA inhibitor encapsulated after 24 h, confirming the responsiveness of the developed carrier to the high levels of intracellular GSH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Olive oil is a key component of the highly cardiovascular protective Mediterranean diet. (-)-Oleocanthal (OLC) is one of the most interesting phenolics present in virgin olive oil, and is formed from secoiridoid ligustroside during the processing of olives to yield the oil. Anti-inflammatory and anti-oxidant properties were identified shortly after OLC isolation, followed by the discovery of anti-tumor activities in a few non-hematopoietic cell lineages. Because of the scarcity of tissues potentially targeted by OLC analyzed so far and the unresolved mechanism(s) for OLC anti-tumor properties, we used a panel of 17 cell lines belonging to 11 tissue lineages to carry out a detailed examination of targets and pathways leading to cell growth inhibition and death. We found that OLC inhibits cell proliferation and induces apoptotic death as revealed by sub-G1 cell cycle analyses and Annexin-V staining in all lineages analyzed except lung carcinoma cell lines. Hematopoietic tumor cell lines, untested until now, were the most sensitive to OLC treatment, whereas non-transformed cells were significantly resistant to cell death. The specificity of OLC-mediated caspase activation was confirmed by blocking experiments and the use of transfectants overexpressing anti apoptotic genes. OLC triggers typical mediators of the intrinsic apoptotic pathway such as production of reactive oxygen species and mitochondrial membrane depolarization (Δ ψ m ). Complete blockade of caspases, however, did not result in parallel abrogation of Annexin-V staining, thus suggesting that complex mechanisms are involved in triggering OLC-mediated cell death. Our results demonstrate that OLC preferentially targets hematopoietic tumor cell lines and support that cell death is mediated by caspase-dependent and independent mechanisms.

A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24−31) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (24−31) were finally selected. These new pyrimidine-quinolone hybrids (24−31)(a−c) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1H)-ones 22/23(a−c) and 4-aryl-2-chloropyrimidines (1−4). The inhibitory activity against hLDHA of the synthesized hybrids was evaluated, resulting IC50 values of the U-shaped hybrids 24−27(a−c) much better than the ones of the 1,4-linked hybrids 28−31(a−c). From these results, a preliminary structure−activity relationship (SAR) was established, which enabled the design of novel 1,3-linked pyrimidine-quinolone hybrids (33−36)(a−c). Compounds 35(a−c), the most promising ones, were synthesized and evaluated, fitting the experimental results with the predictions from docking analysis. In this way, we obtained novel pyrimidine-quinolone hybrids (25a, 25b, and 35a) with good IC50 values (<20 μM) and developed a preliminary SAR.

In this study, new chiral ionic liquids based on the non-protein amino acid L-carnitine as cationic chiral counterpart and several anions (bis(trifluoromethane)sulfonimide (NTf 2 - ), L-lactate - or Cl - ) as counterions were synthesized. Moreover, three different salts based on L-carnitine were also synthesized and the other three were commercially acquired and used for comparison. The synthesized ionic liquids and salts were characterized by nuclear magnetic resonance, fourier transform infrared spectroscopy, high-performance liquid chromatography-mass spectrometry, and elemental analysis. Subsequently, they were used as additives to establish a γ-CD-based dual system for the enantiomeric separation of cysteine and homocysteine (previously derivatized with fluorenylmethoxycarbonyl chloride) by capillary electrokinetic chromatography. The effect of the nature of the anionic counterions and the presence of different substituents on the L-carnitine molecule on the chiral separation of both amino acids was investigated. The enantioseparations obtained with each dual system studied were compared in terms of the enantiomer effective mobilities (μ eff ) and the effective electrophoretic selectivity (α eff ). Practically, all the dual systems evaluated exhibited substantially improved enantioseparations for the two amino acids compared with the single γ-CD system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Bone disease in primary hyperparathyroidism is a clear indication for surgical treatment. However, it is not known whether surgery benefits hypercalcemic primary hyperparathyroidism and normocalcemic primary hyperparathyroidism equally. The aim of our study was to evaluate the bone changes in patients undergoing parathyroidectomy based on the biochemical profile 1 and 2 years after surgery., Methods: This prospective study included 87 consecutive patients diagnosed with primary hyperparathyroidism who underwent surgery between 2016 and 2018. Bone densitometry (1/3 distal radius, lumbar, and femur) and bone remodeling markers (osteocalcin, type 1 procollagen [P1NP], β-cross-linked telopeptide of type I collagen [BCTX]) were performed preoperatively and postoperatively. Postoperative changes in bone mineral density and bone markers were compared and evaluated according to the clinical characteristics and the individual biochemical profile., Results: One year after surgery, all patients showed an increase in bone mineral density at the lumbar site (mean, 0.029 g/cm 2 ; range, 0.017-0.04; P < .001) and femur neck (mean, 0.025 g/cm 2 ; range, 0.002-0.05; P < .001); however, there were no changes in the distal third of the radius (mean, -0.003 g/cm 2 ; range, -0.008 to 0.002; P = NS). There were no significant differences when comparing normocalcemic primary hyperparathyroidism and hypercalcemic primary hyperparathyroidism. Serum osteocalcin (37 ± 17.41), P1NP (67.53 ± 31.81) and BCTX (0.64 ± 0.37) levels were elevated before surgery. One year after the surgery, we observed a significant decrease in P1NP (33.05 ± 13.16, P = .001), osteocalcin (15.80 ± 6.19, P = .001), and BCTX (0.26 ± 0.32, P < .001) levels., Conclusion: Our findings indicate that parathyroidectomy has similar benefits for normocalcemic primary hyperparathyroidism and hypercalcemic primary hyperparathyroidism in terms of bone improvement. Although the most substantial improvement occurred during the first postoperative year in both groups, we consider that studies with longer follow-up are warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Phenolic compounds derived from olive oil have beneficial health properties against cancer, neurodegenerative, and metabolic diseases. Therefore, there are discrepancies in their impact on mitochondrial function that result in changes in oxidative capacity, mitochondrial respiration, and energetic demands. This review focuses on the versatile role of oleuropein, a potent antioxidant that regulates the AMPK/SIRT1/mTOR pathway to modulate autophagy/mitophagy and maintain metabolic homeostasis., Competing Interests: No potential conflict of interest was reported by the authors., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Cinnamtannin B-1 (C-B1) is a commercially-available trimeric A-type procyanidin with remarkable cellular actions mainly derived from its high radical scavenging activity. C-B1 is the main phenolic compound of laurel wood, which has previously been isolated by a combination of conventional chromatographic techniques. The first aim of this work was to find laurel trees containing as much C-B1 as possible, and learn about the influence of variables, such as gender and harvest time, on the production of C-B1 by the tree. It was found that all studied trees tend to give higher C-B1 percentages in the May-July period, from 6 % to 18 %, and lower ones around March (spring) and November (fall), from 1 % to 8 %. In a general way, it also seems that the female trees tend to produce a bit more C-B1 (from 2.8 % to 17.3 %) than male ones (from 1.7 % to 13.4 %). In addition, eight minor phenolic compounds [(-)-ent-catechin (1), (-)-ent-epicatechin-(4α→8)-ent-epicatechin (2), (epi)catechin-(4→8)-(epi)afzelechin-(4→8)-(epi)catechin (3), (+)-epiafzelechin-(4β→8)-epicatechin (4), (-)-epicatechin (5), (-)-afzelechin-(4α→8)-epicatechin (6), (epi)afzelechin-(4→8)-(epi)afzelechin-(4→8)-(epi)catechin (7) and (+)-epicatechin-(4β→8,2β→O-7)-epicatechin-(4β→8)-catechin (C-D1)] were found and quantified in the ethyl acetate extract of the wood samples. The second aim of this work was to improve the recovery of C-B1 from laurel wood. The use of the fast centrifugal partition chromatography (FCPC) technique has allowed for a recovery of 96 % of a technical-grade C-B1 (64 % in a previous protocol using conventional column chromatography on silica gel and size-exclusion chromatography)., (© 2022 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

The potential of Micellar Electrokinetic Chromatography to achieve enantiomeric separations is reviewed in this article. The separation principles and the most frequently employed separation strategies to achieve chiral separations by Micellar Electrokinetic Chromatography are described. The use of chiral micellar systems alone or combined with other micellar systems or chiral selectors, as well as of mixtures of achiral micellar systems with chiral selectors is discussed together with the effect of different additives present in the separation medium. Indirect methods based on the derivatization of analytes with chiral derivatizing reagents and the use of achiral micelles are also considered. Preconcentration techniques employed to improve sensitivity and the main approaches developed to facilitate the coupling with Mass Spectrometry are included. The most recent and relevant methodologies developed by chiral Micellar Electrokinetic Chromatography and their applications in different fields are presented., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Proanthocyanidins (PACs) are oligomers or polymers composed of units of flavanols. A-type PACs are a subclass of PACs characterized by the presence of at least a double linkage between two consecutive monomers of flavanol. These A-type PACs are found in some fruits and spices and possess potential health benefits as a result of their interesting biological activities, and consequently, their isolation and synthesis have given rise to great interest in the past. This review summarizes the synthetic efforts made to obtain both naturally occurring A-type PACs and their structurally simplified analogues. Most of the synthetic protocols reported involve the addition of a π-nucleophilic molecule over a molecule with two electrophilic carbons, such as a chalcone, a flavylium salt, or a flavanol derivative, among others. Synthesis of A-type PACs remains an issue at a very early stage of development compared to that of PACs with single linkages between monomers (B-type PACs), but the advances that are taking place in the last few years point to a significant development of the subject in the near future.

Wound healing is a complex and costly public health problem that should be timely addressed to achieve a rapid and adequate tissue repair avoiding or even eliminating potential pathogenic infection. Chronic infected non-healing wounds represent a serious concern for health care systems. Efficient wound dressings with tailored therapy having the best response and highest safety margin for the management of chronic non-healing wounds are still needed. The use of novel wound dressing materials has emerged as a promising tool to fulfil these requirements. In this work, asymmetric electrospun polycaprolactone (PCL)-based nanofibers (NFs) were decorated with electrosprayed poly(lactic-co-glycolic acid) microparticles (PLGA MPs) containing the natural antibacterial compound thymol (THY) in order to obtain drug eluting antimicrobial dressings having sustained release. The synthesized dressings successfully inhibited the in vitro growth of Staphylococcus aureus ATCC 25923, showing also at the same doses cytocompatibility on human dermal fibroblasts and keratinocyte cultures after treatment for 24 h, which was not observed when using free thymol. An in vivo murine excisional wound splinting model, followed by the experimental infection of the wounds with S. aureus and their treatment with the synthesized dressings, pointed to the reduction of the bacterial load in wounds after 7 days, though the total elimination of the infection was not reached. The findings indicated the relevance of the direct contact between the dressings and the bacteria, highlighting the need to tune their design considering the wound surface and the nature of the antimicrobial cargo contained., Competing Interests: Declaration of Competing Interest No potential conflicts of interest were disclosed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Two analytical methodologies based on the combined use of hydroxypropyl-β-cyclodextrin and two different amino acid-based chiral ionic liquids (tetrabutylammonium-L-lysine or tetrabutylammonium-L-glutamic acid) in electrokinetic chromatography were developed in this work to perform the enantioselective determination of econazole and sulconazole in pharmaceutical formulations. The influence of different experimental variables such as buffer concentration, applied voltage, nature and concentration of the ionic liquid, temperature and injection time, on the enantiomeric separation was investigated. The combination of hydroxypropyl-β-cyclodextrin and tetrabutylammonium-L-lysine under the optimized conditions enabled to achieve the enantiomeric determination of both drugs with high enantiomeric resolution (3.5 for econazole and 2.4 for sulconazole). The analytical characteristics of the developed methodologies were evaluated in terms of linearity, precision, LOD, LOQ and recovery showing good performance for the determination of both drugs which were successfully quantitated in pharmaceutical formulations. This work reports the first analytical methodology enabling the enantiomeric determination of sulconazole in pharmaceutical formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Since the first laparoscopic incisional hernia repair, several minimally invasive procedures have been developed in abdominal wall repair. In 2017, the extended totally extraperitoneal (eTEP) approach for abdominal wall repair was published. We present the results from eTEP implementation at two medical centers by one surgeon., Methods: Prospective descriptive study of the implementation of the eTEP approach, with transversus abdominis release (TAR) when needed. The surgical technique was initiated by accessing the space between the rectus abdominis muscle and posterior rectus sheath, connecting this space with the fatty preperitoneal space at the midline and the contralateral retrorectal space. Identification and dissection of the hernia sac is performed in the created cavity. Additionally, posterior component release in a TAR fashion could be done. Finally, closure of posterior plane and linea alba is completed and mesh prosthesis is deployed along the whole dissected space., Results: Forty patients underwent an eTEP procedure with 20 supraumbilical defects, 10 infraumbilical and 10 lateral hernias. Sixteen cases required a TAR technique. Mean operative time was 126minutes. Median pain reported the first postoperative day was 3 on the visual analogue scale. Median length of stay was 1 day and mean follow-up was 10 months. Only one patient developed recurrence, and two patients underwent reoperation., Conclusions: Implementation of eTEP in abdominal wall repair is safe. Preliminary outcomes of the eTEP approach in ventral hernia repair show good pain control with less hospital stay., (Copyright © 2020 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.)

Four amino acid chiral ionic liquids were evaluated in dual systems with hydroxypropyl-β-cyclodextrin to investigate the enantioseparation by CE of a group of seven drugs as model compounds (duloxetine, verapamil, terbutaline, econazole, sulconazole, metoprolol, and nadolol). The use of two of these chiral ionic liquids (tetramethylammonium L-Lysine ([TMA][L-Lys]) and tetramethylammonium L-glutamic acid ([TMA][L-Glu])) as modifiers in CE is reported for the first time in this work whereas tetrabutylammonium L-lysine ([TBA][L-Lys]) and tetrabutylammonium L-glutamic acid ([TBA][L-Glu]) were employed previously in CE although very scarcely. The effect of the nature and the concentration of each ionic liquid added to the separation buffer containing the neutral cyclodextrin on the enantiomeric resolution and the migration time obtained for each drug, was investigated. A synergistic effect was observed when combining each chiral ionic liquid with hydroxypropyl-β-cyclodextrin in the case of the five compounds for which the cyclodextrin showed enantiomeric discrimination power when used as sole chiral selector (duloxetine, verapamil, terbutaline, econazole, sulconazole). Buffer concentration and pH, temperature and separation voltage were varied in order to optimize the enantiomeric separation of these five compounds using dual systems giving rise to resolutions ranging from 1.1 to 6.6., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To prepare efficient antibacterial carvacrol (CAR) and thymol (THY)-loaded electrospun polycaprolactone (PCL)-based wound dressings. Approach: Using electrospinning we were able to prepare wound dressings with antimicrobial action thanks to their large surface per volume ratio, which allows their loading with therapeutic amounts of active principles. By nuclear magnetic resonance we demonstrated that the antimicrobial compounds are donors of hydrogen bonds to the ester functional group in PCL, which acts as acceptor and that intermolecular interaction is responsible for the high drug loading achieved. Results: Those mats loaded with CAR and THY without the use of solubilizing agents were able to completely eradicate both Gram-positive ( Staphylococcus aureus ATCC 25923) and Gram-negative ( Escherichia coli S17 strain) bacteria at doses inferior to the ones needed when using the free nonsupported compounds. A superior antimicrobial action was observed for THY and CAR against Gram-negative bacteria than against Gram-positive bacteria, despite the higher hydrophilicity of the outer layer of Gram-negative bacteria. Innovation: We demonstrate that a direct contact between the bacteria and the dressing is required to elicit antimicrobial action. We also evaluated drug loadings by gas chromatography coupled with mass spectrometry and nuclear magnetic resonance validating a new analytical approach. Finally we were able to visualize the pathogenic bacteria on the dressings by confocal microscopy. Conclusion: The interaction between the PCL-based mat and the pathogenic bacteria is a key issue to achieve complete pathogen eradication. Under no-contact conditions, released CAR or THY from the electrospun mats did not exert any antimicrobial action at the doses tested., Competing Interests: All authors contributed toward writing this article, and no ghostwriters were used to write this article., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

Triple negative breast cancer is an aggressive type of cancer that does not respond to hormonal therapy and current therapeutic strategies are accompanied by side effects due to cytotoxic actions on normal tissues. Therefore, there is a need for the identification of anti-cancer compounds with negligible effects on non-tumoral cells. Here we show that (-)‑oleocanthal (OLCT), a phenolic compound isolated from olive oil, selectively impairs MDA-MB-231 cell proliferation and viability without affecting the ability of non-tumoral MCF10A cells to proliferate or their viability. Similarly, OLCT selectively impairs the ability of MDA-MB-231 cells to migrate while the ability of MCF10A to migrate was unaffected. The effect of OLCT was not exclusive for triple negative breast cancer cells as we found that OLCT also attenuate cell viability and proliferation of MCF7 cells. Our results indicate that OLCT is unable to induce Ca 2+ mobilization in non-tumoral cells. By contrast, OLCT induces Ca 2+ entry in MCF7 and MDA-MB-231 cells, which is impaired by TRPC6 expression silencing. We have found that MDA-MB-231 and MCF7 cells overexpress the channel TRPC6 as compared to non-tumoral MCF10A and treatment with OLCT for 24-72 h downregulates TRPC6 expression in MDA-MB-231 cells. These findings indicate that OLCT impairs the ability of breast cancer cells to proliferate and migrate via downregulation of TRPC6 channel expression while having no effect on the biology of non-tumoral breast cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)