Quercetin protects human thyroid cells against cadmium toxicity

Various natural compounds have been successfully tested for preventing or counteracting the toxic effects of exposure to heavy metals. In this study, we analyzed the effects of cadmium chloride (CdCl2) on immortalized, non\u2010tumorigenic thyroid cells Nthy\u2010ori\u20103\u20101. We investigated the molecular mechanism underlying its toxic action as well as the potential protective effect of quercetin against CdCl2\u2010induced damage. CdCl2 suppressed cell growth in a dose\u2010 and time\u2010dependent manner (IC50 value ~10 \u3bcM) associated with a decrease in levels of phospho\u2010ERK. In addition, CdCl2 elicited an increase in reactive oxygen species (ROS) production and lipid peroxidation. A significant increase in GRP78, an endoplasmic reticulum (ER) stress\u2010related protein, was also observed. Supplementation of quercetin counteracted the growth\u2010inhibiting action of CdCl2 by recovering ERK protein phosphorylation levels, attenuating ROS overproduction, decreasing MDA content and reducing the expression of GRP78 in cells exposed to CdCl2. Thus, in addition to revealing the molecular effects involved in cadmium\u2010induced toxicity, the present study demonstrated, for the first time, a protective effect of quercetin against cadmium\u2010induced damages to normal thyroid cells

Highly Diastereoselective Multicomponent Synthesis of Spirocyclopropyl Oxindoles Enabled by Rare-Earth Metal Salts

The synthesis of polysubstituted spirocyclopropyl oxindoles using a series of rare-earth metal (REM) salts is reported. REMs, in particular Sc(OTf)3, allowed access to the target compounds by a multicomponent reaction with high diastereoselectivity (≤94:6:0:0). Density functional theory calculations on the model reaction are consistent with the observed selectivity and revealed that the special coordinating capabilities and the oxophilicity of the metal are key factors in inducing the formation of one main diastereoisomer.The authors thank Diana Cabrera, Sebastiaan van Liempd, and Juan M. Falcon-Perez from the CIC bioGUNE Metabolomics Platform for performing the UPLC-MS/MS analyses. The authors also acknowledge the Italian Ministry of University and Research (MUR) for Project SI.F.I.PA.CRO.DE. - Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE. (PON ARS01_00568, CUP: B29C20000360005) and for two doctoral grants. Moreover, the authors thank the University of Calabria and Calabria Region (PAC CALABRIA 2014–2020-Asse Prioritario 12, Azione B 10.5.12 CUP: H28D19000040006) for financial support. This research was also funded by MCIN/AEI/10.13039/501100011033 (Grant PID2021-125946OB-I00 to G.J.-O. and Severo Ochoa Excellence Accreditation CEX2021-001136-S to CIC bioGUNE)

Efficacy and Safety of Novel Aspirin Formulations: A Randomized, Double-Blind, Placebo-Controlled Study.

Low-dose aspirin represents the best option in the secondary prevention of coronary artery disease, but its extensive use in primary prevention is limited by the occurrence of gastric mucosal lesions and increased risk of bleeding. We investigated the safety profile of a novel sublingual aspirin formulation in 200 healthy volunteers, randomly assigned to ten (n = 20 each) different 7-day once-daily treatment regimens. Gastric mucosal injury based on the modified Lanza score (MLS), the histopathology of gastric mucosa and the serum determination of thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 levels were evaluated at basal as well as after 7 days of each placebo or aspirin treatment regimen. In Groups A and B (placebo-oral and sublingual, respectively), no changes in MLS and in gastric mucosal micro-vessel diameter were found at day 7. In contrast, in Groups C and D (oral standard aspirin-100 and 50 mg daily, respectively), the median MLS was significantly increased. Very few changes were found in Groups E and F (standard sublingual aspirin-100 and 50 mg, respectively). Groups G and H (oral administration of micronized collagen-cogrinded aspirin) showed gastric protection compared to Groups C and D. Moreover, Groups I and L (sublingual collagen-cogrinded aspirin-100 and 50 mg, respectively) showed a significant reduction (Group I) or total abolition (Group L) of gastric mucosal lesions and no difference compared to the standard one in serum TXB2 and urinary 11-dehydro-TXB2 levels. In conclusion, our data show that the new formulation leads to a better safety profile compared to standard aspirin, representing a better therapeutic option for extended use in primary and secondary prevention of cardiovascular diseases

Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review.

There is evidence demonstrating that heart failure (HF) occurs in 1-2% of the global population and is often accompanied by comorbidities which contribute to increasing the prevalence of the disease, the rate of hospitalization and the mortality. Although recent advances in both pharmacological and non-pharmacological approaches have led to a significant improvement in clinical outcomes in patients affected by HF, residual unmet needs remain, mostly related to the occurrence of poorly defined strategies in the early stages of myocardial dysfunction. Nutritional support in patients developing HF and nutraceutical supplementation have recently been shown to possibly contribute to protection of the failing myocardium, although their place in the treatment of HF requires further assessment, in order to find better therapeutic solutions. In this context, the Optimal Nutraceutical Supplementation in Heart Failure (ONUS-HF) working group aimed to assess the optimal nutraceutical approach to HF in the early phases of the disease, in order to counteract selected pathways that are imbalanced in the failing myocardium. In particular, we reviewed several of the most relevant pathophysiological and molecular changes occurring during the early stages of myocardial dysfunction. These include mitochondrial and sarcoplasmic reticulum stress, insufficient nitric oxide (NO) release, impaired cardiac stem cell mobilization and an imbalanced regulation of metalloproteinases. Moreover, we reviewed the potential of the nutraceutical supplementation of several natural products, such as coenzyme Q10 (CoQ10), a grape seed extract, Olea Europea L.-related antioxidants, a sodium-glucose cotransporter (SGLT2) inhibitor-rich apple extract and a bergamot polyphenolic fraction, in addition to their support in cardiomyocyte protection, in HF. Such an approach should contribute to optimising the use of nutraceuticals in HF, and the effect needs to be confirmed by means of more targeted clinical trials exploring the efficacy and safety of these compounds

Chemical approaches to inhibitors of isoprenoid biosynthesis: targeting farnesyl and geranylgeranyl pyrophosphate synthases

Post-translational lipid modifications farnesylation and geranylgeranylation of proteins (protein prenylation) have been identified to mediate critical events in cancer, cardiovascular disorders, malaria and bone disorders like osteoporosis. To date eight compounds are commercialized for the treatment of bone disorders, and there are considerable efforts to develop selective small molecules that inhibit protein prenylation. This review summarizes the approaches currently employed to synthesize new inhibitors of isoprenoid biosynthesis. Bisphosphonates are mainly prepared through reaction of carboxylic acids with phosphorus reagents, Michael addition to tetraethylvinylidenebisphosphonate and alkylation of tetralkylmethyl bisphosphonate. Approaches to non-bisphosphonate derivatives include a variety of methodologies depending on the structure of the target compound.This work was supported by the MINECO and FEDER Program (Madrid, Spain, project CTQ2016-76155-R) and the Gobierno de Aragon (Zaragoza, Spain. Bioorganic Chemistry Group. E-10). We thank the Italian Ministry of University and Scientific Research (MIUR) for a doctoral grant and the University of Calabria for financial support.Peer reviewe

Basal nitric oxide release attenuates cell migration of HeLa and endothelial cells

Nitric oxide (NO) generated by endothelial NO synthase (eNOS) is a key regulator of endothelial cell (EC) migration. Whereas the effects of acute NO generation are generally stimulatory, the role of chronic basal NO release has not been explored so far. Here, we addressed this question both in HeLa and in human endothelial cells. In stably transfected HeLa cells, inducibly expressing eNOS, expression of the enzyme per se blunted the phosphorylation of Akt/PKB in response to serum and strongly inhibited chemotaxis, an effect partially blocked by eNOS- and soluble guanylyl cyclase (sGC) inhibitors. Likewise, long-term pre-treatment of non-transfected HeLa cells with nanomolar concentrations of an NO donor inhibited subsequent migration, an effect blocked by sGC inhibition and mimicked by a cGMP analog. Finally, EC migration was stimulated by chronic pre-treatment with an eNOS inhibitor. Thus, in addition to its well-known stimulatory role, eNOS attenuates migration through basal long-term NO release

Telomere and telomerase modulation by bergamot polyphenolic fraction in experimental photoageing in human keratinocytes

Photoageing represents the addition of extrinsic chronic ultraviolet radiation-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. In this study, we evaluated the effect of 38% BPF, a highly concentrated extract of the bergamot fruit (Citrus bergamia) on UVB-induced photoageing by examining inflammatory cytokine expression, telomere length/telomerase alterations and cellular viability in human immortalized HaCaT keratinocytes. Our results suggest that 38% BPF protects HaCaT cells against UVB-induced oxidative stress and markers of photoageing in a dose-dependent manner and could be a useful supplement in skin care products. Together with antioxidant properties, BPF, a highly concentrated extract of the bergamot fruit, appears to modulate basic cellular signal transduction pathways leading to anti-proliferative, anti-aging and immune modulating response