δ-Valerobetaine (δVB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk δVB on human colorectal cancer cells. ...CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3 kDa milk extract, δVB (2 mM) or milk+δVB up to 72 h. Results showed a time- and dose-dependent capability of δVB to inhibit cancer cell viability, with higher potency in LoVo cells. Treatment with milk+δVB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, δVB also increased necrosis (P < 0.01) and when used in combination with milk it improved its activity on live cell reduction (P < 0.05) and necrosis (P < 0.05). δVB-enriched milk activated caspase 3, caspase 9, Bax/Bcl-2 apoptotic pathway and reactive oxygen species (ROS) production, whereas no effects on ROS generation were observed in CCD 841 CoN cells. The altered redox homeostasis induced by milk+δVB was accompanied by upregulation of sirtuin 6 (SIRT6). SIRT6 silencing by small interfering RNA blocked autophagy and apoptosis activated by milk+δVB, unveiling the role of this sirtuin in the ROS-mediated apoptotic LoVo cell death.
Benzodiazepines, including temazepam are described as TSPO antagonists. In fact, TSPO was initially described as a peripheral benzodiazepine receptor (PBR) with a secondary binding site for diazepam. ...TSPO is a potential imaging target of neuroinflammation because there is an amplification of the expression of this receptor.
Herein, we developed a novel fluorinated benzodiazepine ligand,
FFluoroethyltemazepam (
FF-FETEM), for positron emission tomography (PET) imaging of translocator protein (18 kDa).
FF-FETEM was radiolabelled with an automated synthesizer via a one-pot procedure. We conducted a
FF-aliphatic nucleophilic substitution of a tosylated precursor followed by purification on C18 and Alumina N SPE cartridges. Quality control tests was also carried out.
We obtained 2.0-3.0% decay-uncorrected radiochemical activity yield (3.7% decay-corrected) within the whole synthesis time about 33 min. The radiochemical purity of
FF-FETEM was over 90% by TLC analysis.
This automated procedure may be used as basis for future production of
FF-FETEM for preclinical PET imaging studies.
Hydrogen sulfide (H2S) is an endogenous gasotransmitter recently emerged as an important regulatory mediator of numerous human cell functions in health and in disease. In fact, much evidence has ...suggested that hydrogen sulfide plays a significant role in many physio-pathological processes, such as inflammation, oxidation, neurophysiology, ion channels regulation, cardiovascular protection, endocrine regulation, and tumor progression. Considering the plethora of physiological effects of this gasotransmitter, the protective role of H2S donors in different disease models has been extensively studied. Based on the growing interest in H2S-releasing compounds and their importance as tools for biological and pharmacological studies, this review is an exploration of currently available H2S donors, classifying them by the H2S-releasing-triggered mechanism and highlighting those potentially useful as promising drugs in the treatment of cardiovascular diseases.
4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO
-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in ...the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera's method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined.
Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two ...others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.
We recently identified 6-nitrodopamine and other nitro-catecholamines (6-nitrodopa, 6-nitroadrenaline), indicating that the endothelium has the ability to nitrate the classical catecholamines ...(dopamine, noradrenaline, and adrenaline). In order to investigate whether drugs could be subject to the same nitration process, we synthesized 4-nitro- and 7-nitropropranolol as probes to evaluate the possible nitration of the propranolol by the endothelium. The separation of the enantiomers in very high yields and excellent enantiopurity was achieved by chiral HPLC. Finally, we used Riguera's method to determine the absolute configuration of the enantiomers, through double derivatization with MPA and NMR studies.
In Naples, particulate matter PM10 associated with polycyclic aromatic hydrocarbons (PAHs) in ambient air were determined in urban background (NA01) and urban traffic (NA02) sites.
The principal ...objective of the study was to determine the concentration and distribution of PAHs in PM10 for identification of their possible sources (through diagnostic ratio - DR and principal component analysis - PCA) and an estimation of the human health risk (from exposure to airborne TEQ). Airborne PM10 samples were collected on quartz filters using a Low Volume Sampler (LVS) for 24 h with seasonal samples (autumn, winter, spring and summer) of about 15 days each between October 2012 and July 2013. The PM10 mass was gravimetrically determined. The PM10 levels, in all seasons, were significantly higher (P < 0.001) in the urban-traffic site (NA02) than in the urban-background site (NA01). The filters were then extracted with dichloromethane using an ultrasonicator (SONICA) to perform a detailed characterization of 12 priority PAHs proposed by the USEPA, by gas chromatography-mass spectrometer (GC-MS) analysis.
The concentration of BenzoaPyrene, BaP (EU and National limit value: 1 ng m−3 in PM10), varied from 0.065 ng m−3 during autumn time to 0.872 ng m−3 in spring time (NA01) and from 0.120 ng m−3 during autumn time to 1.48 ng m−3 of winter time (NA02) with four overshoots.
In NA02 the trend of Σ12 PAHs was comparable to NA01 but were observed higher values than NA01. In fact, the mean concentration of Σ12 PAHs, in urban-traffic site was generally 2 times greater than in urban-background site in all the campaigns.
PAHs with 5 and 6 ring, many of which are suspected carcinogens or genotoxic agents, (i.e BenzoaPyrene, Indeno1,2,3-cdPyrene, BenzobFluoranthene, BenzokFluoranthene and Benzog,h,iPerylene), had a large contribution (∼50–55%) of total PAHs concentration in PM10 in two sites and in each of the campaigns.
Diagnostic ratio analysis and PCA suggested a substantial contributions from traffic emission with minimal influence from coal combustion and natural gas emissions. In particular diesel vehicular emissions were the major source of PAHs at the studied sites. The use of Toxicity Equivalence Quantity (TEQ) concentration provide a better estimation of carcinogenicity activities; health risk to adults and children associated with PAHs inhalation was assessed by taking into account the lifetime average daily dose and corresponding incremental lifetime cancer risk (ILCR). The ILCR was within the acceptable range (10−6–10−4), indicating a low health risk to residents in these areas.
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•Concentrations of PM10 and PAHs were mean high during winter time in two sites.•5 and 6 ring PAHs had a large contribute of total PAHs concentration in PM10.•Diagnostic ratio analysis and PCA suggested a substantial contributions from traffic emission.•Toxicity equivalent level based on PAHs revealed a low risk to residents in these areas.
Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane ...sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention.
HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks.
Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory.
The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period.
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•Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3.•8 weeks after HI induction in P7 mice, NCX pharmacological stimulation reduced infarct volume.•Neurounina chronically administered is effective in reducing brain damage with a 7 h time window.•The NCX activator neurounina induces an increased expression of NCX3.
Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various ...pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.
Serotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. Thus, the discovery of novel ...compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT
and 5-HT
receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER
cells.
Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT
receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7.
We found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER
cells (IC
range 10.2 μM - 99.2 μM) compared to SKBR3 (IC
range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC
range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF.
These results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER
BC patients.
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