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Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.
Ruscica, M, Pavanello, C, Gandini, S, Macchi, C, Botta, M, Dall'Orto, D, Del Puppo, M, Bertolotti, M, Bosisio, R, Mombelli, G, et al
Nutrition journal. 2019;18(1):13
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Plain language summary
Probiotics have been shown to reduce total cholesterol (TC) and low-density lipoprotein (LDL-C – often called ‘bad’ cholesterol) in people with moderately raised cholesterol levels. A specific strain of probiotic called Bifidobacterium longum BB536, may decrease TC and LDL-C by reducing the reabsorption of cholesterol from the intestine, and, combined with other natural supplements, may be useful to manage high cholesterol in people at low risk of heart disease. This study was conducted to evaluate the effect of a nutraceutical (Lactoflorene Colesterolo®), containing Bifidobacterium longum BB536 (1bn CFUs) combined with red yeast rice (RYR) extract (10 mg/day monacolin K), niacin (16mg) and coenzyme Q10 (20mg) on levels of cholesterol and fats in the blood. This was a 12-week randomised, parallel, double-blind, placebo-controlled study, in which 33 adults at low risk of heart disease were given either the Bifidobacterium combination, or a placebo. Treatment with the Bifidobacterium combination significantly reduced total cholesterol by 16.7%, LDL-C by 25.7%, non-HDL-C by 24% and apolipoprotein-B by 17%. Triglycerides, HDL-C, apolipoprotein AI, lipoprotein (a) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were unchanged. Markers of cholesterol synthesis and absorption suggested that a reduction in the synthesis of cholesterol had occurred without increased absorption of cholesterol. No adverse effects were reported in the study and the compliance rate was high at 97%. The use of nutraceuticals in the prevention of cardiovascular disease, as well as in other areas related to chronic diseases like cancer, is currently expanding.
Abstract
BACKGROUND Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10 mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption. METHODS A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70 years) in primary CV prevention and low CV risk (SCORE 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200 mg/dL) were randomly allocated to either nutraceutical (N = 16) or placebo (N = 17). RESULTS Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (- 16.7%), LDL-C (- 25.7%), non-HDL-C (- 24%) (all p < 0.0001), apoB (- 17%, p = 0.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed. CONCLUSIONS A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects. TRIAL REGISTRATION NCT02689934 .
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From lipoprotein apheresis to proprotein convertase subtilisin/kexin type 9 inhibitors: Impact on low-density lipoprotein cholesterol and C-reactive protein levels in cardiovascular disease patients.
Zenti, MG, Altomari, A, Lupo, MG, Botta, M, Bonora, E, Corsini, A, Ruscica, M, Ferri, N
European journal of preventive cardiology. 2018;(17):1843-1851
Abstract
In this observational study, we compared the effect of lipoprotein apheresis and evolocumab or alirocumab on levels of lipoprotein cholesterol, triglycerides and inflammatory markers (C reactive protein and interleukin 6) in cardiovascular patients ( n = 9). Patients were monitored during the last year of lipoprotein apheresis followed by six months of treatment with proprotein convertase subtilisin/kexin type 9 inhibitors. The biochemical parameters were determined pre- and post- every apheresis procedure for 12 months and then after one, three and six months of treatment with evolocumab (140 mg every two weeks [Q2W]) or alirocumab (75 mg or 150 mg every two weeks [Q2W]). Lipoprotein apheresis significantly reduced low-density lipoprotein cholesterol levels from 138 ± 32 mg/dl to 46 ± 16 mg/dl ( p < 0.001), with an inter-apheresis level of 114 ± 26 mg/dl. Lipoprotein(a) was also reduced from a median of 42 mg/dl to 17 mg/dl ( p < 0.01). Upon anti-proprotein convertase subtilisin/kexin type 9 therapy, low-density lipoprotein cholesterol levels were similar to post-apheresis (59 ± 25, 41 ± 22 and 42 ± 21mg/dl at one, three and six months, respectively) as well as those of lipoprotein(a) (18 mg/dl). However, an opposite effect was observed on high-density lipoprotein cholesterol levels: -16.0% from pre- to post-apheresis and +34.0% between pre-apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors. Apheresis significantly reduced high-sensitivity C-reactive protein levels (1.5 ± 1.2 mg/l pre-apheresis to 0.6 ± 0.6 mg/l post-apheresis), while no changes were found upon proprotein convertase subtilisin/kexin type 9 mAbs administration. In conclusion, our study demonstrated that, by switching from lipoprotein apheresis to anti-proprotein convertase subtilisin/kexin type 9 therapies, patients reached similar low-density lipoprotein cholesterol and lipoprotein(a) levels, increased those of high-density lipoprotein cholesterol, and showed no changes on high-sensitivity C-reactive protein.
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Nucleocapsid Protein: A Desirable Target for Future Therapies Against HIV-1.
Mori, M, Kovalenko, L, Lyonnais, S, Antaki, D, Torbett, BE, Botta, M, Mirambeau, G, Mély, Y
Current topics in microbiology and immunology. 2015;:53-92
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Abstract
The currently available anti-HIV-1 therapeutics is highly beneficial to infected patients. However, clinical failures occur as a result of the ability of HIV-1 to rapidly mutate. One approach to overcome drug resistance is to target HIV-1 proteins that are highly conserved among phylogenetically distant viral strains and currently not targeted by available therapies. In this respect, the nucleocapsid (NC) protein, a zinc finger protein, is particularly attractive, as it is highly conserved and plays a central role in virus replication, mainly by interacting with nucleic acids. The compelling rationale for considering NC as a viable drug target is illustrated by the fact that point mutants of this protein lead to noninfectious viruses and by the inability to select viruses resistant to a first generation of anti-NC drugs. In our review, we discuss the most relevant properties and functions of NC, as well as recent developments of small molecules targeting NC. Zinc ejectors show strong antiviral activity, but are endowed with a low therapeutic index due to their lack of specificity, which has resulted in toxicity. Currently, they are mainly being investigated for use as topical microbicides. Greater specificity may be achieved by using non-covalent NC inhibitors (NCIs) targeting the hydrophobic platform at the top of the zinc fingers or key nucleic acid partners of NC. Within the last few years, innovative methodologies have been developed to identify NCIs. Though the antiviral activity of the identified NCIs needs still to be improved, these compounds strongly support the druggability of NC and pave the way for future structure-based design and optimization of efficient NCIs.
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Structure prediction and validation of the ERK8 kinase domain.
Strambi, A, Mori, M, Rossi, M, Colecchia, D, Manetti, F, Carlomagno, F, Botta, M, Chiariello, M
PloS one. 2013;(1):e52011
Abstract
Extracellular signal-regulated kinase 8 (ERK8) has been already implicated in cell transformation and in the protection of genomic integrity and, therefore, proposed as a novel potential therapeutic target for cancer. In the absence of a crystal structure, we developed a three-dimensional model for its kinase domain. To validate our model we applied a structure-based virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit compounds confirmed that a high percentage of the identified scaffolds was able to inhibit ERK8. We also confirmed an ATP competitive mechanism of action for the two best-performing molecules. Ultimately, we identified an ERK8 drug-resistant "gatekeeper" mutant that corroborated the predicted molecular binding mode, confirming the reliability of the generated structure. We expect that our model will be a valuable tool for the development of specific ERK8 kinase inhibitors.
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Synthesis, biological activity, and ADME properties of novel S-DABOs/N-DABOs as HIV reverse transcriptase inhibitors.
Radi, M, Pagano, M, Franchi, L, Castagnolo, D, Schenone, S, Casaluce, G, Zamperini, C, Dreassi, E, Maga, G, Samuele, A, et al
ChemMedChem. 2012;(5):883-96
Abstract
Previous studies aimed at exploring the SAR of C2-functionalized S-DABOs demonstrated that the substituent at this position plays a key role in the inhibition of both wild-type RT and drug-resistant enzymes, particularly the K103N mutant form. The introduction of a cyclopropyl group led us to the discovery of a potent inhibitor with picomolar activity against wild-type RT and nanomolar activity against many key mutant forms such as K103N. Despite its excellent antiviral profile, this compound suffers from a suboptimal ADME profile typical of many S-DABO analogues, but it could, however, represent a promising candidate as an anti-HIV microbicide. In the present work, a new series of S-DABO/N-DABO derivatives were synthesized to obtain additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. In vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) were also experimentally evaluated for the most interesting compounds to obtain a reliable indication of their plasma levels after oral administration.
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Lanthanide(III) complexes with ligands derived from a cyclen framework containing pyridinecarboxylate pendants. The effect of steric hindrance on the hydration number.
Rodríguez-Rodríguez, A, Esteban-Gómez, D, de Blas, A, Rodríguez-Blas, T, Fekete, M, Botta, M, Tripier, R, Platas-Iglesias, C
Inorganic chemistry. 2012;(4):2509-21
Abstract
Two new macrocyclic ligands, 6,6′-((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2DODPA) and 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb(DODPA)](PF6)·H2O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (q) obtained from luminescence lifetime measurements in aqueous solution of the Eu(III) and Tb(III) complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H2Me-DODPA are q = 0. The structure of the complexes in solution has been investigated by 1H and 13C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb(III) complex [Λ(λλλλ)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb(III)-induced paramagnetic 1H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd(Me-DODPA)]+ are typical of a complex with q = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd(DODPA)]+ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature 17O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd(DODPA)]+. The results show that this system is endowed with a relatively fast water exchange rate k(ex)(298) = 58 × 10(6) s(–1).
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Use of virtual screening for discovering antiretroviral compounds interacting with the HIV-1 nucleocapsid protein.
Mori, M, Schult-Dietrich, P, Szafarowicz, B, Humbert, N, Debaene, F, Sanglier-Cianferani, S, Dietrich, U, Mély, Y, Botta, M
Virus research. 2012;(2):377-87
Abstract
The HIV-1 nucleocapsid protein (NC) is considered as an emerging drug target for the therapy of AIDS. Several studies have highlighted the crucial role of NC within the viral replication cycle. However, although NC inhibition has provided in vitro and in vivo antiretroviral activity, drug-candidates which interfere with NC functions are still missing in the therapeutic arsenal against HIV. Based on previous studies, where the dynamic behavior of NC and its ligand binding properties have been investigated by means of computational methods, here we used a virtual screening protocol for discovering novel antiretroviral compounds which interact with NC. The antiretroviral activity of virtual hits was tested in vitro, whereas biophysical studies elucidated the direct interaction of most active compounds with NC(11-55), a peptide corresponding to the zinc finger domain of NC. Two novel antiretroviral small molecules capable of interacting with NC are presented here.
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Mn(II) complexes of novel hexadentate AAZTA-like chelators: a solution thermodynamics and relaxometric study.
Tei, L, Gugliotta, G, Fekete, M, Kálmán, FK, Botta, M
Dalton transactions (Cambridge, England : 2003). 2011;(9):2025-32
Abstract
Three novel chelators based on the 6-amino-6-methylperhydro-1,4-diazepine scaffold and possessing three pendant N-acetic or N-α-methylacetic acid have been synthesised. The ligands contain six donor atoms for complexation of Mn(II) ions and thus potentially leave an additional site for coordination of a water molecule. The protonation constants of the ligands and the stability constants of their complexes formed with Mn(II) ion were determined by pH-potentiometric titrations in 0.15 M NaCl solution at 25 °C and compared to those of the parent AAZTA ligand (AAZTA = 6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid). In spite of the similar value of the total basicity (Σlog K), the values of the stability constants of the Mn(II)AAZTA-like complexes are more than three orders of magnitude lower than that of MnAAZTA (log K(MnL) = 14.19). A detailed (1)H and (17)O NMR relaxometric study was carried out on the Mn(II) complexes in aqueous solution as a function of pH, temperature and magnetic field strength. The (1)H NMRD profiles of all the complexes show a similar shape, typical of low-molecular weight systems, but amplitudes that markedly differ to indicate a different degree of hydration. A similar behaviour is shown by the (17)O NMR transverse relaxation rates and chemical shift data as a function of temperature. The experimental data can be rationalised by considering the presence in solution of a mixture of two isomeric species differing in coordination number (7 and 6) and in the number (1 and 0) of bound water molecules. Whereas this type of coordination equilibrium has been previously reported for lanthanide(III) complexes, it is observed for the first time on Mn(II) chelates.
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A1 receptors ligands: past, present and future trends.
Schenone, S, Brullo, C, Musumeci, F, Bruno, O, Botta, M
Current topics in medicinal chemistry. 2010;(9):878-901
Abstract
Adenosine is a neuromodulator that interacting with four receptors, A(1), A(2A), A(2B) and A(3), is involved in the regulation of several biological functions in different organs and tissues, including the central nervous system, the cardiovascular system and the airways; many pathophysiological states are associated with changes of adenosine levels. For these reasons pharmaceutical companies and academicians performed intense efforts to obtain agonists, antagonists and allosteric enhancers selective for each adenosine receptor subtypes as potential clinical candidates. In fact, therapeutic modulation of the adenosine system could offer the possibility of a "soft" treatment of different diseases, but, due to the ubiquitous distribution of adenosine and of its receptors, the challenge in therapy development depends from specificity for the different receptor subtypes. Some A(1) agonists and antagonists, very potent and selective, reached clinical trials for the treatment of different diseases. A(1) agonists are clinical candidates for atrial arrhythmias, angina, type 2 diabetes and in pain management, while A(1) antagonists are in study as potassium-sparing diuretics with kidney-protecting properties and in chronic heart diseases. Several reviews, recently published and herein cited reported in detail the biological and clinical aspects of such molecules. This review focuses on the A(1) adenosine receptor (A(1)AR) ligands, both agonists and antagonists, appeared in the literature in the last few years, together with their potential therapeutic application, pointing the attention on their chemical structures and SAR (Structure Activity Relationship) and also reporting new findings on preclinical or clinical trials of some important A(1)AR ligands synthesized in the past.
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New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms.
Schenone, S, Brullo, C, Botta, M
Current medicinal chemistry. 2010;(13):1220-45
Abstract
Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr-Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors. An alternative approach is the use of other compounds that do not bind directly to the Bcr-Abl protein; instead, these molecules act on several downstream pathways, regulated by or linked in different ways to Bcr-Abl, that lead to the malignant transformation of the cells. For this reason, farnesyl transferase inhibitors, MAPK inhibitors, Rac guanosine triphosphatase inhibitors, PI3K inhibitors, JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators and apoptosis inducers have been tested, alone or in combination with ATP-competitive inhibitors, against CML cell lines. This review discusses compounds that act on Bcr-Abl or different cell pathways and reports on the molecules active against the T315I mutation, particularly the most recent findings in this field. New molecules that are claimed by recent patents to be active on this mutation are also reported. When possible, the review will focus on medicinal chemistry in terms of chemical structure, mechanism of action and structure-activity relationships.