In the present paper, we report on the synthesis and antinociceptive activity of a new series of ... more In the present paper, we report on the synthesis and antinociceptive activity of a new series of N-methyl-arylpyrrolidinols that we designed for a rational structure-activity relationship (SAR) study. The antinociceptive properties were investigated in vivo by the hot plate and formalin tests in mice and control on the locomotory activity was also monitored by the rota rod test. With this aim, the evaluation of the lipophilicity of all compounds was performed by the Daylight computational method in order to better understand the SAR. Interesting properties were proven for the compounds of the entire series.
The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalco... more The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalcohols has been performed. The chiral racemic key intermediate 3-dimethylamino-2-methyl-1-(naphthalen-2-yl)propan-1-one and enantiomers were prepared and transformed into the desired compounds by addition of the organometallic reagent. The chemical characterization of all diastereoisomers was accomplished by 1H NMR and HPLC analyses and the absolute configuration assigned by CD spectroscopy. The in vitro and in vivo profile has also been evaluated.
The human microbiota refers to a large variety of microorganisms (bacteria, viruses, and fungi) t... more The human microbiota refers to a large variety of microorganisms (bacteria, viruses, and fungi) that live in different human body sites, including the gut, oral cavity, skin, and eyes. In particular, the presence of an ocular surface microbiota with a crucial role in maintaining ocular surface homeostasis by preventing colonization from pathogen species has been recently demonstrated. Moreover, recent studies underline a potential association between gut microbiota (GM) and ocular health. In this respect, some evidence supports the existence of a gut–eye axis involved in the pathogenesis of several ocular diseases, including age-related macular degeneration, uveitis, diabetic retinopathy, dry eye, and glaucoma. Therefore, understanding the link between the GM and these ocular disorders might be useful for the development of new therapeutic approaches, such as probiotics, prebiotics, symbiotics, or faecal microbiota transplantation through which the GM could be modulated, thus allowi...
Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characte... more Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this c...
After castration rat vasa deferentia exhibited spontaneous activity. Cromakalim which acts by ope... more After castration rat vasa deferentia exhibited spontaneous activity. Cromakalim which acts by opening K+ channels has been shown to suppress this spontaneous activity following castration. Glibenclamide, a potent blocker of the ATP-sensitive K+ channels, inhibited this contrasting effect of cromakalim. The concentrations of cromakalim and glibenclamide that were employed are consistent with those active in different kinds of smooth muscle. The presented data are compatible with the hypothesis that castration decreases potassium conductance and that such an effect could be responsible for spontaneous activity.
A combined study of receptor binding in central neuronal cell membranes and functional responses ... more A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea‐pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5‐HT3 and 5‐HT4 receptors. Clomipramine, paroxetine and fluoxetine inhibited [3H]‐DAU 6215 binding to 5‐HT3 recognition sites in NG 108‐15 cells with IC50 values in the range 1.3–4 μm. Litoxetine had an IC50 of 0.3 μm. The specific binding of [3H]‐GR 113808 to 5‐HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values ≥ 20 μm). In whole ileal segments, concentration‐response curves to 5‐HT were biphasic, with the high‐ and low‐potency phases involving 5‐HT4 and 5‐HT3 receptors, respectively. Curves to 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: a 5‐HT3 receptor agonist) and 5‐methoxytryptamine (5‐MeOT: a 5‐HT4 receptor agonist) were monophasic. All antidepressants were...
The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervo... more The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervous system and is involved in various neurological and psychiatric diseases. In this study, through the creation of an interaction network on HuD and its potential targets, we identified a strong association between HuD and several diseases of the nervous system. Specifically, we focused on the relationship between HuD and the brain-derived neurotrophic factor (BDNF), whose protein is implicated in several neuronal diseases and is involved in the regulation of neuronal development, survival, and function. To better investigate this relationship and given that we previously demonstrated that folic acid (FA) is able to directly bind HuD itself, we performed in vitro experiments in neuron-like human SH-SY5Y cells in the presence of FA, also known to be a pivotal environmental factor influencing the nervous system development. Our findings show that FA exposure results in a significant increa...
The endogenous antioxidant defense plays a big part in the pathogenesis of non-alcoholic fatty li... more The endogenous antioxidant defense plays a big part in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder that can lead to serious complications such as cirrhosis and cancer. HuR, an RNA-binding protein of the ELAV family, controls, among others, the stability of MnSOD and HO-1 mRNA. These two enzymes protect the liver cells from oxidative damage caused by excessive fat accumulation. Our aim was to investigate the expression of HuR and its targets in a methionine-choline deficient (MCD) model of NAFLD. To this aim, we fed male Wistar rats with an MCD diet for 3 and 6 weeks to induce NAFLD; then, we evaluated the expression of HuR, MnSOD, and HO-1. The MCD diet induced fat accumulation, hepatic injury, oxidative stress, and mitochondrial dysfunction. A HuR downregulation was also observed in association with a reduced expression of MnSOD and HO-1. Moreover, the changes in the expression of HuR and its targets were significantly correlated with ...
Medical Devices Made of Substances (MDMS) are increasingly used in the healthcare system alongsid... more Medical Devices Made of Substances (MDMS) are increasingly used in the healthcare system alongside classic medicinal products and constitute an important field of experimentation and innovation in the biomedical field. In fact, these products are rapidly establishing themselves as a valuable therapeutic resource and are available in various forms including, but not limited to, creams, syrups, nasal or oropharyngeal sprays, and eye drops. MDMS are marketed to treat different diseases and the advantages and benefits of the use of these products can be claimed, once proven their clinical activity. What are the differences between medicinal products and MDMS? The substantial difference lies in the mechanism of action: the first case is based on pharmacological, metabolic, and immunological actions while the second one is based on mechanical, or chemical/physical action. Sometimes the boundaries are not well defined and there is a need for a reassessment and a consensus on the underlying...
A pharmacological analysis was carried out in the rat urinary bladder to assess the nature of mus... more A pharmacological analysis was carried out in the rat urinary bladder to assess the nature of muscarinic receptors subtypes functionally involved in the negative feedback mechanism regulating acetylcholine (ACh) secretion from postganglionic cholinergic nerve terminals and in ...
In the present paper, we report on the synthesis and antinociceptive activity of a new series of ... more In the present paper, we report on the synthesis and antinociceptive activity of a new series of N-methyl-arylpyrrolidinols that we designed for a rational structure-activity relationship (SAR) study. The antinociceptive properties were investigated in vivo by the hot plate and formalin tests in mice and control on the locomotory activity was also monitored by the rota rod test. With this aim, the evaluation of the lipophilicity of all compounds was performed by the Daylight computational method in order to better understand the SAR. Interesting properties were proven for the compounds of the entire series.
The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalco... more The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalcohols has been performed. The chiral racemic key intermediate 3-dimethylamino-2-methyl-1-(naphthalen-2-yl)propan-1-one and enantiomers were prepared and transformed into the desired compounds by addition of the organometallic reagent. The chemical characterization of all diastereoisomers was accomplished by 1H NMR and HPLC analyses and the absolute configuration assigned by CD spectroscopy. The in vitro and in vivo profile has also been evaluated.
The human microbiota refers to a large variety of microorganisms (bacteria, viruses, and fungi) t... more The human microbiota refers to a large variety of microorganisms (bacteria, viruses, and fungi) that live in different human body sites, including the gut, oral cavity, skin, and eyes. In particular, the presence of an ocular surface microbiota with a crucial role in maintaining ocular surface homeostasis by preventing colonization from pathogen species has been recently demonstrated. Moreover, recent studies underline a potential association between gut microbiota (GM) and ocular health. In this respect, some evidence supports the existence of a gut–eye axis involved in the pathogenesis of several ocular diseases, including age-related macular degeneration, uveitis, diabetic retinopathy, dry eye, and glaucoma. Therefore, understanding the link between the GM and these ocular disorders might be useful for the development of new therapeutic approaches, such as probiotics, prebiotics, symbiotics, or faecal microbiota transplantation through which the GM could be modulated, thus allowi...
Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characte... more Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this c...
After castration rat vasa deferentia exhibited spontaneous activity. Cromakalim which acts by ope... more After castration rat vasa deferentia exhibited spontaneous activity. Cromakalim which acts by opening K+ channels has been shown to suppress this spontaneous activity following castration. Glibenclamide, a potent blocker of the ATP-sensitive K+ channels, inhibited this contrasting effect of cromakalim. The concentrations of cromakalim and glibenclamide that were employed are consistent with those active in different kinds of smooth muscle. The presented data are compatible with the hypothesis that castration decreases potassium conductance and that such an effect could be responsible for spontaneous activity.
A combined study of receptor binding in central neuronal cell membranes and functional responses ... more A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea‐pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5‐HT3 and 5‐HT4 receptors. Clomipramine, paroxetine and fluoxetine inhibited [3H]‐DAU 6215 binding to 5‐HT3 recognition sites in NG 108‐15 cells with IC50 values in the range 1.3–4 μm. Litoxetine had an IC50 of 0.3 μm. The specific binding of [3H]‐GR 113808 to 5‐HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values ≥ 20 μm). In whole ileal segments, concentration‐response curves to 5‐HT were biphasic, with the high‐ and low‐potency phases involving 5‐HT4 and 5‐HT3 receptors, respectively. Curves to 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT: a 5‐HT3 receptor agonist) and 5‐methoxytryptamine (5‐MeOT: a 5‐HT4 receptor agonist) were monophasic. All antidepressants were...
The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervo... more The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervous system and is involved in various neurological and psychiatric diseases. In this study, through the creation of an interaction network on HuD and its potential targets, we identified a strong association between HuD and several diseases of the nervous system. Specifically, we focused on the relationship between HuD and the brain-derived neurotrophic factor (BDNF), whose protein is implicated in several neuronal diseases and is involved in the regulation of neuronal development, survival, and function. To better investigate this relationship and given that we previously demonstrated that folic acid (FA) is able to directly bind HuD itself, we performed in vitro experiments in neuron-like human SH-SY5Y cells in the presence of FA, also known to be a pivotal environmental factor influencing the nervous system development. Our findings show that FA exposure results in a significant increa...
The endogenous antioxidant defense plays a big part in the pathogenesis of non-alcoholic fatty li... more The endogenous antioxidant defense plays a big part in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder that can lead to serious complications such as cirrhosis and cancer. HuR, an RNA-binding protein of the ELAV family, controls, among others, the stability of MnSOD and HO-1 mRNA. These two enzymes protect the liver cells from oxidative damage caused by excessive fat accumulation. Our aim was to investigate the expression of HuR and its targets in a methionine-choline deficient (MCD) model of NAFLD. To this aim, we fed male Wistar rats with an MCD diet for 3 and 6 weeks to induce NAFLD; then, we evaluated the expression of HuR, MnSOD, and HO-1. The MCD diet induced fat accumulation, hepatic injury, oxidative stress, and mitochondrial dysfunction. A HuR downregulation was also observed in association with a reduced expression of MnSOD and HO-1. Moreover, the changes in the expression of HuR and its targets were significantly correlated with ...
Medical Devices Made of Substances (MDMS) are increasingly used in the healthcare system alongsid... more Medical Devices Made of Substances (MDMS) are increasingly used in the healthcare system alongside classic medicinal products and constitute an important field of experimentation and innovation in the biomedical field. In fact, these products are rapidly establishing themselves as a valuable therapeutic resource and are available in various forms including, but not limited to, creams, syrups, nasal or oropharyngeal sprays, and eye drops. MDMS are marketed to treat different diseases and the advantages and benefits of the use of these products can be claimed, once proven their clinical activity. What are the differences between medicinal products and MDMS? The substantial difference lies in the mechanism of action: the first case is based on pharmacological, metabolic, and immunological actions while the second one is based on mechanical, or chemical/physical action. Sometimes the boundaries are not well defined and there is a need for a reassessment and a consensus on the underlying...
A pharmacological analysis was carried out in the rat urinary bladder to assess the nature of mus... more A pharmacological analysis was carried out in the rat urinary bladder to assess the nature of muscarinic receptors subtypes functionally involved in the negative feedback mechanism regulating acetylcholine (ACh) secretion from postganglionic cholinergic nerve terminals and in ...
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Papers by Annalisa Barbieri