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      Hovenia dulcis Thumberg: Phytochemistry, Pharmacology, Toxicology and Regulatory Framework for Its Use in the European Union

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          Abstract

          Hovenia dulcis Thunberg is an herbal plant, belonging to the Rhamnaceae family, widespread in west Asia, USA, Australia and New Zealand, but still almost unknown in Western countries. H. dulcis has been described to possess several pharmacological properties, such as antidiabetic, anticancer, antioxidant, anti-inflammatory and hepatoprotective, especially in the hangover treatment, validating its use as an herbal remedy in the Chinese Traditional Medicine. These biological properties are related to a variety of secondary metabolites synthesized by the different plant parts. Root, bark and leaves are rich of dammarane-type triterpene saponins; dihydrokaempferol, quercetin, 3,3′,5′,5,7-pentahydroflavone and dihydromyricetin are flavonoids isolated from the seeds; fruits contain mainly dihydroflavonols, such as dihydromyricetin (or ampelopsin) and hovenodulinol, and flavonols such as myricetin and gallocatechin; alkaloids were found in root, barks (frangulanin) and seeds (perlolyrin), and organic acids (vanillic and ferulic) in hot water extract from seeds. Finally, peduncles have plenty of polysaccharides which justify the use as a food supplement. The aim of this work is to review the whole scientific production, with special focus on the last decade, in order to update phytochemistry, biological activities, nutritional properties, toxicological aspect and regulatory classification of H. dulcis extracts for its use in the European Union.

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          Guidance on the preparation and presentation of an application for authorisation of a novel food in the context of Regulation (EU) 2015/2283

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            Dihydromyricetin as a novel anti-alcohol intoxication medication.

            Alcohol use disorders (AUDs) constitute the most common form of substance abuse. The development of AUDs involves repeated alcohol use leading to tolerance, alcohol withdrawal syndrome, and physical and psychological dependence, with loss of ability to control excessive drinking. Currently there is no effective therapeutic agent for AUDs without major side effects. Dihydromyricetin (DHM; 1 mg/kg, i.p. injection), a flavonoid component of herbal medicines, counteracted acute alcohol (EtOH) intoxication, and also withdrawal signs in rats including tolerance, increased anxiety, and seizure susceptibility; DHM greatly reduced EtOH consumption in an intermittent voluntary EtOH intake paradigm in rats. GABA(A) receptors (GABA(A)Rs) are major targets of acute and chronic EtOH actions on the brain. At the cellular levels, DHM (1 μM) antagonized both acute EtOH-induced potentiation of GABA(A)Rs and EtOH exposure/withdrawal-induced GABA(A)R plasticity, including alterations in responsiveness of extrasynaptic and postsynaptic GABA(A)Rs to acute EtOH and, most importantly, increases in GABA(A)R α4 subunit expression in hippocampus and cultured neurons. DHM anti-alcohol effects on both behavior and CNS neurons were antagonized by flumazenil (10 mg/kg in vivo; 10 μM in vitro), the benzodiazepine (BZ) antagonist. DHM competitively inhibited BZ-site [(3)H]flunitrazepam binding (IC(50), 4.36 μM), suggesting DHM interaction with EtOH involves the BZ sites on GABA(A)Rs. In summary, we determined DHM anti-alcoholic effects on animal models and determined a major molecular target and cellular mechanism of DHM for counteracting alcohol intoxication and dependence. We demonstrated pharmacological properties of DHM consistent with those expected to underlie successful medical treatment of AUDs; therefore DHM is a therapeutic candidate.
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              Recognizing the Molecular Multifunctionality and Interactome of TIMP-1

              Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a major player in preserving tissue integrity and has recently also emerged as a decisive factor in several human pathologies. This appreciation has prompted this review addressing the largely underestimated complexity of the functions executed by TIMP-1 and their mechanistic basis. In fact, the versatile impact of TIMP-1 on cellular functions stems from its two-domain structure harboring metalloproteinase-inhibitory and cytokine-like signaling activities. This feature leads to functional interactions with numerous and distinct enzymatic and cell-surface proteins that initiate an exceptionally broad range of downstream effects. We propose here that this multifunctionality and the remarkably large interactome explain the diverse biological consequences of TIMP-1 expression in health and disease.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                09 February 2021
                February 2021
                : 26
                : 4
                : 903
                Affiliations
                [1 ]Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100, 00133 Rome, Italy; manuela.zonfrillo@ 123456ift.cnr.it (M.Z.); pasquale.pierimarchi@ 123456ift.cnr.it (P.P.)
                [2 ]Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy; caterina.temporini@ 123456unipv.it (C.T.); sara.tengattini@ 123456unipv.it (S.T.); or enrica.calleri@ 123456eufan.it (E.C.)
                [3 ]euFAN s.r.l, spin-off University of Pavia, Via Fratelli Cuzio 42, 27100 Pavia, Italy or monica.bononi@ 123456unimi.it (M.B.); or fernando.tateo@ 123456unimi.it (F.T.)
                [4 ]Department of Agricultural and Environmental Sciences, University of Milan, Via Celoria 2, 20133 Milan, Italy
                Author notes
                Author information
                https://orcid.org/0000-0002-0572-3588
                https://orcid.org/0000-0001-7786-3769
                https://orcid.org/0000-0002-8584-5883
                https://orcid.org/0000-0001-6194-7036
                https://orcid.org/0000-0002-3376-6091
                Article
                molecules-26-00903
                10.3390/molecules26040903
                7914479
                33572099
                443535be-1b16-4b3f-9743-55fdeae2eb22
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 December 2020
                : 30 January 2021
                Categories
                Review

                hovenia dulcis,traditional medicine,phytochemistry,pharmacology,toxicology,regulatory science

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