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Molecular dynamics at the allosteric site of PTP-1B for compound 7. (A) Structural models, (B) RMSD and (C) RMSF from molecular trajectories.
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An infusion prepared from the aerial parts of Salvia amarissima Ortega inhibited the enzyme protein tyrosine phosphatase 1B (PTP-1B) (IC50~88 and 33 μg/mL, respectively). Phytochemical analysis of the infusion yielded amarisolide (1), 5,6,4′-trihydroxy-7,3′-dimethoxyflavone (2), 6-hydroxyluteolin (3), rutin (4), rosmarinic acid (5), isoquercitrin (...
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The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge—the inhibition of a human drug target—into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products....
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... Untargeted metabolomic analysis with UPLC-ESI +/− -MS-QTOF allowed the identification of a total of 46 compounds of phenolic and terpene nature in the extracts of salvias and also highlighted that the three species present particular chemical profiles, with only four shared compounds (rutin, rosmarinic acid, 11β-hydroxy-3-oxo-urs-12-en-28-oic acid and 3-hydroxyestran-17-one). The first three are widely distributed, both in Salvia [8,[76][77][78] and in various botanical families [79][80][81], and this is explained because they are compounds that intervene in defence mechanisms against other organisms or that improve tolerance to certain environmental factors such as pollution, UV light and lack of water [82][83][84][85][86]. Phenolic acids such as sagerinic, syringic and salvianolic were first identified in S. cinnabarina, S. longispicata, and S. lavanduloides, respectively. These metabolites have been previously reported in Salvia species [5,8,87]. ...
Mexico is considered one of the countries with the greatest diversity of the Salvia genus. A significant percentage of its species are known for their use in traditional medicine, highlighting their use as an analgesic. The objective of this work was to determine the chemical composition of the methanolic extracts of S. cinnabarina, S. lavanduloides and S. longispicata through untargeted metabolomics, as well as the in vivo evaluation of the antinociceptive effect and acute oral toxicity. The chemical profiling was performed using ultra-high performance liquid chromatography coupled with a high-resolution mass spectrometry (UPLC-ESI+/−-MS-QTOF) system and tentative identifications were performed using a compendium of information on compounds previously isolated from Mexican species of the genus. Pharmacological evaluation was carried out using the formalin test and OECD guidelines. The analysis of the spectrometric features of the mass/charge ratios of the three salvias shows that a low percentage of similarity is shared between them. Likewise, the putative identification allowed the annotation of 46 compounds, mainly of diterpene and phenolic nature, with only four compounds shared between the three species. Additionally, the extracts of the three salvias produced a significant antinociceptive effect at a dose of 300 mg/kg administered orally and did not present an acute oral toxicity effect at the maximum dose tested, indicating a parameter of LD50 > 2000 mg/kg. The exploration of the chemical profile of the three salvias by untargeted metabolomics shows that, despite being species with antinociceptive potential, they have different chemical profiles and therefore different active metabolites.
... It has been shown to protect cardiomyocytes against inflammation and apoptosis in myocardial injury via increasing PPARγ and inhibiting PTGS2 activity [121]. It can also inhibit DPP-4 [122], PTP1B [123] and AMY1C [124,125] activity in vitro. ...
A combination of network pharmacology, molecular docking and ADME/drug-likeness predictions was employed to explore the potential of Salvia officinalis compounds to interact with key targets involved in the pathogenesis of T2DM. These were predicted using the SwissTargetPrediction, Similarity Ensemble Approach and BindingDB databases. Networks were constructed using the STRING online tool and Cytoscape (v.3.9.1) software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis and molecular docking were performed using DAVID, SHINEGO 0.77 and MOE suite, respectively. ADME/drug-likeness parameters were computed using SwissADME and Molsoft L.L.C. The top-ranking targets were CTNNB1, JUN, ESR1, RELA, NR3C1, CREB1, PPARG, PTGS2, CYP3A4, MMP9, UGT2B7, CYP2C19, SLCO1B1, AR, CYP19A1, PARP1, CYP1A2, CYP1B1, HSD17B1, and GSK3B. Apigenin, caffeic acid, oleanolic acid, rosmarinic acid, hispidulin, and salvianolic acid B showed the highest degree of connections in the compound-target network. Gene enrichment analysis identified pathways involved in insulin resistance, adherens junctions, metabolic processes, IL-17, TNF-α, cAMP, relaxin, and AGE-RAGE in diabetic complications. Rosmarinic acid, caffeic acid, and salvianolic acid B showed the most promising interactions with PTGS2, DPP4, AMY1A, PTB1B, PPARG, GSK3B and RELA. Overall, this study enhances understanding of the antidiabetic activity of S. officinalis and provides further insights for future drug discovery purposes.
... tanshinones, clinopodiolides, tilifolidiones) and clerodanes (i.e. salvinorins, hispanines, amarisolides, among others) with the highest number of structures ( Figure 2) (Adams et al., 2005;Bigham et al., 2003;Bustos-Brito et al., 2019;Esquivel & Sánchez, 2005;Fan et al., 2019;Salinas-Arellano et al., 2020). The psychoactive compound, Salvinorin A, a clerodane isolated from S. divinorum, is considered to be a naturally occurring hallucinogen, and unlike other psychoactives such as alkaloids (morphine), it lacks nitrogen. ...
Objective: To report the Genus richness, the traditional uses and the main chemical constituents of Salvia species distributed in Mexico. Design/Methodology/Approach: A bibliographic review was made in several databases such as Scopus, Web of Science, ScienceDirect and Google Scholar to know the diversity of the Genus, compile the traditional uses and the main chemical constituents of Salvia. Books and theses available in the repositories of the National Autonomous University of Mexico (UNAM in Spanish) were also reviewed. Results: In Mexico there are 307 species distributed in three subgenera with an endemism of about 77 %; 63 native species of Salvia have traditional uses, mainly medicinal and only 17 species are edible, ornamental and ceremonial. Sages are used to treat 141 ailments, the most reported being stomach pain, diarrhoea, insomnia, fever, susto, bile, cough and dysentery. Terpenes are the most diverse and abundant constituents in Salvia species, followed by phenolic acids and flavonoids. Study Limitations/Implications: This review provided insight into the great diversity of Mexican salvias and their medicinal importance in treating various ailments. However, few species have been studied phytochemically and pharmacologically. Findings/Conclusions: In the future, with prior implementation of their cultivation, Mexican sages could be a promising resource as a herbal remedy and/or as a source of bioactive compounds to provide medical care in the treatment of diseases, mainly of the digestive system. Keywords: Ethnobotany, phytochemistry, flavonoids, traditional medicine, terpenoids.
... Flores-Bocanegra et al. [11] indicate that the antihyperglycemic action in rat models is due to the inhibitory activity of the enzyme alpha-glucosidase. Additionally, Salinas-Arellano et al. [15] note that the presence of flavonoids and terpenoids, such as the flavonoids rutin, isoquercitrin and pedalitin, which have anxiolytic and/or antinociceptive properties, inhibits the activity of protein tyrosine phosphatase 1B (PTP-1B). ...
... In extracts of S. circinata, compounds such as pedalitin, apigenin-7-O-β-D-glucoside, flavone 2-(3,4-dimethoxyphenyl)-5,6-dihydroxy-7-methoxy-4H-chromen-4-one, apigenin, 5,6-dihydroxy-7,3 ,4 -trimethoxy-flavone, 5,6,4 -trihydroxy-7,3 -dimethoxyflavone, 6-hydroxyluteolin, rutin, isoquercitrin and rosmarinic acid have been identified [10,11,13,15]. In this study, the contents of chlorogenic acid, rosmarinic acid, rutin and isoquercitrin were identified and quantified in methanolic extracts of leaves and young stems of S. circinata, and the effects of sample locality of origin (Po, populations), growth environment (E) and locality-environment interaction (Po × E) and variations in the response pattern between compounds were identified (Table 4). ...
... Rutin and isoquercitrin are antioxidant glycosylated flavonoids present in some species of Salvia, such as S. fruticosa [38], Salvia miltiorrhiza and S. amarissima from Oaxaca, Mexico [15]. The previously identified patterns of chlorogenic and rosmarinic acid contents are confirmed, in some way or in part. ...
The genus Salvia has a worldwide distribution, and its contribution to traditional medicine and as an aromatic plant has been recognized since ancient times, with few documented species having a similar phytochemical composition. In this study, the effects of natural growth conditions (in situ) and ex situ cultivation and sampling locations on the phenolic compound contents and antioxidant activity of methanolic extracts of Salvia circinata from Oaxaca, Mexico, were investigated. Stem and young leaf samples were collected from plants growing in situ in two locations in Oaxaca and later from plants propagated clonally or vegetatively from propagules obtained in situ but grown ex situ. In both sets of samples, the contents of total polyphenols and flavonoids and the antioxidant activity were evaluated by spectrophotometry, and subsequently, the contents of phenols and specific flavonoids were identified and quantified by high-performance liquid chromatography with diode-array detection (HPLC–DAD). The growth conditions and locality of origin of the samples significantly influenced the contents of total polyphenols and flavonoids and antioxidant activity, with the in situ conditions in the locality of Reforma, Oaxaca, favoring higher levels. Two phenolic acids (chlorogenic and rosmarinic) and two flavonoids (isoquercitrin and rutin) were identified, and the concentrations of these compounds were influenced by the growth conditions and localities of origin of the samples.
... In our present study, we evaluated the potential antinociceptive properties of a medium polar extract of S. amarissima and its neoclerodane diterpene metabolite, amarisolide A, using the experimental model of FM induced by reserpine administration in rats [34,35]. Firstly, using conventional chromatographic techniques, amarisolide A was isolated and purified from the bioactive extract, obtaining a yielding of 5.03%, which is a higher amount than that reported by Flores-Bocanegra [52], who reported a yield of 2.58% from a DCM:MeOH extract (1:1), while Salinas-Arellano [53] reported 11.6% from an EtOAc partition from an aqueous extract. This information reinforces that differences in the polarity of the solvent, the preparation, the location, and the collection conditions of the plant material are factors that influence not only the yield of the extracts but also the presence of pure metabolites, as in the case of amarisolide A [54]. ...
Salvia amarissima Ortega is an endemic species of Mexico used in folk medicine to alleviate pain and as a nervous tranquilizer. The S. amarissima extract and one of its abundant metabolites, identified and isolated through chromatographic techniques, were investigated to obtain scientific evidence of its potential effects to relieve nociplastic pain such as fibromyalgia. Then, the extract and amarisolide A (3–300 mg/kg, i.p.) were pharmacologically evaluated in reserpine-induced fibromyalgia-type chronic pain and in depressive-like behavior (as a common comorbidity) by using the forced swimming test in rats. The 5-HT1A serotonin receptor (selective antagonist WAY100635, 1 mg/kg, i.p.) was explored after the prediction of a chemical interaction using in silico analysis to look for a possible mechanism of action of amarisolide A. Both the extract and amarisolide A produced significant and dose-dependent antihyperalgesic and antiallodynic effects in rats, as well as significant antidepressive behavior without sedative effects when the antinociceptive dosages were used. The 5-HT1A serotonin receptor participation was predicted by the in silico descriptors and was corroborated in the presence of WAY100635. In conclusion, S. amarissima possesses antihyperalgesic, antiallodynic, and anti-depressive activities, partially due to the presence of amarisolide A, which involves the 5-HT1A serotonin receptor. This pharmacological evidence suggests that S. amarissima and amarisolide A are both potential alternatives to relieve pain-like fibromyalgia.
... This plant is commonly used to treat cancer, diabetes, gastrointestinal disorders, and rheumatism, and it receives the common names of "hierba del cancer" and "insulina" among others (Fragoso-Serrano et al. 2019;Moreno-Pérez et al. 2021;Solares-Pascasio et al. 2021). Indeed, there are pharmacological reports describing antihyperglycemic, antinociceptive, antiprotozoal, and cytotoxic activities that provide evidence-based support for its ethnomedical uses, which have been associated with the flavone and diterpenoid content (Flores-Bocanegra et al. 2017;Fragoso-Serrano et al. 2019;Moreno-Pérez et al. 2019Calzada et al. 2020;Salinas-Arellano et al. 2020;Solares-Pascasio et al. 2021 Previous chemical studies have identified an extensive group of metabolites that include monomers and dimers of flavones (Flores-Bocanegra et al. 2017), as well as free and glucosylated diterpenoids (Bautista et al. 2016(Bautista et al. , 2015Flores-Bocanegra et al. 2017;Fragoso-Serrano et al. 2019;Salinas-Arellano et al. 2020). Apigenin, isoquercitrin, 6-hydroxyluteolin, pedalitin, and 6,6′′,3′′′-trihydroxy-7,3′,7′′-O-trimethylloniflavone are among the flavones described for this medicinal plant. ...
... This plant is commonly used to treat cancer, diabetes, gastrointestinal disorders, and rheumatism, and it receives the common names of "hierba del cancer" and "insulina" among others (Fragoso-Serrano et al. 2019;Moreno-Pérez et al. 2021;Solares-Pascasio et al. 2021). Indeed, there are pharmacological reports describing antihyperglycemic, antinociceptive, antiprotozoal, and cytotoxic activities that provide evidence-based support for its ethnomedical uses, which have been associated with the flavone and diterpenoid content (Flores-Bocanegra et al. 2017;Fragoso-Serrano et al. 2019;Moreno-Pérez et al. 2019Calzada et al. 2020;Salinas-Arellano et al. 2020;Solares-Pascasio et al. 2021 Previous chemical studies have identified an extensive group of metabolites that include monomers and dimers of flavones (Flores-Bocanegra et al. 2017), as well as free and glucosylated diterpenoids (Bautista et al. 2016(Bautista et al. , 2015Flores-Bocanegra et al. 2017;Fragoso-Serrano et al. 2019;Salinas-Arellano et al. 2020). Apigenin, isoquercitrin, 6-hydroxyluteolin, pedalitin, and 6,6′′,3′′′-trihydroxy-7,3′,7′′-O-trimethylloniflavone are among the flavones described for this medicinal plant. ...
... The first one mainly consists of the diterpenoids amarissinins A-E and teotihuacanin, and the O-acetylglucoside amarisolide F (Bautista et al. 2016(Bautista et al. , 2015Fragoso-Serrano et al. 2019). The second diterpenoid profile is composed of glucoside diterpenoids, namely amarisolides A-E and G (Flores-Bocanegra et al. 2017;Salinas-Arellano et al. 2020). Subsequently, a recent study compared the GC-MS and HPLC-PDA profiles of ten populations of this species with distribution in Mexico and related their metabolomic differences with environmental factors. ...
The HPLC–PDA profiling of an acetone-soluble extract of the leaves of Salvia circinnata Cav. (Syn. Salvia amarissima Ortega), Lamiaceae, collected at Patzcuaro, Michoacan, Mexico, indicated this population corresponds to the chemotype “amarisolide A.” The phytochemical study of the extract led to the isolation of two new diterpenoid glucosides, amarisolide H and 15-epi-amarisolide H, which were obtained as an epimeric mixture, together with the known compounds amarisolides A, D, G, 16-epi-amarisolide G, and 5,6-dihydroxy-7,3′,4′-trimethoxyflavone. The structures of compounds amarisolide H and 15-epi-amarisolide H were determined by the analyses of their NMR and HRMS data. The cytotoxicity and anti-multidrug resistance (MDR) effects of compounds amarisolide H, 15-epi-amarisolide H, amarisolide A, amarisolide G, and 16-epi-amarisolide G in MCF-7 cancer cells sensible and resistant to vinblastine were essayed.
... Most of the triterpenoids are derivatives of oleanolic acid (OA) and ursolic acid (UA) (Tung et al., 2017). The flavonoids in S. milthiorrhiza are mainly luteolin (LUT) and its derivatives (Salinas-Arellano et al., 2020). The polysaccharides in S. milthiorrhiza are mainly composed of mannose, rhamnose, arabinose, glucose, and galactose (Han et al., 2019). ...
MicroRNAs are small non-coding RNAs that play important roles in gene regulation by influencing the translation and longevity of various target mRNAs and the expression of various target genes as well as by modifying histones and DNA methylation of promoter sites. Consequently, when dysregulated, microRNAs are involved in the development and progression of a variety of diseases, including cancer, by affecting cell growth, proliferation, differentiation, migration, and apoptosis. Preparations from the dried root and rhizome of Salvia miltiorrhiza Bge (Lamiaceae), also known as red sage or danshen, are widely used for treating cardiovascular diseases. Accumulating data suggest that certain bioactive constituents of this plant, particularly tanshinones, have broad antitumor effects by interfering with microRNAs and epigenetic enzymes. This paper reviews the evidence for the antineoplastic activities of S. miltiorrhiza constituents by causing or promoting cell cycle arrest, apoptosis, autophagy, epithelial-mesenchymal transition, angiogenesis, and epigenetic changes to provide an outlook on their future roles in the treatment of cancer, both alone and in combination with other modalities.
... Flavonoids extracted from various plant sources have been observed to be effective against PTP-1B inhibition [19][20][21]. They possess significant hypoglycemic effects, low toxicity for cells and are non-competitive inhibitors of PTP-1B [22]. ...
This study deals with designing and validating QSAR models generated for 45 flavonoids having PTP1B inhibition properties. Eight molecular descriptors/pharmacophoric features of each flavonoid along with their reported IC50 values against PTP1B were utilized to prepare training sets and generate models. It was developed by employing linear regression to calculate the predicted IC50 values. The generated models were validated using reported IC50 values of test sets. The correlation R2 values were observed to be in the following order, 92.45% (for an increasing hydrogen bond donor), 92.08% (for randomly sorting), 91.85% (for increasing molecular weight), 84.19% (for increasing hydrogen bond acceptor), 64.91% (for increasing TPSA), 53.90% (for increasing number of rotatable bonds) and 52.28% (for increasing log P); signifying the role of these pharmacophoric features while drug designing. Molecular docking of the flavonoids with the PTP1B active site revealed interactions with catalytic site and adjacent loops. The models would be beneficial for further studies for drug designing against PTP1B inhibition and therapeutic implications for treatment of insulin resistance.
... Their properties have also been reported in metabolic alterations such as diabetes, since they produce a significant antihyperglycemic action in vivo during an oral sucrose tolerance test by an alfa-glucosidase inhibitory activity [104]. The presence of flavonoids and terpenoid bioactive constituents has also been associated with another enzymatic and regulatory protein inhibition such as in protein tyrosine phosphatase 1B (PTP-1B), where different kinds of amarisolide have been characterized [105], as well as flavonoids such as rutin, isoquercitrin and pedalitin already associated with anxiolytic and/or antinociceptive activities [106,107]. Diterpenes derived from S. amarissima also possess modulatory capability in protein multidrug resistance and cytotoxic activity [108]. ...
The search for molecules that contribute to the relief of pain is a field of research in constant development. Lamiaceae is one of the most recognized families world-wide for its use in traditional medicine to treat diseases that include pain and inflammation. Mexico can be considered one of the most important centers of diversification, and due to the high endemism of this family, it is crucial for the in situ conservation of this family. Information about the most common genera and species found in this country and their uses in folk medicine are scarcely reported in the literature. After an extensive inspection in bibliographic databases, mainly Sciencedirect, Pubmed and Springer, almost 1200 articles describing aspects of Lamiaceae were found; however, 217 articles were selected because they recognize the Mexican genera and species with antinociceptive and/or anti-inflammatory potential to relieve pain, such as Salvia and Agastache. The bioactive constituents of these genera were mainly terpenes (volatile and non-volatile) and phenolic compounds such as flavonoids (glycosides and aglycone). The aim of this review is to analyze important aspects of Mexican genera of Lamiaceae, scarcely explored as a potential source of secondary metabolites responsible for the analgesic and anti-inflammatory properties of these species. In addition, we point out the possible mechanisms of action involved and the modulatory pathways investigated in different experimental models. As a result of this review, it is important to mention that scarce information has been reported regarding species of this family from Mexican genera. In fact, despite Calosphace being one of the largest subgenera of Salvia in the world, found mainly in Mexico, it has been barely investigated regarding its potential biological activities and recognized bioactive constituents. The scientific evidence regarding the different bioactive constituents found in species of Lamiaceae demonstrates that several species require further investigation in preclinical studies, and of course also in controlled clinical trials evaluating the efficacy and safety of these natural products to support their therapeutic potential in pain relief and/or inflammation, among other health conditions. Since Mexico is one of the most important centers of diversification, and due to the high endemism of species of this family, it is crucial their rescue, in situ conservation, and investigation of their health benefits.
... Because of this great pharmacological potential, chemical studies of Salvia species have increased over the last 40 years, which allowed as amarisolide F (12), which were identified in an isolated population in the Teotihuacan Valley, State of Mexico (Bautista et al. , 2016Fragoso-Serrano et al. 2019). Although two recent studies have identified mono-and sesquiterpenoids in S. circinnata (Fragoso-Serrano et al. 2019;Salinas-Arellano et al. 2020), it was considered that the characterization of the volatile oil constituents can contribute to elucidate differences in the chemical profiles of this plant. Consequently, three hypotheses can be proposed to explain the observed divergence for the chemical composition of this medicinal plant. ...
... For instance, two terpenoid profiles have been reported for S. circinnata in Mexico. The first one includes neo-clerodane 3-O-glucosides known as amarisolides A-E (1-5) and G (6) in populations from the states of Puebla and Oaxaca (Flores-Bocanegra et al. 2017;Salinas-Arellano et al. 2020). The second profile is constituted by a mixture of neo-clerodanes; 9,10-seco-neo-clerodane; and amarisane-type diterpenoids known as amarissinins A-D (7-10), teotihuacanin (11), and the 17-O-glucoside known ...
... ;Flores-Bocanegra et al. 2017;Salinas-Arellano et al. 2020;Solares-Pascasio et al. 2021). For example, some in vitro essays have indicated promissory applications for cancer treatment of teotihuacanin (11). ...
Salvia circinnata Cav. (Syn. S. amarissima Ortega), Lamiaceae, is a Mexican medicinal plant used in traditional medicine for the treatment of gastrointestinal illness, cancer, and diabetes. Samples of ten natural populations were analyzed by application of a systematic approach which involved the combination of DNA barcoding, GC–MS, HPLC–DAD, and HPLC-FLD for differentiation of their chemical profiles. Taxonomic and phylogenetic analyses indicated that all of them belong to the same analyzed plant species. The GC–MS analysis showed the presence of alkanes, amides, anthraquinones, and sesquiterpenoids in the volatile fraction of the extracts. HPLC–PDA and HPLC-FLD analyses indicated that at least four chemotypes exist for the analyzed species, diverging in the production of clerodane diterpenes: (i) an amarissinin A–rich population; (ii) another single population producer of amarisolide A; (iii) producing populations of teotihuacanin and amarissinin A, (iv) while another population only produced alkanes and sesquiterpenes as distinctive constituents not previously reported for this plant. The multivariate statistical analysis suggests that this chemical diversity depends on environmental factors.Graphical abstract