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Ethnopharmacological Relevance: Bocconia arborea S. Watson (Papaveraceae) is known as "palo llora sangre" and is used in Mexican traditional medicine for the treatment of infections, it is also used as anxiolytic, analgesic, and antidiabetic, among others., Aim of the Study: to evaluate the antinociceptive and gastroprotective activities of extracts from B. arborea and dihydrosanguinarine (DHS) in murine models., Materials and Methods: Organic extracts [hexane (HEX), dichloromethane (DCM) and methanol (MeOH)] were obtained by maceration. DHS was isolated and purified from HEX and DCM by precipitation and chromatographic column, respectively. Organic extracts and DHS were evaluated to determine their antinociceptive effect using formalin test in murine model. Also, the ambulatory effect of the HEX and DHS was determined in Open field test. The possible mechanism of action of DHS was explored in the presence of naltrexone (NTX, 1 mg/kg, i.p.), and picrotoxin (PTX, 1 mg/kg, i.p.). Gastric damage as possible adverse effect or gastroprotection were also investigated. Whereas DHS acute toxicological study was done, and 100 mg/kg of DHS was examined by electroencephalographic (EEG) analysis to discard neurotoxic effects., Results: The B. arborea extracts significantly showed effects in both neurogenic and inflammatory phases of the formalin test, where the HEX extract reached the major antinociceptive effect. A significant and dose-response (10, 30, and 100 mg/kg) antinociceptive activity was observed with the HEX (ED 50  = 69 mg/kg) and DHS (ED 50  = 85 mg/kg) resembling the effect of the reference analgesic drug tramadol (30 mg/kg). The significant effect of DHS was inhibited in the presence of NTX and PTX. Neither the extracts or DHS produced sedative effects or gastric damage per se at antinociceptive doses. The EEG analysis demonstrated central depressant activity but not sedative or neurotoxic effects at the highest antinociceptive dosage tested, and LD 50 is higher than 2000 mg/kg., Conclusions: HEX, DCM, and MeOH extracts showed significant antinociceptive activity, and DHS was identified as one of bioactive compounds without producing sedative, neurotoxic or gastric damage effects, as possible adverse effects reported for analgesic drugs. A role of opioid and GABA A neurotransmission appears to be involved as mechanisms of action of DHS, suggesting its potential for pain therapy and reinforcing the traditional use of B. arborea., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Achillea millefolium L. (Asteraceae), known as yarrow (milenrama), is a plant used in Mexican traditional medicine for the treatment of hypertension, diabetes, and related diseases., Aim: To determine the vasorelaxant and antihypertensive effect of A. millefollium and to isolate the main bioactive antihypertensive agents., Materials and Methods: Organic (hexane, dichloromethane and methanol) and hydro-alcohol (Ethanol-H 2 O: 70:30) extracts obtained from flowers, leaves and stems were evaluated on isolated aorta rat rings with and without endothelium to determine their vasorelaxant effect. Hexane extract from flowers (HEAmF) was studied to evaluate its antihypertensive effect on spontaneously hypertensive rats (SHR). From HEAmF, bioactive compounds were obtained by bio-guided phytochemical separation through chromatography., Results: Organic extracts showed the best vasorelaxant activity. Hexane extract from flowers was the most potent and efficient ex vivo vasorelaxant agent, showing significant decrease of systolic and diastolic blood pressure in SHR (p < 0.05). Phytochemical separation of HEAmF yielded two epimeric sesquiterpene lactones: leucodin (1) and achillin (2), the major components of the extract. Both 1 and 2 showed similar vasorelaxant action ex vivo (p < 0.05), and their effects where modified by L-NAME (10 μM, nitric oxide synthase inhibitor), by ODQ (1 μM, soluble guanylyl cyclase inhibitor), and also relaxed the contraction induced by KCl (80 mM). Finally, 1 and 2 intragastric administration (50 mg/kg) decreased systolic and diastolic blood pressure in SHR., Conclusions: Achillea millefolium showed antihypertensive and vasorelaxant effects, due mainly to leucodin and achillin (epimers). Both compounds showed antihypertensive activity by vasorelaxation putatively by endothelium-dependent NO release and cGMP increase, as well as by calcium channels blockade., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Tagetes lucida Cav. commonly known as "yauhtli" or "pericón" is used in Mexican traditional medicine for the treatment of anxiety, depressant diseases, pain, hypertension, among others., Aim: To evaluate the antihypertensive and vasorelaxant modes of action of a crude ethanolic extract from T. lucida aerial parts and to isolate the bioactive compounds., Materials and Methods: Ethanolic extract was tested in an in vivo assay in SHR rats by intragastric administration at 10 and 100 mg/kg dosages, to measure and to compare hemodynamic parameters like diastolic and systolic blood pressure and heart rate. Also, extract (3.03-1000 μg/ml), fractions (3.03-1000 μg/ml) and pure isolated compounds (1.75-550 μM) were evaluated on isolated aortic rings contracted with noradrenaline (0.1 μM) to determine their vasorelaxant effect and extract-mode of action., Results: Ethanolic extract of T. lucida lowered systolic and diastolic blood pressure on SHR rats without heart rate modification (P > 0.05). Moreover, the extract showed concentration-dependent relaxant effect in a partially endothelium-dependent manner (P < 0.05), through NO/cGMP system activation and calcium channel blockade. 6,7,8-trimethoxycoumarin (1), 6,7-dimethoxycoumarin (2), and 7-methoxycoumarin (3) from T. lucida are the main bioactive compounds of the extract and showed significant vasorelaxant activity., Conclusions: Results provide evidence and endorsed the antihypertensive properties attributed to T. lucida in traditional medicine, which is produced by vasorelaxant effect mainly through multitarget NO/cGMP system activation and calcium channel blockade. Coumarin derivatives 1, 2 and 3 are the responsible of the vasorelaxant activity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Importance: Achillea millefolium L. (Asteraceae) is used for the treatment of respiratory diseases, diabetes, and hypertension., Aim: to explore its tracheal relaxant properties and clarify its functional mechanism of action on smooth muscle cells, which allow us to propose it as a potential anti-asthmatic drug., Material and Methods: organic and hydro-alcoholic extracts from A. millefolium were obtained by macerations, then their relaxing effect on ex vivo isolated rat trachea rings was determined. Most active extract (hexanic extract, EHAm) was studied to determine its functional mechanism of action using synergic, antagonist and inhibitor agents related with the contraction/relaxation process of the smooth muscle. Also, EHAm was subjected to bio-guided fractionation by open-column chromatography (on silica gel) using cyclohexane-EtOAc (80:20) in an isocratic way to isolate main bioactive compounds., Results: organic and hydro-alcoholic extracts showed relaxant effect in a concentration-response dependent manner, being EHAm the most active. The functional mechanism of action indicates that EHAm induced a non-competitive antagonism to the muscarinic receptors ; in addition, the NO/cGMP pathway is involved in the relaxation process of the tracheal smooth muscle. However, the most important mechanism of action showed by EHAm was related with the calcium channel blockade influx into the smooth muscle cells. On the other hand, epimeric sesquiterpene lactones leucodin (1) and achillin (2) were isolated and purified, which are responsible for the observed smooth muscle relaxant activity of the extract., Conclusion: hexanic extract of A. millefollium induced a significant relaxant effect on tracheal rat rings by calcium channel blockade and NO release., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Author contributions to the paper were as follows: Extracts preparation, and leucodin and achillin isolation: L. A-D., M. H-M, F. Ch-S. Structural elucidation: G. N–V., I. L-R. Pharmacological evaluation: R. V-M., M. I–B., L. A-D., S. E-S. Identification and recollection of plant material: I. P-A. Study design: S. E-S. Manuscript preparation: all authors. Notes: The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Importance: CORDIA MORELOSANA: Standley (Boraginaceae) is commonly used in folk medicine for the treatment of diarrhoea, kidney inflammation, diabetes, lung pain, bronchitis, asthma, hoarseness, cough and fever., Aim: Current work was conducted to develop a bio-guided isolation of antidiabetic compounds from ethanolic extract of Cordia morelosana (EECm)., Material and Methods: The phytochemical bio-guided study was conducted by successive chromatographic techniques, and isolated compounds were characterized by 1D and 2D-NMR experiments. The in vivo antihyperglycemic and antidiabetic activities of EECm (100 mg/kg), and methyl rosmarinate (MR, 50 mg/kg) were determined on normoglycemic and diabetic murine models. Additionally, the in vitro activity was conducted to determine α-glucosidase inhibitory effect, and PPARs, GLUT4 and FATP expression on 3T3-L1 cells by RT-PCR. Acute and sub-chronic toxicological studies for EECm were conducted on rats, following the OECD guidelines (No. 420 and 407)., Results: EECm promotes significant α-glucosidase inhibition (55.6%) at 1 mg/kg respect to the control. Also, EECm (100 mg/kg) showed significant antihyperglycemic effect on oral glucose tolerance test (OGTT), and in non-insulin dependent type 2 diabetes (NIDD) model, had antidiabetic activity (p < 0.001) compared to controls. The bio-guided isolation allowed to obtain four known compounds described as rosmarinic acid (RA), methyl rosmarinate (MR), nicotiflorine and 1-O-methyl-scyllo-inositol. On the other hand, MR showed significant antidiabetic and anthiyperglycemic activities (p < 0.05), and overexpression of PPARγ, PPARα, GLUT-4 and FATP than control. Docking studies were conducted with PPARγ and PPARα, showing interesting binding mode profile on those targets. Finally, EECm displayed a LD 50  > 2000 mg/kg and sub-chronic toxicological study reveals no toxic signs in animals tested compared to control., Conclusion: EECm showed significant antihyperglycemic and antidiabetic actions being RA and MR the main antidiabetic metabolites., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare. Authors’ contributions to the paper were as follows: study design and coordination: S. Estrada-Soto, B. Aguilar Guadarrama, D. Giles-Rivas; RT-PCR from 3T3-L1 cells studies: J. Almanza-Pérez and D. Giles-Rivas; preparation of the extracts and Phytochemical studies: S. Estrada-Soto, B. Aguilar Guadarrama, D. Giles-Rivas; in vivo studies: D. Giles-Rivas, S. Estrada-Soto and R. Villalbobos-Molina; α-glucosidases inhibition determination: R. Villalobos-Molina, D. Giles-Rivas and S. Estrada-Soto; In silico studies: B. Colin-Lozano and G. Navarrete-Vázquez; preparation and writing of the manuscript D. Giles-Rivas, S. Estrada-Soto and R. Villalobos-Molina; Finally, all authors contributed to the writing and revised the manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Importance: Achillea millefolium L. (Asteraceae) is a perennial herb used in Mexican folk medicine for treatment of several pathologies, including inflammatory and spasmodic gastrointestinal disorders, hepatobiliary complaints, overactive cardiovascular, respiratory ailments and diabetes., Aim of the Study: To evaluate the potential antidiabetic effect in vivo and to establish the potential mode of action through in vitro approaches of Achillea millefolium., Materials and Methods: The antidiabetic effect of hydroalcoholic extract of Achillea millefolium (HAEAm) was evaluated on the oral glucose tolerance tests, in normoglycemic and experimental Type 2 diabetic mice models. In addition, we evaluated the possible mode of action in in vitro assays to determine α-glucosidases inhibition, the insulin secretion and calcium mobilization in RINm5F cells and PPARγ and GLUT4 expression in 3T3-L1 cells., Results: HAEAm showed significant glucose diminution on oral glucose tolerance test and in acute experimental Type 2 diabetic assay with respect to the control (p < 0.05). In addition, HAEAm promoted the α-glucosidases inhibition by 55% at 1mg/ml respect to control. On the other hand, HAEAm increased the PPARγ (five-times) and GLUT4 (two-fold) relative expression than control (p < 0.05). Finally, HAEAm significantly increased the insulin secretion and [Ca 2+ ] i compared with control., Conclusion: The HAEAm possesses in vivo antidiabetic effect, having such effect through multitarget modes of action that involve antihyperglycemic (α-glucosidases inhibition), hypoglycemic (insulin secretion) and potential insulin sensitizer (PPARγ/GLUT4 overexpression) actions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Brickellia cavanillesii (Asteraceae) (Cass.) A. Gray is one of the popular plants consumed in Central America and Mexico for the treatment of several diseases such as hypertension, diabetes and anxiety, among others., Aim of the Study: To determine the anxiolytic-like effect of B. Cavanillesii and the safety of its use through toxicological studies., Material and Methods: Anxiolytic-like effects of soluble-methanol extract of B. cavanillesii (MEBc) were evaluated in ambulatory activity (open-field test), hole-board test, cylinder of exploration, the elevated plus-maze and the potentiation of the sodium pentobarbital-induced hypnosis mice models. On the other hand, in vivo toxicological studies were conducted on acute and sub-acute mice models recommended by OECD. Active MEBc was subjected to phytochemical studies through conventional chromatographic techniques to isolate bioactive compounds., Results: MEBc (100mg/Kg) showed significant anxiolytic-like effect on animal model used (p<0.05). The phytochemical analysis of MEBc allowed the isolation of two major compounds nicotiflorin and acacetin, among others. Both compounds were found to be partially responsible for the anxiolytic-like effects. Moreover, a median lethal dose (LD 50 ) higher than 2000mg/Kg was determined in mice and sub-acute oral administration of MEBc (100mg/Kg) did not alter body weight, clinical chemistry parameters (ALT and AST) and it did not induce any toxic nor alteration in the liver, kidney and heart functions., Conclusions: In current investigation, we have shown that MEBc has a wide range of pharmacology-toxicology patterns. The results support further investigation of MEBc as a potential anxiolytic phytomedicinal agent., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Agastache mexicana is used in Mexican traditional medicine for the treatment of hypertension, anxiety and related diseases., Aim of the Study: Current work was developed to establish pharmacological/toxicological parameters of tilianin, a flavone extracted from Agastache mexicana in order to propose it for clinical trials., Materials and Methods: Acute and sub-acute toxicology studies in Imprinting Control Region (ICR) mice and median effective dose (ED50) determination in conscious spontaneously hypertensive rats (SHR) were done., Results: A median lethal dose (LD50) of 6624 mg/kg (6201, 7076) in mice and significant antihypertensive effect (ED50=53.51 mg/kg) in SHR were determined. Moreover, sub-acute oral administration of tilianin did not alter body weight, clinical chemistry parameters (alanine amino-transferase, aspartate amino-transferase, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, glucose and insulin), and also did not induce any toxic or adverse effects on kidney, heart, liver, and lung functions., Conclusions: We have shown that tilianin, isolated from Agastache mexicana, was not toxic for rodents. Also, its antihypertensive effect was dose-dependent and ED50 (53.51 mg/kg) calculated was lesser than LD50 determined (6624 mg/kg), which suggest a wide range of pharmacology-toxicology patterns. Results support the hypothesis that tilianin must be investigated and developed for clinical trials as antihypertensive drug., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Artemisia ludoviciana spp. mexicana (Willd. Ex.) Spring D.D. Keck (Asteraceae), known as "estafiate" is employed for the treatment of diarrhea, dysentery, parasites, abdominal pain, vomiting, stomach ache, and also as antispasmodic agent. The aim of the present study was to evaluate the relaxant effect of hexanic (HEAl), dichloromethanic (DEAl) and methanolic (MEAl) extracts on isolated trachea, ileum and aorta rat rings, and to establish the tracheo-relaxant mode of action of DEAl., Materials and Methods: All extracts were investigated based on their capacity of to inhibit the rat ileum spontaneous contraction, to relax contraction induced by noradrenaline (0.1 μM) on endothelium-intact and endothelium-denuded thoracic aorta rat rings, and also to inhibit contraction provoked by carbachol (1 μM) on rat trachea., Results: Organic extracts had no spasmolytic action on ileum strips compared to positive control (papaverine, p<0.05). On the other hand, all extracts induced a significant concentration- and partial endothelium-dependent vasorelaxant activity. Extracts also showed significant relaxant effect on pre-contracted tracheal tissue in a concentration-dependent manner. In last two experiments, DEAl was the most potent and efficient extract; however, it was less potent than papaverine and theophylline, used as positive controls (p<0.05). In tracheal preparation, DEAl shifted to the right, in a parallel manner, the concentration-response curves induced by carbachol (p<0.05). Also, DEAl induced a significant relaxant effect on the contraction produced by potassium chloride (KCl, 80 mM). Pre-incubation with 1-H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (ODQ, 10 μM), indomethacin (10 μM), N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 μM), glibenclamide (10 μM) and 2-aminopyridine (2-AP, 100 μM) did not modify the DEAl-relaxant curves., Conclusions: Functional experiments suggest that the most active extract, DEAl, induced its relaxant effect by possible muscarinic receptors antagonism and calcium channel blockade in tracheal rings. On the other hand, significant vasorelaxant activity showed by DEAl is partially endothelium-dependent. Finally, spasmolytic activity induced by the extracts in the rat ileum was not significant, which suggests that the antidiarrheic effect of the plant is related to antimicrobial and antiparasitic properties previously described., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: To optimize the obtention of tilianin, an antihypertensive flavonoid isolated from Agastache mexicana (Lamiaceae), a medicinal plant used in Mexico for the treatment of hypertension. Also, a validated HPLC method to quantify tilianin from different extracts, obtained by several extraction methods, was developed., Materials and Methods: The aerial parts of Agastache mexicana were dried at different temperatures (22, 40, 50, 90, 100 and 180°C) and the dry material was extracted with methanol by maceration to compare the content of the active constituent tilianin in the samples. Furthermore, EtOH:H(2)O (7:3), infusion and decoction extracts were prepared from air-dried samples at room temperature to compare the content and composition of the different extraction methods. Moreover, an ex vivo vasorelaxant test on endothelium-intact aortic rat rings was conducted, in order to correlate the presence of tilianin with the activity of each extract., Results: Higher concentration and amounts of tilianin were determined from chromatograms in the obtained methanolic extracts from plant material dried at 90, 50, 40 and 22°C, followed by 100°C; however, lower concentrations were observed in dried at 180°C and EtOH:H(2)O (7:3). It is worth to notice that methanolic extracts with higher amount of tilianin were the most potent vasorelaxant extracts, even though these extracts were less potent than carbachol, a positive control used. Finally, decoction, infusion and EtOH:H(2)O (7:3) extracts did not show any vasorelaxant effect., Conclusion: Results suggest that extracts with higher concentration of tilianin possess the best vasorelaxant activity, which allowed us to have a HPLC method for future quality control for this medicinal plant., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aim of the Study: Cochlospermum vitifolium is a medicinal plant used for the treatment of diabetes, hepatobilary and cardiovascular illnesses. The aim of current study was to determine the in vivo antihypertensive and in vitro functional vasorelaxant mechanism of methanol extract of Cochlospermum vitifolium (MECv) and naringenin (NG)., Materials and Methods: Test material was assayed on rat isolated aorta rings test with- and without-endothelium to determine their vasorelaxant mechanism. Also, the in vivo antihypertensive effect was evaluated on spontaneously hypertensive rat (SHR) model. In addition, presence of NG into the extract was confirmed by reverse phase high performance liquid chromatography (RP-HPLC) analysis., Results: MECv (120 mg/kg) and NG (50 and 160 mg/kg) showed acute antihypertensive effects on SHR when systolic and diastolic pressure were decreased at 1 h and 24 h after administration, respectively. Vasorelaxant effect of MECv and NG was shifted to the right when endothelium-intact aortic rings were pre-incubated with L-NAME (10 microM) and ODQ (1 microM). Also, NG relaxant curves were displaced to the right in the presence of tetraethylammonium (TEA, 1 mM) and 2-aminopyridine (2-AP, 100 microM) on endothelium-denuded aortic rings., Conclusion: Experiments described above showed that MECv play an important role in hypertension regulation through NO synthesis and may be PGI(2) production and potassium channel activation on excessive endothelial dysfunction conditions. Unfortunately, presence of NG into the extract is not significant on bioactivity of the extract; however, this compound could be tested and evaluated as structural scaffold for future drug design for development of antihypertensive agents., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)