Molecular Docking Integrated with Network Pharmacology Explores the Therapeutic Mechanism of Cannabis sativa against Type 2 Diabetes.

The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. sativa in treating T2D. We identified the active compounds in C. sativa and their targets. From there, we examined the genes associated with T2D and found overlapping genes. We conducted an enrichment analysis and created a protein-protein and target-compound interactions network. We confirmed the binding activities of the hub proteins and compounds with molecular docking. We identified thirteen active compounds from C. sativa, which have 150 therapeutic targets in T2D. The enrichment analysis showed that these proteins are involved in the hormone, lipid, and stress responses. They bind transcription factors and metals and participate in the insulin, PI3K/Akt, HIF-1, and FoxO signaling pathways. We found four hub proteins (EGFR, ESR1, HSP90AA1, and SRC) that bind to the thirteen bioactive compounds. This was verified using molecular docking. Our findings suggest that C. sativa's antidiabetic action is carried out through the insulin signaling pathway, with the participation of HIF-1 and FoxO.

Neuropharmacological Effects of the Dichloromethane Extract from the Stems of Argemone ochroleuca Sweet (Papaveraceae) and Its Active Compound Dihydrosanguinarine.

Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography-mass spectrometry (GC-MS), and its active compound dihydrosanguinarine (DHS). The anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of the AOE (0.1-50 mg/kg p.o.) and DHS (0.1-10 mg/kg p.o.) were evaluated using murine models. A possible mechanism for the neurological actions induced by the AOE or DHS was assessed using inhibitors of neurotransmission pathways and molecular docking. Effective dose 50 (ED50) values were calculated by a linear regression analysis. The AOE showed anxiolytic-like activity in the cylinder exploratory test (ED50 = 33 mg/kg), and antidepressant-like effects in the forced swimming test (ED50 = 3 mg/kg) and the tail suspension test (ED50 = 23 mg/kg), whereas DHS showed anxiolytic-like activity (ED50 = 2 mg/kg) in the hole board test. The AOE (1-50 mg/kg) showed no locomotive affectations or sedation in mice. A docking study revealed the affinity of DHS for α2-adrenoreceptors and GABAA receptors. The anxiolytic-like and anticonvulsant effects of the AOE are due to GABAergic participation, whereas the antidepressant-like effects of the AOE are due to the noradrenergic system. The noradrenergic and GABAergic systems are involved in the anxiolytic-like actions of DHS.

Physiological Effects and Human Health Benefits of Hibiscus sabdariffa: A Review of Clinical Trials.

Hibiscus sabdariffa Linn. Malvaceae (HS) is characterized by its edible calyxes. The HS calyxes are widely used for cosmetic, food, and medicinal applications. According to ethnobotanical evidence, decoction, infusion, or maceration extracts from HS calyxes have been used in folk medicine to treat many ailments. Moreover, several in vitro and in vivo studies have demonstrated the pharmacological properties and potential human health benefits of HS consumption. On the other hand, the evaluation of the physiological effects and health benefits of HS in clinical studies is most challenging. Therefore, this narrative review summarizes and discusses the physiological effects and health benefits of HS calyxes reported in clinical trials. Preparations obtained from HS calyxes (extracts, infusions, decoction, teas, beverages, capsules, and pills) are used as non-pharmacological therapies to prevent/control diverse chronic non-communicable diseases. The most-reported HS health benefits are its antihypertensive, antidyslipidemic, hypoglycemic, body fat mass reduction, nephroprotective, antianemic, antioxidant, anti-inflammatory, and anti-xerostomic activities; these effects are associated with the phytochemicals found in HS. Moreover, no adverse effects were reported during the clinical trials. However, clinical studies exhibited some limitations; thus, further studies are required to validate the clinical efficacy of HS in large-scale studies with higher doses and a good experimental design.

Antinociceptive effects of Laelia anceps Lindl. and Cyrtopodium macrobulbon (Lex.) G.A. Romero & Carnevali, and comparative evaluation of their metabolomic profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Laelia anceps and Cyrtopodium macrobulbon are two orchids used in Mexican traditional medicine for treating pain. AIM OF THE STUDY: The individual antinociceptive activity of ethanol extracts from the roots of Laelia anceps (LAE) and Cyrtopodium macrobulbon (CME) was evaluated, and their metabolomic profiles were comparatively evaluated. The antinociceptive activity of CME and naproxen combination (1:1) was also addressed. MATERIALS AND METHODS: The antinociceptive actions of LAE and CME were examined using three nociceptive tests. The combination of CME with naproxen was evaluated in the acetic acid test using isobologram analysis. Metabolomic analysis was performed using capillary reversed phase liquid chromatography-electrospray ionization-high resolution mass spectrometry and the MS-DIAL 4.70 software was used for data analysis and statistics. RESULTS: LAE (ED50 = 48.4 mg/kg) and CME (ED50 = 17.8 mg/kg) showed antinociceptive activity in the acetic acid test. Pre-treatment with L-NAME reverted the antinociceptive effects of LAE and CME in the acetic acid test. LAE (ED50 = 97 mg/kg) and CME (ED50 = 29 mg/kg) also induced antinociceptive activity in the second phase of the formalin test. The combination of CME with naproxen induced synergistic (interaction index = 0.434) antinociceptive effects (ED50 = 10.6 mg/kg). Overall, 156 compounds allocated in 97 different ontologies were found to be differentially expressed in the two orchids; among them, 125 compounds corresponded to LAE and 31 to CME. Three phenanthrene derivatives annotated in CME might be associated with its antinociceptive activity. CONCLUSION: LAE and CME induced antinociceptive activity with the possible participation of the nitric oxide pathway. CME in combination with naproxen synergistically produces antinociceptive effects in the acetic acid test. The untargeted metabolomic analysis allowed for annotation of several compounds potentially involved in the therapeutic potential of two plants; among them, three phenanthrene derivatives might contribute to the observed antinociceptive activity.

Myristic acid reduces skin inflammation and nociception.

This study evaluated the inhibitory effect of myristic acid (MA) on models of inflammation and nociception. The in vitro anti-inflammatory activities of MA were assessed on LPS-stimulated macrophages, membrane stabilization assay, and inhibition of protein denaturation, whereas the inhibitory activity of MA on in vivo inflammation was assessed on TPA-induced ear edema using acute and chronic assays in mice. The inhibitory effect of MA on nociception was assessed using three in vivo models. MA exerted in vitro anti-inflammatory activity by the increase (58%) in the production of IL-10 in LPS-stimulated macrophages. In the in vivo assay, MA showed good anti-inflammatory effects on the acute (ED50 = 62 mg/kg) and chronic (ED50 = 77 mg/kg) TPA-induced ear edema. The antinociceptive activity of MA was related to the participation of the nitrergic system in the formalin-induced paw licking test. PRACTICAL APPLICATIONS: Previous studies with different plant extracts containing MA, as one of their major components, have demonstrated anti-inflammatory and antinociceptive actions. However, the anti-inflammatory and antinociceptive actions of myristic acid have not been previously reported. The results suggest that MA induced anti-inflammatory effects in LPS-stimulated macrophages through the participation of IL-10. The antinociceptive effects of MA are attributed to the participation of the nitrergic system.

In vitro and in vivo anti-inflammatory effects of an ethanol extract from the aerial parts of Eryngium carlinae F. Delaroche (Apiaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Eryngium carlinae F. Delaroche (Apiaceae) is an herb used in folk medicine as a diuretic, analgesic, and anti-inflammatory agent. AIM OF THE STUDY: This work assessed the diuretic, antinociceptive, and anti-inflammatory actions of an ethanol extract from the leaves and stems of Eryngium carlinae (ECE). These ethnomedicinal properties of ECE were scientifically validated using in vitro and in vivo assays. MATERIALS AND METHODS: The antinociceptive and diuretic actions of ECE (10-200 mg/kg p.o.) were assessed with the acetic acid-induced writhing test and by using metabolic cages to house mice, respectively. The in vitro anti-inflammatory actions of ECE (1-500 µg/ml) were evaluated using LPS-stimulated primary murine macrophages, and the in vivo anti-inflammatory actions were assessed using the TPA-induced ear edema test (2 mg/ear) and carrageenan-induced paw edema test (50-200 mg/kg p.o.). The production of inflammatory mediators was estimated using in vitro and in vivo assays. RESULTS: ECE lacked antinociceptive and diuretic effects. ECE increased the production of IL-10 in LPS-stimulated macrophages (EC50 = 37.8 pg/ml) and the carrageenan-induced paw edema test (ED50 = 82.6 mg/kg). ECE showed similar in vivo anti-inflammatory actions compared to those observed with indomethacin. CONCLUSION: ECE exerts in vitro and in vivo anti-inflammatory effects by increasing the release of IL-10.

Anti-inflammatory and antinociceptive effects of an ethanol extract from Senna septemtrionalis.

Senna septemtrionalis (Viv.) H.S. Irwin & Barneby (Fabaceae) is a medicinal plant used as a folk remedy for inflammation and pain. The objective of this study was to evaluate the anti-inflammatory and antinociceptive actions of an ethanol extract of Senna septemtrionalis aerial parts (SSE). The in vitro anti-inflammatory effects of SSE were assessed using LPS-stimulated macrophages and the subsequent quantification of the levels of cytokines (IL-6, IL-1ß, and TNF-α) with ELISA kits, nitric oxide (NO), and hydrogen peroxide (H2O2). The in vivo anti-inflammatory actions of SSE were evaluated with the TPA-induced ear oedema test and the carrageenan-induced paw oedema test. The antinociceptive actions of SSE (10-200 mg/kg p.o.) were assessed using three models: two chemical assays (formalin-induced orofacial pain and acetic acid-induced visceral pain) and one thermal assay (hot plate). SSE showed in vitro anti-inflammatory actions with IC50 values calculated as follows: 163.3 µg/ml (IL-6), 154.7 µg/ml (H2O2) and > 200 µg/ml (IL-1ß, TNF-α, and NO). SSE showed also in vivo anti-inflammatory actions in the TPA test (40% of inhibition of ear oedema) and the carrageenan test (ED50 = 137.8 mg/kg p.o.). SSE induced antinociceptive activity in the formalin orofacial pain test (ED50 = 80.1 mg/kg) and the acetic acid-induced writhing test (ED50 = 110 mg/kg). SSE showed no antinociceptive actions in the hot plate assay. The pre-treatment with glibenclamide abolished the antinociceptive action shown by SSE alone. Overall, SSE exerted in vitro and in vivo anti-inflammatory actions, and in vivo antinociceptive effects by the possible involvement of ATP-sensitive K + channels.

Pharmacological and toxicological study of a chemical-standardized ethanol extract of the branches and leaves from Eysenhardtia polystachya (Ortega) Sarg. (Fabaceae).

Eysenhardtia polystachya is used for the empirical treatment of cancer, infections, diarrhea, inflammation, and pain. This study identified, using GC-MS, the main chemical components in an ethanol extract of E. polystachya branches and leaves (EPE) and tested its cytotoxic, antimicrobial, anti-diarrheal, anti-inflammatory, and antinociceptive effects. The in vitro and in vivo toxicity of EPE was evaluated using the comet assay in human peripheral blood mononuclear cells (PBMC) and the acute toxicity test in mice, respectively. The cytotoxic and the antimicrobial effects were performed using the MTT assay and the minimum inhibitory concentration (MIC) test, respectively. The levels of pro-inflammatory mediators in LPS-stimulated macrophages were measured to evaluate the in vitro anti-inflammatory effects of EPE. The antidiarrheal (castor oil test, small intestine transit, and castor oil-induced enteropooling), and anti-inflammatory activities (TPA and carrageenan) of EPE were also performed. The antinociceptive actions of EPE were carried out with the following tests: acetic acid, formalin, and hot plate. The hypnotic and locomotor effects were analyzed using pentobarbital and a rotarod system, respectively. The main component in EPE was D-pinitol (26.93%). The antidiarrheal and antinociceptive effects of D-pinitol were also evaluated. EPE showed low in vitro toxicity (DNA damage in PBMC at concentrations higher than 200 µg/ml), and low in vivo toxicity (LD50 > 2000 mg/kg i.p. and p.o.). Furthermore, EPE lacked cytotoxic activity (IC50 > 300 µg/ml) on human cancer cells, but showed good antimicrobial effects in E. coli (MIC=1.56 µg/ml) and S. aureus (MIC = 0.78 µg/ml). In multi-drug resistant microorganisms, EPE showed MIC> 100 µg/ml. EPE exerted in vitro anti-inflammatory effects, mainly, by the decrease in the production of H2O2 (IC50 = 43.9 ±â€¯3.8 µg/ml), and IL-6 (73.3 ±â€¯6.9 µg/ml). EPE (ED50 =7.5 ±â€¯0.9 mg/kg) and D-pinitol (ED50 = 0.1 ±â€¯0.03 mg/kg) showed antidiarrheal activity, and antinociceptive effects in the acetic acid test with ED50 = 117 ±â€¯14.5 mg/kg for EPE and 33 ±â€¯3.2 mg/kg for D-pinitol. EPE showed also antinociceptive activity in the phase 2 of the formalin test (ED50 = 48.9 ±â€¯3.9 mg/kg), without inducing hypnotic effects or altering the locomotor activity in mice. The results here presented corroborate the folk medicinal use of Eysenhardtia polystachya in the treatment of infections, diarrhea, inflammation, and pain. D-pinitol, the main metabolite of EPE, showed antinociceptive and antidiarrheal effects with similar potency compared to standard drugs.

Use of medicinal plants by health professionals in Mexico.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of medicinal plants in Mexico has been documented since pre-Hispanic times. Nevertheless, the level of use of medicinal plants by health professionals in Mexico remains to be explored. AIM OF THE STUDY: To evaluate the use, acceptance and prescription of medicinal plants by health professionals in 9 of the states of Mexico. MATERIALS AND METHODS: Direct and indirect interviews, regarding the use and acceptance of medicinal plants, with health professionals (n=1614), including nurses, physicians, pharmacists, and odontologists from nine states in Mexico were performed from January 2015 to July 2016. The interviews were analyzed with the factor the informant consensus (FIC). RESULTS: The information obtained indicated that 46% of those interviewed feel patients should not use medicinal plants as an alternative therapy. Moreover, 54% of health professionals, and 49% of the physicians have used medicinal plants as an alternative therapy for several diseases. Twenty eight percent of health professionals, and 26% of the physicians, have recommended or prescribed medicinal plants to their patients, whereas 73% of health professionals were in agreement with receiving academic information regarding the use and prescription of medicinal plants. A total of 77 plant species used for medicinal purposes, belonging to 40 botanical families were reported by the interviewed. The results of the FIC showed that the categories of diseases of the digestive system (FIC=0.901) and diseases of the respiratory system (FIC=0.898) had the greatest agreement. CONCLUSIONS: This study shows that medicinal plants are used for primary health care in Mexico by health professionals.