Chemical composition and evaluation of the antinociceptive, antioxidant and antimicrobial effects of essential oil from Hymenaea cangaceira (Pinto, Mansano & Azevedo) native to Brazil: A natural medicine Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Bruno Oliveira de Veras, Maria Betânia Melo de Oliveira, Fernanda Granja da Silva Oliveira, Yago Queiroz dos Santos, João Ricardhis Saturnino de Oliveira, Vera Lúcia de Menezes Lima, Jackson Roberto Guedes da Silva Almeida, Daniela Maria do Amaral Ferraz Navarro, Júlio César Ribeiro de Oliveira Farias de Aguiar, Jaciana dos Santos Aguiar, Krystyna Gorlach-Lira, Caio Rodrigo Dias de Assis, Márcia Vanusa da Silva, Ana Catarina de Souza Lopes Abstract Ethnopharmacological relevance Hymenaea cangaceira Pinto, Mansano & Azevedo (Fabaceae) is a Brazilian medicinal plant widely known as “Jatobá”. In folk medicine, it is used to treat infections, respiratory problems, rheumatism, antitumoral, inflammation and pain, however, no activity has been scientifically validated. Aim of the study This study investigated chemical composition of essential oil from Hymenaea cangaceira (EOHc), antimicrobial, antinociceptive and antioxidant activities besides protection against DNA damage and hemolysis. Material and methods The essential oil was obtained by hydrodistillation, and characterized by GC-MS and GC-FID. The evaluation of antimicrobial activity was performed by microdilution method. The evaluation of the antioxidant activity was performed using the radicals DPPH, ABTS, O2- and OH-, and the protection of DNA damage using plasmid pBR322. Different experimental models were used to evaluate the antinociceptive effect (acetic acid and formalin), and evaluate the mechanisms of action involved with pharmacological antagonists (naloxone, atropine and gibenclamide) in mice. The essential oil was evaluated for hemolysis on human erythrocytes. Results The extraction of EOHc showed a yield of 0.18% on a dry basis, presenting high content of hydrocarbon sesquiterpenes (79.04%), high antioxidant activity and protect DNA from damage, besides presenting antifungal and antibacterial activity against Gram-positive and Gram-negative bacteria in vitro. It was found that the essential oil had no acute toxicity in mice up to 5000 mg/kg oral administration (o.a.), in addition to no hemolysis on human erythrocytes. The reduction of antinociceptive activity was 75%, with the opioid system as the mechanism of action. Conclusion Our results validate the main activities by the traditional use attributed to H. cangaceira for antimicrobial and analgesic activity. In addition, the oil has a potent antioxidant activity, protecting the body against oxidative stress damage, adding new value to an endemic species not known to the industry. Graphical abstract

Cacao extract enriched in polyphenols prevents endocrine-metabolic disturbances in a rat model of prediabetes triggered by a sucrose rich diet Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): María Cecilia Castro, Hernán Villagarcía, Ada Nazar, Luisa González Arbeláez, María Laura Massa, Héctor Del Zotto, José Luis Ríos, Guillermo R. Schinella, Flavio Francini Abstract Ethnopharmacological relevance Cocoa extracts rich in polyphenols are used as potential agent for treating diabetes. Cocoa polyphenols have been proved to ameliorate important hallmarks of type-2 diabetes (T2D). They can regulate glucose levels by increasing insulin secretion, promoting β-cell proliferation and a reduction of insulin resistance. In addition, epidemiological evidence indicates that consumption of flavonoid decreases the incidence of T2D. Aim of the study T2D is preceded by a prediabetic state in which the endocrine-metabolic changes described in T2D are already present. Since epidemiological evidence indicates that consumption of flavonoid decreases its incidence, we evaluated possible preventive effects of polyphenol-enriched cocoa extract on a model of prediabetes induced by sucrose. Materials and methods We determined circulating parameters and insulin sensitivity indexes, liver protein carbonyl groups and reduced glutathione, liver mRNA expression levels of lipogenic enzymes, expression of different pro-inflammatory mediators, fructokinase activity and liver glycogen content. For that, radioimmunoassay, real-time polymerase chain reaction, Western blot, spectrophotometry, and immunohistochemistry were used. Results We demonstrated that sucrose administration triggered hypertriglyceridemia, insulin-resistance, and liver increased oxidative stress and inflammation markers compared to control rats. Additionally, we found an increase in glycogen deposit, fructokinase activity, and lipogenic genes expression (SREBP-1c, FAS and GPAT) together with a decrease in P-Akt and P-eNOS protein content (P < 0.05). Sucrose-induced insulin resistance, hepatic carbohydrate and lipid dysmetabolism, oxidative stress, and inflammation were effectively disrupted by polyphenol-enriched cocoa extract (PECE) co-administration (P < 0.05). Conclusion Dietary administration of cocoa flavanols may be an effective and complementary tool for preventing or reverting T2D at an early stage of its development (prediabetes). Graphical abstract

The effect of Shengpuhuang-tang on retinal inflammation in streptozotocin-induced diabetic rats by NF-κB pathway Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Wencan Li, Xiaohui Shen, Yanping Wang, Jiani Zhang Abstract: Ethnopharmacological relevance Diabetic retinopathy (DR) is a terrible microvascular disorder causing blindness. Retinal inflammation is the early stage in DR, which is believed to play a crucial role in the development of it. Shengpuhuang-tang (ST), a traditional herbal formula, which has effective treatment of fundus bleeding disorder. ST exerts protective effects against DR in rats, but its underlying mechanism of this efficacy remains unknown. Thus, the objective of this study is to examine the mechanism and the efficacy of ST on retinal inflammation in streptozotocin-induced diabetic rats. Materials and methods The administration of ST was initiated at 4 weeks after diabetes induction and continued for 12 weeks. Retinal vessel permeability was evaluated by using FITC-dextran and Evans blue. Retinal leukostasis was evaluated with FITC-coupled concanavalin A lectin (ConA). Moreover, western blotting was performed to detect TNF-α, ICAM-1 and the relative expression levels of IκBα, IKKβ, and p65 in vivo. Results The results showed that the retinal inflammation in streptozotocin-induced diabetic rats was significantly decreased by ST. ST could decreased the expression levels of TNF-α, ICAM-1 and inhibited the expression of p-IKKβ, p-p65 and IκBα. It could also inhibited the nuclear transfer of p65. Conclusions In conclusion, these data suggested that ST may have potential treatment strategies against early stage of diabetic retinopathy through NF-κB pathway. Graphical abstract

The use of jarilla native plants in a Diaguita-Calchaquí indigenous community from northwestern Argentina: An ethnobotanical, phytochemical and biological approach Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Mónica Patricia Antonella Carabajal, María Cristina Perea, María Inés Isla, Iris Catiana Zampini Abstract Ethnopharmacological relevance In northwestern Argentina inhabit several ancient indigenous communities with diverse cultural and historical background. Geographical isolation has contributed to the prevalence of a native plant-based folk medicine; “jarilla” species are medicinal plants widely used in local communities for the treatment of mycosis, respiratory, gastrointestinal and rheumatic disorders. The aim of the study To assemble the traditional knowledge acquired through years with scientific data concerning to phytochemistry, antioxidant and anti-inflammatory potential of three “jarillas” species. Material and methods Ethnobotanical data of three “jarillas”, Zuccagnia punctata (Zp), Larrea cuneifolia (Lc), and Larrea divaricata (Ld), were explored by interviewing native people from Indigenous Community of Amaicha del Valle, Tucumán. Phenolic profiles from each infusion were analyzed by HPLC-ESI-MS/MS. Antioxidant activity was determined by superoxide anion and hydrogen peroxide scavenging capacity, lipoperoxidation inhibition, and ferrous iron chelating activity. It was also assessed their ability to inhibit pro-inflammatory enzymes, such as xanthine oxidase, lipoxygenase, and hyaluronidase. Results Ethnobotanical interviews showed that local people use “jarillas” mainly as infusions and baths. It was reported different categories of uses, such as medicinal (10 curative applications), to religious purposes, tinctorial, as construction material and as fuel. From infusions prepared, the MS and MS/MS data allowed the identification of 27 compounds from Z. punctata, and 11 from both Larrea sp. The infusions showed an important antioxidant activity through different mechanisms, highlighting Zp and Lc in free radical scavenging capacity and Ld on lipid peroxidation inhibition and iron binding. They were also capable of inhibit xanthine oxidase and lipoxygenase enzymes, being Lc the most active one. Conclusions This research work provides novel information concerning to several categories of traditional uses of “jarilla” species in a Diaguita-Calchaquí community and focus attention to infusions from a phytochemical and biological approach. Graphical abstract

Inventing a herbal tradition: The complex roots of the current popularity of Epilobium angustifolium in Eastern Europe Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Renata Sõukand, Giulia Mattalia, Valeria Kolosova, Nataliya Stryamets, Julia Prakofjewa, Olga Belichenko, Natalia Kuznetsova, Sabrina Minuzzi, Liisi Keedus, Baiba Prūse, Andra Simanova, Aleksandra Ippolitova, Raivo Kalle Abstract Ethnopharmacological relevance Currently various scientific and popular sources provide a wide spectrum of ethnopharmacological information on many plants, yet the sources of that information, as well as the information itself, are often not clear, potentially resulting in the erroneous use of plants among lay people or even in official medicine. Our field studies in seven countries on the Eastern edge of Europe have revealed an unusual increase in the medicinal use of Epilobium angustifolium L., especially in Estonia, where the majority of uses were specifically related to “men's problems”. The aim of the current work is to understand the recent and sudden increase in the interest in the use of E. angustifolium in Estonia; to evaluate the extent of documented traditional use of E. angustifolium among sources of knowledge considered traditional; to track different sources describing (or attributed as describing) the benefits of E. angustifolium; and to detect direct and indirect influences of the written sources on the currently documented local uses of E. angustifolium on the Eastern edge of Europe. Materials and methods In this study we used a variety of methods: semi-structured interviews with 599 people in 7 countries, historical data analysis and historical ethnopharmacological source analysis. We researched historical and archival sources, and academic and popular literature published on the medicinal use of E. angustifolium in the regions of our field sites as well as internationally, paying close attention to the literature that might have directly or indirectly contributed to the popularity of E. angustifolium at different times in history. Results Our results show that the sudden and recent popularity in the medical use of E. angustifolium in Estonia has been caused by local popular authors with academic medical backgrounds, relying simultaneously on “western” and Russian sources. While Russian sources have propagated (partially unpublished) results from the 1930s, “western” sources are scientific insights derived from the popularization of other Epilobium species by Austrian herbalist Maria Treben. The information Treben disseminated could have been originated from a previous peak in popularity of E. angustifolium in USA in the second half of the 19th century, caused in turn by misinterpretation of ancient herbals. The traditional uses of E. angustifolium were related to wounds and skin diseases, fever, pain (headache, sore throat, childbirth), and abdominal-related problems (constipation, stomach ache) and intestinal bleeding. Few more uses were based on the similarity principle. The main theme, however, is the fragmentation of use and its lack of consistency apart from wounds and skin diseases. Conclusions Historical ethnobotanical investigations could help to avoid creating repeating waves of popularity of plants that have already been tried for certain diseases and later abandoned as not fully effective. There is, of course, a chance that E. angustifolium could also finally be proven to be clinically safe and cost-effective for treating benign prostatic hyperplasia, but this has not yet happened despite recent intensive research. Documented traditional use would suggest investigating the dermatological, intestinal anti-hemorrhagic and pain inhibiting properties of this plant, if any. Graphical abstract

Efficacy of oral administration of licorice as an adjunct therapy on improving the symptoms of patients with Parkinson's disease, A randomized double blinded clinical trial Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Peyman Petramfar, Fatemeh Hajari, Gholamhossein Yousefi, Samar Azadi, Azadeh Hamedi Abstract Ethnopharmacological relevance Licorice preparations are used as neuroprotective remedies in Persian ethnomedicine, in order to prevent from disabilities in neurodegenerative conditions like Parkinson's disease (PD). Aim of the study This study was designed to determine the licorice (root of Glycyrrhiza glabra L.) effectiveness as an adjunct treatment in the PD management. Material and methods In this double-blinded trial, 128 patients were assessed for eligibility criteria. Seventy-eight patients were ineligible and 11 of them refused from participating. Thirty-nine PD patients (YAHR staging ≤ 3) were divided into two groups by random. The patients received oral licorice or placebo syrups with a dose of 5 cc, twice a day for 6 months. High-performance liquid chromatography and spectrophotometric instruments determined licorice syrup constituents. The patients' situation for Unified Parkinson's rating scale (UPDRS) was assessed every 6 weeks for the duration of six months. In addition, patients' blood pressure, blood glucose, sodium and potassium levels, quality of life and dizziness were determined. Results Six weeks after intervention, total UPDRS, daily activities and tremor were significantly improved with a considerable effect size. A significant better motor test and rigidity scores were observed 4 months after licorice intake (p > 0.05). No electrolyte abnormality, significant changes in blood pressure or blood glucose levels were observed during the study. Each 5cc of syrup contained 136 mg of licorice extract with 12.14 mg glycyrrhizic acid, and also 136 μg of polyphenols. Conclusion The licorice intake could improve the symptoms in PD patients without serious adverse events. Graphical abstract

Phytochemical study, molecular docking, genotoxicity and therapeutic efficacy of the aqueous extract of the stem bark of Ximenia americana L. in the treatment of experimental COPD in rats Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Gilmânia Francisca Sousa Carvalho, Laura Karina Marques, Herbert Gonzaga Sousa, Laryssa Roque Silva, Danniel Cabral Leão Ferreira, Fabrício Pires de Moura do Amaral, Antônio Luiz Martins Maia Filho, José Figueredo-Silva, Wellington dos Santos Alves, Maria das Dores Alves de Oliveira, Joaquim Soares da Costa Júnior, Fabio Luis Cardoso Costa Junior, Ricardo Martins Ramos, Mahendra Rai, Valdiléia Teixeira Uchôa Abstract Ethnopharmacological relevance Ximenia americana L. is popularly known as yellow plum, brave plum or tallow wood. All the parts of this plant are used in popular medicine. Its reddish and smooth bark are used to treat skin infections, inflammation of the mucous membranes and in the wound healing process. Objective Verification of phytochemical profile, the molecular interaction between flavonoid, (−) epi-catechin and 5-LOX enzyme, by means of in silico study, the genotoxic effect and to investigate the pharmacological action of the aqueous extract of the stem bark of X. americana in pulmonary alterations caused by experimental COPD in Rattus norvegicus. Materials and methods The identification of secondary metabolites was carried out by TLC and HPLC chromatographic methods, molecular anchoring tests were applied to analyze the interaction of flavonoid present in the extract with the enzyme involved in pulmonary inflammation process and the genotoxic effect was assessed by comet assay and micronucleus test. For induction of COPD, male rats were distributed in seven groups. The control group was exposed only to ambient air and six were subjected to passive smoke inhalations for 20 min/day for 60 days. One of the groups exposed to cigarette smoke did not receive treatment. The others were treated by inhalation with beclomethasone dipropionate (400 mcg/kg) and aqueous and lyophilized extracts of X. americana (500 mg/kg) separately or in combination for a period of 15 days. The structural and inflammatory pulmonary alterations were evaluated by histological examination. Additional morphometric analyses were performed, including the alveolar diameter and the thickness of the right ventricle wall. Results The results showed that the aqueous extract of the bark of X. americana possesses (−) epi -catechin, in silico studies with 5-LOX indicate that the EpiC ligand showed better affinity parameters than the AracA ligand, which is in accordance with the results obtained in vivo studies. Genotoxity was not observed at the dose tested and the extract was able to stagnate the alveolar enlargement caused by the destruction of the interalveolar septa, attenuation of mucus production and decrease the presence of collagen fibers in the bronchi of animals submitted to cigarette smoke. Conclusion Altogether, the results proved that the aqueous extract of X. americana presents itself as a new option of therapeutic approach in the treatment of COPD. Graphical abstract

Loganin ameliorates cartilage degeneration and osteoarthritis development in an osteoarthritis mouse model through inhibition of NF-κB activity and pyroptosis in chondrocytes Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Jiaming Hu, Jinyi Zhou, Jinting Wu, Quan Chen, Weibin Du, Fangda Fu, Huan Yu, Sai Yao, Hongting Jin, Peijian Tong, Di Chen, Chengliang Wu, Hongfeng Ruan Abstract Ethnopharmacological relevance Corni Fructus (CF), the red fruit of Cornus officinalis Siebold & Zucc, has been used both as food and medicinal herb in traditional Chinese medicine (TCM). Loganin is a major iridoid glycoside and one of the quality control indexes of CF. In TCM clinical practice, prescription containing CF is commonly used to treat osteoarthritis (OA), but the underlying mechanisms of loganin are not yet utterly understood. Aim of the study The aims of the present study are to confirm the therapeutic effects of loganin in an OA mouse model and to determine the mechanisms involved in the OA protective effects. Materials and methods The destabilization of the medial meniscus (DMM) procedure was performed on the right knee of 8-week-old C57BL/6 male mice. 30 or 100 μg/ml of loganin was then injected into articular space twice a week for 8 and 12-week. Safranin O/Fast green staining, H&E staining, micro-CT analysis were performed to analyze structural and morphological changes. The protein expression of collagen type II (Col2), metalloproteinase-3 (Mmp3), matrix metalloproteinase 13 (Mmp13) collagen type X (Col10), cryopyrin and caspase-1 were detected by immunochemistry staining. Immuno-fluorescence assay was performed to assess changes in expression of CD31, endomucin, p65 and p-I-κB. Results Results of histomorphometry showed that loganin delays the progression of OA in the DMM model. In cartilage, loganin decreased the OARSI score, increasing hyaline cartilage (HC) thickness and decreasing calcified cartilage (CC) thickness. Moreover, loganin inhibited osteophyte formation, reduced the bone volume fraction (BV/TV), lowered trabecular thickness (Tb.Th) and increased trabecular separation (Tb.Sp) in subchondral bone. Mechanistically, loganin increased the expressions of Col2, decreases the expression of Mmp3, Mmp13, Col10, cryopyrin and caspase-1 in cartilage. In parallel, loganin inhibited the expression of CD31 and endomucin in subchondral bone. Furthermore, loganin suppressed nuclear translocation of p65 protein, and decreased the amount of p-I-κB in chondrocytes. Conclusions In summary, these results uncovered that loganin inhibits NF-κB signaling and attenuates cartilage matrix catabolism and pyroptosis of chondrocytes in articular cartilage. Loganin may serve as a potential therapeutic agent for OA treatment. Graphical abstract

Anti-hyperglycemic and anti-hyperlipidemic effects of a special fraction of Luohanguo extract on obese T2DM rats Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Yulong Zhang, Guisheng Zhou, Ying Peng, Mengyue Wang, Xiaobo Li Abstract Ethnopharmacological relevance Luohanguo (LHG), a traditional Chinese medicine, could clear heat, moisten the lung, soothe the throat, restore the voice, and lubricate intestine and open the bowels. LHG has been utilized for the treatment of sore throats and hyperglycemia in folk medicine as a homology of medicine and food. The hypoglycemic pharmacology of LHG has attracted considerable attention, and mogrosides have been considered to be active ingredients against diabetes mellitus. We have found that these mogrosides could be metabolized into their secondary glycosides containing 1–3 glucose residues in type 2 diabetes mellitus (T2DM) rats in previous studies. These metabolites may be the antidiabetic components of LHG in vivo. Thus far, no reports have been found on reducing blood glucose of mogrosides containing 1–3 glucose residues. Aims of the study The aim of this study was to confirm that mogrosides containing 1–3 glucose residues were the active components of LHG for antidiabetic effects and to understand their potential mechanisms of action. Materials and methods First, the special fraction of mogrosides containing 1–3 glucose residues was separated from a 50% ethanol extract of LHG, and the chemical components were identified by ultra-performance liquid chromatography (UPLC) and named low-polar Siraitia grosvenorii glycosides (L-SGgly). Second, the antidiabetic effects of L-SGgly were evaluated by HFD/STZ-induced (high-fat diet and streptozocin) obese T2DM rats by indexing fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance, and then compared with other fractions in the separation process. The changes in serum lipid levels were also detected. Finally, possible mechanisms of antidiabetic activity of L-SGgly were identified as increasing GLP-1 levels and activating liver AMPK in T2DM rats. Results The chemical analysis of L-SGgly showed that they contain 11-oxomogroside V, mogroside V, mogroside III, mogroside IIE, mogroside IIIA1, mogroside IIA1, and mogroside IA1, respectively. The total content of the mogrosides in L-SGgly was 54.4%, including 15.7% mogroside IIA1 and 12.6% mogroside IA1. L-SGgly showed excellent effects on obese T2DM rats compared with the other fractions of LHG extract, including significantly reducing the levels of FBG (p < 0.001) and modifying insulin resistance (p < 0.05). Meanwhile, they could significantly decrease the content of triglyceride (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and free fatty acid (p < 0.001) and increase the content of high-density lipoprotein cholesterol (p < 0.001) in serum of T2DM rats. Moreover, L-SGgly can significantly increase (p < 0.01) GLP-1 levels and decrease (p < 0.01) IL-6 levels in T2DM rat serum. AMPK-activating activity in T2DM rats was also upregulated by L-SGgly, but no statistical significance was shown. Conclusion L-SGgly, fractions separated from LHG extract, were verified to have obvious anti-hyperglycemic and anti-hyperlipidemic effects on T2DM rats. Furthermore, L-SGgly regulated insulin secretion in T2DM rats by increasing GLP-1 levels. These findings provide an explanation for the antidiabetic role of LHG. Graphical abstract L-SGgly can play a role in anti-hyperglycemia and anti-hyperlipidemia by increasing the levels of GLP-1. L-SGgly were the active antidiabetic components of LHG.

UPLC-HDMS-based on serum metabolomics reveals the toxicity of arecae semen Publication date: 30 January 2020 Source: Journal of Ethnopharmacology, Volume 247 Author(s): Qinghua Lin, Chunguo Wang, Zhe Jia, Hui Xiong, Xue Xue, Mengnan Liu, Xinfang Xu, Wenjia Qu, Xiangri Li Abstract Ethnopharmacological relevance Arecae semen has been used as vermifuge and digestant in traditional Chinese medicine (TCM) for more than one thousand years. However, the toxicity effect of areca semen and its underlying mechanism are still unclear. The aim of the study: This study was aimed to investigate the toxicity of arecae semen and to explore its mechanisms by serum metabolomics. Materials and methods The male Wistar rats were divided into the control group and treated group (n = 6 in each group), which were given by gavage with distill water or arecae semen aqueous extract (ASAE) once a day for 30 days, respectively. Serum samples were collected from all the rats after treatment of 7-day, 14-day and 30-day for metabolomics analysis. Moreover, biochemistry analysis and histopathological examination were performed at the end of study. Results The phenomenon of diarrhea, less physical activity, tremors and body curl up were observed in the treated group. Additionally, the body weights of treated rats were significantly decreased compared with control rats from the 8th day after oral administration. Except the level of creatinekinase (CK) in the treated group significantly increased compared with the control group, there were no differences on biochemistry parameters and histopathological test in the two groups. Combined with the methods of principal component analysis (PCA), orthogonal projection to latent structure-discrimination analysis (OPLS-DA) and available databases, the treated and control rats were clearly distinguished from each other and 19 metabolites were identified as the potential biomarkers in the arecae semen treated rats. The identified biomarkers indicated that there were perturbations of the phospholipid metabolism, amino acid metabolism and fat acid metabolism in the treated group. Conclusions This indicated that arecae semen possessed certain cardiotoxicity and inhibited the normal growth in Wistar male rats. In addition, the metabolomics approach is a useful tool to study the toxicity in TCM. Graphical abstract