Showing papers in "Planta Medica in 2020"

Challenges at the Time of COVID-19: Opportunities and Innovations in Antivirals from Nature.

Abstract: As viral infections are an increasing threat to human societies, the need for new therapeutic strategies is becoming even more obvious. As no vaccine is available for COVID-19, the development of directly acting antiviral agents and preventive strategies have to be considered. Nature provides a huge reservoir of anti-infectious compounds, from which we can deduce innovative ideas, therapies, and products. Anti-adhesive natural products interact with the receptor-mediated recognition and early interaction of viruses with the host cells, leading to a reduced internalisation of the virus and reduced infections (e.g., procyanidin-B-2-di-O-gallate against influenza and herpes virus). Lignans like podophyllotoxin and bicyclol show strong antiviral activities against different viruses, and essential oils can directly interact with viral membranes and reduce the hostʼs inflammatory responses (e.g., 1,8-cineol). Echinacea extracts stimulate the immune system, and bioavailable alkamides are key players by interacting with immunomodulating cannabinoid receptors. COVID-19 and SARS-CoV-2 infections have, in part, successfully been treated in China by preparations from traditional Chinese medicine and, while it is too early to draw conclusions, some promising data are available. There is huge potential, but intensified research is needed to develop evidence-based medicines with a clearly defined chemical profile. Intensified research and development, and therefore funding, are needed for exploiting natureʼs reservoir against viral infections. Combined action for basic research, chemistry, pharmacognosy, virology, and clinical studies, but also supply chain, sustainable sourcing, and economic aspects have to be considered. This review calls for intensified innovative science on natural products for the patients and for a healthier world!

Effects of Ginkgo biloba on Diseases Related to Oxidative Stress

Abstract: Ginkgo biloba (GB) is one of the most widely used phytotherapeutic products in the world, and its extract has beneficial properties for the treatment of several pathologies, such as diabetic cardiomyopathy, neurodegenerative diseases, cataracts, hearing loss, myocardial lesion, hippocampus neuronal lesions, morphometry testicular changes, and liver damage. This review aims to investigate the effects of GB on diseases related to oxidative stress. Databases such as MEDLINE/PUBMED and EMBASE were consulted, and PRISMA guidelines were used to build the review. This plant has antioxidant properties since it regulates the expression of antioxidant enzymes positively and reduces reactive oxygen and nitrogen species, contributing to the reduction of lipid peroxidation. It also exhibits anti-inflammatory properties, inhibiting the expression of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α. In animal models, the use of GB can show positive effects on brain damage, neurodegenerative diseases, myocardial injury, and renal and liver damage. In humans, the positive effects were shown in diabetes, metabolic syndrome, and ischemic colitis. These effects are due to the presence of compounds such as bilobalide, isoramnetina, quercetin, kaempferol, and ginkgolides A, B, and C. For these reasons, GB can be a low-cost alternative to the therapeutic approach of several pathologies since it acts in the prevention, treatment, and inhibition of several complications of common comorbidities.

Scientists’ Warning on Climate Change and Medicinal Plants

Abstract: The recent publication of a World Scientistsʼ Warning to Humanity highlighted the fact that climate change, absent strenuous mitigation or adaptation efforts, will have profound negative effects for humanity and other species, affecting numerous aspects of life. In this paper, we call attention to one of these aspects, the effects of climate change on medicinal plants. These plants provide many benefits for human health, particularly in communities where Western medicine is unavailable. As for other species, their populations may be threatened by changing temperature and precipitation regimes, disruption of commensal relationships, and increases in pests and pathogens, combined with anthropogenic habitat fragmentation that impedes migration. Additionally, medicinal species are often harvested unsustainably, and this combination of pressures may push many populations to extinction. A second issue is that some species may respond to increased environmental stresses not only with declines in biomass production but with changes in chemical content, potentially affecting quality or even safety of medicinal products. We therefore recommend actions including conservation and local cultivation of valued plants, sustainability training for harvesters and certification of commercial material, preservation of traditional knowledge, and programs to monitor raw material quality in addition to, of course, efforts to mitigate climate change.

Plant Endophytes and Epiphytes: Burgeoning Sources of Known and "Unknown" Cytotoxic and Antibiotic Agents?

Abstract: In the last 20 or so years, the influence of endophytes and, quite recently, epiphytes of plants upon the compounds found in those plants, which were usually assumed to be phytochemicals produced by the plant for a variety of reasons, often as a defense against predators, is becoming more evident, in particular in the case of antitumor agents originally isolated from plant sources, though antibiotic agents might also be found, particularly from epiphytes. In this review, we started with the first report in 1993 of a taxol-producing endophyte and then expanded the compounds discussed to include camptothecin, the vinca alkaloids, podophyllotoxin, and homoharringtonine from endophytic microbes and then the realization that maytansine is not a plant secondary metabolite at all, and that even such a well-studied plant such as Arabidopsis thaliana has a vast repertoire of potential bioactive agents in its leaf epiphytic bacteria. We have taken data from a variety of sources, including a reasonable history of these discoveries that were not given in recent papers by us, nor in other papers covering this topic. The sources included the Scopus database, but we also performed other searches using bibliographic tools, thus, the majority of the papers referenced are the originals, though we note some very recent papers that have built on previous results. We concluded with a discussion of the more modern techniques that can be utilized to “persuade” endophytes and epiphytes to switch on silent biosynthetic pathways and how current analytical techniques may aid in evaluating such programs. We also comment at times on some findings, particularly in the case of homoharringtonine, where there are repetitious data reports differing by a few years claiming the same endophyte as the producer.

Harnessing the Phytotherapeutic Treasure Troves of the Ancient Medicinal Plant Azadirachta indica (Neem) and Associated Endophytic Microorganisms

Abstract: Azadirachta indica, commonly known as neem, is an evergreen tree of the tropics and sub-tropics native to the Indian subcontinent with demonstrated ethnomedicinal value and importance in agriculture as well as in the pharmaceutical industry. This ancient medicinal tree, often called the “wonder tree”, is regarded as a chemical factory of diverse and complex compounds with a plethora of structural scaffolds that is very difficult to mimic by chemical synthesis. Such multifaceted chemical diversity leads to a fantastic repertoire of functional traits, encompassing a wide variety of biological activity and unique modes of action against specific and generalist pathogens and pests. Until now, more than 400 compounds have been isolated from different parts of neem including important bioactive secondary metabolites such as azadirachtin, nimbidin, nimbin, nimbolide, gedunin, and many more. In addition to its insecticidal property, the plant is also known for antimicrobial, antimalarial, antiviral, anti-inflammatory, analgesic, antipyretic, hypoglycaemic, antiulcer, antifertility, anticarcinogenic, hepatoprotective, antioxidant, anxiolytic, molluscicidal, acaricidal, and antifilarial properties. Notwithstanding the chemical and biological virtuosity of neem, it has also been extensively explored for associated microorganisms, especially a class of mutualists called endophytic microorganisms (or endophytes). More than 30 compounds, including neem “mimetic” compounds, have been reported from endophytes harbored in the neem trees in different ecological niches. In this review, we provide an informative and in-depth overview of the topic that can serve as a point of reference for an understanding of the functions and applications of a medicinal plant such as neem, including associated endophytes, within the overall theme of phytopathology. Our review further exemplifies the already-noted current surge of interest in plant and microbial natural products for implications both within the ecological and clinical settings, for a more secure and sustainable future.

Verbena officinalis (Common Vervain) - A Review on the Investigations of This Medicinally Important Plant Species.

Abstract: Verbena officinalis (common vervain) is a medicinal plant species widely distributed in the world and commonly used in folk medicine of different countries, including traditional Chinese medicine. Monographs on “Verbenae herba” have been included in the European Pharmacopoeia since 2008, and in the Chinese Pharmacopoeia since 1995. This work presents botanical characteristics of this species. It reviews the current knowledge of its chemical composition, which is a rich source mostly of iridoids, phenylpropanoid glycosides, phenolic acids, flavonoids, terpenoids, and essential oil. A large part of this article summarizes traditional medicinal uses and professional pharmacological in vitro and in vivo studies that prove new important applications, e.g., antioxidant, antimicrobial, anti-inflammatory, neuroprotective anticancer, analgesic, or anticonvulsant of verbena herb extracts and individual metabolites. Moreover, emphasis is put on the use of V. officinalis in the food and cosmetics industries, especially due to its antioxidant, antibacterial, and anti-inflammatory properties, and the presence of essential oil with an attractive fragrance composition. This paper also presents the state of biotechnological studies of this species.

Anti-biofilm and Virulence Factor-Reducing Activities of Essential Oils and Oil Components as a Possible Option for Bacterial Infection Control.

Abstract: Pathogenic biofilm-associated bacteria that adhere to biological or nonbiological surfaces are a big challenge to the healthcare and food industries. Antibiotics or disinfectants often fail in an attempt to eliminate biofilms from those surfaces. Based on selected experimental research, this review deals with the potential biofilm-inhibiting, virulence factor-reducing, and biofilm-eradicating activities of essential oils and single essential oil compounds using Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Chromobacterium violaceum as model organisms. In addition, for the bacteria reviewed in this overview, different essential oils and essential oil compounds were reported to be able to modulate the expression of genes that are involved in the formation of autoinducer molecules, biofilms, and virulence factors. The anti-quorum sensing activity of some essential oils and single essential oil compounds was demonstrated using the gram-negative bacterium C. violaceum. Reporter strains of this bacterium produce the violet-colored compound violacein whose synthesis is regulated by quorum sensing autoinducer molecules called acylhomeserinlactones. Of great interest was the discovery that enantiomeric monoterpenes affected the quorum sensing regulation system in different ways. While the (+)-enantiomers of carvone, limonene, and borneol increased violacein formation, their (−)-analogues inhibited violacein production. For the successful eradication of biofilms and the bacteria living inside them, it is absolutely necessary that the lipophilic volatile substances can penetrate into the aqueous channels of biofilms. As shown in recent work, hydrophilic nano-delivery systems encapsulating essential oils/essential oil compounds with antibacterial effects may contribute to overcome this problem.

A Mechanistic Review on Medicinal Mushrooms-Derived Bioactive Compounds: Potential Mycotherapy Candidates for Alleviating Neurological Disorders.

Abstract: According to the World Health Organization, neurological and neurodegenerative diseases are highly debilitating and pose the greatest threats to public health. Diseases of the nervous system are caused by a particular pathological process that negatively affects the central and peripheral nervous systems. These diseases also lead to the loss of neuronal cell function, which causes alterations in the nervous system structure, resulting in the degeneration or death of nerve cells throughout the body. This causes problems with movement (ataxia) and mental dysfunction (dementia), both of which are commonly observed symptoms in Alzheimerʼs disease, Parkinsonʼs disease, Huntingtonʼs disease, and multiple sclerosis. Medicinal mushrooms are higher fungi with nutraceutical properties and are low in calories and fat. They are also a rich source of nutrients and bioactive compounds such as carbohydrates, proteins, fibers, and vitamins that have been used in the treatment of many ailments. Medicinal mushrooms such as Pleurotus giganteus, Ganoderma lucidium, and Hericium erinaceus are commonly produced worldwide for use as health supplements and medicine. Medicinal mushrooms and their extracts have a large number of bioactive compounds, such as polysaccharide β-glucan, or polysaccharide-protein complexes, like lectins, lactones, terpenoids, alkaloids, antibiotics, and metal-chelating agents. This review will focus on the role of the medicinal properties of different medicinal mushrooms that contain bioactive compounds with a protective effect against neuronal dysfunction. This information will facilitate the development of drugs against neurodegenerative diseases.

Salazinic Acid-Derived Depsidones and Diphenylethers with α-Glucosidase Inhibitory Activity from the Lichen Parmotrema dilatatum.

Abstract: Three new depsidones, parmosidones F – G (1 – 2), and 8′-O-methylsalazinic acid (3), and 3 new diphenylethers, parmetherines A – C (4 – 6), together with 2 known congeners were isolated from the whole thalli of Parmotrema dilatatum, a foliose chlorolichen. Their structures were unambiguously determined by extensive spectroscopic analyses and comparison with literature data. The isolated polyphenolics were assayed for their α-glucosidase inhibitory activities. Newly reported benzylated depsidones 1 and 2 in particular inhibited α-glucosidase with IC50 values of 2.2 and 4.3 µM, respectively, and are thus more potent than the positive control, acarbose.

Punica granatum Leaf Ethanolic Extract and Ellagic Acid as Inhibitors of Zika Virus Infection

Abstract: Zika virus, an arthropod-borne flavivirus, is an emerging healthcare threat worldwide. Zika virus is responsible for severe neurological effects, such as paralytic Guillain-Barre syndrome, in adults, and also congenital malformations, especially microcephaly. No specific antiviral drugs and vaccines are currently available, and treatments are palliative, but medicinal plants show great potential as natural sources of anti-Zika phytochemicals. This study deals with the investigation of the composition, cytotoxicity, and anti-Zika activity of Punica granatum leaf ethanolic extract, fractions, and phytoconstituents. P. granatum leaves were collected from different areas in Italy and Greece in different seasons. Crude extracts were analyzed and fractionated, and the pure compounds were isolated. The phytochemical and biomolecular fingerprint of the pomegranate leaves was determined. The antiviral activities of the leaf extract, fractions, and compounds were investigated against the MR766 and HPF2013 Zika virus strains in vitro. Both the extract and its fractions were found to be active against Zika virus infection. Of the compounds isolated, ellagic acid showed particular anti-Zika activities, with EC50 values of 30.86 µM for MR766 and 46.23 µM for HPF2013. The mechanism of action was investigated using specific antiviral assays, and it was demonstrated that ellagic acid was primarily active as it prevented Zika virus infection and was able to significantly reduce Zika virus progeny production. Our data demonstrate the anti-Zika activity of pomegranate leaf extract and ellagic acid for the first time. These findings identify ellagic acid as a possible anti-Zika candidate compound that can be used for preventive and therapeutic interventions.

Current State of the Art on the Antioxidant Activity of Sage (Salvia spp.) and Its Bioactive Components.

Abstract: Common sage (Salvia spp., with the most common species Salvia officinalis) is an important medicinal and aromatic plant due to its bioactive components, secondary products of its metabolism. These components are mainly phenolics, terpenoids, polyphenols, and flavonoids. Many studies have identified their important role in fighting oxidative stress in cells and organisms, together with their anticancer, antimicrobial, and anti-inflammatory role. There are many methods measuring the antioxidant activity of sage phenolic components, usually based on radical scavenging of free radical species, such as 2,2-diphenyl-1-picrylydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), and determining the absorbance of the reduced product by a photometric assay. In addition, there are several in vitro and in vivo studies determining the protection of sage extracts in cells in culture or animals, respectively, after induction of oxidative stress. In this review, results from the currently available studies that unravel the significant role of sage bioactive compounds, as antioxidant compounds, and the variety of methods used have been critically analyzed and discussed.

Antiviral Activity of a Arisaema Tortuosum Leaf Extract and Some of its Constituents against Herpes Simplex Virus Type 2

Abstract: Infections caused by HSV-2 are a public health concern worldwide, and there is still a great demand for the discovery of novel anti-herpes virus agents effective against strains resistant to current antiviral agents. In this context, medicinal plants represent an alternative source of active compounds for developing efficient antiviral therapies. The aim of this study was to evaluate the antiviral activity of Arisaema tortuosum, a plant used in the traditional medicine of India. A chloroform soluble fraction of the leaves exhibited anti-HSV-2 activity with a selectivity index of 758. The extract was also active against acyclovir-resistant HSV-2 and HSV-1. The mechanism of action of the extract was investigated evidencing inhibition of both early and late events of the HSV-2 replicative cycle. A HPLC-PDA-MS/MS analysis showed the presence of flavonoids including apigenin and luteolin in the chloroform extract (CE). Apigenin and luteolin showed a high inhibitory activity with EC50 values of 0.05 and 0.41 µg/mL, respectively. Both compounds exhibited antiviral activity when added up to 6 h post infection and were able to reduce the viral progeny production. In addition, apigenin interfered with cell-to-cell virus spread.

Protective Role of Casuarinin from Melaleuca leucadendra against Ethanol-Induced Gastric Ulcer in Rats

Abstract: Gastric ulcer is a major health problem. Current treatment options of gastric ulcer, including antagonists of histamine H2 receptor and inhibitors of the proton pump, do not cure gastric ulcers, but only provide temporary relief of symptoms and can be associated with severe side effects. The lack of effective and safe medications for this global health problem urges for the discovery of novel classes of compounds with potent activity and an acceptable safety profile. Ethanol-induced ulceration in rats was used to evaluate the gastroprotective activity of casuarinin, an ellagitannin isolated from Melaleuca leucadendra. Casuarinin (25, 50, and 100 mg/kg) reduced the ulcer area by 45, 78, and 99%, respectively, compared with the ulcer group. Casuarinin (100 mg/kg) increased mucin content by 1.8-fold and reduced acidity by 42%. At the same dose, it also increased the levels of reduced glutathione by 194%, catalase by 586%, and prostaglandin E2 to its normal level. In contrast, it attenuated the ethanol-increased levels of malondialdehyde by 56%, TNF-α by 58%, and caspase-3 by 87%. Histological findings demonstrated that casuarinin exhibited a protective effect against tissue alterations in response to the ethanol-induced ulcer. Casuarinin suppressed the immunoexpression of nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase to their normal values. It also induced the expression of heat shock protein-70, reaching up to 4.9-fold in comparison with the ulcer group. The potent gastroprotective effect of casuarinin was thus attributed to its anti-inflammatory, antioxidant, and antiapoptotic effects. Our results suggest the potential application of casuarinin as an antiulcer agent from natural sources.

Identification of Flavonoids and Bufadienolides and Cytotoxic Effects of Kalanchoe daigremontiana Extracts on Human Cancer Cell Lines.

Abstract: Kalanchoe species are well-known medicinal plants used in traditional medicine as anti-inflammatory and analgesic remedies. Recently, it has been reported that Kalanchoe plants have cytotoxic properties; however, data on traditional use of these plants in tumor treatment are extremely limited. Kalanchoe daigremontiana is one of the most popular species cultivated in Europe, and it is used, among other things, as a remedy in treating skin injuries and wounds. Studies on the biological activity of this species are scarce, and there is a lack of data on the cytotoxic activity of K. daigremontiana extracts on epithelial cancer cells in the literature. In our present study, we analyzed the phytochemical composition of K. daigremontiana ethanol extract and fractions–water and dichloromethane–by the HPLC-DAD-ESI-MS method and estimated cytotoxic activity of the extracts on human adenocarcinoma (HeLa), ovarian (SKOV-3), breast (MCF-7), and melanoma (A375) cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, real-time cell analyzer (RTCA), and flow cytometry. We identified 6 bufadienolide compounds and 19 flavonoids, mostly kaempferol, quercetin, isorhamnetin, and myricetin glycosides, of which only 3 flavonoids have been identified in K. daigremontiana to date. Other flavonoids that were characterized in our study have not yet been found in this plant. The ethanol extract and water fraction of K. daigremontiana did not show significant cytotoxic activity on the tested cell lines. In contrast, the dichloromethane fraction showed the strongest activity against all cell lines with IC50 values of ≤ 10 µg/mL. The results indicated that this activity is mainly due to the presence of bersaldegenin-1,3,5-orthoacetate.

A Systematic Review on Secondary Metabolites of Paecilomyces Species: Chemical Diversity and Biological Activity.

Abstract: Fungi are well known for their ability to synthesize secondary metabolites, which have proven to be a rich resource for exploring lead compounds with medicinal and/or agricultural importance. The genera Aspergillus, Penicillium, and Talaromyces are the most widely studied fungal groups, from which a plethora of bioactive metabolites have been characterized. However, relatively little attention has been paid to the genus Paecilomyces, which has been reported to possess great potential for its application as a biocontrol agent. Meanwhile, a wide structural array of metabolites with attractive bioactivities has been reported from this genus. This review attempts to provide a comprehensive overview of Paecilomyces species, with emphasis on the chemical diversity and relevant biological activities of these metabolic products. Herein, a total of 148 compounds and 80 references are cited in this review, which is expected to be beneficial for the development of medicines and agrochemicals in the near future.

α-Glucosidase Inhibitory Depsidones from the Lichen Parmotrema tsavoense.

Abstract: Chemical investigation of the lichen Parmotrema tsavoense led to the isolation of 5 new depsidones, parmosidones F – J (1 – 5). These compounds were structurally elucidated using spectroscopic methods including HRESIMS and 2D NMR data. Compounds 1, 3, and 4 were evaluated for their inhibition of α-glucosidase. All exhibited potent α-glucosidase inhibitory activity with IC50 values ranging from 10.7 to 17.6 µM, which was much lower than that of the positive control acarbose (IC50 449 µM).

Evaluation of the Effects of Peritoneal Lavage with Rosmarinus officinalis Extract against the Prevention of Postsurgical-Induced Peritoneal Adhesion.

Abstract: Postoperative adhesions are regarded as the major complication following abdominal surgery. Rosmarinus officinalis has shown antioxidative and anti-inflammatory effects. Therefore, we aimed to assess the influence of 70% v/v hydro-ethanolic extract of the aerial parts of R. officinalis against postoperative abdominal adhesions in a rat model. Forty-eight male Wistar rats (190 ± 20 g) were divided into six groups of eight: group 1 = normal group, without any surgical procedures, group 2 = control group, group 3 = vehicle group, and groups 3, 4, and 5 = experimental groups receiving 2 mL of 4, 2, or 1% w/v R. officinalis treatment. Adhesion levels were macroscopically examined. Additionally, the levels of inflammatory cytokines (interleukin-6, interleukin-1β, and TNF-α), growth factors (transforming growth factor-β1, and vascular endothelial growth factor), oxidative (NO, nitric oxide and MDA, malondialdehyde), and antioxidative (GSH, glutathione) factors were evaluated. Our results revealed that the adhesion score, interleukin-6, interleukin-1β, TNF-α, transforming growth factor-β1, vascular endothelial growth factor, NO, and MDA levels were significantly increased in the vehicle group, while the GSH level was diminished. R. officinalis treatment notably ameliorated the adhesion score following postoperative abdominal adhesions compared with the vehicle group. Our results also revealed that R. officinalis markedly reduced inflammatory cytokines, oxidative factors, fibrosis, and angiogenesis biomarkers, whereas it increased the antioxidative factor. Therefore, R. officinalis may be a potential candidate for the management of postoperative peritoneal adhesion.

GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa.

Abstract: Phytochemical investigation of the lipids extracted from seeds of Cannabis sativa by GC-MS showed 43 cannabinoids, 16 of which are new. The extract is dominated by Δ9-tetrahydrocannabinolic acid (A) and its neutral derivative trans-Δ9-tetrahydrocannabinol-C5 (THC) Cis and trans-Δ9-tetrahydrocannabinol-C7 isomers with an ethyl-pentyl branched chain together with minor amounts of trans-Δ9-tetrahydrocannabinol with a methyl-pentyl C6 branched side chain were identified as new natural compounds. Four cannabichromene isomers with a C5 side chain are postulated to be derived from the double bond migration at the terminal isoprenyl unit. C7 cannabichromene together with the neutral and acidic forms of cannabinol-C7 were also detected. The mass spectrum of these homologues as trimethylsilyl (TMS) derivatives are presented, and the fragmentation patterns are discussed.

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

Abstract: Mitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

A Systematic Review of the Potential Effects of Nigella sativa on Rheumatoid Arthritis.

Abstract: Considering the different untoward effects of the drugs prescribed for the treatment of rheumatoid arthritis (RA), there has been an increasing interest in adjuvant therapies devoid of such unfavorable reactions. Although the beneficial effects of Nigella sativa (N. sativa) on RA have been established, it seems that its mechanisms of action have not still been reviewed. The present review is designed to evaluate the effects of N. sativa on RA systematically. We searched these electronic databases until April 2019: PubMed, Scopus, ISI Web of Science, Cochrane Library, Embase, Ovid, ProQuest, and Google scholar. No restriction was conducted based on language or publication date. We selected all of the related clinical, animal, and in vitro studies. Review papers, abstracts in conferences, book chapters, and papers regarding the effects of N. sativa combined with other herbs, as well as articles regarding the effects of N. sativa on other diseases, were excluded. Each article was assessed critically for the possible risk of bias. Nineteen articles were reviewed. Animal and in vitro investigations supported the favorable effects of N. sativa on clinical, inflammatory, oxidative, and immunologic parameters on RA, whereas results of limited clinical studies did not illustrate any change or improvement of inflammatory and oxidative biomarkers in RA. N. sativa could control RA via multiple ways such as decreasing inflammation, inhibiting oxidative stress, and modulating the immune system. This paper provides persuasive clues to defend the efficacy of N. sativa in RA and justifies the significance of subsequent clinical trials.

Volatile Antimicrobial Agents and In Vitro Methods for Evaluating Their Activity in the Vapour Phase: A Review.

Abstract: This review summarizes data on the in vitro antimicrobial effectiveness of volatile agents of plant origin and in vitro methods for evaluating their activity in the vapour phase. As a result of literature analysis, the antimicrobial efficacy of vapours from 122 different plant species and 19 pure compounds examined in 61 studies using different in vitro tests against a broad spectrum of microorganisms was identified and summarized. In addition, 11 different techniques found in the literature are described in detail. An original classification of methods based on the solid and liquid matrix volatilization principle is proposed because carrier medium/matrix selection is crucial for the volatilization of any agents tested. This review should be useful for medicinal, pharmaceutical, food, and agricultural experts working in areas related to the management of infectious diseases (especially respiratory and skin infections), food preservation (active packaging), and protection of agriculture products (controlled atmosphere). It may also stimulate the interest of pharmaceutical, cosmetic, food, and agriculture industries in the research and development of new antimicrobial agents of natural origin. Since several original apparatuses previously developed for antimicrobial susceptibility testing in the vapour phase are described in this review, labware manufacturers may also be interested in this topic. The review also provides specific guidelines and recommendations for researchers studying the antimicrobial activity of volatile agents. The article will therefore appeal to communities of industrial stakeholders, pharmacists, physicians, food experts, agriculturists, and researchers in related areas such as pharmacology, medicinal chemistry, microbiology, natural product chemistry, food preservation and plant protection.

Antiviral Potential of Spondias mombin L. Leaves Extract Against Herpes Simplex Virus Type-1 Replication Using In Vitro and In Silico Approaches.

Abstract: Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.

Vasorelaxant and Antihypertensive Effects of Neferine in Rats: An In Vitro and In Vivo Study.

Abstract: The present study was performed to examine the antihypertensive effect of neferine in hypertensive rats and its relaxant mechanisms in isolated rat thoracic aorta. The antihypertensive effect was evaluated by tail-cuff methods on NG-nitro-L-arginine methyl ester (L-NAME) (40 mg/kg BW) 4-week hypertensive-induced hypertensive rats. The vasorelaxant effect and its mechanisms were studied by the organ bath technique in the thoracic aorta isolated from normotensive rats. The results indicated that the treatment of neferine (1 mg/kg and 10 mg/kg) markedly decreased the systolic blood pressure (SBP) when compared with the hypertension group (137.75 ± 10.14 mmHg and 132.23 ± 9.5 mmHg, respectively, p

Metabolic Profiling and Untargeted 1H-NMR-Based Metabolomics Study of Different Iranian Pomegranate (Punica granatum) Ecotypes.

Abstract: Pomegranate (Punica granatum) is an ancient fruit that is widely consumed as fresh fruit and juice. The aim of the present study was to compare the metabolic profile of pomegranate ecotypes from different geographical origins of Iran, the largest producer of pomegranates in the world. 1H-NMR and 2D NMR spectroscopy were applied to investigate the ecotypic variation. Multivariate data analyses were used to identify overall metabolic differences. Mazandaran pomegranate samples were found to be different from the other ecotypes, having a high content of citric and succinic acids. Bajestan, Ferdows, and Yazd pomegranates contained comparatively higher amounts of anthocyanins and ellagic acid derivatives than other pomegranate ecotypes. The distribution of metabolites among different ecotypes of pomegranate is discussed on the basis of these findings.

Antidepressant Effects and Mechanisms of the Total Iridoids of Valeriana jatamansi on the Brain-Gut Axis

Abstract: Valeriana jatamansi is widely used in Chinese folk medicine and contains iridoids as important active ingredients. The brain-gut axis describes a complex bidirectional system between the central nervous system and the gastrointestinal tract. Herein, we evaluated the antidepressant effects of total iridoids of Valeriana jatamansi (TIV) and preliminarily investigated the effects of gut microbiota on their antidepressant effects using a chronic, unpredictable mild-stress mouse model. Mice were given 5.7, 11.4, or 22.9 mg/kg TIV for 1 week. Fluoxetine (2.6 mg/kg) served as a positive control. Body weight was measured, and behavioral tests including SPT and TST were applied. Colon pathology was assessed through hematoxylin-eosin staining. Additionally, levels of serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE), substance P (SP) and corticotropin-releasing factor (CRF) in the hippocampus and colon were measured by ELISA. In addition, 16SrRNA gene sequencing was performed to explore changes in intestinal microbiota richness and diversity. Our results demonstrated that the model group showed significant depression-like behavior, while the fluoxetine group showed improved depression-like symptoms; after administration, TIV increased body weight, sucrose solution consumption, and ameliorated depression-like behaviors. The overall cell degeneration in colons also improved. In addition, TIV modulated the levels of 5-HT, NE, SP, and CRF expression in the hippocampus and colon. The diversity and richness of gut microbes increased compared to the model group. We therefore conclude that the antidepressant effects of TIV may be related to gut flora structures and regulation of 5-HT, NE, SP, and CRF in the brain and intestine.

Natural Phenolic Compounds and Derivatives as Potential Antimalarial Agents.

Abstract: Malaria is a parasitic disease endemic to tropical and subtropical regions responsible for hundreds of millions of clinical cases and hundreds of thousands of deaths yearly. Its agent, the Plasmodium sp., has a highly variable antigenicity, which accounts for the emergence and spread of resistance to all available treatments. In light of this rising problem, scientists have turned to naturally occurring compounds obtained from plants recurrently used in traditional medicine in endemic areas. Ethnopharmacological approaches seem to be helpful in selecting the most interesting plants for the search of new antiplasmodial and antimalarial molecules. However, this search for new antimalarials is complex and time-consuming and ultimately leads to a great number of interesting compounds with a lack of discussion of their characteristics. This review aims to examine the most promising antiplasmodial phenolic compounds (phenolic acids, flavonoids, xanthones, coumarins, lignans, among others) and derivatives isolated over the course of the last 28 y (1990 – 2018) and discuss their structure-activity relationships, mechanisms of action, toxicity, new perspectives they could add to the fight against malaria, and finally, the difficulties of transforming these potential compounds into new antimalarials.

Endophytic Microbiota Comparison of Dendrobium huoshanense Root and Stem in Different Growth Years.

Abstract: The endophytic microbiome in medicinal plants is rich and diverse, but few studies have followed the endophytic microbiome of medicinal plants in different tissues with their growth. In this study, we examined the endophytic bacterial and fungal community structures associated with both the stem and root compartments of Dendrobium huoshanense at different growth years via high-throughput sequencing of 16S rRNA genes and nrDNA fragments of internal transcribed spacer regions. Results indicated that more diverse prokaryotic and fungal operational taxonomic units were detected in roots than in stems, and the alpha diversity of endophytic prokaryotic significantly differed among the 1-, 2-, and 3-year-old roots. The dominant bacterial phyla Proteobacteria Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteria, and fungal phyla Ascomycota, Basidiomycota, and Ascomycota were detected in the stems and roots with 3 growth years. Moreover, linear discriminant effect size analysis revealed 138 differentially abundant taxonomic clades in the bacterial level, and 197 in the fungal level in six groups. Our results provide evidence for endophytic microbiota communities depending on the tissues and growth years of D. huoshanense. The results from this study should be useful to better understand medicinal plant-microbe interactions.

Antiviral Medicinal Plants of Veterinary Importance: A Literature Review.

Abstract: Viruses have a high mutation rate, and, thus, there is a continual emergence of new antiviral-resistant strains. Therefore, it becomes imperative to explore and develop new antiviral compounds continually. The search for pharmacological substances of plant origin that are effective against animal viruses, which have a high mortality rate or cause large economic losses, has garnered interest in the last few decades. This systematic review compiles 130 plant species that exhibit antiviral activity on 37 different virus species causing serious diseases in animals. The kind of extract, fraction, or compound exhibiting the antiviral activity and the design of the trial were particularly considered for review. The literature revealed details regarding plant species exhibiting antiviral activities against pathogenic animal virus species of the following families–Herpesviridae, Orthomyxoviridae, Paramyxoviridae, Parvoviridae, Poxviridae, Nimaviridae, Coronaviridae, Reoviridae, and Rhabdoviridae–that cause infections, among others, in poultry, cattle, pigs, horses, shrimps, and fish. Overall, 30 plant species exhibited activity against various influenza viruses, most of them causing avian influenza. Furthermore, 30 plant species were noted to be active against Newcastle disease virus. In addition, regarding the pathogens most frequently investigated, this review provides a compilation of 20 plant species active against bovine herpesvirus, 16 against fowlpox virus, 12 against white spot syndrome virus in marine shrimps, and 10 against suide herpesvirus. Nevertheless, some plant extracts, particularly their compounds, are promising candidates for the development of new antiviral remedies, which are urgently required.

Melaleuca alternifolia Essential Oil: Evaluation of Skin Permeation and Distribution from Topical Formulations with a Solvent-Free Analytical Method.

Abstract: Melaleuca alternifolia essential oil (tea tree oil) is widely used as an ingredient in skin care products because of its recognized biological activities. The European Scientific Committee on Consumer Products constantly promotes research and collection of data on both skin distribution and systemic exposure to tea tree oil components after the application of topical formulations. This study quantitatively evaluates permeation, skin layer distribution (stratum corneum, epidermis, and dermis), and release into the surrounding environment of bioactive tea tree oil markers (i.e., α-pinene, β-pinene, α-terpinene, 1,8-cineole, γ-terpinene, 4-terpineol, α-terpineol) when a 5% tea tree oil formulation is applied at a finite dosing regimen. Permeation kinetics were studied in vitro on pig ear skin using conventional static glass Franz diffusion cells and cells ad hoc modified to monitor the release of markers into the atmosphere. Formulation, receiving phases, and skin layers were analyzed using a fully automatic and solvent-free method based on headspace solid-phase microextraction/gas chromatography-mass spectrometry. This approach affords, for the first time, to quantify tea tree oil markers in the different skin layers while avoiding using solvents and overcoming the existing methods based on solvent extraction. The skin layers contained less than 1% of each tea tree oil marker in total. Only oxygenated terpenes significantly permeated across the skin, while hydrocarbons were only absorbed at trace level. Substantial amounts of markers were released into the atmosphere.

Biochanin A, the Most Potent of 16 Isoflavones, Induces Relaxation of the Coronary Artery Through the Calcium Channel and cGMP-dependent Pathway.

Abstract: The dietary intake of flavonoids seems to be inversely related to cardiovascular mortality. The consumption of isoflavonoids is increasing in the general population, especially due to the use of food supplements and a variety of isoflavonoid-rich foods. However, detailed studies on the vascular influence of individual pure isoflavonoids are mostly missing. For this study, 16 isoflavonoids were initially screened for their vasorelaxant properties on rat aortas. The 2 most potent of them, biochanin A and glycitein, were further tested for the mechanism of action on porcine coronary arteries. They both induced an endothelium independent vascular relaxation, with EC50 below 6 and 17 µM, respectively. Biochanin A, but not glycitein, was able to block the vasoconstriction caused by KCl, CaCl2, serotonin, and U46619 in a dose-dependent manner. Another series of experiments suggested that the major mechanism of action of biochanin A was the inhibition of L-type calcium channels. Moreover, biochanin A in relatively small concentrations (2 – 4 µM) interfered with the cGMP, but not cAMP, pathway in isolated coronary arteries. These results indicate that some isoflavonoids, in particular biochanin A, are able to have vasodilatory effects in micromolar concentrations, which is of potential clinical interest for the management of cardiovascular pathologies.