Medicinal and mechanistic overview of artemisinin in the treatment of human diseases.

Artemisinin (ART) is a bioactive compound isolated from the plant Artemisia annua and has been traditionally used to treat conditions such as malaria, cancer, viral infections, bacterial infections, and some cardiovascular diseases, especially in Asia, North America, Europe and other parts of the world. This comprehensive review aims to update the biomedical potential of ART and its derivatives for treating human diseases highlighting its pharmacokinetic and pharmacological properties based on the results of experimental pharmacological studies in vitro and in vivo. Cellular and molecular mechanisms of action, tested doses and toxic effects of artemisinin were also described. The analysis of data based on an up-to-date literature search showed that ART and its derivatives display anticancer effects along with a wide range of pharmacological activities such as antibacterial, antiviral, antimalarial, antioxidant and cardioprotective effects. These compounds have great potential for discovering new drugs used as adjunctive therapies in cancer and various other diseases. Detailed translational and experimental studies are however needed to fully understand the pharmacological effects of these compounds.

Phytochemical profiling, in vitro biological activity, docking studies, and cytotoxicity assessments of Rondeletia odorata Jacquin: An unexplored plant of the coffee family.

Rondeletia odorata Jacquin is a flowering plant that belongs to the coffee family. As a rich source of polyphenols with significant antioxidant potential, R. odorata may have health benefits. Therefore, in the current work, ethanolic extract of aerial parts and its n-hexane, ethyl acetate, and n-butanol soluble fractions were analyzed for their antioxidant potential and various enzyme inhibition properties. The total phenolic and flavonoid contents of the crude ethanol extract (ROE) and its n-hexane (ROH), ethyl acetate (ROEA), and n-butanol (ROB) fractions were determined spectrophotometrically, while metabolic profiling was established through UHPLC-MS analysis, which revealed the presence of 58 phytochemicals. Total phenolic and flavonoid contents of ROE extract were measured as 51.92 mg GA.Eq./g of dry extract and 52.35 mg Qu.Eq./g of the dry extract, respectively. In the DPPH radical scavenging activity assay, ROE and ROEA showed the highest potential with values of 62.13 ± 0.62 and 76.31% ± 1.86%, respectively, comparable to quercetin (80.89% ± 0.54%). Similarly, in the FRAP assay, the same pattern of the activity was observed with ROE and ROEA, which displayed absorbance values of 1.32 ± 0.01 and 0.80 ± 0.02 at 700 nm, respectively, which are comparable (1.76 ± 0.02) with the reference compound quercetin, whereas the ROH showed maximum metal-chelating capacity (62.61% ± 1.01%) among all extracts and fractions. Antibacterial activity assay indicated that the ROEA fraction was the most active against Serratia marcescens, Stenotrophomonas maltophilia, Bacillus subtilis, Klebsiella pneumonia, and Staphylococcus aureus, while the rest of the fractions showed good to moderate activity. Enzyme inhibition assays showed that ROEA fraction exhibited the highest activity with IC50 values of 2.78 ± 0.42 and 3.95 ± 0.13 mg/mL against urease and carbonic anhydrase (CA), respectively. Furthermore, the docking studies of some of the major compounds identified in the extract revealed a strong correlation with their inhibitory activity. All extracts and fractions were also tested for their thrombolytic activity, and the ROB fraction showed a notable potential. Antiviral assay led to remarkable outcomes. Thus, it can be inferred that aerial parts of R. odorata are potential sources of bioactive components with several significant pharmacological activities.

Kombucha - An ancient fermented beverage with desired bioactivities: A narrowed review.

Kombucha, originated in China 2000  years ago, is a sour and sweet-tasted drink, prepared traditionally through fermentation of black tea. During the fermentation of kombucha, consisting of mainly acidic compounds, microorganisms, and a tiny amount of alcohol, a biofilm called SCOBY forms. The bacteria in kombucha has been generally identified as Acetobacteraceae. Kombucha is a noteworthy source of B complex vitamins, polyphenols, and organic acids (mainly acetic acid). Nowadays, kombucha is tended to be prepared with some other plant species, which, therefore, lead to variations in its composition. Pre-clinical studies conducted on kombucha revealed that it has desired bioactivities such as antimicrobial, antioxidant, hepatoprotective, anti-hypercholestorelomic, anticancer, anti-inflammatory, etc. Only a few clinical studies have been also reported. In the current review, we aimed to overhaul pre-clinical bioactivities reported on kombucha as well as its brief compositional chemistry. The literature data indicate that kombucha has valuable biological effects on human health.

Antiproliferative and cytotoxic activity of Geraniaceae plant extracts against five tumor cell lines.

AIM: To determine the antiproliferative and cytotoxic activities of Geranium and Erodium species against human cancer and noncancer cell lines, respectively. METHODS: Twenty-one species of Geranium and Erodium were extracted and screened against cancerous and noncancerous human cell lines. RESULTS: In a dose-response manner, G. glaberrimum, G. asphodeloides, E. brandianum and E. leucanthum were able, with variable potency, to inhibit cellular proliferation. Except for E. brandianum, all extracts induced cellular autophagy in tumor cells with similar levels to that of rapamycin; but, only E. brandianum induced cellular apoptosis, likely through Bcl2 and BAX protein expressions. DISCUSSION: This is the first study to report the potential antiproliferative effects of ethanol extracts of several Geraniaceae species.

Profiling the annual change of the neurobiological and antioxidant effects of five Origanum species in correlation with their phytochemical composition.

The ethanol extracts of five Origanum species: O. majorana L., O. onites L., O. syriacum L., O. vulgare subsp. hirtum (Link) Ietsw., and O. vulgare subsp. viride (Boiss.) Hayek, collected annually (each month), were investigated for their cholinesterase inhibition and antioxidant effects. The phytochemical composition of a total of 60 extracts was assessed by HPLC-DAD-ESI/HRMS, revealing the presence of a total of 73 compounds. Possible correlation between the bioactivity and metabolite profiles during 12 months was monitored. Acetylcholinesterase (AChE) inhibitory activity was found to be the highest between April and November (50.29-75.95%, 200 µg/mL), while the highest inhibition towards butyrylcholinesterase (BChE) was observed for the extracts between April and October (71.68-88.97%). Aromadendrin showed good correlation with anti-AChE, anti-BChE and reducing power activities. Furthermore, molecular docking data with aromadendrin, caffeoylarbutin and eriodictyol indicated that caffeoylarbutin had the lowest binding energy against both enzymes.

Natural Molecules as Talented Inhibitors of Nucleotide Pyrophosphatases/ Phosphodiesterases (PDEs).

BACKGROUND: Phosphodiesterases (PDEs) are a wide group of enzymes with multiple therapeutic actions, including vasorelaxation, cardiotonic, antidepressant, anti-inflammatory, antithrombotic, anti-spasmolytic, memory-enhancing, and anti-asthmatic. PDEs with eleven subtypes from PDE-1 to PDE-11 typically catalyze the cleavage of the phosphodiester bond and, hence, degrades either cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). OBJECTIVE: Several selective or non-selective inhibitors of the PDE subtypes are used clinically, i.e. sildenafil, rolipram, cysteine, etc. Recently, interest in plant-based pharmacologically bioactive compounds having potent PDEs inhibitory potential has increased. Purposely, extensive research has been carried out on natural products to explore new inhibitors of various PDEs. Therefore, this review summarizes the published data on natural PDEs inhibitors and their potential therapeutic applications. METHODS: For this purpose, natural compounds with PDE inhibitory potential have been surveyed through several databases, including PubMed, Web of Sciences (WoS), Scopus, and Google Scholar. RESULTS: According to a detailed literature survey, the most promising class of herbal compounds with PDE-inhibiting property has been found to belong to phenolics, including flavonoids (luteolin, kaempferol, icariin, etc.). Many other encouraging inhibitors from plants have also been identified, such as coumarins (23, 24) (licoarylcoumarin and glycocoumarin,), saponins (agapanthussaponins), lignans (31, 33) [(±)-schizandrin and kobusin], terpenes (28, 29, 31) (perianradulcin A, quinovic acid, and ursolic acid), anthraquinones (18, 19) (emodin and chrysophanol), and alkaloids (Sanjoinine-D) (36). CONCLUSION: In this review, studies have revealed the PDE-inhibitory potential of natural plant extracts and their bioactive constituents in treating various diseases; however, further clinical studies comprising synergistic use of different therapies (synthetic & natural) to acquire multi-targeted results might also be a promising option.

The neuroprotective effects of polyphenols, their role in innate immunity and the interplay with the microbiota.

Neurodegenerative disorders, particularly in the elderly population, represent one of the most pressing social and health-care problems in the world. Besides the well-established role of both oxidative stress and inflammation, alterations of the immune response have been found to be closely linked to the development of neurodegenerative diseases. Interestingly, various scientific evidence reported that an altered gut microbiota composition may contribute to the development of neuroinflammatory disorders. This leads to the proposal of the concept of the gut-brain-immune axis. In this scenario, polyphenols play a pivotal role due to their ability to exert neuroprotective, immunomodulatory and microbiota-remodeling activities. In the present review, we summarized the available literature to provide a scientific evidence regarding this neuroprotective and immunomodulatory effects and the interaction with gut microbiota of polyphenols and, the main signaling pathways involved that can explain their potential therapeutic application in neurodegenerative diseases.

Evaluation of the status quo of polyphenols analysis: Part II-Analysis methods and food processing effects.

Nowadays due to the concern with the environmental impact of analytical techniques and in order to reduce the ecological footprint there is a tendency to use more efficient and faster procedures that use a smaller amount of organic solvents. Polyphenols have been widely studied in plant-based matrices due to their wide and potent biological properties; however there are no standardized procedures both for sample preparation and analysis of these compounds. The second of a two-part review will carry out a critical review of the extraction procedures and analytical methods applied to polyphenols and their selection criteria over a wide range of factors in relation to commerce-associated, environmental, and economic factors. It is foreseen that in the future the analysis of polyphenols in plant-based matrices includes the use of techniques that allow the simultaneous determination of different subclasses of polyphenols using fast, sophisticated, and automated techniques that allow the minimal consumption of solvents.

Chrysin: Pharmacological and therapeutic properties.

Chrysin is a promising phytochemical that is categorized under the class of flavonoids based on its chemical structure. Naturally, it is widely present in propolis, honey, passion fruit, and even in mushrooms and other plant sources, whereas its synthetic counterparts are also being employed for pharmacological purposes. It has widely been employed in treatment of various degenerative disorders and provides cytotoxic and anti-inflammatory functions. Its antioxidant and disease preventing abilities are attributed to its structural diversity arising in ring-A and absence of oxygenation in B and C ring. In this review, the scientific studies are being reported emphasizing benefits and its allied health claims on chrysin in numerous metabolic malfunctions.

Phosphodiesterase inhibitors say NO to Alzheimer's disease.

Phosphodiesterases (PDEs) consisted of 11 subtypes (PDE1 to PDE11) and over 40 isoforms that regulate levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the second messengers in cell functions. PDE inhibitors (PDEIs) have been attractive therapeutic targets due to their involvement in diverse medical conditions, e.g. cardiovascular diseases, autoimmune diseases, Alzheimer's disease (AD), etc. Among them; AD with a complex pathology is a progressive neurodegenerative disorder which affect mostly senile people in the world and only symptomatic treatment particularly using cholinesterase inhibitors in clinic is available at the moment for AD. Consequently, novel treatment strategies towards AD are still searched extensively. Since PDEs are broadly expressed in the brain, PDEIs are considered to modulate neurodegenerative conditions through regulating cAMP and cGMP in the brain. In this sense, several synthetic or natural molecules inhibiting various PDE subtypes such as rolipram and roflumilast (PDE4 inhibitors), vinpocetine (PDE1 inhibitor), cilostazol and milrinone (PDE3 inhibitors), sildenafil and tadalafil (PDE5 inhibitors), etc have been reported showing encouraging results for the treatment of AD. In this review, PDE superfamily will be scrutinized from the view point of structural features, isoforms, functions and pharmacology particularly attributed to PDEs as target for AD therapy.

Luteolin, a flavonoid, as an anticancer agent: A review.

Many food-derived phytochemicals and their derivatives represent a cornucopia of new anti-cancer compounds. Luteolin (3,4,5,7-tetrahydroxy flavone) is a flavonoid found in different plants such as vegetables, medicinal herbs, and fruits. It acts as an anticancer agent against various types of human malignancies such as lung, breast, glioblastoma, prostate, colon, and pancreatic cancers. It also blocks cancer development in vitro and in vivo by inhibition of proliferation of tumor cells, protection from carcinogenic stimuli, and activation of cell cycle arrest, and by inducing apoptosis through different signaling pathways. Luteolin can additionally reverse epithelial-mesenchymal transition (EMT) through a mechanism that involves cytoskeleton shrinkage, induction of the epithelial biomarker E-cadherin expression, and by down-regulation of the mesenchymal biomarkers N-cadherin, snail, and vimentin. Furthermore, luteolin increases levels of intracellular reactive oxygen species (ROS) by activation of lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells, and by activation of ER stress-associated proteins expressions, including phosphorylation of eIF2α, PERK, CHOP, ATF4, and cleaved-caspase 12. Accordingly, the present review article summarizes the progress of recent research on luteolin against several human cancers.

Targeting Hedgehog signaling pathway: Paving the road for cancer therapy.

The Hedgehog pathway is essential for embryonic development but also for tissue and organ homeostasis in adult organisms. Activation of this pathway leads to the expression of target genes involved in proliferation, angiogenesis and stem cell self-renewal. Moreover, abnormal persistence of Hedgehog signaling is directly involved in a wide range of human cancers. Development of novel strategies targeting the Hedgehog pathway has become a subject of increased interest in anticancer therapy. These data are sustained by pre-clinical studies demonstrating that Hedgehog pathway inhibitors could represent an effective strategy against a heterogeneous panel of malignancies. Limited activity in other tumor types could be explained by the existence of crosstalk between the Hedgehog pathway and other signaling pathways that can compensate for its function. This review describes the Hedgehog pathway in detail, with its physiological roles during embryogenesis and adult tissues, and summarizing the preclinical evidence on its inhibition, the crosstalk between Hedgehog and other cancer-related pathways and finally the potential therapeutic effects of emerging compounds.

In Vitro Antioxidant and Cytotoxic Activities of 18 Plants from the Erkowit Region, Eastern Sudan.

We investigated the antioxidant potential and cytotoxicity towards human CCRF-CEM leukemia cells of 57 extracts obtained from 18 plants collected in the Erkowit region, eastern Sudan. The antioxidant activity was determined by measuring the radical scavenging effects against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and N,N-dimethyl-p-phenylendiamine (DMPD), metal-chelation capacity, ferric-reducing (FRAP) and phosphomolibdenum-reducing antioxidant power (PRAP) methods using ELISA microtiter assays. Total phenol and flavonoid amounts of the extracts were determined spectrophotometrically. Cytotoxicity towards CCRF-CEM cells was evaluated by the resazurin reduction assay. Geranium favosum followed by Kalanchoe glaucescens, Malva parviflora, Aizoon canariense, and Coleus barbatus, respectively, possessed the highest antioxidant activity among the studied plants. Chrozophora oblongifolia and K. glaucescens exerted considerable cytotoxicity against CCRF-CEM leukemia cells. These plants may serve as source for the further development of natural antioxidant and antitumor agents.

Curcumin and Melanoma: From Chemistry to Medicine.

Melanoma is the most deadly form of skin cancer, with about 48,000 deaths each year worldwide. Growing evidence suggests that individual nutrients or dietary patterns might have important roles in the prevention of melanoma. Considering that melanoma is a potentially life-threatening cancer, novel protective and adjuvant treatments are needed to improve its prognosis. Curcumin is a bioactive substance extracted from rhizome of Curcuma longa L. Its global market is expected to grow in the next few years, especially in the pharmaceutical industry, due to its numerous physiological and pharmacological properties. For this review, we collected the available data on the protective and therapeutic role of curcumin against melanoma. We also discuss the chemistry, dietary sources, bioavailability, and metabolism of curcumin, and the mechanisms of action of its potential anticancer effects at the molecular level. Current challenges and future directions for research are also critically discussed.

Phytochemical and Pharmacological Activity Profile of Crataegus oxyacantha L. (Hawthorn) - A Cardiotonic Herb.

Crataegus oxyacantha L. (syn. C. rhipidophylla Gand.) (Rosac-eae) is one of the two medicinally recognized hawthorn species in European Pharmacopeia. Standardization of the extract prepared from the berry and flowers of the plant is required according to its oligomeric procyanidins. C. oxyacantha is well-known for its use in the treatment of various heart problems particularly, including heart failure in cases of declining cardiac performance equivalent to stages I and II of the New York Heart Association classification, angina pectoris, hypertension with myocardial insufficiency, mild alterations of cardiac rhythm, and atherosclerosis. C. oxyacantha has been reported to exert several other pharmacological activities such as hypotensive, antihyperlipidemic, antihyperglycemic, anxiolytic, immunomodulatory, and antimutagenic. Oligomeric procyanidins and flavone/flavonol types of flavonoids, which are considered to be the chief groups of active substances, phenolic acids, triterpenes, fatty acids, and sterols are present in the plant. The present review aims mainly to outline cardiotonic effect of C. oxyacantha as well as its brief phytochemistry. Numerous experiments and clinical studies have underlined cardiovascular efficacy of the plant through various mechanisms including positive inotropic and negative chronotropic effects, escalation in coronary blood flow and exercise tolerance, inhibition of the enzymes such as angiotensinconverting enzyme (ACE) and phosphodiesterase, anti-inflammatory and antihyperlipidemic effects, improving status of antioxidant enzymes, etc., which support its cardioactive efficacy. The plant possesses several other bioactivities for human health usually concomitant to its rich polyphenolic content.

A comprehensive review of agrimoniin.

Plant tannins are a unique class of polyphenols with relatively high molecular weights. Within the ellagitannins group, agrimoniin--dimeric ellagitannin--is one of the most representative compounds found in many plant materials belonging to the Rosaceae family. Agrimoniin was first isolated in 1982 from roots of Agrimonia pilosa Ledeb. (Rosaceae), a plant traditionally used in Japan and China as an antidiarrheal, hemostatic, and antiparasitic agent. Agrimoniin is a constituent of medicinal plants, which are often applied orally in the form of infusions, decoctions, or tinctures. It is also present in commonly consumed food products, such as strawberries and raspberries. It is metabolized by human gut microbiota into a series of low-molecular-weight urolithins with proven anti-inflammatory and anticancer in vivo and in vitro bioactivities. The compound has received widespread interest owing to some interesting biological effects and therapeutic activities, which we elaborate in the present review. Additionally, we present an overview of the techniques used for the analysis, isolation, and separation of agrimoniin from the practical perspective.

Promising anticancer activity of Cyclotrichium niveum L. extracts through induction of both apoptosis and necrosis.

In this study, cytotoxic effects of the dichloromethane, ethyl acetate, ethanol, and aqueous extracts of the aerial parts of Cyclotrichium niveum (Boiss.) Manden. & Scheng (Lamiaceae) were evaluated. We tested HeLa, MCF-7 cancer cells, and MRC-5 and MCF-10A normal cells. The ethyl acetate and dichloromethane extracts induced cytotoxicity whereas the ethanol and aqueous extracts had no cytotoxic activity against both cancer cells. IC50 values of the dichloromethane extract were 353.0 ± 84.30 µg/ml, 114.8 ± 40.34 µg/ml, 39 ± 0.56 µg/ml, and 49 ± 13 µg/ml in HeLa, MCF-7, MRC-5, MCF-10A cells, respectively. IC50 values of the ethyl acetate extract were 117.0 ± 36.24 µg/ml in HeLa cells, 156.3 ± 19.86 µg/ml in MCF-7 cells, 1100 ± 340 µg/ml in MRC-5 cells and 7900 ± 1200 µg/ml in MCF-10A cells. Additionally, the ethyl acetate extract showed more selectivity to HeLa and MCF-7 cancer cells than MRC-5 and MCF-10A normal cells. Our results of HPLC analysis showed that apigenin in the ethyl acetate extract (2.2518 ± 0.0005 mg/100 mg extract) might be responsible of that selective cytotoxic effect. In the current work, we have shown for the first time that C. niveum has cytotoxic properties in the cancer cell lines tested.

Elucidation of Phosphodiesterase-1 Inhibitory Effect of Some Selected Natural Polyphenolics Using In Vitro and In Silico Methods.

BACKGROUND: Polyphenols are organic compounds widely found in plants and possess many diverse biological activities. In the current study, eleven polyphenolic compounds [rutin (1), trans-ferulic acid (2), epigallaocatechin gallate (3), fumaric acid (4), chlorogenic acid (5), gallic acid (6), trans-resveratrol (7), propyl gallate (8), (+)-catechin (9), quercetin (10), and kaempferol-3-O-ß-D-galactoside (11)] have been evaluated for their in vitro inhibitory activity against phosphodiesterase- 1 (PDE-1). The active compounds 1, 5, 6, and 7 possessed IC50 values of 173.90 ± 2.58, 36.67 ± 1.60, 325.19 ± 3.62, and 323.81 ± 4.25 µM, respectively. In silico experiments were performed to elucidate the binding patterns of inhibitor molecules with the active sites of the enzymes. RESULT: Molecular docking studies have shown that compounds 1 and 5 have better docking results than standard inhibitor (EDTA) against the PDE-1. In conclusion, chlorogenic acid, rutin, gallic acid, and resveratrol could be promising PDE-1 inhibitors and leads to identify new drug candidates against PDE-1-associated disorders.

Mechanisms Underlying Anti-hyperalgesic Properties of Kaempferol-3,7- di-O-α-L-rhamnopyranoside Isolated from Dryopteris cycadina.

BACKGROUND: The present study was designed to evaluate the anti-hyperalgesic effect of kaempferol-3,7-di-O-α-L-rhamnopyranoside isolated from the ethyl acetate soluble part of Dryopteris cycadina. Pretreatment of the compound at the doses of 2.5, 5, and 10 mg/kg caused a significant reduction in abdominal constrictions in acetic acid-induced writhing test with maximum effect of 63.03% (P < 0.001) at 10 mg/kg i.p. When subjected in formalin test, it evoked a marked antinociceptive effect in both phases in a dose-dependent manner. The maximum (p < 0.01) pain-inhibiting effects were 61.36% and 65.89% in 1st and 2nd phases at 10 mg/kg i.p., respectively. Administration of atropine (non-selective cholinergic receptor antagonist) significantly (p < 0.05) antagonized the antihyperalgesic effect of the compound, while glibenclamide and naloxone did not alter the induced antinociceptive effect and thus, antinociceptive activity of the compound is mediated, at least in part, through cholinergic system antagonism; independent of calcium channel and opioidergic receptor participation. Furthermore, docking studies underlined strong COX-2 inhibitory activity of the compound. RESULT: Our data concluded that overall analgesic activity of the compound seems to involve COX-2 inhibition and activation of cholinergic receptors. However, further detailed studies are required in this direction to confirm the analgesic effect of the compound for its possible clinical utility.

Rhodiola rosea L. and Alzheimer's Disease: From Farm to Pharmacy.

Rhodiola rosea L. (roseroot) is a common member of the family Crassulaceae, known as one of the most important popular medicinal plants in the northern region of Europe. The roots of R. rosea possess a wide range of pharmacological activities such as antioxidant, antiinflammatory, anticancer, cardioprotective, and neuroprotective effects that are because of the presence of different phytochemicals such as phenols and flavonoids. In addition, the presence of salidroside, rosavins, and p-tyrosol are responsible for its beneficial effects for the treatment of on depression, fatigue, and cognitive dysfunction. A plethora of studies report that R. rosea has potent neuroprotective effects through the suppression of oxidative stress, neuroinflammation, and excitotoxicity in brain tissues and antagonism of oncogenic p21-activated kinase. However, to our knowledge, no review articles have been published addressing the neuroprotective effects of R. rosea. Therefore, the present article aims at critically reviewing the available literature on the beneficial effects of R. rosea on as a therapeutic strategy for the treatment of Alzheimer's disease and other neurodegenerative diseases where oxidative stress plays a major role in disease development and progression. We also discuss the cultivation, phytochemistry, clinical impacts, and adverse effects of R. rosea to provide a broader insight on the therapeutic potential for this plant.