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.

An updated overview of cyanidins for chemoprevention and cancer therapy.

Anthocyanins are colored polyphenolic compounds that belong to the flavonoids family and are largely present in many vegetables and fruits. They have been used in traditional medicine in many cultures for a long time. The most common and abundant anthocyanins are those presenting an O-glycosylation at C-3 (C ring) of the flavonoid skeleton to form -O-ß-glucoside derivatives. The present comprehensive review summarized recent data on the anticancer properties of cyanidings along with natural sources, phytochemical data, traditional medical applications, molecular mechanisms and recent nanostrategies to increase the bioavailability and anticancer effects of cyanidins. For this analysis, in vitro, in vivo and clinical studies published up to the year 2022 were sourced from scientific databases and search engines such as PubMed/Medline, Google scholar, Web of Science, Scopus, Wiley and TRIP database. Cyanidins' antitumor properties are exerted during different stages of carcinogenesis and are based on a wide variety of biological activities. The data gathered and discussed in this review allows for affirming that cyanidins have relevant anticancer activity in vitro, in vivo and clinical studies. Future research should focus on studies that bring new data on improving the bioavailability of anthocyanins and on conducting detailed translational pharmacological studies to accurately establish the effective anticancer dose in humans as well as the correct route of administration.

Low concentrations of Ambrosia maritima L. phenolic extract protect endothelial cells from oxidative cell death induced by H2O2 and sera from Crohn's disease patients.

ETHNOPHARMACOLOGICAL RELEVANCE: A rising resort to herbal therapies in Crohn's disease (CD) alternative treatments has been recently observed due to their remarkable natural efficiency. In this context, the weed plant Ambrosia maritima L., traditionally known as Hachich el Aouinet in Algeria and as Damsissa in Egypt and Sudan, is widely used in North African folk medicine to treat infections, inflammatory diseases, gastrointestinal and urinary tract disturbances, rheumatic pain, respiratory problems, diabetes, hypertension and cancer. AIM OF THE STUDY: To assess an Ambrosia maritima L. phenolic extract for its phenolic profile composition, its potential antioxidant activity in vitro, and its cytoprotective effect on cultured primary human endothelial cells (ECs) stressed with H2O2 and sera from CD patients. MATERIALS AND METHODS: Phenolic compound extraction was performed with a low-temperature method. Extract chemical profile was attained by HPLC-DAD/ESI-MS. The extract in vitro antioxidant activity was assessed using several methods including cupric ion reducing power, DPPH radical scavenging assay, O-Phenanthroline free radical reducing activity, ABTS cation radical decolourisation assay, Galvinoxyl free radicals scavenging assay. Intracellular reactive oxygen species levels were evaluated in human endothelial cells by H2DCFDA, while cell viability was assessed by MTT. RESULTS: The phenolic compounds extraction showed a yield of 17.66% with three di-caffeoylquinic acid isomers detected for the first time in Ambrosia maritima L. Using different analytical methods, a significant in vitro antioxidant activity was reported for the Ambrosia maritima L. extract, with an IC50 value of 14.33 ± 3.86 µg/mL for the Galvinoxyl antioxidant activity method. Challenged with ECs the Ambrosia maritima L. extract showed a biphasic dose-dependent effect on H2O2-treated cells, cytoprotective and antioxidant at low doses, and cytotoxic and prooxidant at high doses, respectively. Viability and ROS levels data also demonstrated a prooxidant and cytotoxic effect of CD sera on cultured ECs. Interestingly, 10 µg/mL of Ambrosia maritima L. extract was able to counteract both CD sera-induced oxidative stress and ECs death. CONCLUSION: Our data indicated Ambrosia maritima L. as a source of bioactive phenolics potentially employable as a natural alternative for CD treatment.

Propolis: An update on its chemistry and pharmacological applications.

Propolis, a resinous substance produced by honeybees from various plant sources, has been used for thousands of years in traditional medicine for several purposes all over the world. The precise composition of propolis varies according to plant source, seasons harvesting, geography, type of bee flora, climate changes, and honeybee species at the site of collection. This apiary product has broad clinical applications such as antioxidant, anti-inflammatory, antimicrobial, anticancer, analgesic, antidepressant, and anxiolytic as well asimmunomodulatory effects. It is also well known from traditional uses in treating purulent disorders, improving the wound healing, and alleviating many of the related discomforts. Even if its use was already widespread since ancient times, after the First and Second World War, it has grown even more as well as the studies to identify its chemical and pharmacological features, allowing to discriminate the qualities of propolis in terms of the chemical profile and relative biological activity based on the geographic place of origin. Recently, several in vitro and in vivo studies have been carried out and new insights into the pharmaceutical prospects of this bee product in the management of different disorders, have been highlighted. Specifically, the available literature confirms the efficacy of propolis and its bioactive compounds in the reduction of cancer progression, inhibition of bacterial and viral infections as well as mitigation of parasitic-related symptoms, paving the way to the use of propolis as an alternative approach to improve the human health. However, a more conscious use of propolis in terms of standardized extracts as well as new clinical studies are needed to substantiate these health claims.

Nano-targeting vascular remodeling in cancer: Recent developments and future directions.

Tumor growth and progression are strictly dependent on the adequate blood supply of oxygen and nutrients. The formation of new blood vessels and vascular networks is essential to ensure this demand. Blood vessels also facilitate the invasion of cancer cells into nearby tissues and their subsequent metastasis. Tumor cells represent the main driver of the neovascularization process through the direct or indirect, by neighboring non-cancer cells, release of pro-angiogenic molecules. The mediators (e.g., growth factors and extracellular matrix components), signaling pathways, cellular components, and processes (e.g., endothelial cell proliferation and migration) activated in tumor angiogenesis are similar to those involved in normal vascular development, except they lack efficient control mechanisms. Consequently, newly formed tumor vessels are typically fragile and hyperpermeable with a reduced and erratic blood flow. Targeting the tumor vasculature has been the focus of intense research over the last 20 years. However, despite the initial interest and expectations, the systemic use of anti-angiogenic drugs has not always led to therapeutic breakthroughs and, in some cases, has been associated with the development of tumor adaptive resistance resulting in a more aggressive phenotype. Therefore, new therapeutic approaches have focused on combining anti-angiogenic agents with chemotherapy or immunotherapy and/or optimizing (normalizing) the structure and function of tumor blood vessels to ensure a more efficient drug delivery. In this context, nanomedicine offers the significant advantage of targeting and releasing anti-angiogenic drugs at specific sites, minimizing toxicity in healthy tissues. Several nanoparticles possess intrinsic modulatory effects on angiogenesis, while others have been developed to facilitate drug delivery in association with chemotherapy, thermotherapy, radiotherapy or in response to specific stimuli within the tumor environment (e.g., enzymes, ions, redox potential) or exogenous stimuli (e.g., temperature, electricity, magnetic fields, and ultrasound). Other nanoparticles can modify, under specific conditions, their physical properties (e.g., dimensions, structure, and interactions) to increase penetration in tumor cells. This review provides a comprehensive appraisal of the critical modulators of tumor vascular biology, the most promising nano-strategies that specifically target such modulators, and the directions for future research and clinical applications.

Nano-Derived Therapeutic Formulations with Curcumin in Inflammation-Related Diseases.

Due to its vast therapeutic potential, the plant-derived polyphenol curcumin is utilized in an ever-growing number of health-related applications. Here, we report the extraction methodologies, therapeutic properties, advantages and disadvantages linked to curcumin employment, and the new strategies addressed to improve its effectiveness by employing advanced nanocarriers. The emerging nanotechnology applications used to enhance CUR bioavailability and its targeted delivery in specific pathological conditions are collected and discussed. In particular, new aspects concerning the main strategic nanocarriers employed for treating inflammation and oxidative stress-related diseases are reported and discussed, with specific emphasis on those topically employed in conditions such as wounds, arthritis, or psoriasis and others used in pathologies such as bowel (colitis), neurodegenerative (Alzheimer's or dementia), cardiovascular (atherosclerosis), and lung (asthma and chronic obstructive pulmonary disease) diseases. A brief overview of the relevant clinical trials is also included. We believe the review can provide the readers with an overview of the nanostrategies currently employed to improve CUR therapeutic applications in the highlighted pathological conditions.

Pharmacological and Antioxidant Activities of Rhus coriaria L. (Sumac).

Rhus coriaria L. (Anacardiaceae), commonly known as sumac, is a commonly used spice, condiment, and flavoring agent, especially in the Mediterranean region. Owing to its bountiful beneficial values, sumac has been used in traditional medicine for the management and treatment of many ailments including hemorrhoids, wound healing, diarrhea, ulcer, and eye inflammation. This plant is rich in various classes of phytochemicals including flavonoids, tannins, polyphenolic compounds, organic acids, and many others. By virtue of its bioactive, Rhus coriaria possesses powerful antioxidant capacities that have ameliorative and therapeutic benefits for many common diseases including cardiovascular disease, diabetes, and cancer. This review describes the phytochemical properties of R. coriaria and then focuses on the potent antioxidant capacities of sumac. We then dissect the cellular and molecular mechanisms of sumac's action in modulating many pathophysiological instigators. We show how accumulating evidence supports the antibacterial, antinociceptive, antidiabetic, cardioprotective, neuroprotective, and anticancer effects of this plant, especially that toxicity studies show that sumac is very safe to consume by humans and has little toxicity. Taken together, the findings we summarize here support the utilization of this plant as an attractive target for drug discovery.

Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety.

Cardiovascular diseases (CVDs) are a significant health burden with an ever-increasing prevalence. They remain the leading causes of morbidity and mortality worldwide. The use of medicinal herbs continues to be an alternative treatment approach for several diseases including CVDs. Currently, there is an unprecedented drive for the use of herbal preparations in modern medicinal systems. This drive is powered by several aspects, prime among which are their cost-effective therapeutic promise compared to standard modern therapies and the general belief that they are safe. Nonetheless, the claimed safety of herbal preparations yet remains to be properly tested. Consequently, public awareness should be raised regarding medicinal herbs safety, toxicity, potentially life-threatening adverse effects, and possible herb-drug interactions. Over the years, laboratory data have shown that medicinal herbs may have therapeutic value in CVDs as they can interfere with several CVD risk factors. Accordingly, there have been many attempts to move studies on medicinal herbs from the bench to the bedside, in order to effectively employ herbs in CVD treatments. In this review, we introduce CVDs and their risk factors. Then we overview the use of herbs for disease treatment in general and CVDs in particular. Further, data on the ethnopharmacological therapeutic potentials and medicinal properties against CVDs of four widely used plants, namely Ginseng, Ginkgo biloba, Ganoderma lucidum, and Gynostemma pentaphyllum, are gathered and reviewed. In particular, the employment of these four plants in the context of CVDs, such as myocardial infarction, hypertension, peripheral vascular diseases, coronary heart disease, cardiomyopathies, and dyslipidemias has been reviewed, analyzed, and critically discussed. We also endeavor to document the recent studies aimed to dissect the cellular and molecular cardio-protective mechanisms of the four plants, using recently reported in vitro and in vivo studies. Finally, we reviewed and reported the results of the recent clinical trials that have been conducted using these four medicinal herbs with special emphasis on their efficacy, safety, and toxicity.

Herbal Medicine for Slowing Aging and Aging-associated Conditions: Efficacy, Mechanisms and Safety.

Aging and aging-associated diseases are issues with unsatisfactory answers in the medical field. Aging causes important physical changes which, even in the absence of the usual risk factors, render the cardiovascular system prone to some diseases. Although aging cannot be prevented, slowing down the rate of aging is entirely possible to achieve. In some traditional medicine, medicinal herbs such as Ginseng, Radix Astragali, Ganoderma lucidum, Ginkgo biloba, and Gynostemma pentaphyllum are recognized by the "nourishing of life" and their role as anti-aging phytotherapeutics is increasingly gaining attention. By mainly employing PubMed here we identify and critically analysed 30 years of published studies focusing on the above herbs' active components against aging and aging-associated conditions. Although many plant-based compounds appear to exert an anti-aging effect, the most effective resulted in being flavonoids, terpenoids, saponins, and polysaccharides, which include astragaloside, ginkgolide, ginsenoside, and gypenoside specifically covered in this review. Their effects as antiaging factors, improvers of cognitive impairments, and reducers of cardiovascular risks are described, as well as the molecular mechanisms underlying the above-mentioned effects along with their potential safety. Telomere and telomerase, PPAR-α, GLUTs, FOXO1, caspase-3, bcl-2, along with SIRT1/AMPK, PI3K/Akt, NF-κB, and insulin/insulin-like growth factor-1 pathways appear to be their preferential targets. Moreover, their ability to work as antioxidants and to improve the resistance to DNA damage is also discussed. Although our literature review indicates that these traditional herbal medicines are safe, tolerable, and free of toxic effects, additional well-designed, large-scale randomized control trials need to be performed to evaluate short- and long-term effects and efficacy of these medicinal herbs.

Plasmonic MXene-based nanocomposites exhibiting photothermal therapeutic effects with lower acute toxicity than pure MXene.

Purpose: Here, we fabricated two plasmonic 2D Ti3C2Tx-based nanocomposites (Au/MXene and Au/Fe3O4/MXene) with similarly high anti-cancer photothermal therapy (PTT) capabilities, but with less in vivo toxicity than a pure MXene. Methods: Au/MXene was synthesized by in situ reduction of tetrachloroauric acid using NaBH4 on Ti3C2Tx flakes. For targeted PTT, magnetic Au/Fe3O4/MXene was synthesized via a reaction between freshly prepared magnetite Fe3O4 NPs and MXene solution, followed by in situ integration of gold nanoparticles (AuNPs). Results: Morphological characterization by XRD, SEM, and TEM revealed the successful synthesis of Au/MXene and Au/Fe3O4/MXene. Both new composites exhibited a significant in vitro dose-dependent PTT effect against human breast cancer cells MCF7. Interestingly, in vivo acute toxicity assays using zebrafish embryos indicated that Au/MXene and Au/Fe3O4/MXene had less embryonic mortality (LC50 ≫ 1000 µg/mL) than pure MXene (LC50=257.46 µg/mL). Conclusion: Our new Au/MXene and Au/Fe3O4/MXene nanocomposites could be safer and more suitable than the pure MXene for biomedical applications, especially when targeted PTT is warranted.

Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway.

Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. Origanum majorana is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, we subjected rat thoracic aortae to increasing doses of an ethanolic extract of Origanummajorana (OME). OME induced relaxation in a dose-dependent manner in endothelium-intact rings. This relaxation was significantly blunted in denuded rings. N(ω)-nitro-l-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) significantly reduced the OME-induced vasorelaxation. Cyclic guanosine monophosphate (cGMP) levels were also increased by OME. Moreover, wortmannin or LY294002 significantly reduced OME-induced vasorelaxation. Blockers of ATP-sensitive or Ca2+-activated potassium channels such as glibenclamide or tetraethylamonium (TEA), respectively, did not significantly affect OME-induced relaxation. Similarly, verapamil, a Ca2+ channel blocker, indomethacin, a non-selective cyclooxygenase inhibitor, and pyrilamine, a H1 histamine receptor blocker, did not significantly modulate the observed relaxation. Taken together, our results show that OME induces vasorelaxation via an endothelium-dependent mechanism involving the phosphoinositide 3-kinase (PI3-K)/ endothelial nitric oxide (NO) synthase (eNOS)/cGMP pathway. Our findings further support the medicinal value of marjoram and provide a basis for its beneficial intake. Although consuming marjoram may have an antihypertensive effect, further studies are needed to better determine its effects in different vascular beds.

Protective Effect of Cyclically Pressurized Solid⁻Liquid Extraction Polyphenols from Cagnulari Grape Pomace on Oxidative Endothelial Cell Death.

The aim of this work is the evaluation of a green extraction technology to exploit winery waste byproducts. Specifically, a solid⁻liquid extraction technology (Naviglio Extractor®) was used to obtain polyphenolic antioxidants from the Cagnulari grape marc. The extract was then chemically characterized by spectrophotometric analysis, high-performance liquid chromatography, and mass spectrometry, revealing a total polyphenol content of 4.00 g/L ± 0.05, and the presence of anthocyanins, one of the most representative groups among the total polyphenols in grapes. To investigate potential biological activities of the extract, its ability to counteract hydrogen peroxide-induced oxidative stress and cell death was assessed in primary human endothelial cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, used to assess potential extract cytotoxicity, failed to show any deleterious effect on cultured cells. Fluorescence measurements, attained with the intracellular reactive oxygen species (ROS) probe 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA), revealed a strong antioxidant potential of the marc extract on the used cells, as indicated by the inhibition of the hydrogen peroxide-induced ROS generation and the counteraction of the oxidative-induced cell death. Our results indicate the Naviglio extraction, as a green technology process, can be used to exploit wine waste to obtain antioxidants which can be used to produce enriched foods and nutraceuticals high in antioxidants.

Oxidative stress-induced Akt downregulation mediates green tea toxicity towards prostate cancer cells.

Green tea consumption has been shown to possess cancer chemopreventive activity. Polyphenol E (PE) is a widely used standardized green tea extract formulation. This study was designed to investigate the impact of PE on prostate cancer cells (PC3), analyze the potential signals involved and elucidate whether anti- or pro-oxidant effects may be implicated. Treatment of PC3 cells with 30 and 100µg/ml PE significantly decreased cell viability and proliferation. At the tested concentrations, PE did not exert any antioxidant activity, eliciting instead a pro-oxidant effect at concentrations 30 and 100µg/ml, which was consistent with the observed PE cytotoxicity. PE-induced cell death was associated with mitochondrial dysfunction and downregulation of Akt activation, thus suggesting their implication in the PE-elicited cell dysfunction. Cell exposure to the ROS scavenger N-Acetyl Cysteine prevented PE-induced ROS increase, pAkt impairment, and cell death, clearly indicating the causative role of ROS in the observed phenomena. Failure of PE to induce PC3 damage in cells overexpressing Akt further confirms its implication in the PE-elicited cell death. Our findings showed an association between the antiproliferative and the pro-oxidant effect elicited by PE on PC3 cells and delineates a molecular signaling pattern potentially implicated in the toxicity of PE towards prostate cancer cells.

Human Serum Albumin Increases the Stability of Green Tea Catechins in Aqueous Physiological Conditions.

Epicatechin (EC), epigallocatechin (EGC), epicatechingallate (ECG) and epigallocatechingallate (EGCG) are antioxidants present in the green tea, a widely used beverage whose health benefits are largely recognized. Nevertheless, major physicochemical limitations, such as the high instability of catechins, pose important questions concerning their potential pharmacological use. Recent studies indicate that binding of catechins with plasmatic proteins may modulate their plasma concentration, tissue delivery and biological activity. After 5 minutes of incubation with HSA both ECG and EGCG were fully bound to HSA, while after 48h incubation only 41% of EC and 70% of EGC resulted linked. HSA had a strong stabilizing effect on all catechins, which could be found in solution between 29 and 85% even after 48h of incubation. In the absence of HSA, EGC and EGCG disappeared in less than 24h, while ECG and EC were found after 48h at 5 and 50%, respectively. The stabilizing effect of HSA toward EGCG, obtained in aqueous physiological conditions, resulted stronger in comparison to cysteine and HCl, previously reported to stabilize this polyphenol. Because of the multitude of contradictory data concerning in vivo and in vitro antioxidant-based experimentations, we believe our work may shed some light on this debated field of research.

Evaluation of non-covalent interactions between serum albumin and green tea catechins by affinity capillary electrophoresis.

The natural antioxidant-associated biological responses appear contradictory since biologically active dosages registered in vitro experiments are considerably higher if compared to concentrations found in vivo. The recent research indicates that natural antioxidants, including the major catechins of green tea epicatechin (EC), epigallocatechin (EGC), epicatechingallate (ECG) and epigallocatechingallate (EGCG) form non-covalent complexes with albumin, a crucial aspect that may modulate their plasma concentration, tissue delivery and biological activity. Affinity capillary electrophoresis (ACE) was used to characterize the binding of the four catechins to human serum albumin (HSA) and bovine serum albumin (BSA) at near-physiological conditions: 10 mmol/L phosphate buffer, HEPES 50 mmol/L (pH 7.5), temperature 37°C. The studied flavonoids displayed affinities toward the albumin with binding constants in the range 10(3)-10(5)M(-1), with a greater affinity of catechins toward HSA than BSA (between 3 and 3.5 fold higher). We also confirmed that catechins having a galloyl moiety (ECG and EGCG) have a higher binding affinity toward albumin than the catechins lacking the galloyl moiety (EC and EGC), and that for both albumins the order of affinity is EC