Antioxidative and Anti-inflammatory Effects of Plant-derived Hypoglycemic Medicines: An In vivo/In vitro Systematic Review.

BACKGROUND: The activation of oxidative stress and inflammatory conditions has been associated with acceleration in diabetes (DM) onset and complications. Despite various anti-DM medications, there is a growing trend to discover inexpensive and effective treatments with low adverse effects from plants as one of the promising sources for drug development. OBJECTIVE: This study aimed to systematically investigate the simultaneous anti-inflammatory and antioxidant effects of plant-derived hypoglycemic medicines in diabetic experimental models. METHODS: The search terms consisted of "diabetes", "herbal medicine", "antioxidant", "Inflammatory biomarker", and their equivalents among PubMed, Scopus, Web of Science, and Cochrane Library databases up to 17 August 2021. RESULTS: Throughout the search of databases, 201 eligible experimental studies were recorded. The results showed that the most commonly assessed inflammatory and oxidative stress biomarkers were tumor necrosis factor (TNF)-α, interleukin (IL) 6, IL-1ß, IL-10, malondialdehyde (MDA), and nitric oxide (NO). The activity of antioxidant enzymes, including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) were assessed in the present review. Among herbal treatments, Trigonella foenum-graecum L., Centella asiatica (L.) Urb., Vitis vinifera L., and Moringa oleifera Lam. were most commonly used for diabetic complications. Due to the dispersion of the treatments, meta-analysis was not applicable. CONCLUSION: Our findings showed that the application of different plant-derived hypoglycemic treatments in animal models improved diabetes and its complications, as well as modulated concomitant inflammatory and oxidative stress biomarkers. These findings suggest that plant-based antidiabetic medicines and food supplements have the potential to manage diabetes and its complications.

Cedrus deodara: In Vivo Investigation of Burn Wound Healing Properties.

Objective: Cedrus deodara (Roxb. Ex Lamb.) G. Don possesses various biological activities, which have been documented in modern and traditional medicine. In this study, burn wound healing activity of the methanol extract of C. deodara wood was evaluated via a burn wound model in Wistar rats. Methods: The methanol extract of C. deodara was evaluated for the contents of phenolic compounds, flavonoids, and tannins. Also, its antioxidant activity was determined using the DPPH assay. Then, a topical ointment containing the methanol extract of C. deodara (10%) was used to evaluate the healing effects on a model of second-degree thermal burn in 4 groups of 7 rats within 21 days. In this respect, average wound surface area, wound closure, and various histological features were examined. Results: Our findings revealed that the wounds treated with the methanol extract of C. deodara showed higher wound contraction (33.6, 87.1, and 93.4% on days 7, 14, and 21, respectively) compared with the positive control (27.6, 80.7, and 88.3% on days 7, 14, and 21, respectively) and the negative control (20.1, 77.9, and 80.2% on days 7, 14, and 21, respectively). According to the results from epitheliogenesis score, the number of inflammatory cells, neovascularization, and collagen density, good burn wound healing activity of the methanol extract of C. deodarawas demonstrated. Conclusion: Using the methanol extract of C. deodara in an ointment formulation can be developed to prevent or reduce burn injury progression.

Investigation of biological activities of two cultivars of Cicer arietinum proteins mass associated with Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with some known classical factors. Cicer arietinum (Leguminosae) is a source of protein for humans and contains albumin, globulin, glutelin, and prolamin. The protein content of two cultivars of C. arietinum, Hashem and Mansour, was isolated to evaluate their inhibition activity against acetylcholinesterase (AChE), butyrylcholine esterase (BChE), and ß-amyloid peptide (ßA) aggregation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and molecular docking were also applied to evaluate the content and determine the potential of each chickpea protein to interact with AChE, respectively. Obtained data showed that proteins from both cultivars could inhibit AChE with IC50 of 17.73 (0.03) and 22.20 (0.06) µg/mL, respectively, with no activity on BChE. The 50 µg/mL protein concentration of each cultivar suppressed ßA accumulation (Mansour: 25.66% and Hashem: 21.69%) and showed biometal chelating activity. SDS-PAGE analysis revealed relatively different protein patterns, though the Mansour cultivar contained some protein bands with molecular weights of 18, 24, and 70 kDa were estimated to belong to vicilin and legumin, which were absent in the Hashem protein mass. Molecular docking showed that legumin and especially vicilin have good potential to interact with AChE. The chickpea proteins showed inhibitory activity against AChE, which might be due to the vicilin and legumin fractions. The characterization of the inhibitory effect of each protein band could be promising in finding new therapeutic peptide candidates to treat Alzheimer's in the future, although more experimental work is needed in this issue.

Phytochemical investigation and biological activity of Doronicum pardalianches L. roots against Alzheimer's disease.

The methanol extract of Doronicum pardalianches L. was fractionated using n-hexane, chloroform, and ethyl acetate to evaluate their cholinesterase (ChE) inhibitory activity via modified Ellman's method. It was perceived that only the ethyl acetate fraction was active toward acetylcholinesterase (AChE) with IC50 value of 172.21 µg/mL. Also, all fractions showed no butyrylcholinesterase (BChE) inhibitory activity. The ethyl acetate fraction was also investigated for its neuroprotectivity and metal chelating ability (Zn2+, Fe2+, and Cu2+) which demonstrated desired activity. Phytochemical analysis of the ethyl acetate fraction led to isolation and identification of formononetin 7-O-ß-D-glucopyranoside which has not been previously reported for this plant.

Phytochemical analysis and anticholinesterase activity of aril of Myristica fragrans Houtt.

In this study, the ethyl acetate fraction of Myristica fragrans Houtt. was investigated for its in vitro anticholinesterase activity as well as neuroprotectivity against H2O2-induced cell death in PC12 neuronal cells and the ability to chelate bio-metals (Zn2+, Fe2+, and Cu2+). The fraction was inactive toward acetylcholinesterase (AChE); however, it inhibited the butyrylcholinesterase (BChE) with IC50 value of 68.16 µg/mL, compared with donepezil as the reference drug (IC50 = 1.97 µg/mL) via Ellman's method. It also showed good percentage of neuroprotection (86.28% at 100 µg/mL) against H2O2-induced neurotoxicity and moderate metal chelating ability toward Zn2+, Fe2+, and Cu2+. The phytochemical study led to isolation and identification of malabaricone A (1), malabaricone C (2), 4-(4-(3,4-dimethoxyphenyl)-2,3-dimethylbutyl)benzene-1,2-diol (3), nectandrin B (4), macelignan (5), and 4-(4-(benzo[d][1,3]dioxol-5-yl)-1-methoxy-2,3-dimethylbutyl)-2-methoxyphenol (6) which were assayed for their cholinesterase (ChE) inhibitory activity. Compounds 1 and 3 were not previously reported for M. fragrans. Among isolated compounds, compound 2 showed the best activity toward both AChE and BChE with IC50 values of 25.02 and 22.36 µM, respectively, compared with donepezil (0.07 and 4.73 µM, respectively).

Cytotoxic abietane diterpenoids from Salvia leriifolia Benth.

The Phytochemical profiling of the root extract of Salvia leriifolia, an endemic plant of Iran, was investigated and 16 abietane diterpenes were isolated, and three were original compounds. 1D and 2D NMR and HRMS performed structural elucidation. The absolute configuration of the previously unreported compounds was determined by circular dichroism (ECD). The cytotoxicity of the isolated compounds was investigated against AGS, MIA PaCa-2, HeLa, and MCF-7 cell lines by the MTT assay. The known diterpene pisiferal possesses high cytotoxicity against all investigated cell lines at a concentration between 9.3 ± 0.6 and 14.38 ± 1.4 µM.

The potential of pumpkin seed oil as a functional food-A comprehensive review of chemical composition, health benefits, and safety.

The growing interest in foods that can be beneficial to human health is bringing into focus some products that have been used locally for centuries but have recently gained worldwide attention. One of these foods is pumpkin seed oil, which has been used in culinary and traditional medicine, but recent data also show its use in the pharmaceutical and cosmetic industries. In addition, some sources refer to it as a potential functional food, mainly because it is obtained from pumpkin seeds, which contain many functional components. However, the production process of the oil may affect the content of these components and consequently the biological activity of the oil. In this review, we have focused on summarizing scientific data that explore the potential of pumpkin seed oil as a functional food ingredient. We provide a comprehensive overview of pumpkin seed oil chemical composition, phytochemical content, biological activity, and safety, as well as the overview of production processes and contemporary use. The main phytochemicals in pumpkin seed oil with health-related properties are polyphenols, phytoestrogens, and fatty acids, but carotenoids, squalene, tocopherols, and minerals may also contribute to health benefits. Most studies have been conducted in vitro and support the claim that pumpkin seed oil has antioxidant and antimicrobial activities. Clinical studies have shown that pumpkin seed oil may be beneficial in the treatment of cardiovascular problems of menopausal women and ailments associated with imbalance of sex hormones.

Phytochemical investigation and anticholinesterase activity of ethyl acetate fraction of Myristica fragrans Houtt. seeds.

In this work, n-hexane, chloroform, and ethyl acetate fractions of the methanol extract of Myristica fragrans Houtt. seeds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) via Ellman's method. It was found that all fractions depicted no anti-AChE activity, however, they were active toward BChE with IC50 values of 361.8, 215.0, and 145.8 µg/mL, respectively comparing with donepezil as the reference drug (IC50 = 1.97 µg/mL). The ethyl acetate fraction which also showed high neuroprotectivity and metal chelating ability was selected for the phytochemical analysis. Our results confirmed the presence of trimyristin and 5,7-diacetyl chrysin (reported for the first time in M. fragrans) in the corresponding fraction.

Characteristics of published/registered clinical trials on COVID-19 treatment: A systematic review.

OBJECTIVES: Due to the rapid spread of COVID-19 worldwide, many countries have designed clinical trials to find efficient treatments. We aimed to critically report the characteristics of all the registered and published randomized clinical trials (RCTs) conducted on COVID-19, and summarize the evaluation of potential therapies developed in various regions. EVIDENCE ACQUISITION: We comprehensively searched PubMed, Cochrane Library, Web of Science, Scopus, and Clinicaltrial.gov databases to retrieve all the relevant studies up to July 19, 2021, in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. We included all English-language published/registered RCTs on COVID-19, and excluded non-RCT, in-vitro/in-vivo, editorials, and review studies. Two reviewers independently evaluated all the records, and then analyzed by using SPSS 17. RESULTS: Within 3018 included studies, 2801 (92.8%) and 217 (7.2%) were registered or published RCTs consisting of about 600 synthetic drugs. Herbal medicines have been studied in 23 trials (10.6%) among the published RCTs and in 357 registered RCTs (12.7%). Hydroxychloroquine 23 (10.6%) and convalescent plasma 194 (6.9%) alone or in combination with other agents were the most frequently used interventions in published and registered RCTs, respectively. Most published RCTs have been conducted in Western Pacific Region (WPRO) (50 trials, 23.0%) including 45 trials from China. Also, a greater proportion of registered RCTs have been conducted in the Region of the Americas (PAHO) (885 trials, 31.6%) including 596 RCTs from the United States (U.S). Globally, 283 registered trials have been conducted to assess new developed vaccines for COVID or previously established for other disorders. CONCLUSION: The present study highlighted the wide range of potential therapeutic agents in published and registered COVID-19 clinical trials across a wide range of regions. However, it is urgently required to global coordination in order to conduct more well-designed trials and progress in discovering safe and effective treatments.

Arglabin could target inflammasome-induced ARDS and cytokine storm associated with COVID-19.

Arglabin (l(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),ll(13)-dien-6,12-olide), is a natural sesquiterpene γ-lactone which was first isolated from Artemisia glabella. The compound has been shown to possess anti-inflammatory activity through inhibition of the NLR Family pyrin domain-containing 3 (NLRP3) inflammasome and production of proinflammatory cytokines including interleukin (IL)-1ß and IL-18. A more hydrophilic derivative of the compound also exhibited antitumor activity in the breast, colon, ovarian, and lung cancer. Some other synthetic derivatives of the compound have also been synthesized with antitumor, cytotoxic, antibacterial, and antifungal activities. Since both NLRP3 inflammasome and cytokine storm are associated with the pathogenesis of COVID-19 and its lethality, compounds like arglabin might have therapeutic potential to attenuate the inflammasome-induced acute respiratory distress syndrome and/or the cytokine storm associated with COVID-19.

The pro-apoptosis effects of Echinacea purpurea and Cannabis sativa extracts in human lung cancer cells through caspase-dependent pathway.

BACKGROUND: Considering the advantages of using medicinal herbs as supplementary treatments to sensitize conventional anti-cancer drugs, studying functional mechanisms and regulatory effects of Echinacea purpurea (as a non-cannabinoid plant) and Cannabis sativa (as a cannabinoid plant) are timely and required. The potential effects of such herbs on lung cancer cell growth, apoptosis, cell cycle distribution, cellular reactive oxygen species (ROS) level, caspase activity and their cannabinomimetic properties on the CB2 receptor are addressed in the current study. METHODS: The cytotoxic effect of both herb extracts on the growth of lung cancer cells (A549) was assessed using the MTT assay. The annexin-V-FITC staining and propidium iodide (PI) staining methods were applied for the detection of apoptosis and cell cycle distribution using flow cytometry. The cellular level of ROS was measured using 7'-dichlorofluorescin diacetate (DCFH-DA) as a fluorescent probe in flow cytometry. The caspase 3 activity was assessed using a colorimetric assay Kit. RESULTS: Echinacea purpurea (EP) root extract induced a considerable decrease in A549 viable cells, showing a time and dose-dependent response. The cell toxicity of EP was accompanied by induction of early apoptosis and cell accumulation at the sub G1 phase of the cell cycle. The elevation of cellular ROS level and caspase 3 activity indicate ROS-induced caspase-dependent apoptosis following the treatment of A549 cells by EP extract. The observed effects of EP extract on A549 growth and death were abrogated following blockage of CB2 using AM630, a specific antagonist of the CB2 receptor. Increasing concentrations of Cannabis sativa (CS) induced A549 cell death in a time-dependent manner, followed by induction of early apoptosis, cell cycle arrest at sub G1 phase, elevation of ROS level, and activation of caspase 3. The CB2 blockage caused attenuation of CS effects on A549 cell death which revealed consistency with the effects of EP extract on A549 cells. CONCLUSIONS: The pro-apoptotic effects of EP and CS extracts on A549 cells and their possible regulatory role of CB2 activity might be attributed to metabolites of both herbs. These effects deserve receiving more attention as alternative anti-cancer agents.

Phytostilbenes as agrochemicals: biosynthesis, bioactivity, metabolic engineering and biotechnology.

Covering: 1976 to 2020. Although constituting a limited chemical family, phytostilbenes represent an emblematic group of molecules among natural compounds. Ever since their discovery as antifungal compounds in plants and their ascribed role in human health and disease, phytostilbenes have never ceased to arouse interest for researchers, leading to a huge development of the literature in this field. Owing to this, the number of references to this class of compounds has reached the tens of thousands. The objective of this article is thus to offer an overview of the different aspects of these compounds through a large bibliography analysis of more than 500 articles. All the aspects regarding phytostilbenes will be covered including their chemistry and biochemistry, regulation of their biosynthesis, biological activities in plants, molecular engineering of stilbene pathways in plants and microbes as well as their biotechnological production by plant cell systems.

Effects of Monoterpenes of Trachyspermum ammi on the Viability of Spermatogonia Stem Cells In Vitro.

Trachyspermum ammi (Apiaceae) plants have several medicinal and condimentary applications and are considered an aphrodisiac agent in Iranian Traditional Medicine. Thus, the present study aims to evaluate the effects of oil from Iranian T. ammi plants on the viability of spermatogonial stem cells in vitro. The essential oil of T. ammi fruits was extracted by hydrodistillation, and the amount of thymol was calculated by a gas-chromatography method. Spermatogonial stem cells were isolated from the testes of mice using enzyme digestion. Real-time polymerase chain reaction (RT-PCR) was applied to assess the gene expressions of promyelocytic leukemia zinc finger protein (Plzf), DNA-binding protein inhibitor (ID-4), tyrosine-protein kinase (c-Kit), B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (BAX). The number and diameter of colonies were also measured in the treated cells. The amount of thymol in the oil was 130.7 ± 7.6 µg/mL. Flow cytometry analysis showed that 92.8% of all cells expressed stimulated by retinoic acid 8 (Stra8), a spermatogonial stem cell marker. Expression of Plzf and ID-4 genes significantly increased in the treatment groups, while c-Kit and BAX decreased, and Bcl2 increased in the presence of essential oil. The numbers and diameters of cells were also improved by the application of the plant oil. These data indicated that monoterpenes from the oil of T. ammi improved the quality and viability of spermatogonia cells in the cell culture.

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.

Bio-guided isolation of Centaurea bruguierana subsp. belangerana cytotoxic components.

Centaurea bruguierana subsp. belangerana was extracted by 80% ethanol. The total extract was then partitioned into four fractions including chloroform, ethyl acetate and methanol. Cytotoxic effect of fractions was examined by MTT assay in K562 (chronic myelogenous leukemia), AGS (gastric adenocarcinoma), MCF-7 (breast adenocarcinoma) and SW742 (colon adenocarcinoma) cell lines. The Chloroform fraction, with the lowest LC50 against K-562 cell lines, was partitioned into 14 subfractions and subjected to further purification by reversed-phase (C18) silica gel and sephadex LH-20 column chromatography. Three flavonoids including cirsimaritin, cirsilinelol and eupatilin were isolated for the first time from the species and the structures were confirmed by spectroscopic data. The high selectivity index of the purified flavonoids indicates valuable components with potential few side effects for normal cell lines. However, solubility tests for isolated components indicates the need for novel pharmaceutical dosage forms, in the case for using natural flavonoids as chemotherapeutic agents.

Natural activators of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and their pharmacological activities.

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric enzyme which monitors cellular energy status and regulates metabolism with energy balance. AMPK activation, as a master regulator of metabolism, plays role in key tissues like liver, skeletal muscles, and heart as well as central nervous system (CNS). Activation of the enzyme by indirect activators attracts scientific attentions to treat diabetes, obesity, cancer, and other related metabolic disorders like physiological and pathophysiological states in CNS. A number of hormones and pharmacological agents have been reported to activate AMPK including paroxetine, metformin, thiazolidinediones, adiponectin, leptin, interleukin-6, and etc. AMPK activity is prominent in regulation of glucose, lipid, and proteins metabolism as well as mitochondrial biogenesis and autophagy. Activation of AMPK in the liver decrease blood glucose and in skeletal muscles stimulates glucose uptake independently of insulin through modulation of activity of several downstream substrates. Activation of AMPK inhibits synthesis and induces oxidation of fatty acids, which may reduce ectopic lipid accumulation and improve insulin action. The enzyme activation promotes cardiovascular homeostasis by ensuring optimum redox balance of heart and vascular tissue. In addition, AMPK signaling may link to cancer development via regulation of checkpoints of cell cycle. Numerous of conventional drugs have been derived from natural resources, while the application of this fruitful source of chemical structures have not been explored in depth. A number of these compounds are discussed in this review that exhibit beneficial effects in metabolic disorders through AMPK activation.

Investigation of ß-Sitosterol and Prangol Extracted from Achillea Tenoifolia Along with Whole Root Extract on Isolated Rat Pancreatic Islets.

The genus Achillea (Asteraceae) consisting of important medicinal species, growing wildly in Iran, of which A. tenuifolia is found in Iran-o-Turan regions. Regarding the traditional use of Achillea species for treatment of diabetes and also lack of information on phyto-constituents of A. tenuifolia underground parts, in this study anti-diabetic activity of the plant have been reported. In order to find the main active components, underground parts of the plant were extracted with water and fractioned by hexane, ethyl acetate, and methanol and the separation of the main compounds were carried out via medium pressure liquid chromatography (MPLC). Also, anti-diabetic effects of the extract were investigated on rat pancreatic islets. The root extract of the plant as well as the compound ß-sitosterol showed moderate α-amylase inhibitory activity, however prangol did not suppress the enzyme activity. The results of islet cells' bio-function assays revealed that the herb root extract was able to increase the secretion of insulin in high concentration (10 mg/mL) and improved the cell viability with no toxicity in all doses. Furthermore, the herbal extract could reduce the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO). The plant extract also significantly decreased the enzyme activity for both caspase-3 and -9 and increased the antioxidant capacity of the isolated cells. Taking together, preparations or extracts from the underground parts of the plant are good candidates for further anti-diabetic investigation and clinical trials.

Phthalate contamination of some plants and herbal products / Contaminación de algunas plantas y productos herbales con ftalatos

Phthalate derivatives cause a number of risks to human health and the environment. Essential oil and volatile fractions of some vegetables and herbal products were extracted by hydrodistillation and percolation methods to analyze using gas chromatography and mass spectrometry (GC-MS) for evaluation of phthalate contaminations. The results revealed that four vegetables and all aromatic waters were contaminated by phthalate derivatives including di-n-butyl phthalate (DBP), diisobutyl phthalate and di-(2-ethylhexyl) phthalate (DEHP) (0.1-7.95%). Butylated hydroxytoluene (BHT), a widely used synthetic antioxidant, was also found in the most of the aromatic waters in the range of 3.15-61.3%. In addition, three vegetable samples contained diazinon (0.36-4.61%), an organophosphorus insecticide. Plants and herbal preparations may be contaminated by the absorption of phthalates from contaminated water or soil or by the migration of phthalates from inexpensive recycled plastic. Regarding the widespread use and associated health risks of phthalates, effective quality and safety regulations for herbal products should be implemented with respect to their phthalate content.

Los derivados de ftalato causan una serie de riesgos para la salud humana y el medio ambiente. El aceite esencial y las fracciones volátiles de algunos vegetales y productos a base de hierbas fueron extraídos mediante hidrodestilación y métodos de percolación y luego fueron analizados mediante cromatografía de gases y espectrometría de masas (GC-MS) con el propósito de identificar contaminación con ftalatos. Los resultados revelaron que cuatro productos herbales y todas las aguas aromáticas analizadas estaban contaminadas con derivados de ftalato, incluyendo el ftalato de dibutulo (DBP), ftalato de diisobutilo y ftalato de bis(2-etilhexilo) (DEHP) (0.1-7.95%). El butilhidroxitolueno (BHT), un antioxidante sintético ampliamente utilizado, también se encontró en aguas aromáticas en el rango de 3.15- 61.3%. Además, tres muestras vegetales contenían diazinón (0.36-4.61%), un insecticida organofosforado. Las plantas y las preparaciones herbales pueden ser contaminadas a partir de absorción de ftalatos del agua o el suelo contaminados o por la migración de ftalatos desde plástico reciclado de bajo costo. Con respecto al uso generalizado y los riesgos asociados a la salud de los ftalatos, deben implementarse normas efectivas de calidad y seguridad para los productos a base de hierbas con respecto a su contenido de ftalato.

Advances in the Anticancer Value of the Ursolic Acid Through Nanodelivery.

Ursolic acid, a natural pentacyclic triterpenoid is commonly found in plants and foods with promising biological and pharmacological activities. The compound has been under the attention of researchers due to its considerable anticancer effects through suppression of differentiation, angiogenesis, invasion, and metastasis of tumor cells via different pathways with low toxicity. Bioavailability of ursolic acid is poor due to poor solubility of the compound in water. Low bioavailability and short plasma half-life of ursolic acid along with non-specific distribution in the body are considered as impediments in the therapeutic development of the compound. Nano-drug delivery systems may improve the pharmacokinetic, bioavailability, and therapeutic activity of some medicines. The present review has focused on recent developments regarding nano-drug delivery systems of ursolic acid in cancer therapy.

Piperine as a Potential Anti-cancer Agent: A Review on Preclinical Studies.

Recently many studies showed anticancer activities of piperine, a pungent alkaloid found in black pepper and some other Piper species. We attempted to summarize acquired data that support anticancer potential of this natural agent. Piperine has been reported to possess effective chemopreventive activity. It has been studied to affect via several mechanisms of action, in brief enhancing antioxidant system, increasing level and activity of detoxifying enzymes and suppressing stem cell self-renewal. Moreover, piperine has been found to inhibit proliferation and survival of various cancerous cell lines via modulating cell cycle progression and exhibiting anti-apoptotic activity, respectively. This compound has been shown to modify activity of various enzymes and transcription factors to inhibit invasion, metastasis and angiogenesis. Interestingly, piperine has exhibited antimutagenic activity and also inhibited activity and expression of multidrug resistance transporters such as P-gp and MRP-1. Besides, about all reviewed studies have reported selective cytotoxic activity of piperine on cancerous cells in compared with normal cells. Altogether, the studies completely underline promising candidacy of piperine for further development. The collected preclinical data we provided in this article can be useful in the design of future researches especially clinical trials with piperine.