A review of natural products and small-molecule therapeutics acting on central nervous system malignancies: Approaches for drug development, targeting pathways, clinical trials, and challenges.

In 2021, the World Health Organization released the fifth edition of the central nervous system (CNS) tumor classification. This classification uses histopathology and molecular pathogenesis to group tumors into more biologically and molecularly defined entities. The prognosis of brain cancer, particularly malignant tumors, has remained poor worldwide, approximately 308,102 new cases of brain and other CNS tumors were diagnosed in the year 2020, with an estimated 251,329 deaths. The cost and time-consuming nature of studies to find new anticancer agents makes it necessary to have well-designed studies. In the present study, the pathways that can be targeted for drug development are discussed in detail. Some of the important cellular origins, signaling, and pathways involved in the efficacy of bioactive molecules against CNS tumorigenesis or progression, as well as prognosis and common approaches for treatment of different types of brain tumors, are reviewed. Moreover, different study tools, including cell lines, in vitro, in vivo, and clinical trial challenges, are discussed. In addition, in this article, natural products as one of the most important sources for finding new chemotherapeutics were reviewed and over 700 reported molecules with efficacy against CNS cancer cells are gathered and classified according to their structure. Based on the clinical trials that have been registered, very few of these natural or semi-synthetic derivatives have been studied in humans. The review can help researchers understand the involved mechanisms and design new goal-oriented studies for drug development against CNS malignancies.

Anti-Toxoplasma In Vitro and In Vivo Activity of Pyrus boissieriana Arbutin-Rich Fraction.

PURPOSE: Pyrus boissieriana is a rich source of arbutin and has been used in herbal medicine to treat infectious diseases. This study aimed to investigate the effect of the arbutin-rich fraction of Pyrus boissieriana aerial parts on Toxoplasma gondii In Vitro and In Vivo. METHODS: An arbutin-rich fraction of P. boissieriana was prepared beforehand. Flow cytometry was used to evaluate the effect of different concentrations (1-512 µg/ml) of the P. boissieriana arbutin-rich fraction on Toxoplasma tachyzoites (RH strain). The cytotoxicity of the concentrations on the macrophage J774 cell line was also investigated by MTT assay. For In Vivo investigation, 4-6-week-old female mice infected with the RH strain of T. gondii were treated with different doses (16, 32, 64, 256, and 512 mg/kg) of the fraction using gavage. RESULTS: The highest and lowest lethality of the tachyzoites were 89.6% and 25.9% related to the concentrations of 512 µg/ml and 1 µg/ml, respectively, with an IC50 value of 18.1 µg/ml ± 0.37. The cytotoxicity test showed an IC50 value of 984.3 µg/ml ± 0.76 after 48 h incubation. The mean survival of mice at the lowest treated dose (16 mg/kg) was 6.6 days, and it was 15 days at the highest dose (512 mg/kg). The concentrations of 512, 256, 128, and 64 mg/kg of the fraction compared to the negative control (6.2 days mean survival) significantly increased the survival time of mice (P < 0.001, P = 0.009, P = 0.018, and P = 0.021, respectively). CONCLUSION: The results showed that the arbutin-rich fraction of P. boissieriana is effective against T. gondii In Vitro and In Vivo and may be a reliable alternative to conventional treatment for toxoplasmosis, although further studies are necessary.

A Review of the Chemistry and Biological Activities of Natural Colorants, Dyes, and Pigments: Challenges, and Opportunities for Food, Cosmetics, and Pharmaceutical Application.

Natural pigments are important sources for the screening of bioactive lead compounds. This article reviewed the chemistry and therapeutic potentials of over 570 colored molecules from plants, fungi, bacteria, insects, algae, and marine sources. Moreover, related biological activities, advanced extraction, and identification approaches were reviewed. A variety of biological activities, including cytotoxicity against cancer cells, antioxidant, anti-inflammatory, wound healing, anti-microbial, antiviral, and anti-protozoal activities, have been reported for different pigments. Considering their structural backbone, they were classified as naphthoquinones, carotenoids, flavonoids, xanthones, anthocyanins, benzotropolones, alkaloids, terpenoids, isoprenoids, and non-isoprenoids. Alkaloid pigments were mostly isolated from bacteria and marine sources, while flavonoids were mostly found in plants and mushrooms. Colored quinones and xanthones were mostly extracted from plants and fungi, while colored polyketides and terpenoids are often found in marine sources and fungi. Carotenoids are mostly distributed among bacteria, followed by fungi and plants. The pigments isolated from insects have different structures, but among them, carotenoids and quinone/xanthone are the most important. Considering good manufacturing practices, the current permitted natural colorants are: Carotenoids (canthaxanthin, ß-carotene, ß-apo-8'-carotenal, annatto, astaxanthin) and their sources, lycopene, anthocyanins, betanin, chlorophyllins, spirulina extract, carmine and cochineal extract, henna, riboflavin, pyrogallol, logwood extract, guaiazulene, turmeric, and soy leghemoglobin.

A review of citrus plants as functional foods and dietary supplements for human health, with an emphasis on meta-analyses, clinical trials, and their chemical composition.

Fruits, flowers, leaves, essential oils, hydrosols, and juices of citrus spp. Are utilized to prepare various forms of food products. Along with their nutritional values, in the health industry, different parts of the plants of the citrus genus have been used as supplements or remedies to prevent or control diseases. This review focused on reported meta-analyses and clinical trials on the health benefits of citrus plants as functional foods. Also, chemical compounds of various citrus species were reviewed. The following information sources were used for data collection: Google Scholar, the Web of Science, Scopus, and PubMed. Various keywords, including "citrus AND chemical compounds," "citrus AND phytochemicals," "citrus species," "citrus AND meta-analysis," "nutritional and therapeutical values of citrus spp.," "clinical trials AND citrus," "clinical trials AND Rutaceae," "health benefits of citrus spp.," "citrus edible or non-edible applications," and scientific names of the citrus plants were utilized to collect data for the review. The scientific name and common name of all twenty-eight citrus species, along with any of the above keywords, were also searched in the mentioned databases. Scientific papers and data sources were sought to review and discuss the citrus plant's nutritional and therapeutic importance. Several meta-analyses and clinical trials have reported beneficial effects of citrus spices on a variety of cancer risks, cardiovascular risk factors, neurologic disorders, urinary tract conditions, and gastrointestinal tract conditions. They have shown anxiolytic, antimicrobial, and pain-alleviating effects. Some of them can be helpful in managing obesity and cardiovascular risk factors.

The effects of lavandula aromatherapy on pain relief after coronary artery bypass graft surgery: A randomized clinical trial.

BACKGROUND AND AIMS: Coronary artery bypass graft surgery (CABG) is a primary treatment in coronary artery disease (CAD). Patients experience pain after CABG. Pain may increase postoperative complications and decrease quality of life (QoL). This study aims to determine the lavandula aromatherapy effect on patients' pain after CABG. METHODS: 98 patients undergoing CABG were randomly assigned to intervention and placebo groups. The intervention group inhaled 5-drops of 20 % lavandula essential oil (LEO) and the placebo group was exposed to 5-drop of distilled water. LEO or distilled water were dropped into a sterile gauze converted to the form of a necklace. The subjects wore necklace for three consecutive days and intervention was performed each 24 h. The pain intensity, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured before each intervention and 30 min after it. Also, the mean analgesic intake was recorded. SPSS version 16 was used to analyze the data. RESULTS: The mean pain score measured in the intervention group showed a more decrease than that obtained in the placebo group after the first and second interventions. Additionally, the mean pain score in the intervention group demonstrated a significant decrease than the placebo group after the second intervention (P=0.008). Moreover, mean SBP after the second intervention (P=0.046) and mean DBP after the first intervention (P=0.029) revealed a significant difference between two groups. Moreover, the intervention group received less analgesic than the placebo group. CONCLUSIONS: Lavandula aromatherapy can reduce pain and received analgesic dose after CABG.

A new cytotoxic sesquiterpene lactone from Euphorbia microsphaera Boiss against human breast cancer (MCF-7) and human fibrosarcoma (HT1080) cells.

A new guaianolide sesquiterpene lactone with cytotoxic properties was isolated from Euphorbia microsphaera Boiss. To determine the highest active fraction and isolate bioactive compounds, a bioassay guided fractionation approach was used. The general toxicity properties of the plant's extracts and fractions (fr1-10) were assessed against Artemia salina, Oryzeaphilus mercator, and Tribolium castaneum. Cytotoxic activities were investigated against normal human foreskin fibroblasts and two malignant cell lines, including human breast cancer (MCF-7) and human fibrosarcoma cells (HT1080) using the MTT assay at different time points of 24, 48, and 72 h. Single crystal X-ray diffraction (SC-XRD) and mass spectrometry data were used to determine the structure of the active guaianolide sesquiterpene lactone (3aR,4S,4aS,5R,7aS,9aS)-5-hydroxy-5,8-dimethyl-3-methylene-2-oxo-2,3,3a,4,4a,5,6,7,7a, 9a decahydroazuleno [6,5-b] furan-4-yl acetate (named aryanin). Chloroformic fraction 7 (fr7, LC50 = 93.50 µg/mL for general toxicity) had the highest toxicity result, with a mortality rate of more than 50% for both insect species after 12 h at 15 mg/mL. The highest cytotoxicity of aryanin was observed on 24 h treated MCF-7 with an IC50 of 13.81 µg/mL. After 24 h, the inhibition of MCF-7 cell proliferation was 92%-94% at concentrations of 25-50 µg/mL, respectively. On MCF-7, the IC50 was found to be 49.35 µg/mL after 72 h. This compound had a considerable cytotoxicity (IC50 ≤ 12.5 µg/mL, 24 h) on human foreskin fibroblasts. In contrast to the MCF-7 cell line, the proliferation of human foreskin fibroblasts was increased after 72 h.

An Assay on the Possible Effect of Essential Oil Constituents on Receptors Involved in Women's Hormonal Health and Reproductive System Diseases.

Aromatic herbal remedies, hydrosols, and essential oils are widely used for women's hormonal health. Scientific investigation of their major constituents may prevent unwanted infertility cases, fetal abnormalities, and drug-herb interactions. It also may lead to development of new medications. A list of 265 volatile molecules (mainly monoterpenes and sesquiterpenes) were prepared from a literature survey in Scopus and PubMed (2000-2019) on hydrosols and essential oils that are used for women's hormonal and reproductive health conditions. The PDB (protein data bank) files of the receptors (136 native PDB files) that involve with oxytocin, progesterone, estrogen, prolactin, acetyl choline, androgen, dopamine, human chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone, aromatase, and HER2 receptors were downloaded from Protein Data Bank. An in silico study using AutoDock 4.2 and Vina in parallel mode was performed to investigate possible interactions of the ligands with the receptors. Drug likeliness was investigated for the most active molecules using DruLiTo software. Aristola-1(10),8-diene, bergapten (5-methoxypsoralen), α-bergamotene, bicyclogermacrene, α-bisabolol oxide A, α-bisabolone oxide, p-cymen-8-ol, 10-epi elemol, α-elemol, ß-eudesmol, 7-epi-ß-eudesmol, ficusin, ß-humulene, methyl jasmonate, nerolidol, pinocarvone, (+)-spathulenol, and thujone had better interactions with some androgen, aromatase, estrogen, progesterone, HER2, AChR, and/or dopamine receptors. Most of these molecules had an acceptable drug likeliness except for α-bergamotene, bicyclogermacrene, ß-humulene, and aristola-1(10),8-diene. Some volatile natural molecules can be considered as lead compound for drug development to treat hormonal conditions.

A randomized controlled double blinded trial to evaluate efficacy of oral administration of black strap molasses (sugarcane extract) in comparison with polyethylene glycol on pediatric functional constipation.

ETHNOPHARMACOLOGICAL RELEVANCE: As a significant health issue, Functional Constipation (FC) has a high prevalence of 0.7%-29% worldwide. In Persian ethnomedicine, several formulations of sugarcane extracts including faniz, shekar-e- sorkh and black strap molasses have been used to treat pediatric constipation. AIM OF THE STUDY: To evaluate efficacy and safety of oral intake of black strap molasses syrup (BSM) on FC in children. MATERIALS AND METHODS: A randomized controlled double blinded trial was performed on children aged 4-12 years diagnosed with FC according to ROMIII Constipation Measurement Questionnaire. Ninety-two patients were randomly divided in two groups of BSM or PEG syrups (40%) with a dose of 1 mL/kg body weight/day for 1 month. Symptoms were evaluated every two weeks. Possible serological side-effects and changes in children's body weight were investigated. BSM syrup constituents were determined by pharmacognostic methods. RESULTS: Treatment was successful with both interventions with no significant difference between the groups. Defecation per week was significantly improved in both groups. Symptoms including volitional stool retention, large diameter stool, painful or hard stool and large fecal mass in the rectum decreased significantly two and four weeks after intervention (P < 0.05). There was no significant difference between groups except for the rate of large diameter stool. No side -effects were observed. The BSM naturally contained polyphenols (960 µg/mL), potassium (12430 µg/mL), iron (80 µg/mL) and calcium (3320 µg/mL). CONCLUSION: BSM and PEG syrups had similar efficacy on FC. Compared with PEG, BSM syrup contained different natural micronutrients.

Cytotoxic and Apoptotic Activities of Methanolic Subfractions of Scrophularia oxysepala against Human Breast Cancer Cell Line.

Herbs have played a positive role in medicine for thousands of years. In the current study, we investigated the cytotoxicity effects of Scrophularia oxysepala methanolic subfractions and the underlying mechanism responsible for cell death in human breast carcinoma (MCF-7 cells) and mouse fibrosarcoma (WEHI-164 cells). From 60% and 80% methanolic fractions, four subfractions (Fa, Fb, Fc, and Fd), yielded from size exclusion by Sephadex-LH20 column chromatography, were chosen. MTT assay revealed that all subfractions significantly reduced cell viability after 24 h and 36 h in a dose-dependent manner; it is worth noting that Fa and Fb subfractions had the highest cytotoxicity, with IC50 values of 52.9 and 61.2 µg/mL in MCF-7 at 24 h, respectively. ELISA, TUNEL, and DNA fragmentation assay revealed that antiproliferative effects of all subfractions were associated with apoptosis on cancer cells, without any significant effect on L929 normal cells. qRT-PCR data showed that, after 24 h treatment with IC50 concentrations of the subfractions, caspase-3 expression was increased in cancer cells while the expression of Bcl-2 was decreased. S. oxysepala methanolic subfractions induce apoptosis in MCF-7 and WEHI-164 cells and could be considered as a source of natural anticancer agents.

Dichloromethane fractions of Scrophularia oxysepala extract induce apoptosis in MCF-7 human breast cancer cells.

Breast cancer is a prevalent malignancy among women, especially in developing countries. A large number of anticancer agents with herbal origins have been reported. Hence, herbals may play an essential role in prevention and treatment of cancers. We investigated cytotoxic effects of dichloromethane fractions of Scrophularia oxysepala extract on the MCF-7 breast cancer cell line. The cytotoxic activity of Scrophularia oxysepala fractions on the MCF-7 cells was assessed using Trypan Blue dye exclusion and MTT (3-(4, 5-dimetylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) assays. In addition, apoptosis induction was determined using TUNEL (terminal deoxy transferase (TdT)-mediated dUTP nick- end labeling) assay and DNA fragmentation analysis. Quantitative Real-Time PCR was also used for analyzing the changes in Caspase-3, Caspase-9, and Bcl-2 genes' expression. Results revealed an effective inhibition of growth and viability in MCF-7 cells treated with dichloromethane fractions. Cell death assay and DNA fragmentation analysis using the TUNEL test confirmed the induction of apoptosis in the MCF-7 cell line. Further, the fractions have resulted in an increased expression of Caspase-3 and Caspase-9 mRNA, which highlights the possibility of apoptosis in the treatments. The expression study of Caspase-9 mRNA confirmed that, the fractions have triggered apoptosis via intrinsic mitochondrial pathway. In summary, fractions of Scrophularia oxysepala extract were found to be promising in growth inhibition and induction of apoptosis in MCF-7 breast cancer cells.

Dichloromethane and Methanol Extracts of Scrophularia oxysepala Induces Apoptosis in MCF-7 Human Breast Cancer Cells.

PURPOSE: Breast cancer is the most common cause of cancer-related death in women worldwide. Therefore, there is an urgent need to identify and develop therapeutic strategies against this deadly disease. This study is the first to investigate the cytotoxic effects and the mechanism of cell death of Scrophularia oxysepala extracts in MCF-7 human breast cancer cells. METHODS: Three extracts of Scrophularia oxysepala including the n-hexane, dichloromethane and methanol extracts were examined. MTT (3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and Trypan-blue assays were performed in MCF-7 cells as well as Human umbilical vein endothelial cells (HUVEC) to analyze the cytotoxic activity of the extracts of Scrophularia oxysepala. Further, the apoptosis inducing action of the extracts was determined by TUNEL (terminal deoxy transferase (TdT)-mediated dUTP nick- end labeling) test and cell death assay. RESULTS: The results showed that the n-hexane extract had no cytotoxic effects but dichloromethane and methanol extracts significantly inhibited cell growth and viability in a dose and time dependent manner without inducing damage to non-cancerous cell line HUVEC. In addition, Cell death assay and DNA fragmentation analysis using TUNEL indicated induction of apoptosis by dichloromethane and methanol extracts of Scrophularia oxysepala in MCF-7 cells. CONCLUSION: Our studies suggest that this plant may contain potential bioactive compound(s) for the treatment of breast cancer.

Evaluation of antimalarial, free-radical-scavenging and insecticidal activities of Artemisia scoparia and A. Spicigera, Asteraceae

Artemisia species (Asteraceae), widespread throughout the world, are a group of important medicinal plants. The extracts of two medicinal plants of this genus, Artemisia scoparia Waldst. & Kit. and A. spicigera C. Koch, were evaluated for potential antimalarial, free-radical-scavenging and insecticidal properties, using the heme biocrystallisation and inhibition assay, the DPPH assay and the contact toxicity bioassay using the pest Tribolium castaneum, respectively. The methanol extracts of both species showed strong free-radical-scavenging activity and the RC50 values were 0.0317 and 0.0458 mg/mL, respectively, for A. scoparia and A. spicigera. The dichloromethane extracts of both species displayed a moderate level of potential antimalarial activity providing IC50 at 0.778 and 0.999 mg/mL for A. scoparia and A. spicigera, respectively. Both species of Artemisia showed insecticidal properties. However, A. spicigera was more effective than A. scoparia.