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Context: The genus Glaucium Mill., one of the important Papaveraceae family plants, is rich in isoquinoline alkaloids and distributed worldwide. Objective: Isolation and identification of bioactive alkaloids from Glaucium grandiflorum Boiss. & Huet. subsp. refractum (Nabelek) Mory var. torquatum (Cullen) Mory and G. corniculatum (L.) Rudolph var. corniculatum (Aslan 2012), and investigation of their antioxidant and anticholinesterase activities. Materials and methods: The aerial parts of each plant were dried, powdered, and percolated with methanol, then each extract was fractionated between 50% aqueous acetic acid and petroleum. Their aqueous acidic layer was adjusted to pH 7-8 with NH4OH and extracted with chloroform, the extract was subjected to CC separation and isolation. Structures of the isolated alkaloids were elucidated by 1D and 2D-NMR and mass spectral analyses. The alkaloid extracts and their pure alkaloids were tested for anti-cholinesterase (AChE and BuChE) and antioxidant (ABTS, CUPRAC, β-carotene linoleic acid tests) activities in vitro. Results: Methanol extracts of Glaucium grandiflorum subsp. refractum var. torquatum and G. corniculatum var. corniculatum afforded a novel compound glauciumoline and seven known isoquinoline alkaloids three of which have an aporphine-type and the other five have a protopine-type skeleton. Among them, trans-protopinium (7) and cis-protopinium (8) were isolated from a Glaucium species for the first time. Tertiary amine extracts (TAEs) of both plants showed very strong acetylcholinesterase inhibitory activity. The TAE of the plants also showed strong antioxidant activity while the isolated alkaloids showed no meaningful activity in the anticholinesterase and antioxidant tests. Discussion and conclusions: Glaucium species are considered promising therapeutic agents in the treatment of Alzheimer's disease.

Caulerpa cylindracea Sonder is a green alga belonging to the CauIerpaceae family. This is the first chemical investigation of C. cylindracea in the Dardanelles which resulted in the isolation of four compounds, caulerpin (1), monomethyl caulerpinate (2), beta-sitosterol (3), and palmitic acid (4). Their structures were elucidated by spectroscopic analyses including 1D- and 2D NMR and mass. The isolated compounds 1 and 2 were tested against the SARS-CoV-2 viral targets spike protein and main protease (3CL) enzyme, and both compounds significantly inhibit the interaction of spike protein and ACE2, while the main protease activity was not significantly reduced. Docking studies suggested that compounds 1 and 2 may bind to the ACE2 binding pocket on spike, and compound 2 may aka bind to an allosteric site on spike. As such, these compounds may inhibit the spike-ACE2 complex formation competitively and/or allosterically and have the potential to be used against SARS-CoV-2 virus infection. In addition, compounds 1 and 2 showed at [east two-fold higher cytotoxicity against breast cancer cell Lines MCF7 and MDA-MB-231 compared to the CCD fibroblast control cell Line

Multiple sclerosis (MS) treatment has received much attention, yet there is still no certain cure. We herein investigate the therapeutic effect of olean-12-en-28-ol, 3 beta- pentacosanoate (OPCA) on a preclinical model of MS. First, OPCA was synthesized semisynthetically and characterized. Then, the mice with MOG35-55-induced experimental autoimmune/ allergic encephalomyelitis (EAE) were given OPCA along with a reference drug (FTY720). Biochemical, cellular, and molecular analyses were performed in serum and brain tissues to measure anti-inflammatory and neuroprotective responses. OPCA treat-ment protected EAE-induced changes in mouse brains maintaining blood-brain barrier integrity and preventing inflammation. Moreover, the protein and mRNA levels of MS-related genes such as HLD-DR1, CCL5, TNF-alpha, IL6, and TGFB1 were significantly reduced in OPCA-treated mouse brains. Notably, the expression of genes, including PLP, MBP, and MAG, involved in the development and structure of myelin was significantly elevated in OPCA-treated EAE. Furthermore, therapeutic OPCA effects included a substantial reduction in pro-inflammatory cytokines in the serum of treated EAE animals. Lastly, following OPCA treatment, the promoter regions for most inflammatory reGülators were hypermethylated. These data support that OPCA is a valuable and appealing candidate for human MS treatment sİnce OPCA not only normalizes the pro-and anti-inflammatory immunological bias but also stimulates remyelination in EAE.

Multiple sclerosis (MS) is a common disease affecting about 2.9 million people worldwide. It is a chronic demyelinating autoimmune disease with a complex genetic background of unknown primary etiology. MS treatment has received much attention, yet there is still no certain cure. We herein investigate the potential therapeutic effect of a natural compound olean-12-en-28-ol, 3β pentacosanoate (OPCA) on the preclinical model of MS, i.e., EAE. First, OPCA was synthesized semi-synthetically and characterized. OPCA was also coupled with biotin to monitor the OPC in the cell and identify the proteins with which it interacts. Then, the mice with MOG35–55-induced EAE were given OPCA or vehicle, along with a reference drug (FTY720), and their clinical symptoms were monitored on a daily basis. Biochemical, cellular, and molecular analyses were performed in serum and brain tissues to measure anti-inflammatory and neuroprotective responses. To detect and localize the molecular targets of the OPC within the cell, biotin-streptavidin pulldown and LC-MS/MS proteomics analysis and immunostaining studies were applied, respectively.The purity and the structure of the OPCA were confirmed with NMR and MS analyses. OPCA treatment protected EAE-induced changes in mice-s brains, maintaining blood-brain barrier integrity and preventing inflammation. Bain levels of inflammatory infiltrating cells were consistently and significantly reduced in OPCA-treated EAE mice. Moreover, the protein and mRNA levels of MS-associated genes such as HLD-DR1, CCL5, TNFA, IL6, and TGFB1 were significantly reduced in OPCA-treated mice. Notably, expression of genes including PLP, MBP, and MAG involved in the development and structure of myelin was significantly elevated in OPCA-treated EAE but was not observed with the reference drug. Furthermore, therapeutic OPCA effects included a substantial reduction in pro-inflammatory cytokines in the serum of treated EAE animals. Lastly, following OPCA treatment, the CpG island of the promoter regions for the majority of inflammatory regulators was hypermethylated. It was found that biotinylated OPC is localized in the cell, especially in the ER in close vicinity to the nucleus and the ribosomes, on which were located. Several proteins were identified with proteomics to be the target of the OPCA, but studies are still underway to confirm. These data show that OPCA ameliorates brain abnormalities in EAE mice. It supports the hypothesis that OPCA is a valuable multitargeting molecule for treating the disease and is an appealing candidate for human MS treatment since OPCA not only normalizes the pro- and anti-inflammatory immunological bias but also stimulates remyelination in EAE via targeting proteins expressed in ER.Keywords: Experimental Autoimmune Encephalomyelitis (EAE), Remyelination, Anti-Inflammatory, Multiple Sclerosis, Olean-12-En-28-Ol, 3β Pentacosanoate (OPCA), Cytokines, Proteomics

Ulcerative colitis (UC) is a chronic and inflammatory disorder of the gastrointestinal (GI) tract. UC usually worsens the daily life of the patient and may sometimes become mortal. There is no known remedy discovered against UC, yet. Rosmarinus officinalis consists of many flavonoids, phenolics, and terpenoids possessing various biological activities such as anti-inflammatory. For this reason, in the present study, anti-ulcerative colitis effect of ROME (Rosmarinus officinalis methanol extract) was investigated comprehensively by histopathological studies, a number of in vivo anti-inflammatory activities and several in vivo antioxidant activities, in addition to in vitro antioxidant activities and biochemical analyses. In addition, the toxic effects of ROME were examined. The results showed that ROME provided a significant healing effect against ulcerative colitis in rats. Both in vitro and in vivo assay results correlated with histopathological examinations. ROME exhibited minimal toxic alterations. When the results of rosemary are compared with the results of sulfasalazine, it can be suggested that instead of synthetic drugs with side effects, natural sources can be used for the treatment of various diseases. Although some activities of rosemary have been investigated in vitro in the previous studies, this is the first study revealing anti-ulcerative colitis effect of rosemary through histopathological studies, in vivo and in vitro assays as well as biochemical analyses overall. PRACTICAL APPLICATIONS: The results revealed and proved that ROME provided a significant healing effect against ulcerative colitis in rats. When the results of rosemary are compared with the results of sulfasalazine, a commercially available drug on the market, it can be suggested that instead of synthetic drugs with side effects, natural sources can be used for the treatment of various inflammatory diseases such as UC disease. In addition, ROME possesses limited toxic alterations, but not much more than the commercial drug. As a future perspective, lethal and therapeutic doses can be examined and determined. Thus, human studies can be started through this comprehensive in vivo study on rosemary which is commonly used as an edible plant and spice all over the world.

Polygonaceae familyası, yaklaşık 48 cins ve 1200 tür ile temsil edilmektedir. ÜlkemizdePolygonumtürleri ile yapılan çalışmalar daha çok, Türkiye’de madımak olarak bilinenPolygonum cognatumMeissn. bitkisi üzerinedir1.Bu çalışmada ise endemikPolygonum sivasicumKit Tan &Yıldız(Sivas madımağı) türünün toprak üstü kısmından farklı ekstraksiyon yöntemleriyle elde edilen ekstrelerin antioksidan aktiviteleri metal bağlama ve CUPRAC yöntemleri, antiradikal aktiviteleri ise DPPH serbest radikal giderimi ve ABTS katyon radikali giderimi yöntemleriyle belirlendi.Diyetimizin bir parçası olarak, polifenoller birçok sağlık faydası ile bağırsakta sindirim sürecinden geçerek sindirim yoluyla dolaşıma katılmaktadır.Diyet polifenollerinin, insanlarda mide sağlığı açısından etkilerini anlamak için bu bileşenlerinin vitrobiyoerişilebilirlik çalışması ağız, mide ve bağırsakda sindirime uğratıldı. Sindirim öncesi ve sonrası fenolik bileşik profili LC-MS ile belirlendi, 27 bileşiğin tanımlandığı analizde rutin, hiperosit ve klorojenik asit majör fenolik bileşikler olarak belirlendi.

Caulerpaceae familyasına ait olanCaulerpa cylindraceaSonder yeşil bir deniz yosunudur. Gelibolu yarımadası kıyılarından SCUBA dalışlatoplananCaulerpacylindracea-nın builk kimyasal araştırması ile caulerpin1, mono metil caulerpinat2, beta-sitosterol ve palmitik asit izole edildi. İzole edilen bileşiklerin kimyasal yapıları, 1D- ve 2D-NMR ve kütle spektroskopik analizlerle aydınlatıldı. Caulerpin ve mono metil caulerpinatınin vitroanti-viral aktivitesi, Spike proteini ve main proteaza (3CL) karşı incelendi. Bu çalışmanın bulguları, caulerpin ve mono metil caulerpinatın Spike ve ACE2 etkileşimini önemli ölçüde inhibe ettiğini ortaya koymaktadır. Ayrıca, izole edilen bileşiklerin sitotoksik aktivitesi, sağlıklı fibroblast hücre hattı CCD-1079Sk ve iki meme kanseri hücre hattı; MDA-MB-231 ve MCF-7’ye karşı incelendi.

Since ancient time, Salvia L. species have been commonly used to treat colds, bronchitis, tuberculosis, heart diseases, and menstrual and digestive disorders in traditional medicine all around the world. They have been also used as tea and spice. Studies indicated that diterpenes and triterpenes isolated from Salvia species possess various pharmacological and biological effects such as anti-inflammatory, antiviral, cytotoxic, antioxidant, and hepatotoxic activities. Flavones were also shown to have antimicrobial, antioxidant, and cytotoxic potentials. Salvia extracts also exhibit anti-Alzheimer, antiseptic, cardiovascular, antihypertensive, and antituberculous effects. To investigate the effects of 63 secondary metabolites from Salvia species on cell viability and apoptosis, Salvia secondary metabolites including 25 phenolics, 4 fatty acids, 19 abietane diterpenoids, 12 triterpenoids, and three steroids were examined on healthy cell line (PDF), breast cancer (MCF-7), and colon cancer (HT-29) cell lines using MTT method. In addition, the effects of rosmarinic acid, 6,7-dehydroroyleanone, acetyl royleanone, ferruginol, carnosic acid, carnosol, cryptotanshinone, beta-sitosterol, and ursolic acid on pro-apoptotic Bax and antiapoptotic Bcl-2 protein expression levels were investigated by Western Blot method. Practical applications Phenolic compounds (apigenin, chrysin, and luteolin) and diterpenes (especially dihydrotanshinone I, carnosic acid, and carnosol), and almost all of the triterpenes exhibited high toxic effects on healthy cell line. Cytotoxic effects of cryptotanshinone, 12-hydroxy abieta-1,3,5(10),8,11,13-hexaene, 12-demethylmulticauline, 6,7-dehydroroyleanone, acetyl royleanone, ferruginol, ursolic acid, and 3-acetyl lupeol were relatively higher than their toxic effects. Acetyl royleanone, 6,7-dehydroroyleanone, carnosic acid, and cryptotanshinone were found to have anticancer potential based on their modulating effects on the expression levels of Bax and Bcl-2 proteins which play important roles in the regulation of apoptosis. The results of the present study showed that acetyl royleanone, cryptotanshinone, 6,7-dehydroroyleanone, carnosic acid, and cryptotanshinone have potential to be used in the pharmaceutical industry.

Kılıç, Turgut (Balikesir Author), The genus Sideritis (Lamiaceae) is represented by 45 species (54 taxa) in Anatolia with high endemism ratio (74%), and Turkey is one of the gene centers of the genus along with Spain. Acetone extract of the aerial parts of Sideritis lycia afforded eight known ent-kaurene diterpenoids, structures of which have been identified as linearol, isolinearol, isosidol, sidol, siderol, sideridiol, 7-epi-candicandiol and foliol through 1H NMR, 13 C NMR and mass spectroscopic analyses. Cytotoxic and antiviral activities of the acetone extract, linearol, sidol and isosidol were investigated together with insecticidal activity of species. The antiviral index of linearol, isosidol and acetone extract of S. lycia were determined as 2.31, 2.01 and 2.58, respectively, except sidol. 7-Epi-candicandiol was found to be the most active diterpene against a series of cancer cell lines with ED50 values; KB (13.3 mu g/mL), COL-2 (11.8 mu g/mL), LU1 (17.9 mu g/mL), LNCaP (14.9 mu g/mL) and A2780 (9.0 mu g/mL). Activity results of this study indicated that ent-kaurane diterpenes have potential to be considered as antiviral and cytotoxic lead compounds.

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettre first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-kappa B, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.

PubMed: 31061621, Chloroform, ethyl acetate and methanol extracts from the aerial parts of Ferula caspica M. Bieb. were tested for their antioxidant capacities by CUPRAC, ABTS, FRAP, Folin-Ciocalteu and aluminum chloride methods and for antimicrobial activities by the broth microdilution method. Chloroform and ethyl acetate extracts showed the highest antioxidant capacity and antimicrobial activity. Three known sesquiterpene derivatives; 1-(2',4'-dihydroxyphenyl)-3,7,11-trimethyl-3-vinyl-6(E), 10-dodecadien-1-one (1), 2,3-dihydro-7-hydroxy-2,3-dimethyl-2-[4',8'-dimethyl-3',7'-nonadienyl]-furo[3,2,c]coumarin (2), 2,3-dihydro-7-hydroxy-2,3-dimethyl-3-[4',8'-dimethyl-3',7'-nonadienyl]-furo[3,2,c]coumarin(3); phenylpropanoid; laserine/2-epilaserine (4/5) and steroid mixtures; stigmasterol and beta-sitosterol (6/7) were isolated from chloroform extract; three known flavonoids; kaempferol-3-O-beta-glucopyranoside (8), kaempferol-3-O-alpha-rhamnopyranoside (9), quercetin-3-O-beta-glucopyranoside (10), and one benzoic acid derivative; 2,4-dihydroxybenzoic acid (11) were isolated from the ethyl acetate extract. The structures were elucidated by spectroscopic methods. (C) 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.

In this study the antioxidant and anticholinesterase activities of the crude ethanol extract, as well as the dichloromethane and water extracts obtained from partitioning of the crude ethanol extract, of the plant Salvia cassia Samuelss ex. Rech. Fil, were determined. The extracts were screened for their total phenolic and flavonoid contents. The dichloromethane extract, which showed higher inhibition of lipid peroxidation, higher metal chelating capacity and also a higher flavonoid content than the other extracts was analyzed for its constituents. GC-MS analysis resulted in the identification of a total of 30 long chain hydrocarbons. A series of b-amyrin fatty acid esters, a triterpene acid oleanolic acid, a diterpenoid manoyloxide, and two flavonoids apigenin 7, 4′-dimethyl ether and salvigenin were isolated by open column chromatography. Their structures were identified based on NMR and mass spectrometric techniques. The isolated compounds were also tested for their anticholinesterase activities. The triterpenoids as well as the water extract exhibited promising anticholinesterase activity.

In the current study, the ethanol extracts prepared from the aerial parts and roots of an endemicspecies, Salvia cerino-pruinosa Rech. f. var. cerino-pruinosa were fractionated on silica gel columns and testedfor determination of their antioxidant activity using DPPH free radical and ABTS cation radical scavenging, andcupric reducing antioxidant capacity (CUPRAC) test assays. Twenty known secondary metabolites were isolatedfrom the active antioxidant fractions; rosmarinic acid (1), chlorogenic acid (2), caffeic acid (3), 4-hydroxybenzoic acid (4), benzoic acid (5), luteolin 7-O-glucoside (6), bis-(2-ethylhexyl)benzene-1,2-dicarboxylate (7), salvianolic acid A (8), salvianolic acid B (9), 7-acetylroyleanone (10), 6,7-dehydroroyleanone(11), ferruginol (12), inuroyleanol (13), 12-hydroxy-6,7-secoabieta-8,11,13-triene-6,7-dial (14), ursolic acid(15), oleanolic acid (16), taraxasterol (17), lupenone (18), β-sitosterol (19), and stigmasterol (20). Rosmarinicacid, which was obtained from the aerial parts, was found to be the best antioxidant compound among theisolated secondary metabolites in DPPH free radical and ABTS cation radical scavenging, and CUPRAC assays(IC50: 1.20±0.04 μg/mL, IC50: 1.74±0.06 μg/mL, A0.5: 1.22±0.02 μg/mL, respectively). Chlorogenic and caffeicacids, luteolin 7-O-glucoside, salvianolic acids A and B, and inuroyleanol exhibited also high antioxidantactivity in the mentioned assays.

Aim The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS-1 cells and to study its effect on cell death with related mechanisms in vitro. Methods Polylactide-co-glycolide (PLGA) nano-micelles were used for preparation of esculetin nano-formulation (nano-esculetin). The cells were treated with nano-esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS-1 cells for both free and nano-esculetin formulations. Results About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow-release behaviour was observed during release studies. Nano-esculetin bearing 25, 50 and 100 μg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 μg esculetin bearing nano-formulation and its equivalent free esculetin. Conclusions The results revealed that esculetin is able to show its anti-tumor afficacy after loading to PLGA nano-micelles and nano-encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.

Dirmenci, Tuncay (Balikesir Author), The aerial parts of Satureja metastasiantha were hydrodistilled for 3 h using a Clevenger-type apparatus. The essential oils were analyzed by gas chromatography/flame ionization detector and gas chromatography/mass spectrometry, simultaneously, the main compounds of which were characterized as p-cymene (22.3%), thymol (21.0%), carvacrol (18.45%), and gamma-terpinene (12.1%). Antioxidant capacity, acetylcholinesterase and butyryl-cholinesterase inhibition effects, and antimicrobial and antifungal properties of the species were evaluated. The anticholinesterase activity of the essential oil of S. metastasiantha was observed with 30% inhibition at 200 mu g/mL. The essential oil of the species showed activity against Staphylococcus aureus with 128 mu g/mL minimum inhibitory concentration value.