[Show abstract][Hide abstract] ABSTRACT: Chronic inflammation has been implicated in the pathogenesis of various neurodegenerative diseases. During the neuroinflammatory process, microglial cells release neurotoxic and proinflammatory mediators. In the present study, using activity-guided fractionation, we have purified an anti-inflammatory compound determined by spectroscopic methods to be a sesquiterpene lactone named achillolide A from Achillea fragrantissima (Forsk.) Sch. Bip. In primary cultures of lipopolysaccharide-activated microglial cells, achillolide A inhibited the lipopolysaccharide-induced levels of proinflammatory and toxic mediators including glutamate, nitric oxide, matrix metalloproteinase-9, cyclooxygenase-2, induced nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α. Achillolide A also exhibited an antioxidant capacity, as was shown in a cell free system as well as by its ability to reduce intracellular reactive oxygen species levels in microglial cells. Thus, achillolide A might have therapeutic potential for treatment of neurodegenerative diseases and deserves further studies.
Georg Thieme Verlag KG Stuttgart · New York.
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is tightly involved in various neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, and conditions such as ischemia. Astrocytes, the most abundant glial cells in the brain, protect neurons from reactive oxygen species (ROS) and provide them with trophic support. Therefore, any damage to astrocytes will affect neuronal survival. In a previous study we have demonstrated that an extract prepared from the plant Achillea fragrantissima (Af) prevented the oxidative stress-induced death of astrocytes and attenuated the intracellular accumulation of ROS in astrocytes under oxidative stress. In the present study, using activity guided fractionation, we have purified from this plant the active compound, determined to be a flavonoid named 3,5,4'-trihydroxy-6,7,3'-trimethoxyflavone (TTF). The effects of TTF in any biological system have not been studied previously, and this is the first study to characterize the anti-oxidant and protective effects of this compound in the context of neurodegenerative diseases. Using primary cultures of astrocytes we have found that TTF prevented the hydrogen peroxide (H2O2)-induced death of astrocytes, and attenuated the intracellular accumulation of ROS following treatment of these cells with H2O2 or the peroxyl radicals generating molecule 2,2'-Azobis(amidinopropane) (ABAP). TTF also interfered with cell signaling events and inhibited the phosphorylation of the signaling proteins stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), extracellular signal regulated kinase (ERK 1/2) and mitogen activated protein kinase kinase (MEK1) and the phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB). The mechanism of the protective effect of TTF against H2O2 -cytotoxicity could not be attributed to a direct H2O2 scavenging but rather to the scavenging of free radicals as was shown in cell free systems. Thus, TTF might be a therapeutic candidate for the prevention/treatment of neurodegenerative diseases where oxidative stress is part of the pathophysiology.
Neurochemistry International 09/2014; 78. DOI:10.1016/j.neuint.2014.09.003 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two-step synthesis of coumestrol involved a modified aerobic oxidative cross-coupling between ethyl 2-(2,4-dimethoxybenzoyl)acetate and 3-methoxyphenol, with FeCl3 (10 mol %) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59 % overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER)-dependent MCF-7 and of the ER-independent MDA-MB-231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9-hydroxyl group of coumestrol were discovered. Both 9-acetamido-coumestrol and 8-acetamidocoumestrol were found more active than the natural product against estrogen-dependent MCF-7 breast cancer cells, with IC50 values of 30 and 9 nM, respectively.
Chemistry - A European Journal 03/2014; 19(40). DOI:10.1002/chem.201300389 · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is involved in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Astrocytes, the most abundant glial cells in the brain, protect neurons from reactive oxygen species (ROS) and provide them with trophic support, such as glial-derived neurotrophic factor (GDNF). Thus, any damage to astrocytes will affect neuronal survival. In the present study, by activity-guided fractionation, we have purified from the desert plant Pulicaria incisa two protective compounds and determined their structures by spectroscopic methods. The compounds were found to be new chalcones-pulichalconoid B and pulichalconoid C. This is the first study to characterize the antioxidant and protective effects of these compounds in any biological system. Using primary cultures of astrocytes, we have found that pulichalconoid B attenuated the accumulation of ROS following treatment of these cells with hydrogen peroxide by 89% and prevented 89% of the H2O2-induced death of astrocytes. Pulichalconoid B exhibited an antioxidant effect both in vitro and in the cellular antioxidant assay in astrocytes and microglial cells. Pulichalconoid B also caused a fourfold increase in GDNF transcription in these cells. Thus, this chalcone deserves further studies in order to evaluate if beneficial therapeutic effect exists.
Oxidative Medicine and Cellular Longevity 08/2013; 2013(3):694398. DOI:10.1155/2013/694398 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is involved in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Astrocytes, the most abundant glial cells in the brain, protect neurons from reactive oxygen species (ROS) and provide them with trophic support, such as glial-derived neurotrophic factor (GDNF). Thus, any damage to astrocytes will affect neuronal survival. In the present study, by activity-guided fractionation, we have purified from the desert plant Pulicaria incisa two protective compounds and determined their structures by spectroscopic methods. The compounds were found to be new chalcones—pulichalconoid B and pulichalconoid C. This is the first study to characterize the antioxidant and protective effects of these compounds in any biological system. Using primary cultures of astrocytes, we have found that pulichalconoid B attenuated the accumulation of ROS following treatment of these cells with hydrogen peroxide by 89% and prevented 89% of the H 2 O 2 -induced death of astrocytes. Pulichalconoid B exhibited an antioxidant effect both in vitro and in the cellular antioxidant assay in astrocytes and microglial cells. Pulichalconoid B also caused a fourfold increase in GDNF transcription in these cells. Thus, this chalcone deserves further studies in order to evaluate if beneficial therapeutic effect exists.
[Show abstract][Hide abstract] ABSTRACT: The rapidly increasing incidence of diabetes mellitus is becoming a serious threat to mankind's health in all parts of the world. In fact, known cases reflect only part of the problem, as many diabetics, especially with type 2 diabetes, are unaware of their disease, which initially shows no definitive symptoms. Despite the great efforts invested in diabetes research, its prevalence continues to grow, while current medications do not cover all of the symptoms and complications of the disease. The present review highlights a plethora of studies focusing on the antidiabetic properties of desert and semidesert (steppic) plants, many of them being used for centuries in traditional medicine by Bedouins living in the arid zones of the Middle East and also by ethnic groups in other arid and semiarid parts of the world. The review concludes in summarizing the work done on the subject and also in pointing to the yet existing gaps in diabetes research of desert and steppic plants, and suggests directions for future exploration.
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is involved in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Astrocytes, the most abundant glial cells in the brain, protect neurons from reactive oxygen species (ROS) and provide them with trophic support, such as glial-derived neurotrophic factor (GDNF). Thus, any damage to astrocytes will affect neuronal survival. In the present study, an infusion prepared from the desert plant Pulicaria incisa (Pi) was tested for its protective and antioxidant effects on astrocytes subjected to oxidative stress. The Pi infusion attenuated the intracellular accumulation of ROS following treatment with hydrogen peroxide and zinc and prevented the H(2)O(2)-induced death of astrocytes. The Pi infusion also exhibited an antioxidant effect in vitro and induced GDNF transcription in astrocytes. It is proposed that this Pi infusion be further evaluated for use as a functional beverage for the prevention and/or treatment of brain injuries and neurodegenerative diseases in which oxidative stress plays a role.
Oxidative Medicine and Cellular Longevity 12/2012; 2012(3):157598. DOI:10.1155/2012/157598 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aloe is a genus of medicinal plants with a notable history of medical use. Basic research over the past couple of decades has begun to reveal the extent of Aloe's pharmaceutical potential, particularly against neoplastic disease. This review looks at Aloe, both the genus and the folk medicine, often being called informally "aloes", and delineates their chemistry and anticancer pharmacognosy. Structures of key compounds are provided, and their pharmacological activities reviewed. Particular attention is given to their free radical scavenging, antiproliferative, and immunostimulatory properties. This review highlights major research directions on aloes, reflecting the enormous potential of natural sources, and of the genus Aloe in particular, in preventing and treating cancer.
[Show abstract][Hide abstract] ABSTRACT: Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage.
The American Journal of Human Genetics 04/2012; 90(5):893-9. DOI:10.1016/j.ajhg.2012.03.022 · 10.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The biblical balm of Gilead (Commiphora gileadensis) was investigated in this study for anticancerous activity against tumor cell lines. The results obtained from ethanol-based extracts and from essential oils indicated that β-caryophyllene (trans-(1R,9S)-8-methylene-4,11,11-trimethylbicyclo[7.2.0]undec-4-ene) is a key component in essential oils extracted from the balm of Gilead. β-Caryophyllene can be found in spice blends, citrus flavors, soaps, detergents, creams, and lotions, as well as in a variety of food and beverage products, and it is known for its anti-inflammatory, local anaesthetic, and antifungal properties. It is also a potent cytotoxic compound over a wide range of cell lines. In the current paper, we found that Commiphora gileadensis stem extracts and essential oil have an antiproliferative proapoptotic effect against tumor cells and not against normal cells. β-caryophyllene caused a potent induction of apoptosis accompanied by DNA ladder and caspase-3 catalytic activity in tumor cell lines. In summary, we showed that C. gileadensis stems contain an apoptosis inducer that acts, in a selective manner, against tumor cell lines and not against normal cells.
Evidence-based Complementary and Alternative Medicine 04/2012; 2012:872394. DOI:10.1155/2012/872394 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The neuroinflammatory process plays a central role in the initiation and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, and involves the activation of brain microglial cells. During the neuroinflammatory process, microglial cells release proinflammatory mediators such as cytokines, matrix metalloproteinases (MMP), Reactive oxygen species (ROS) and nitric oxide (NO). In the present study, extracts from 66 different desert plants were tested for their effect on lipopolysaccharide (LPS) - induced production of NO by primary microglial cells. The extract of Achillea fragrantissima (Af), which is a desert plant that has been used for many years in traditional medicine for the treatment of various diseases, was the most efficient extract, and was further studied for additional anti-neuroinflammatory effects in these cells.
In the present study, the ethanolic extract prepared from Af was tested for its anti-inflammatory effects on lipopolysaccharide (LPS)-activated primary cultures of brain microglial cells. The levels of the proinflammatory cytokines interleukin1β (IL-1β) and tumor necrosis factor-α (TNFα) secreted by the cells were determined by reverse transcriptase-PCR and Enzyme-linked immunosorbent assay (ELISA), respectively. NO levels secreted by the activate cells were measured using Griess reagent, ROS levels were measured by 2'7'-dichlorofluorescein diacetate (DCF-DA), MMP-9 activity was measured using gel zymography, and the protein levels of the proinflammatory enzymes cyclooxygenase-2 (COX-2) and induced nitric oxide synthase (iNOS) were measured by Western blot analysis. Cell viability was assessed using Lactate dehydrogenase (LDH) activity in the media conditioned by the cells or by the crystal violet cell staining.
We have found that out of the 66 desert plants tested, the extract of Af was the most efficient extract and inhibited ~70% of the NO produced by the LPS-activated microglial cells, without affecting cell viability. In addition, this extract inhibited the LPS - elicited expression of the proinflammatory mediators IL-1β, TNFα, MMP-9, COX-2 and iNOS in these cells.
Thus, phytochemicals present in the Af extract could be beneficial in preventing/treating neurodegenerative diseases in which neuroinflammation is part of the pathophysiology.
BMC Complementary and Alternative Medicine 10/2011; 11:98. DOI:10.1186/1472-6882-11-98 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autosomal-recessive high-grade axial myopia was diagnosed in Bedouin Israeli consanguineous kindred. Some affected individuals also had variable expressivity of early-onset cataracts, peripheral vitreo-retinal degeneration, and secondary sight loss due to severe retinal detachments. Through genome-wide linkage analysis, the disease-associated gene was mapped to ∼1.7 Mb on chromosome 3q28 (the maximum LOD score was 11.5 at θ = 0 for marker D3S1314). Sequencing of the entire coding regions and intron-exon boundaries of the six genes within the defined locus identified a single mutation (c.1523G>T) in exon 10 of LEPREL1, encoding prolyl 3-hydroxylase 2 (P3H2), a 2-oxoglutarate-dependent dioxygenase that hydroxylates collagens. The mutation affects a glycine that is conserved within P3H isozymes. Analysis of wild-type and p.Gly508Val (c.1523G>T) mutant recombinant P3H2 polypeptides expressed in insect cells showed that the mutation led to complete inactivation of P3H2.
The American Journal of Human Genetics 09/2011; 89(3):438-45. DOI:10.1016/j.ajhg.2011.08.003 · 10.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: α-Hederin, a natural triterpene saponin and its derivative kalopanaxsaponin I (ksI) exhibit cytotoxicity against various cancer cell lines and IN VIVO tumors. We studied the genetic variants contributing to the activity of these two anticancer compounds. Cell lines derived from 30 trios of European descent (Centre d'Etude du Polymorphisme Human, CEPH; CEU) and 30 trios of African descent (Yoruban, YRI) were used. Cytotoxicity was determined as inhibition of cell growth at increasing concentrations of α-hederin or ksI for 24 h. In comparison to the European, the Yoruban populations revealed a higher sensitivity to α-hederin and to ksI that can be attributed to several unique SNPs. These SNPs are located near 111 and 130 genes in the European and the Yoruban populations, respectively, raising the possibility that some of these genes contribute to the differential sensitivity to these compounds.
[Show abstract][Hide abstract] ABSTRACT: The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans.
The American Journal of Human Genetics 10/2010; 87(4):538-44. DOI:10.1016/j.ajhg.2010.09.007 · 10.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO₂ hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).
The American Journal of Human Genetics 10/2010; 87(5):713-20. DOI:10.1016/j.ajhg.2010.10.008 · 10.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibacterial and antiparasitic agents and a cysteine protease inhibitor (E-64) were tested against Tetrahymena infection, a serious problem in guppy production worldwide. Chemicals were tested in vitro by a colorimetric assay for Tetrahymena survival. The most effective were niclosamide, albendazole and chloroquine, with 23%, 35% and 60% survival, respectively, following 2-h exposure to 100 ppm. Longer incubation periods resulted in greater reductions in survival. Niclosamide was further studied in vivo at different dosages, administered orally to Tetrahymena-infected guppies. Mortality rates were significantly lower in all treatment groups; in trial I, 30% and 33% mortality in 5 and 40 mg kg(-1) niclosamide-fed fish vs. 59% mortality in controls; in trial II, 35%, 13% and 10% in 50, 100 and 200 mg kg(-1) niclosamide-fed fish vs. 64% in controls. The effect of the cysteine protease inhibitor E64 was tested in tissue culture, by measuring histolytic activity of the parasite (Tet-NI) on a guppy-fin cell line, based on cell depletion. Tet-NI feeding activity was significantly reduced following pretreatment with E-64 relative to non-treated Tet-NI. E-64-pretreated Tet-NI was injected i.p. into guppies: recorded mortality rates were significantly lower (35%) than that in non-treated Tet-NI (60%), suggesting inhibition of the parasite's cysteine protease as a possible therapeutic approach.
Journal of Fish Diseases 03/2010; 33(6):473-80. DOI:10.1111/j.1365-2761.2010.01143.x · 1.51 Impact Factor