The antileukemic effects of saffron (Crocus sativus L.) and its related molecular targets: A mini review

Saffron (Crocus sativus L.), and its main constituents, crocin, and crocetin have shown promising effects as an antileukemic agent in animal models and cell culture systems. Saffron retards the growth of cancer cells via inhibiting nucleic acid synthesis and enhancing antioxidative system. It can induce apoptosis and chemosensitivity via inhibiting multidrug resistance proteins. Saffron also induces differentiation pathways via inhibiting promyelocytic leukemia/retinoic acid receptor-α, histone deacetylase1, and tyrosyl DNA phosphodiesterase-1 as well. The present review highlights the most recent findings on the antileukemic effects of saffron and its underlying molecular targets. The emerging evidence suggests that saffron has a selective toxicity effect against leukemic cells while is safe for the normal cells.     

Saffron (Crocus sativus) in the treatment of gastrointestinal cancers: Current findings and potential mechanisms of action

Gastrointestinal (GI) cancers are major causes of cancer-related mortality worldwide and include malignancies of the GI tract such as the stomach, liver, pancreas, small intestine, colon, and rectum. Promising and selective anticancer effects of pharmacologically active components of saffron (Crocus sativus L.) have been shown in preclinical in vitro and in vivo studies. Saffron and its active components including crocin, crocetin, and safranal exert their anticancer effects through different mechanisms, including induction of apoptosis, influence on the cell cycle, and regulation of host immune response and anti-inflammatory activities. This review summarizes the recent literature on the chemopreventive properties of saffron in GI cancers to have a better understanding of the potential underlying mechanisms and hence the appropriate management of these malignancies.     

藏红花不同类型愈伤组织器官形态发生能力的差异

藏红花不同类型愈伤组织器官形态发生能力的差异杨永华郭子彪（南京大学生物科学与技术系,南京２１００９３）（南京农业大学农业与生命科学学院,南京２１００９５）萧凤（云南农业大学农业科学技术学院,昆明６５０２０１）Ｄｉｆｅｒｅｎｃｅｓｏｎｏｒｇａｎｏｇｅ...     

诱导子对藏红花悬浮培养细胞生产藏红花色素的影响

考察壳聚糖（chitosan）、壳寡糖（chitosanoligosaccharides,COS）、茉莉酸甲酯（methyljasmonate,MJ）、水杨酸（salicylicacid,SA）和Cu2＋等诱导子对藏红花悬浮培养细胞生长和藏红花色素合成的影响。结果表明：在实验考察浓度范围内,壳寡糖（1～500mg／L）和较低浓度壳聚糖（≤10mrdL）、MJ（≤10μmol／L）、SA（≤10μμmol／L）和Cu2＋（≤1μmoL／L）对细胞生长无显著影响;较高浓度壳聚糖（≥100mg／L）、MJ（≥100μmol／L）、SA（≥100μmoL／L）和cu“（≥10μmoL／L）显著抑制细胞生长。5种诱导子对藏红花色素合成的诱导效果不同,并且与诱导子作用浓度和添加时间有关。MJ诱导效果最好,在细胞培养第0天添加终浓度100仙moL／LMJ,藏红花色素含量（以1克干细胞计）达到28．57mg,比对照提高177．9％。其次是cu“,在细胞培养第4天添加终浓度500μmoL／LCu2＋,色素含量达到19．82mg,比对照提高108．2％。再次是壳聚糖和壳寡糖,在细胞培养第14天分别添加终质量浓度100mg／L壳聚糖和壳寡糖,色素含量分别达到18．33和17．39mg,比对照提高69．1％和69．0％。最后是SA,在细胞培养第14天添加终浓度10μmoL／LSA,色素含量达到14．65mg,比对照提高45．4％。     

Chemical and sensory analysis of saffron produced through tissue cultures of Crocus sativus

Stigma-like structures were produced in tissue cultures (TC stigmas) from the ovary explants of C. sativus on MS medium supplemented with NAA and BA. The size of these structures was 2 to 3 cm in length. At higher concentrations of both NAA (54 µM) and BA (44 µM) white tubular abnormal structures were observed from ovary explants in addition to the TC stigmas. Crocin and picrocrocin, responsible for colour and bitter taste respectively, were found to be 6 and 11 times lower in TC stigmas than in the natural stigmas. The saffron obtained from tissue cultures was subjected to sensory analysis and compared with the data obtained from chemical analysis. The sensory data indicated that the saffron pigments produced in tissue cultures were one tenth that of natural stigmas. Sensory profile test showed that the tissue culture saffron was low in floral, spicy and fatty characteristics as compared to saffron obtained from flowers. This is the first report on the sensory analysis of a spice produced in tissue cultures.Abbreviations BA benzyladenine - NAA naphthaleneacetic acid     

In vitro proliferation of saffron (Crocus sativus L.) stigma

Excised young intact stigmas plus ovaries of Crocus sativus L. were cultured on Linsmaier-Skoog media supplemented with either a cytokinin or an auxin alone or in combinations. Benzyladenine and kinetin at concentrations of 0.1, 1, and 5 mgl^-1 supported growth, and crocin was biosynthesized in the stigmas in vitro. Auxins had little effect. Young excised single stigmas or half ovaries were also cultured so as to form stigma-like structures in order to explore a possible new approach to industrial production of the spice, saffron. On Linsmaier-Skoog and Nitsch media supplemented with kinetin at concentration of 1 or 5 mgl^-1 and alpha-naphthalene acetic acid or indole-butyric acid at concentration of 0.1 or 10 mgl^-1 in combinations, stigma-like structures appeared directly and indirectly (through meristematic tissue), grew and matured. The maximum number of structures were 75 per half ovary. Three kinds of yellow pigments including crocin were tentatively identified by TLC in the stigma-like structures as was the case for the in vivo grown natural stigma, although the contents were lower.Abbreviations BA benzyladenine - 2,4-D 2,4-dichlorophenoxy-acetic acid - IAA indole-acetic acid - IBA indole-butyric acid - NAA alpha-naphthalene-acetic acid - TLC thin layer chromatography     

Preparation of monoclonal antibody against crocin and its characterization

Three crocin-carrier protein conjugates were synthesized and their hapten numbers were determined by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Three monoclonal antibodies against crocin were produced by hybridomas fused with the splenocytes immunized with crocin hemisuccinate-bovine serum albumin conjugate and HAT-sensitive mouse myeloma cell line, P3-X63-Ag8-653. They were identified as IgG2a and IgG2b possessing light chain, respectively. Their wide reactivities against crocetin glycosides were discussed.     

Molecular mechanisms by which aerobic exercise induces insulin sensitivity

Insulin resistance is a key feature of Type 2 diabetes and an important therapeutic target to address glycemic control to prevent diabetic complications. Lifestyle advice is the first step in the ADA/EASD consensus guidelines followed by metformin therapy. Aerobic exercise (AE) can increase insulin sensitivity by several molecular pathways including upregulation of insulin transporters in the cellular membrane of insulin-dependent cells. In addition, AE improves insulin sensitivity by amelioration of the pathophysiologic pathways involved in insulin resistance such as the reduction of adipokines, inflammatory and oxidative stress responses, and improvement of insulin signal transduction via different molecular pathways. This review details the molecular pathways by which AE induces beneficial effects on insulin resistance     

Ultrastructure of chromoplasts and other plastids in Crocus sativus L. (Iridaceae)

Saffron (Crocus sativus L. Iridaceae) chromoplasts and other plastids were studied by electron microscope to determine their structure, origin and pigment localization. Plastids from pistils of floral buds and flowers at anthesis, dried and decoloured stigmas, and green and senescent leaves were examined. Results indicated that mature saffron chromoplasts occur in the red parts of stigmas and have a reticulo-tubular structure. They contain a reticulum of tubules and plastoglobules. Tubules formed dilated vesicles mainly while plastoglobules appeared numerous and scattered on the whole chromoplast. Chromoplasts appeared in red stigma of very young floral buds. They originated from amyloplasts, the only plastids occurring in the colourless basal portion of style, as well as in the parenchyma of ovary and corm. Transition forms of plastid as amylo-chromoplast, occur in the yellow parts of stigma and style. Senescent leaves did not show plastids with structure similar to the chromoplast of red stigma. Red pigmented and scented stigmas might cooperate in saffron reproduction by attracting pollinator.     

Allozyme differentiation in four species of the Crocus cartwrightianus group and in cultivated saffron (Crocus sativus)

The genetic variability and divergence of four species of the genus Crocus L., related to Crocus cartwrightianus group, namely Crocus thomasii Ten., Crocus hadriaticus Herbert, Crocus oreocreticus B.L. Burtt, C. cartwrightianus Herbert, has been studied by means of starch gel isozyme electrophoresis. For each population the following enzymatic loci were analyzed: PGI-1, PGI-2, G6PDH-1, G6PDH-2, IDH-1, IDH-2, 6PGDH-1, 6PGDH-2, SKDH-1, SKDH-2, AK-1 and AK-2. The genetic variability was estimated through the parameters A (mean number of alleles per locus), P (percent of polymorphic loci), H_o (mean observed heterozygosity), and H_e (mean expected heterozygosity). The genetic differentiation has been assayed by Wrigth's F-statistics, and the genetic divergence by Nei's index. Our data confirmed that the taxa are distinct species, in spite of their similar morphology and karyology. C. thomasii is more genetically similar to C. cartwrightianus and C. oreocreticus than to C. hadriaticus. We hypothesized an autopolyploid origin of saffron, probably from C. cartwrightianus, considering the genotypic classes of Crocus sativus and the other related species of the C. cartwrightianus group studied here.     

Fibrillation of α‐lactalbumin: Effect of crocin and safranal,two natural small molecules from Crocus sativus

Formation of toxic amyloid structures is believed to be associated with various late‐onset neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The fact that many proteins in addition to those that are associated with clinical conditions have the potential to form amyloid fibrils in vitro provides opportunities for studying the fundamentals of protein aggregation and amyloid formation in model systems. Accordingly, considerable interest and effort has been directed toward developing small molecules to inhibit the formation of fibrillar assemblies and their associated toxicities. In the present study, we investigated the inhibitory effect of crocin and safranal, two principal components of saffron, on fibrillation of apo‐α‐lactalbumin (a‐α‐LA), used as a model protein, under amyloidogenic conditions. In the absence of any ligand, formation of soluble oligomers became evident after 18 h of incubation, followed by subsequent appearance of mature fibrils. Upon incubation with crocin or safranal, while transition phase to monomeric beta structures was not significantly affected, formation of soluble oligomers and following fibrillar assemblies were inhibited. While both safranal and crocin had the ability to bind to hydrophobic patches provided in the intermediate structures, and thereby inhibit protein aggregation, crocin was found more effective, possibly due to its simultaneous hydrophobic and hydrophilic character. Cell viability assay indicated that crocin could diminish toxicity while safranal act in reverse order. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 854–865, 2010.     

Effects of crocin in reducing DNA damage,inflammation, and oxidative stress in multiple sclerosis patients: A double‐blind,randomized, and placebo‐controlled trial

Multiple sclerosis (MS) is an autoimmune disease in which the immune system attacks the nerve cells, resulting in neurological disorders. Oxidative stress, free radicals, and neuritis have important roles in MS pathogenesis. Here, we aim to evaluate the effect of crocin on inflammatory markers, oxidative damage, and deoxyribonucleic acid (DNA) damage in the blood of patients with MS. A total of 40 patients were divided into two groups, drug and placebo‐treated groups, using random assignment. Participants of the intervention and control groups received two crocin capsules or placebo per day for 28 days, respectively. Findings revealed a significant decrease in the level of important pathogenic factors in MS, including lipid peroxidation, DNA damage, tumor necrosis factor‐alpha, and interleukin 17 as well as a significant increase in the total antioxidant capacity in the serum of patients treated with crocin compared with the placebo group. Our results suggest the beneficial and therapeutic effects of crocin in MS.     

西红花水提物对实验性糖尿病小鼠血糖水平的影响

目的：观察西红花水提物对链脲佐菌素（STZ）诱导的糖尿病小鼠血糖、血脂及胰腺组织的影响。方法：采用STZ （60 mg/kg）连续2 d腹腔注射建立糖尿病小鼠模型。将造模成功后的小鼠随机分为3组（n=10）：糖尿病模型（DM）组、西红花水提物（SE）组、阳性对照二甲双胍（MH）组。另取10只正常小鼠设为正常对照（NC）组。给药组每天灌胃1次,连续6周,模型组和正常对照组灌胃生理盐水。给药期间每周测定小鼠进食量、饮水量及体重,给药6周后测定空腹血糖（FBG）、口服糖耐量（OGTT）、糖化血清蛋白（GSP）、血清胰岛素（INS）和血脂等指标的变化情况;HE染色观察胰腺组织病理变化。结果：与NC组相比,DM组进食量、饮水量、线下曲线面积、FBG、GSP以及血脂中的总胆固醇（TC）均显著升高,空腹体重、血清胰岛素（INS）及高密度脂蛋白胆固醇（HDL-c）均显著降低;与DM组相比,SE组小鼠饮水量、FBG、线下曲线面积、TC显著降低,HDL-c以及INS显著升高。病理学显示DM组胰岛结构破坏、胰岛细胞数量明显减少、胰岛血管增生、形态不规则等变化,SE能明显修复受损胰腺组织。结论：SE对链脲佐菌素诱导的糖尿病小鼠有一定降血糖、降血脂作用,可以有效改善胰腺病变的情况,提示西红花可能用于糖尿病的防治。     

Bioactive compounds of Crocus sativus L. and their semi-synthetic derivatives as promising anti-Helicobacter pylori,anti-malarial and anti-leishmanial agents

Abstract

Crocus sativus L. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties toward Helicobacter pylori, Plasmodium spp. and Leishmania spp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components in C. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the main H. pylori enzymes in order to unravel their putative mechanism of action.     

Fenofibrate and PBA prevent fatty acid-induced loss of adiponectin receptor and pAMPK in human hepatoma cells and in hepatitis C virus-induced steatosis

Adiponectin receptors play a key role in steatosis and inflammation; however, very little is known about regulation of adiponectin receptors in liver. Here, we examined the effects of palmitate loading, endoplasmic reticulum (ER) stress, and the hypolipidemic agent fenofibrate on adiponectin receptor R2 (AdipoR2) levels and AMP-activated protein kinase (AMPK) in human hepatoma Huh7 cells and in Huh.8 cells, a model of hepatitis C-induced steatosis. Palmitate treatment reduced AdipoR2 protein and basal AMPK phosphorylation in Huh7 cells. Fenofibrate treatment preserved AdipoR2 and phosphorylated AMPK (pAMPK) levels in palmitate-treated cells accompanied by reduced triglyceride (TG) accumulation and less activation of ER stress markers CCAAT/enhancer binding (C/EBPβ) and eukaryotic translation initiation factor 2 α. ER stress agents thapsigargin and tunicamycin suppressed AdipoR2 and pAMPK levels in Huh7 cells, while fenofibrate and the chemical chaperone 4-phenylbutyrate (PBA) prevented these changes. AdipoR2 levels were lower in Huh.8 cells and fenofibrate treatment increased AdipoR2 while reducing activation of c-Jun N-terminal kinase and C/EBPβ expression without changing TG levels. Taken together, these results suggest that fatty acids and ER stress reduce AdipoR2 protein and pAMPK levels, while fenofibrate and PBA might be important therapeutic agents to correct lipid- and ER stress-mediated loss of AdipoR2 and pAMPK associated with nonalcoholic steatohepatitis.     

Is Taurine Beneficial in Reducing Risk Factors for Diabetes Mellitus?

Taurine is a semiessential amino acid, and its deficiency is involved in retinal and cardiac degenerations. In recent years, it was found that diabetes mellitus (DM) is associated with taurine, and many in vivo experimental studies showed that taurine administration is able to reduce the alterations induced by DM in the retina, lens, and peripheral nerve, although its effects on diabetic kidney are dubious. Interestingly, long-term taurine supplementation reduces the mortality rate in diabetic rats. The mechanisms by which taurine exerts beneficial effects in DM are discussed below. Recently, it has been suggested that taurine deficiency may alter the endocrine pancreas "fetal programming," increasing the risk of insulin resistance in adult life. The bulk of experimental data suggests that taurine administration could be useful in the treatment of type 1 DM and in the prevention of insulin resistance.     

Oxidative stress associated to dysfunctional adipose tissue: a potential link between obesity,type 2 diabetes mellitus and breast cancer

Abstract

Diabetes mellitus and breast cancer are two important health problems. Type 2 diabetes (T2DM) and obesity are closely linked with both being associated with breast cancer. Despite abundant epidemiological data, there is no definitive evidence regarding the mechanisms responsible for this association. The proposed mechanisms by which diabetes affects breast cancer risk and prognosis are the same as the mechanisms hypothesised for the contribution of obesity to breast cancer risk. The obesity-induced inflammation promoted by adipose tissue dysfunction is a key feature, which is thought to be an important link between obesity and cancer. Inflammation induces an increase in free radicals and subsequently promotes oxidative stress, which may create a microenvironment favourable to the tumor development in obese persons. Oxidative stress is also proposed as the link between obesity and diabetes mellitus. Therefore, obesity-related oxidative stress could be a direct cause of neoplastic transformation associated with obesity and T2DM in breast cancer cells. This review is focused on the role of obesity-related oxidative stress in the context of chronic inflammation, on the time of breast cancer onset and progression, which provide targets for preventive and therapeutic strategies in the fields of diabetes and obesity-related breast cancer.     

A review of the chemistry and uses of crocins and crocetin,the carotenoid natural dyes in saffron,with particular emphasis on applications as colorants including their use as biological stains

The perennial flowering plant, saffron crocus (Crocus sativus L.), is the source of the most expensive spice in the world. The dried stigmas of saffron flowers are the source of a natural dye, saffron, which has been used from ancient times for dyeing silk and fabric rugs, and for painting; it also has been used for cooking and in medicine. The yellow compounds present in the dye include crocins, which are 20-carbon water soluble glycosyl derivatives of the carotenoid, crocetin, and the dicarboxylic acid itself. We review the chemistry of these compounds and discuss various applications of saffron as a natural dye. We review in particular the use of saffron or its constituents in histopathologic techniques.     

Ebselen enhances insulin sensitivity and decreases oxidative stress by inhibiting SHIP2 and protects from inflammation in diabetic mice

Ebselen, a multifunctional organoselenium compound, has been recognized as a potential treatment for diabetes-related disorders. However, the underlying mechanisms whereby ebselen regulates metabolic pathways remain elusive. We discovered that ebselen inhibits lipid phosphatase SHIP2 (Src homology 2 domain-containing inositol-5-phosphatase 2), an emerging drug target to ameliorate insulin resistance in diabetes. We found that ebselen directly binds to and inhibits the catalytic activity of the recombinant SHIP2 phosphatase domain and SHIP2 in cultured cells, the skeletal muscle and liver of the diabetic db/db mice, and the liver of the SHIP2 overexpressing (SHIP2-Tg) mice. Ebselen increased insulin-induced Akt phosphorylation in cultured myotubes, enhanced insulin sensitivity and protected liver tissue from lipid peroxidation and inflammation in the db/db mice, and improved glucose tolerance more efficiently than metformin in the SHIP2-Tg mice. SHIP2 overexpression abrogated the ability of ebselen to induce glucose uptake and reduce ROS production in myotubes and blunted the effect of ebselen to inhibit SHIP2 in the skeletal muscle of the SHIP2-Tg mice. Our data reveal ebselen as a potent SHIP2 inhibitor and demonstrate that the ability of ebselen to ameliorate insulin resistance and act as an antioxidant is at least in part mediated by the reduction of SHIP2 activity.