Review Special Issues

D-pinitol, a highly valuable product from carob pods: Health-promoting effects and metabolic pathways of this natural super-food ingredient and its derivatives

  • Correction on: AIMS Agriculture and Food 6: 752-753
  • Received: 12 December 2017 Accepted: 05 February 2018 Published: 27 February 2018
  • D-pinitol is a natural compound related to the important family of inositols. It can be found and isolated from many plants, being the active component of ayurvedic remedies such as Talisa patra (Abies webbiana, A. pindrow) or antidiabetic as Bougainvillea (Bougainvillea spectabilis). Although many synthetic and semi-synthetic methods have been reported for D-pinitol and its derivatives, through chemical and biochemical transformations, Ceratonia siliqua L. (Carob), a Mediterranean tree now in decline, known because of its environmental advantages, is the only raw material from which D-pinitol can be isolated in quantities enough for a viable commercial exploitation. Fortunately, the pharmacological interest in this compound has risen enormously in the last years owing to their established multifunctional properties through a variety of signalling pathways: ⅰ) anti-cancer, through inhibition of TNF-ᾳ and suppression of NF-ⱪB pathway; ⅱ) insulinomimetic and metabolic regulator in type 2 diabetes mellitus, via a post-receptor pathway of insulin action; ⅲ) antioxidant; ⅳ) hepatoprotective; ⅴ) immuno-modulator, balancing Th1/Th2 cytokines; ⅵ) osteoporosis preventive, through p38/JNK and NF-ⱪB pathways; ⅶ) anti-aging, via reduction of the insulin/IGF-1 signaling (IIS) pathway; ⅷ) improver of creatine retention; ⅸ) preventive and ameliorative of Alzheimer's disease through selective g-secretase modulation.

    Thus, the present review compress the literature reported to date in relation to the health-promoting effects and metabolic pathways of this naturally occurring super-food ingredient and its derivatives, providing an extensive guide for a future utilization of all of its potentialities, aiming a positive impact in the promotion and recovery of carob crops.

    Citation: JoséIgnacio López-Sánchez, Diego A. Moreno, Cristina García-Viguer. D-pinitol, a highly valuable product from carob pods: Health-promoting effects and metabolic pathways of this natural super-food ingredient and its derivatives[J]. AIMS Agriculture and Food, 2018, 3(1): 41-63. doi: 10.3934/agrfood.2018.1.41

    Related Papers:

    [1] José Ignacio López-Sánchez, Diego A. Moreno, Cristina García-Viguera . Correction: D-pinitol, a highly valuable product from carob pods: Health-promoting effects and metabolic pathways of this natural super-food ingredient and its derivatives. AIMS Agriculture and Food, 2021, 6(2): 752-753. doi: 10.3934/agrfood.2021044
    [2] Alexandros Tsoupras, Eirini A. Panagopoulou, George Z. Kyzas . Anti-inflammatory, antithrombotic and anti-oxidant bioactives of beer and brewery by-products, as ingredients of bio-functional foods, nutraceuticals, cosmetics, cosmeceuticals and pharmaceuticals with health promoting properties. AIMS Agriculture and Food, 2024, 9(2): 568-606. doi: 10.3934/agrfood.2024032
    [3] Anna Chizhayeva, Yelena Oleinikova, Margarita Saubenova, Amankeldy Sadanov, Alma Amangeldi, Aida Aitzhanova, Aigul Alybaeva, Makpal Yelubaeva . Impact of probiotics and their metabolites in enhancement the functional properties of whey-based beverages. AIMS Agriculture and Food, 2020, 5(3): 521-542. doi: 10.3934/agrfood.2020.3.521
    [4] Asma Hussain Alkatheri, Mahra Saleh Alkatheeri, Wan-Hee Cheng, Warren Thomas, Kok-Song Lai, Swee-Hua Erin Lim . Innovations in extractable compounds from date seeds: Farms to future. AIMS Agriculture and Food, 2024, 9(1): 256-281. doi: 10.3934/agrfood.2024016
    [5] Alexandros Tsoupras, Eirini Panagopoulou, George Z. Kyzas . Olive pomace bioactives for functional foods and cosmetics. AIMS Agriculture and Food, 2024, 9(3): 743-766. doi: 10.3934/agrfood.2024040
    [6] Andrea Ertani, Ornella Francioso, Serenella Nardi . Mini review: fruit residues as plant biostimulants for bio-based product recovery. AIMS Agriculture and Food, 2017, 2(3): 251-257. doi: 10.3934/agrfood.2017.3.251
    [7] Anthony Temitope Idowu, Oluwakemi Osarumwense Igiehon, Ademola Ezekiel Adekoya, Solomon Idowu . Dates palm fruits: A review of their nutritional components, bioactivities and functional food applications. AIMS Agriculture and Food, 2020, 5(4): 734-755. doi: 10.3934/agrfood.2020.4.734
    [8] Seyyed Abbas Hashemi, Sayeh Ghorbanoghli, Ali Asghar Manouchehri, Mahdi Babaei Hatkehlouei . Pharmacological effect of Allium sativum on coagulation, blood pressure, diabetic nephropathy, neurological disorders, spermatogenesis, antibacterial effects. AIMS Agriculture and Food, 2019, 4(2): 386-398. doi: 10.3934/agrfood.2019.2.386
    [9] Thi Thuy Le, Trung Kien Nguyen, Nu Minh Nguyet Ton, Thi Thu Tra Tran, Van Viet Man Le . Quality of cookies supplemented with various levels of turmeric by-product powder. AIMS Agriculture and Food, 2024, 9(1): 209-219. doi: 10.3934/agrfood.2024012
    [10] Orbe Chamorro Mayra, Luis- Armando Manosalvas-Quiroz, Nicolás Pinto Mosquera, Iván Samaniego . Effect of fermentation parameters on the antioxidant activity of Ecuadorian cocoa (Theobroma cacao L.). AIMS Agriculture and Food, 2024, 9(3): 872-886. doi: 10.3934/agrfood.2024047
  • D-pinitol is a natural compound related to the important family of inositols. It can be found and isolated from many plants, being the active component of ayurvedic remedies such as Talisa patra (Abies webbiana, A. pindrow) or antidiabetic as Bougainvillea (Bougainvillea spectabilis). Although many synthetic and semi-synthetic methods have been reported for D-pinitol and its derivatives, through chemical and biochemical transformations, Ceratonia siliqua L. (Carob), a Mediterranean tree now in decline, known because of its environmental advantages, is the only raw material from which D-pinitol can be isolated in quantities enough for a viable commercial exploitation. Fortunately, the pharmacological interest in this compound has risen enormously in the last years owing to their established multifunctional properties through a variety of signalling pathways: ⅰ) anti-cancer, through inhibition of TNF-ᾳ and suppression of NF-ⱪB pathway; ⅱ) insulinomimetic and metabolic regulator in type 2 diabetes mellitus, via a post-receptor pathway of insulin action; ⅲ) antioxidant; ⅳ) hepatoprotective; ⅴ) immuno-modulator, balancing Th1/Th2 cytokines; ⅵ) osteoporosis preventive, through p38/JNK and NF-ⱪB pathways; ⅶ) anti-aging, via reduction of the insulin/IGF-1 signaling (IIS) pathway; ⅷ) improver of creatine retention; ⅸ) preventive and ameliorative of Alzheimer's disease through selective g-secretase modulation.

    Thus, the present review compress the literature reported to date in relation to the health-promoting effects and metabolic pathways of this naturally occurring super-food ingredient and its derivatives, providing an extensive guide for a future utilization of all of its potentialities, aiming a positive impact in the promotion and recovery of carob crops.



    1. Structure and properties


    1.1. Structure

    D-pinitol (Figure 1) is a natural compound, whose name etymologically derives from "pine", as it was first isolated and structurally characterized from the pine tree. D-pinitol is a member of the methylated inositol family (cyclitols), that are cyclohexane-1, 2, 3, 4, 5, 6-hexaols existing as nine isomers according to the different configurations of the hydroxyl groups. However, only 5 inositols are naturally occurring: myo-, chiro-, scyllo-, muco-, neo-inositol [1]. More specifically, D-pinitol is the 3-O-methyl ether of D-chiro-inositol [2], that is to say the (1R, 2S, 3R, 4S, 5S, 6S)-6-methoxycyclohexane-1, 2, 3, 4, 5-pentaol [3,4,5,6,7,8].

    Figure 1. D-pinitol.

    1.2. Physico-chemical properties

    D-pinitol exists as a white to off-white solid with a melting point of 186–187 ºC [9]. This compound is very soluble in water and slightly soluble in ethanol. Its specific rotation in water is [ᾳ]D = + 65º (c 0.4, H2O) [9,10]; [ᾳ]D = + 67º (c 0.30, H2O). Spectroscopic data have been reported previously [8,11]. Comprehensive characterization of D-Pinitol and cyclitols in general, with information about the sample preparation, extraction, purification and analytic methods can be revised in Al-Suod et al. [12] and references therein.


    2. Sources


    2.1. Natural abundance

    D-pinitol and cyclitols as a group can be commonly found in most plants [12,13,14]. However, members of the Leguminosae family are the major natural source of this compound [11,13,15,16]. Within them, Ceratonia siliqua L. (Carob), an evergreen tree that contains much higher amounts of D-pinitol than any other legume [1,14,17]. Other plant families from which has been isolated are: Pinaceae, Asteraceae, Caryophyllaceae, Zygophyllaceae, Cupressaceae, Aristolochiaceae, Sapindaceae [11,18]. Worthy to note, the carob tree has been growing since antiquity in the Mediterranean area, where it is recognized because of its environmental benefits, such as for example that it can fix three times more CO2 than other common woody crops with half of the water requirements, at the time that it is resistant to eroded soils and fires [19]. Unfortunately, carob trees have been mainly used traditionally to obtain LBG (thickener E410) from the seeds, that account only for a 10% of the pod's weight, but the emergence of cheaper substitutes for LBG, such as guar or xantam gum, made the carob tree cultivation no longer profitable in the EU. As a consequence, crops have been abandoned. The promotion of the carob tree by exploiting the potential of this agro-food product would strength the competitiveness of the economies in rural areas, preventing population from abandoning these areas. Notwithstanding the concentration of D-pinitol in carob pods varies significantly depending on the variety and location of the tree, from 5% [20] to more than 10% in some Spanish varieties [1], carob pods are by difference their most cost-effective natural source [21,22,23]. The main described function in plants is as an osmolyte that improves the tolerance to abiotic stress such as drought or high temperatures [24,25].


    2.2. Synthetic D-pinitol

    Even if D-pinitol is naturally derived from D-chiro-inositol, pertaining to the family of inositols, a few preparative methods have been reported for the synthesis, through the combination of chemical and biochemical transformations [26,27,28,29,30], as well as by means of a total synthesis [31]. Thus, the first method was reported by Ley et al. [30], who accomplished the preparation of D-pinitol in 35% overall yield starting from benzene (compound 2 in Scheme 1), involving the microbial oxidation of this compound to (1R, 2S)-cyclohexa-3, 5-diene-1, 2-diol (3) followed by 5 synthetic steps (see Ley et al., 1987 for details). Later, these authors improved the strategy to achieve a 49% overall yield [29].

    Scheme 1. Synthesis of D-pinitol (1) from benzene (2).

    Additionally, Hudlicky et al. [26,27] reported a similar methodology starting from microbial oxidation of bromobencene (compound 4 in Scheme 2) to (1S, 2S)-3-bromocyclohexa-3, 5-diene-1, 2-diol (5). Later on, Aceña et al. [31] reported the total synthesis of D-pinitol starting from chiral accessible building blocks in seven synthetic steps with a 10% yield.

    Scheme 2. Synthesis of D-pinitol (1) from bromobenzene (4).

    3. Health promoting effects of D-pinitol

    D-pinitol is thought to be the active component of the traditional remedy Talisa patra (called Morinda in Hindi), derived from the plant Abies pindrow (Pinaceae, Pindrow Fir), which has been used for centuries in folk medicine, also described in Ayurveda for various respiratory and inflammatory ailments [32]. Moreover, it has been identified as an active principle in soy foods and legumes [24,25]. Nevertheless, as it would be extensively described hereinafter, this natural inositol has a much higher pharmacological potential because of its multifunctional properties (e.g., inositol phosphoglycans generated from lipid and/or protein precursors in cell membranes act as insulin-like factors in vitro and in vivo) [24,33,34,35,36,37].


    3.1. Anticancer

    Breast cancer represents an enormous public health problem nowadays. Thus, for example, it is the principal cause of mortality and the most frequent cancer in women in the U.S. [38,39,40,41]. On the other hand, prostate cancer that is at epidemic proportions, is particularly dangerous because it has a very high tendency to metastasize, particularly to the bone [24,42,43,44]. It is known that cancer metastasis is in the origin of most tumour progressions and consequently the majority of patients suffering cancer finally die because of this reason [24]. More specifically, it has been demonstrated that prostate cancer expands to distant organs including the liver, bladder, bone, lungs, spine and lymph nodes [45,46,47]. Fortunately, a very important source of potentially efficient chemotherapeutic compounds against cancer can be found in natural products [48]. In fact, through an extant of epidemiological studies it has been proved that a considerable lesser risk of cancer exists in those people who regularly ingest fruits and vegetables, which could be attributed to their concentration of combined phytochemicals. Obviously, the prevention of cancer through the implementation of an equilibrated diet is a promising opportunity aiming to reduce its incidence [49,50]. In this context, the National Cancer Institute (NCI) has highlighted a number of foods for which there are evidences of a reduced risk of suffering cancer if incorporated in the regular diet, including plant-derived foods such as soybean (51a and b).

    It has been discovered that D-pinitol reduces the progress and attack of certain prostate cancer cells in vitro at non-cytotoxic concentrations [24,45]. Also, D-pinitol has demonstrated preventive efficacy against breast cancer induced in rats [52,53] as well as tumour-growth inhibitory activity through the modulation of the balance between inflammatory cytokines, hormones, tumour markers, lipids and other biochemical processes [38,39], finally resulting in the growth retardation of tumour cells (see also [42]). Moreover, D-pinitol has a proven protective effect against the dangerous consequences of oxidative stress suffered by the hepatic and renal tissues in breast cancer [54,55,56]. Thus, the elevated levels of total cholesterol, free cholesterol, phospholipids, triglycerides and free fatty acids observed in rats with cancer became significantly at almost normal levels after administration of D-pinitol [39]. It is worth to mention the work of Song et al. [57], at the Chungbuk National University in South Korea, patenting the use of D-pinitol for cancer treatment and prevention of cancer relapse.

    The mode of action of the D-pinitol to exert its anti-cancer biological activityhas been suggested to be the active blocking of the Nuclear Factor kappa B (NF-ⱪB) pathway, a transcription factor inactively present in the cytoplasm that is activated through its reallocation to the nucleus by an important number of carcinogens and inflammatory agents [58]. The NF-ⱪB is a major target nowadays for the development of new, more potent and less noxious, cancer drugs. Its blockage is a potential strategy because it leads to the inhibition of TNF-induced cell invasion and to the down-regulation of a few gene products that are capable to prevent apoptosis and promote inflammation and tumour metastasis [32,39,59]. More specifically, as NF-ⱪB is involved in the regulation of several genes that are related with invasion in cancer cells, such as the Matrix Metalloproteinase MMP-9 [60] capable to degrade components of the extracellular matrix facilitating the invasion of malignant cells, targeting the NF-ⱪB pathway is as a prospective strategy to suppress the tumour invasion that is mediated through MMP-9 [45]. Specifically, Jayasooriya et al. [45] demonstrated that D-pinitol is capable to inhibit certain prostate cancer cells that act by means of TNF-ᾳ-induced invasion, through the amelioration of the MMP-9 expression and the resulting invasion with repression of the NF-ⱪB pathway.

    In addition, Lin et al. [24,61] found that D-pinitol diminishes in a dose-dependent manner the Focal adhesion kinase (FAK protein) phosphorylation, precisely this is of high interest for treating cancer because FAK is involved in tumour migration and invasion [24,62,63]. Specifically, it has been proven that D-pinitol inhibits cell motility in human prostate cancer cells via the FAK/c-Src signalling pathway [24]. Taking into account that an inefficient degradation of lipids is associated to the development of certain types of cancer [39,64,65], Rengarajan et al. demonstrated that D-pinitol is capable to prevent the elevation of lipid peroxidation, thus resulting in the protection of the cell membrane against mammary carcinogenesis [39,54,66].


    3.2. Anti-diabetic

    Non-insulin dependent (Type 2) Diabetes Mellitus (T2DM) is a chronic disease with associated comorbidities. Nowadays, it is estimated that every year 6.8% of the world's population die due to complications related with this illness [67,68]. Even more, if we do not adopt the adequate precautions, the prevalence of this malignancy is expected to increase worldwide from 171 million in 2000 to 366 million in 2030. About 90% of the diabetes cases are T2DM [69], is considered one of the most complicated worldwide epidemics which has taken place in the recent decades [33,70]. The T2DM is characterized by levels of blood glucose that are abnormally high due to a deficiency in the secretion of insulin, or maybe also associated to other insulin receptor or post-receptor events, leading to disequilibrium in the metabolisms of carbohydrates, proteins and fats. Additionally, this perturbed metabolic status directs the progression and aggravation of oxidative stress through a series of phenomena such as the glucose autoxidation, protein glycation and the formation of the adverse advanced-glycation-end products (AGEs), resulting in the development of other important secondary diabetic complications such as nephropathy, retinopathy, neuropathy, macro and microvascular damages and increased risk of coronary heart disease [71,72]. As Gao et al. pointed out, it is of the greatest importance to find appropriate and better treatments and preventive strategies for this pathology [33] that allow a more effective control of blood glucose, as well as a reduction of the oxidative stress and the normalization of some disturbances occurring in the lipid metabolism that predispose patients to cardiovascular complications [72]. Additionally, it is worthy to note here the opinion of an expert committee on diabetes mellitus at the World Health Organization (WHO) nearly forty years ago, of prioritizing the evaluation of the effectiveness of plants, and natural compounds derived from them, in this condition [73].

    Regarding to this, it can be pointed out that D-pinitol is an active principle of the antidiabetic plant Bougainvillea spectabilis, traditionally known because of its insulin-like effects [74,75]. Also, different plant extracts containing D-pinitol have demonstrated efficacy in animals and humans in the amelioration of a number of metabolic disturbances originated by diabetes mellitus, such as soybean, buckwheat, tartary buckwheat or carob tree extracts, to name a few [76]. Therefore, the insulinomimetic properties of this inositol and its capability to reduce hyperglycaemia as well as to regulate other metabolic complications associated to T2DM, have been extensively demonstrated in vivo and in human subjects [see 26, 33, 71, 72, 74, 76-93 and references therein]. The efficacy of D-pinitol has been proved different models studying the postprandial response of glucose and the modifications of the lipid profile in diabetic rats and monkeys, and in human subjects [72,74,81,82,84,85,89]. Accordingly, Kim et al. postulated that a defective metabolism of D-chiro-inositol, the parent compound of D-pinitol, could be in the origin of impaired insulin action and the development of insulin resistance in Type 2 Diabetes [89]. Moreover, Sivakumar et al. [71,78,79] established that D-pinitol is capable to attenuate the oxidative stress suffered by Sreptozotocin-induced diabetic rats, through the reduction of lipid peroxidation and the amelioration of the prevalence in pro-inflammatory factors, successfully leading to the protection of hepatic, kidney and pancreatic tissues. Also, Nascimento et al. [77], similarly corroborated the improvement of metabolic descriptors related to the kidney function in type 2 diabetic patients administered with D-pinitol. But the usefulness of this compound is not limited to the medical context, as very positive effects in decreasing hyperglycaemia and circulating insulin levels have been demonstrated also in healthy subjects [94], pointing out to the convenience of considering D-pinitol as a beneficial dietary supplement.

    As a result of the growing interest on D-pinitol for the treatment of diabetes mellitus and for the pathologies associated to this disease, there are a number of patents protecting these potential exploitations. For example, an international patent was developed by Rademacher Group Ltd., [95] to defend uses of D-pinitol as an equivalent of inositol phosphoglycans, for different pathologic conditions (e.g., T2DM and obesity). Additionally, specific uses of compositions containing D-pinitol for treating T2DM and related health complications were claimed in USA., by the University of Washington [96] and by the University of Virginia [97], as well as in Korea by Solgent Co. Ltd. [98,99] and by Amicogen Co. Ltd. [100].

    Dealing with the biological mechanisms by which D-pinitol regulates the metabolic complications associated to T2DM, it has been postulated that it acts in a pathway following the insulin action after the glucose absorption [74], as it has been demonstrated that the ability of D-pinitol to reduce hyperglycaemia is not consequence of increased insulin concentrations neither of augmentation of the insulin activity, concluding that this inositol exerts an insulin-like effect on glucose transport independently of insulin, acting downstream in the insulin signalling pathway [82,89].

    Moreover, Dang et al. [86] demonstrated that the effectiveness of D-pinitol is related to the ability of this compound to stimulate the mobility of Glucose Transporter 4 (GLUT4), which according to its sensitivity to insulin, plays an important role in the regulation of glucose transportation to the skeletal muscle and the adipose tissue. PI3K/Akt signalling pathway is involved in this process through a protein phosphorylation cascade. Therefore, D-pinitol stimulates a reduction of plasma glucose levels under certain conditions of high glucose levels. In concordance, Gao et al. [33] pointed out that the amelioration of insulin resistance in T2DM promoted by D-pinitol occurred through the PI3K/Akt pathway, similarly to other inositol phosphates, implicating the PI3Kp85 and PI3Kp110 subunits [101,102,103]. Thus, the PI3K/Akt pathway that is implicated in a number of human diseases including cancer, diabetes, cardiovascular and neurological diseases [104], is regulated by D-pinitol, resulting in an effective reduction of the concentration of blood glucose through promotion of glycogen synthesis [33].

    On the other hand, the capacity of D-pinitol to normalize other metabolic complications associated to T2DM (e.g., lipid profiles, attenuation of oxidative stress with reduction of lipid peroxidation, amelioration of pro-inflammatory factors as well as protection of hepatic, kidney and pancreatic tissues) is directly related with the normalization of blood glucose levels, leading to lesser glucose autoxidation processes, but also with the intrinsic free radical scavenging potential and antioxidant nature of D-pinitol [71]. Additionally, it is worth to mention that D-pinitol has the capacity to suppress the NF-ⱪB pathway, regulating the oxidative stress provoked as a consequence of NF-ⱪB activation during abnormal hyperglycaemic states, also regulating the elevation of proinflammatory cytokines (i.e., TNF-ᾳ, IL-1β and IL-6). As Yu et al. pointed out [87] (see also section 3.1). D-pinitol might be a good candidate for treating inflammatory bone-related diseases and secondary osteoporosis in T2DM.


    3.3. Antioxidant

    Oxidative stress is considered a pathologic state in which the equilibrium between the activity of oxidants and antioxidants in the body is perturbed, in favour of the oxidants. That is to say, oxidants are present in the body under normal conditions, formed for example as products of aerobic metabolism, but under certain abnormal situations they can be produced with a very high elevated rate which can't be compensated. During the last decades, oxidative stress has been one of the most important topics for researchers of diverse areas all over the world (e.g., medicine, biochemistry or food technology) [105], due to the close relationship that exists between oxidative stress and altered immune functions, increases in the incidence of autoimmune diseases, higher susceptibility to infections, and accentuated prevalence of carcinogenesis phenomena. Additionally, there exists an intimate connection between oxidative stress and aging. At the cellular level, redox homeostasis is partly maintained by means of endogenous enzymatic and non-enzymatic antioxidant mechanisms, which take place within the cytoplasm and in a diversity of cell organelles. Natural food-derived antioxidant compounds have received major attention in the last years because of its capacity to contribute to the normalization of the cellular redox status in the organism with little or negligible side effects.

    Sivakumar et al. recently demonstrated the beneficial effect of D-pinitol against oxidative stress [78,79], which could be attributed to its free radical scavenging capacity. Additionally, different uses of D-pinitol, and derived compositions, have been protected considering this antioxidant potential [100,106].


    3.4. Hepatoprotective

    As it has been mentioned above, D-pinitol exerts a protective effect of the hepatic, kidney and pancreatic tissues against oxidative stress [71,78,79]. Special mention is given here to the hepatoprotective action because of the importance of the liver as a vital organ, with critical functions such as for example the detoxification of the body from hazardous substances. Unfortunately, a number of reactive species, including free radicals, can damage the liver leading to jaundice, cirrhosis or fatty liver, to name a few. Additionally, viral hepatitis is considered a major health problem throughout the world [107].

    Zhou et al. [108] evidenced that D-pinitol exerts a protective effect against human viral hepatitis caused by D-galactosamine (GalN) in rat model. More specifically, this inositol improves the liver function by lowering the levels of certain serum aminotransferases, such as aspartate transaminase (AST) and alanine transaminase (ALT), as well as of the inflammatory cytokine TNF-ᾳ. Consistently, Choi et al. [37] demonstrated that the regular administration of D-pinitol protects against the hepatotoxic effects of a hypercholesterolemic diet at least in part, by the antioxidant nature of D-pinitol and its capacity to activate cell antioxidant enzyme systems, even if this is not well understood yet [35]. In line with these results, Amicogen Inc. (USA) patented the exploitation of D-pinitol and formulas containing this compound, for protecting the liver [106].


    3.5. Immuno-suppressor

    A proper functioning of the immune system is of vital importance, because a prolonged debilitation can be the cause of recurrent infections or, for example, of a higher risk of cancer [39,109,110,111]. Immunodeficiency may occur as a result of certain diseases (e.g., HIV/AIDS), or it can be induced if desirable (e.g., to avoid transplantation rejections). On the other hand, a hyperactive immune system leads to serious health problems or autoimmune diseases such as rheumatoid arthritis, type 1 diabetes or lupus erythematosus, to name a few. Asthma, chronic inflammatory processes and a propensity for allergic responses are also the manifestation of a hyperactive immune system [112]. T-lymphocites Th1 and Th2 play a major role in immunity and so, several immunological diseases are associated with the deregulation of these cytokines. Therefore, the modulation of the Th1/Th2 balance has become a new paradigm in immunomodulatory therapy [113]. Immunosuppressive drugs (e.g., cyclosporine, cyclophosphamide, tacrolimus, mycophenolate mofetil or rapamycin) are chemical compounds used for organ transplantation and to treat some serious autoimmune diseases. However, they are very problematic as their efficacy depends on the particular differences between subjects, with a very high concomitant risk of therapeutic failure [113].

    The immunomodulatory capacity of D-pinitol, thoroughly investigated for treating pathologies such as asthma, chronic inflammation, rheumatoid arthritis or multiple sclerosis [113,114,115,116], has demonstrated to be a promising strategy to attain a more equilibrated immunological system with negligible side effects. Thus, D-pinitol administration in rats showed very good anti-inflammatory activity, demonstrated by means of the adequate models of chronic inflammation, such as the induction with carrageenan and cotton pellets [114], as well as a remarkable inhibitory capacity of asthma [115]. Dealing with the mechanism by which D-pinitol exerts its immunomodulatory activity, it seems clear that this bioactive compound acts as a regulator of the Th1/Th2 balance [113,115,116]. Nevertheless, some contradictory results arise after a scrupulous analysis of the literature. Thus, Lee et al. [115,116] found that D-pinitol reduced the increased levels of the Th2 cytokine IL-4, a result corroborated by Chauhan et al. [113]. Contrary, Lee et al. [115] asserted that simultaneously, an increase in the production of the Th1 cytokine IFN-γ occurred, while Chauhan et al. [113] claimed exactly the opposite, a reduction of this precise cytokine caused by D-pinitol consumption. Moreover, the regulation of Th1/Th2 balance might take place, according to Lee et al. [115], via the suppression of GATA-3 and increase of T-bet expression.

    In order to summarize the findings about the health-promoting potential of D-pinitol, we could highlight its high potency in the modulation of the immunological system responses with potentially less side effects than the currently available synthetic drugs such as cyclophosphamide. This inositol is capable to regulate the production of Th1/Th2 cytokines, offering new potential therapeutic targets for the prevention and management of autoimmune and related diseases [113,115,116]. Taking this into consideration, has prompted the patenting of the immunosuppressive activity of certain formulations containing D-pinitol [117] to prevent and treat inflammatory diseases [118].


    3.6. Inhibitory action of osteoclastogenesis (anti-osteoporosis)

    Bone is a complex tissue made of different types of cells which are continuously experiencing a range of equilibrated processes of formation and resorption. Osteoporosis results from an imbalance between these processes of bone resorption and bone formation leading to a net bone lost. This imbalance can be originated as a consequence of several conditions such as hormonal disturbances or certain diseases or medications (e.g., corticosteroids or anti-epileptic agents) [34,119]. Drugs for treating osteoporosis (e.g., bisphosphonates, calcitonin and oestrogen) act by inhibiting the function of osteoclasts that are responsible for bone resorption [34,120]. Unfortunately, these drugs have limited success on recovering bone mass (maximum 2% per year) [34]. Inflammatory cytokines (e.g., tumour necrosis factor, TNF) play a major role in osteoclastogenesis, favouring bone resorption associated with osteoporosis. Indeed, receptor activator of the NF-kB Ligand (RANKL), a protein member of the TNF superfamily, contributes to control bone regeneration processes and so, suppressing RANKL signalling pathway is a potential strategy to suppress bone loss [34]. In this concern, Liu et al. [34] showed that D-pinitol is capable to inhibit the formation of osteoclasts induced by RANKL. Specifically, this inositol exerts this effect through the p38/JNK and NF-ⱪB pathways. In conclusion, D-pinitol has potential to be used for treatment and prevention of osteoporosis. Taking this into account, Solgent Co protected a composition for prevention or treatment of bone metabolism disorders comprising D-pinitol as an active ingredient [121].


    3.7. Anti-aging

    Aging can be viewed as an accumulation of changes over time, accompanied with a functional and reproductive decline that is associated with an increased mortality [122,123]. Dietary restriction (DR), the continuous reduction of nutrients without malnutrition, has demonstrated to be an effective strategy [123,124]. However, it is not obviously a generally applicable therapeutic strategy. D-pinitol is one of a few compounds known to be capable to mimic DR. Thus, Hada et al. [123] showed that D-pinitol treatment considerably extended life span of Drosophila melanogaster, reducing oxidative stress and improving health, with evident benefits in locomotion. Worth noting, no reduction in fecundity was observed. These authors pointed out a deactivation of the insulin/IGF-1 signaling (IIS) pathway as the most probable mechanism [125,126]. Specifically, it was postulated that supplementation of D-pinitol may reduce the cellular levels of the intracellular messenger phosphatidylinositol (3, 4, 5)-triphosphate (PIP3), a compound structurally related to D-pinitol that is capable to inhibit dFOXO (single Drosophila melanogaster forkhead box O transcription factor). Then, as dFOXO plays important functions in cell growth, proliferation, differentiation and longevity, D-pinitol facilitates its activation through reduction of its inhibitor PIP3. Indeed, Hada et al. [123,127] demonstrated that the activation of dFOXO by D-pinitol was acquired by means of the S6K and JNK signalling pathways. Furthermore, a reduction of the inflammatory response, closely related to aging, may contribute to the anti-aging effect of D-pinitol, through the biological mechanisms previously explained in detail (see section 2.5, immunosuppressor effect of D-Pinitol). Therefore, it was concluded that D-pinitol has great potential to be used as a functional ingredient with anti-aging properties [123]. Consequently, the National Institute of Advanced Industrial Science and Technology (AIST) associated with Tsujiko Co. Ltd., in Japan [128], as well as at Dermalab Co. Ltd., in Korea [129,130] have protected compositions containing D-pinitol with anti-aging properties.


    3.8. Creatine retention stimulant

    Creatine is a natural organic compound that exists in vertebrates with the main function to promote the conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP), the energy currency of cells, primarily in muscle and brain tissues [131]. It is produced in the organism, predominately in the liver, kidneys, pancreas, and complemented through the diet [132]. Additionally, creatine is one of the most consumed natural supplements with the aim to improve performance in sport. However, improvements in strength and resistance have been shown to be more or less advantageous depending on the individual capabilities to storage it, a condition mediated by insulin. Notably, co-ingestion of creatine with large amounts of sugars, with or without proteins, has shown to improve creatine uptake and retention, but the problem with this strategy is that great excesses of calories are needed to attain the desired effect.

    Co-ingestion of D-pinitol and creatine seems to improve the retention of creatine [133]. However, some controversy exists as it has been explicitly manifested in relevant literature. Thus, Cooke and Cribb [134] pointed out in a current comprehensive book about sports nutrition that further research is necessary to attain a clear conclusion, and similar arguments where emphasized by Chantler and Smit [135] in a recent guide for nutritional supplements-supplements in sport, exercise and health: An A-Z Guide. The foundations for such allegations (see also the original works [133,136]) are briefly discussed hereinafter. On the one hand, Greenwood et al. [133] showed that low doses of D-pinitol (1 g day–1) administered with creatine resulted in an increase of the whole body creatine retention, comparable to previously reported enhancements through co-ingestion of creatine with sugars. Nevertheless, Kerksick et al. [136] proved that co-administration of higher doses of D-pinitol (20 g day–1) resulted in the absence of a significant improvement of creatine retention nor in any other physiological benefit.

    Taking into account that insulin facilitates creatine uptake, insulin-mimetic properties of D-pinitol have been alleged as the cause of the benefit of D-pinitol supplementation at low doses on creatine retention [133]. Notwithstanding more profound investigations are recommended, the potential applicability of D-pinitol to improve performance in sports has generated a large number of patents. Briefly, two international patents [137,138] and various from different nationalities [139,140,141,142,143,144,145], are claiming about the advantages of this compound on relation to strength, endurance, muscle growth, performance in sports and similar effects. For example, Humanetics Corporation [137] protected worldwide formulations combining D-pinitol and creatine, or an active derivative thereof, to improve muscle performance and to enhance muscle hypertrophy, while New Nitro Formulations Ltd. [138], protected D-pinitol and compositions thereof to enhance skeletal muscle growth, reduce skeletal muscle loss and increase the energy supply to the skeletal muscle.


    3.9. Ameliorative of Alzheimer's disease

    Alzheimer's disease is a serious neurodegenerative condition that provokes a progressive deteriorated status of dementia in which synapses are lost [146,147]. Unfortunately, nowadays this illness, that affects 13% of people older than 65 in developing countries, is untreatable and fatal [146]. A number of strategies to alleviate Alzheimer's disease have been designed according to the plausible cause of the illness [146]. Between them, compounds directed to reduce beta Amyloid (Aβ) peptide formation and to facilitate Aβ plaques dissolution are of principal interest, as it is the case for D-pinitol [146,147], a molecule with a high potential for treating this disease [146,147,148,149,150,151,152,153,154,155,156].

    D-pinitol has demonstrated improving activity in preclinical models of Alzheimer's disease, making this compound an excellent candidate as a therapeutic agent for this malignancy. Moreover, Phase-Ⅱ studies have been carried out showing good tolerability and stabilization of cognition (clinical trials NCT00470418 [157a] and NCT01928420 [157b]). Thus, D-pinitol, also known as NIC5-15 in clinical trials, is considered a selective γ-secretase modulator (SGSM) that is the general denomination used to identify those molecules that are selectively capable to block the amyloid precursor protein (APP) without interfering with other signalling pathways. Concretely, D-pinitol is alleged to modulate γ-secretase and to reduce Aβ production, although these findings are still in a preliminary stage [146]. Pasinetti in the U.S.A. [154,155] and McLaurin in Europe [156] have patented compositions and uses of D-pinitol for treating Alzheimer's disease.


    4. Synthetic D-pinitol derivatives

    The access to D-pinitol derivatives is of great interest because of the remarkable biological properties of these compounds [2,5,95,96,158,159,160,161]. Early in 1989, Tegge and Ballau [161] described the synthesis of D-myo-inositol-1, 4, 5-triphosphate (6), a naturally occurring compound first isolated from bovine brain [161], starting from D-pinitol (1) through a complex route of 8 synthetic steps (see Scheme 3), with very poor overall yields [161,162].

    Scheme 3. Synthesis of D-myo-inositol 1, 4, 5-triphosphate (6) from D-Pinitol.

    More recently, Catelani et al. [5] with the aim to obtain biomimetic compounds of ᾳ-L-rhamnopyranose, a molecular unit present in many more complex bioactive saccharides, accomplished the stereoselective synthesis of 3, 5-di-O-benzyl-D-pinitol (compound 8 in Scheme 4) starting from the partially protected aldohexos-5-ulose (7), through a 6 steps synthetic route with moderate yield.

    Scheme 4. Synthesis of 3, 5-di-O-benzyl-D-Pinitol (8) from 2, 6-di-O-benzyl-L-arabino-hexos-5-ulose (7).

    Using D-pinitol as a chiral building block, Li et al. [5,160] accomplished the total synthesis of (+)-Pancratistatin (Figure 2), an important naturally occurring alkaloid possessing growth inhibitory activity against certain in-vitro and in-vivo cancer cells.

    Figure 2. (+)-Pancratistatin.

    Additionally, Bhat et al. [2] carried out the semi-synthesis of various selectively acylated D-pinitol derivatives (compounds 9, 10 and 11 in Figure 3), through biochemical and chemical transformations. Moreover, they evaluated their potential as inhibitors of TNF-ᾳ cytokine expression in human neutrophils, with positive results in some cases (Table 1).

    Figure 3. D-pinitol derivatives prepared and evaluated as inhibitors of TNF-ᾳ cytokine expression in human neutrophils.
    Table 1. Inhibitory capacity of TNF-ᾳ expression by D-pinitol derivatives (compounds showing more than 50% inhibition can be considered as potent inhibitors; revised from Bhat et al., 2009).
    Compound R1 R2 Inhibitory capacity at 1 µg/mL Compound R1 Inhibitory capacity at 1 µg/mL
    D-Pinitol H H 30.03% 10a H 13.09%
    9a Acetyl- H 2.28% 10b Acetyl- 42.58%
    9b Butanoyl- H 8.36% 10c Butanoyl- 39.54%
    9c Propanoyl- H 20.91% 10d Propanoyl- 32.14%
    9d Iso-butanoyl- H 17.85% 10e Iso-butanoyl- 20.65%
    9e COCH3 = R1 33.46% 10f All 34.98%
    9f COCH2CH3 = R1 30.79% 10g Me 33.33%
    9g COCH2CH2CH3 = R1 52.47% 10h Et 38.40%
    9h COPh = R1 51.71% 11a Cl 37.64%
    9i All H 29.65% 11b = O 50.57%
    9j Me H 39.16% Compound Inhibitory capacity (%) at 10 µg/mL
    9k Et H 36.50% Rolipram 52.85%
     | Show Table
    DownLoad: CSV

    Additionally, Zhan and Lou [159] carried out the synthesis of azole nucleoside analogues of D-Pinitol (compounds 12 and 13 in Scheme 5), and evaluated their growth inhibitory potential for various human cancel cell lines of lung and bladder, with positive results in some cases as can be shown in Table 2.

    Scheme 5. Synthesis of azole nucleoside analogues (12, 13) of D-pinitol (1).
    Table 2. Synthetic azole nucleoside analogues (12, 13) of D-pinitol (1) and evaluation of their cytotoxicity in human lung and bladder cancer cell lines PG and T24 respectively (revised from Zhan and Lou, 2007).
    Compound R Yield (%) EC50(µM)
    PG T24
    12a 1H-1, 2, 4-triazol-1-yl 74 11.3 78.5
    12b 1H-benzo[d][1, 2, 3]triazol-1-yl 68 22.6 83.8
    12c 6-nitro-1H-indazol-1-yl 66 > 100 > 100
    12d/13a (ratio = 1.71) 5-nitro-1H-indazol-1-yl 62 > 100 > 100
    Sangivamycin 0.012 0.008
     | Show Table
    DownLoad: CSV

    Moreover, Falshaw et al. [158] accomplished the semi-synthesis of the very interesting biologically active compound 1D-Conduritol B epoxide (compound 14, in Scheme 6) from D-pinitol, through seven synthetic steps with poor overall yield. They also established that it is this isomer, and not the L-analog, the one that exerts the biological activity, acting as an irreversible inhibitor of various β-glucosidases.

    Scheme 6. Synthesis of 1D-Conduritol B epoxide (14).

    Interestingly, researchers at Rademacher Group Ltd. reported in an international patent a considerable amount of D-Pinitol derivatives and protected them and their pharmaceutical uses for the amelioration of different dysfunctions [95].


    Acknowledgments

    Author JILS gratefully acknowledge the financial support of -Instituto de Fomento de la Región de Murcia (INFO)-and -Fondo Europeo de Desarrollo Regional of the European Commission-(Project 2015.08.ID+I.0038) and the funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 790025.

    Authors DAM and CGV would also like to thank the Grant for Research Groups of Excellence from the Murcia Regional Agency for Science and Technology (Fundación Séneca), Project 19900/GERM/15.


    Conflict of interest

    All authors declare no conflicts of interest in this paper.

    This work reflects only the co-authors's view. The Agency and the Commission are not responsible for any use that may be made of the information it contains.


    [1] Nasar-Abbas SM, E-Huma Z, Vu T, et al. (2016) Carob Kibble: A Bioactive-Rich Food Ingredient. Compr Rev Food Sci Food Saf 15: 63-72. doi: 10.1111/1541-4337.12177
    [2] Bhat KA, Shah BA, Gupta KK, et al. (2009) Semi-synthetic analogs of pinitol as potential inhibitors of TNF-alpha cytokine expression in human neutrophils. Bioorg Med Chem Lett 19: 1939-1943. doi: 10.1016/j.bmcl.2009.02.050
    [3] Anderson AB, MacDonald DL, Fischer HOL (1952) The structure of pinitol. J Am Chem Soc 74: 1479-1480. doi: 10.1021/ja01126a036
    [4] Posternak T (1936) Recherches dans la série des cyclites Ⅲ. Sur la configuration des inosites actives. Helv Chim Acta 19: 1007-1010. doi: 10.1002/hlca.193601901132
    [5] Catelani G, D'Andrea F, Griselli A, et al. (2008) A new stereoselective approach to a selectively protected derivative of D-pinitol and its evaluation as alpha-L-rhamnopyranose mimetic. Tetrahedron Lett 49: 4534-4536. doi: 10.1016/j.tetlet.2008.05.040
    [6] Dowd M, Stevens E (2002) The crystal structures of D-Pinitol and 1-Quebrachitol by low-temperature X-ray diffraction. J Carbohydr Chem 21: 373-383. doi: 10.1081/CAR-120014901
    [7] Dowd MK, Stevens ED, Experimental Crystal Structure Determination. CCDC 172582,2014. Available from: https://dx.doi.org/10.5517/cc5sl5p.
    [8] Raya-Gonzalez D, Pamatz-Bolanos T, Rio-Torres R, et al. (2008) D-(+)-Pinitol, a component of the heartwood of Enterolobium cyclocarpum (Jacq.) Griseb. Z Naturforsch C: J Biosci 63: 922-924. doi: 10.1515/znc-2008-11-1225
    [9] Anderson I, (1972) The cyclitols, In: Pigman W, Horton D. Eds. The Carbohydrates, 2nd ed., New York and London: Academic Press, Inc., Vol. 1A Chemistry and Biochemisty.
    [10] Calle J, Rivera A, Josephnathan P (1987) Pinitol from leaves of Gliricidia sepium. Planta Med 53: 303. doi: 10.1055/s-2006-962717
    [11] Poongothai G, Sripathi SK (2013) A review on insulinomimetic pinitol from plants. Int J Pharm Bio Sci 4: 992-1009.
    [12] Al-Suod H, Lior M, Ratiu IA, et al. (2016) A window on cyclitols: Characterization and analytics of inositols. Phytochem Lett 20: 507-519. doi: 10.1016/j.phytol.2016.12.009
    [13] Labed A, Ferhat M, Labed-Zouad I, et al. (2016) Compounds from the pods of Astragalus armatus with antioxidant, anticholinesterase, antibacterial and phagocytic activities. Pharm Biol 54: 3026-3032. doi: 10.1080/13880209.2016.1200632
    [14] Lahuta LB, Ciak M, Rybinski W, et al. (2017) Diversity of the composition and content of soluble carbohydrates in seeds of the genus Vicia (Leguminosae). Genet Resour Crop Evol 2017: 1-14.
    [15] Phillips DV, Dougherty DE, Smith AE (1982) Cyclitols in soybean. J Agric Food Chem 30: 456-458. doi: 10.1021/jf00111a011
    [16] Adinarayana D, Ramachandraiah P (1985) C-Glycosylphenolics from Rhynchosia suaveolens. J Nat Prod 48: 156-157. doi: 10.1021/np50037a042
    [17] Tetik N, Turhan I, Oziyci HR, et al. (2011) Determination of D-pinitol in carob syrup. Int J Food Sci Nutr 62: 672-676. doi: 10.3109/09637486.2011.560564
    [18] Sharma N, Verma MK, Gupta DK, et al. (2016) Isolation and quantification of pinitol in Argyrolobium roseum plant, by 1H-NMR. J Saudi Chem Soc 20: 81-87. doi: 10.1016/j.jscs.2014.07.002
    [19] Pérez-Pastor A, Soares-Neto JP, de la Rosa JM, et al. (2016) Carbon footprint assessment in carob tree plantations. Vida Rural April: 52-60.
    [20] Baumgartner S, Gennerritzmann R, Haas J, et al. (1986) Isolation and identification of cyclitols in carob pods (Ceratonia siliqua L.). J Agric Food Chem 34: 827-829. doi: 10.1021/jf00071a015
    [21] Oziyci HR, Turhan I, Tetik N (2015) Concentration of D-pinitol in carob extract by using multi-stage enrichment processes. GIDA 40: 125-131.
    [22] Turhan I (2011) Optimization of extraction of D-pinitol and phenolics from cultivated and wild types of carob pods using response surface methodology. Int J Food Eng 7: 639-646.
    [23] Turhan I (2014) Relationship between sugar profile and D-pinitol content of pods of wild and cultivated types of carob bean (Ceratonia siiqua L.). Int J Food Prop 17: 363-370. doi: 10.1080/10942912.2011.631255
    [24] Lin TH, Tan TW, Tsai TH, et al. (2013) D-pinitol inhibits prostate cancer metastasis through inhibition of aVb3 integrin by modulating FAK, c-Src and NF-kB pathways. Int J Mol Sci 14: 9790-9802. doi: 10.3390/ijms14059790
    [25] Streeter JG (1980) Carbohydrates in soybean nodules: Ⅱ. Distribution of compounds in seedlings during the onset of nitrogen fixation. Plant Physiol 66: 471-476. doi: 10.1104/pp.66.3.471
    [26] Hudlicky T, Price JD, Rulin F, et al. (1990) Efficient and enantiodivergent synthesis of (+)-and (-)-pinitol. J Am Chem Soc 112: 9439-9440. doi: 10.1021/ja00181a081
    [27] Hudlicky T, Rulin F, Tsunoda T, et al. (1991) Biocatalysis as a rational approach to enantiodivergent synthesis of highly oxygenated compounds: (+)-and (-)-Pinitol and Other Cyclitols. Isr J Chem 31: 229-238. doi: 10.1002/ijch.199100027
    [28] Hudlicky T, Mandel M, Rouden J, et al. (1994) Microbial Oxidation of Aromatics in Enantiocontrolled Synthesis. Part 1. Expedient and General Asymmetric Synthesis of lnositols and Carbohydrates via an Unusual Oxidation of a Polarized Diene with Potassium Permanganate. J Chem Soc Perkin Trans 1 1: 1553-1567. doi: 10.1039/p19940001553
    [29] Ley SV, Sternfeld F (1989) Microbial oxidation in synthesis: Preparation of (+)-and (-)-pinitol from benzene. Tetrahedron 45: 3463-3476. doi: 10.1016/S0040-4020(01)81025-5
    [30] Ley SV, Sternfeld F, Taylor S (1987) Microbial oxidation in synthesis: A six step preparation of (+)-Pinitol from benzene. Tetrahedron Lett 28: 225-226. doi: 10.1016/S0040-4039(00)95692-2
    [31] Aceña JL, Arjona O, Plumet J (1996) Total synthesis of (+)-pinitol. Tetrahedron: Asymmetry 7: 3535-3544. doi: 10.1016/S0957-4166(96)00461-2
    [32] Sethi G, Ahn KS, Sung B, et al. (2008) Pinitol targets nuclear factor-kB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis. Mol Cancer Ther 7: 1604-1614. doi: 10.1158/1535-7163.MCT-07-2424
    [33] Gao Y, Zhang M, Wu T, et al. (2015) Effects of D-pinitol on insulin resistance through the PI3K/Akt signaling pathway in type 2 diabetes mellitus rats. J Agric Food Chem 63: 6019-6026. doi: 10.1021/acs.jafc.5b01238
    [34] Liu SC, Chuang SM, Tang CH (2012) D-pinitol inhibits RANKL-induced osteoclasteogenesis. Int Immunopharmacol 12: 494-500. doi: 10.1016/j.intimp.2012.01.002
    [35] Zhou Y, Park CM, Cho CW, et al. (2008) Protective effect of pinitol against D-galactosamine-induced hepatotoxicity in rats fed on a high-fat diet. Biosci Biotechnol Biochem 72: 1657-1666. doi: 10.1271/bbb.70473
    [36] Shin YC, Jeon JY (2004) The physiological activities of pinitol isolated from soybean. Food Ind Nutr 30: 2680-2688.
    [37] Choi MS, Lee MK, Jung UJ, et al. (2009) Metabolic response of soy pinitol on lipid-lowering, antioxidant and hepatoprotective action in hamsters fed-high fat and high cholesterol diet. Mol Nutr Food Res 53: 751-759. doi: 10.1002/mnfr.200800241
    [38] Rengarajan T, Nandakumar N, Rajendran P, et al. (2014) D-pinitol promotes apoptosis in MCF-7 cells via induction of p53 and Bax and inhibition of Bcl-2 and NF-kB. Asian Pac J Cancer Prev 15: 1757-1762. doi: 10.7314/APJCP.2014.15.4.1757
    [39] Rengarajan T, Nandakumar N, Rajendran P, et al. (2015) D-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-kB. J Physiol Biochem 71: 191-204. doi: 10.1007/s13105-015-0397-9
    [40] Fentiman IS (2001) Fixed and modifiable risk factors for breast cancer. Int J Clin Pract 55: 527-530.
    [41] Parkin DM, Bray F, Ferlay J, et al. (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94: 153-156. doi: 10.1002/ijc.1440
    [42] Mundy GR (2002) Metastasis: Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat Rev Cancer 2: 584-593. doi: 10.1038/nrc867
    [43] Bryant RJ, Hamdy FC (2008) Screening for prostate cancer: An update. Eur Urol 53: 37-44. doi: 10.1016/j.eururo.2007.08.034
    [44] Ernst DS, Hanson J, Venner PM (1991) Analysis of prognostic factors in men with metastatic prostate cancer. Uro-Oncology Group of Northern Alberta. J Urol 146: 372-376. doi: 10.1016/S0022-5347(17)37797-2
    [45] Jayasooriya R, Kang CK, Park SR, et al. (2015) Pinitol suppresses tumor necrosis factor-a-induced invasion of prostate cancer LNCaP cells by inhibiting nuclear factor-kB-Mediated matrix metalloproteinase-9 expression. Trop J Pharm Res 14: 1357-1364. doi: 10.4314/tjpr.v14i8.6
    [46] Ayala GE, Dai H, Ittmann M, et al. (2004) Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res 64: 6082-6090. doi: 10.1158/0008-5472.CAN-04-0838
    [47] Nakamachi H, Suzuki H, Akakura K, et al. (2002) Clinical significance of pulmonary metastases in stage D2 prostate cancer patients. Prostate Cancer Prostatic Dis 5: 159-163. doi: 10.1038/sj.pcan.4500573
    [48] Pezzuto JM (1997) Plant-derived anticancer agents. Biochem Pharmacol 53: 121-133. doi: 10.1016/S0006-2952(96)00654-5
    [49] Conney AH, Lou YR, Xie JG, et al. (1997) Some perspectives on dietary inhibition of carcinogenesis: Studies with curcumin and tea. Proc Soc Exp Biol Med 216: 243-245. doi: 10.3181/00379727-216-44173
    [50] Park EJ, Pezzuto JM (2002) Botanicals in cancer chemoprevention. Cancer Metastasis Rev 21: 231-255. doi: 10.1023/A:1021254725842
    [51] Available from: a) https://www.cancer.gov/about-cancer/treatment/cam/patient/suns-soup-pdq. b) https://www.cancer.gov/about-cancer/treatment/cam/patient/prostate-supplements-pdq#section/_95.
    [52] Rengarajan T, Nandakumar N, Balasubramanian MP (2013) D-pinitol prevents rat breast carcinogenesis induced by 7, 12-dimethylbenz (a) anthracene through inhibition of Bcl-2 and induction of p53, caspase-3 proteins and modulation of hepatic biotransformation enzymes and antioxidants. Biomed Prev Nutr 3: 31-41. doi: 10.1016/j.bionut.2012.07.001
    [53] Kim YS, Park JS, Kim MJ, et al. (2014) Inhibitory effect of D-pinitol on both growth and recurrence of breast tumor from MDA-MB-231 Cancer Cells. Korean J Pharmacogn 45: 174-180.
    [54] Rengarajan T, Nandakumar N (2012) Protective efficacy of dietary D-pinitol on hepatic and renal tissues during experimental breast cancer in rats challenged with 7, 12-Dimethylbenz (a) anthracene: A biochemical approach. Biomed Aging Pathol 2: 85-93. doi: 10.1016/j.biomag.2012.07.008
    [55] Rengarajan T, Rajendran P, Nandakumar N, et al. (2014) Free radical scavenging and antioxidant activity of D-pinitol against 7, 12-Dimethylbenz (a) anthracene induced breast cancer in sprague dawley rats. Asian Pac J Trop Dis 4: 384-390. doi: 10.1016/S2222-1808(14)60592-2
    [56] Rengarajan T, Nandakumar N, Balasubramanian MP (2012) D-pinitol attenuates 7, 12-dimethylbenz (a) anthracene induced hazards through modulating protein bound carbohydrates, adenosine triphosphatases and lysosomal enzymes during experimental mammary carcinogenesis. J Exp Ther Oncol 10: 39-49.
    [57] Song SG, Park JS, Kim YS (2015) Use of pinitol and D-chiro inositol in cancer treatment and prevention of cancer relapse. Korean patent KR 20150088589 (A).
    [58] Kumar A, Takada Y, Boriek AM, et al. (2004) Nuclear factor-kB: Its role in health and disease. J Mol Med 82: 434-448. doi: 10.1007/s00109-004-0555-y
    [59] Chaturvedi MM, Sung B, Yadav VR, et al. (2011) NF-kB addiction and its role in cancer: 'One size does not fit all'. Oncogene 30: 161-1630. doi: 10.1038/onc.2010.566
    [60] Kong D, Li Y, Wang Z, et al. (2007) Inhibition of angiogenesis and invasion by 3, 3'-diindolylmethane is mediated by the nuclear factor-kB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 67: 3310-3319. doi: 10.1158/0008-5472.CAN-06-4277
    [61] Lechertier T, Hodivala-Dilke K (2012) Focal adhesion kinase and tumour angiogenesis. J Pathol 226: 404-412. doi: 10.1002/path.3018
    [62] Hwangbo C, Kim J, Lee JJ, et al. (2010) Activation of the integrin effector kinase focal adhesion kinase in cancer cells is regulated by crosstalk between protein kinase Calpha and the PDZ adapter protein mda-9/Syntenin. Cancer Res 70: 1645-1655. doi: 10.1158/0008-5472.CAN-09-2447
    [63] Boukerche H, Su ZZ, Prévot C, et al. (2008) Mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. Proc Natl Acad Sci USA 105: 15914-15919. doi: 10.1073/pnas.0808171105
    [64] Kumar K, Sachdanandam P, Arivazhagan R (1991) Studies on the changes in plasma lipids and lipoproteins proteins in patients with benign and malignant breast cancer. Biochem Int 23: 581-589.
    [65] Damen J, Ramshorst JV, Hoeven RPV, et al. (1984) Alterations in plasma lipoprotein and heparin-releasable lipase activities in mice bearing the grsl ascites tumor. Biochim Biophys Acta 793: 287-296. doi: 10.1016/0005-2760(84)90331-X
    [66] Rengarajan T, Nandakumar N, Balasubramanian MP (2012) D-pinitol a low molecular cyclitol prevents 7, 12-dimethylbenz (a) anthracene induced experimental breast cancer through regulating anti-apoptotic protein Bcl-2, mitochondrial and carbohydrate key metabolizing enzymes. Biomed Prev Nutr 2: 25-30. doi: 10.1016/j.bionut.2011.11.001
    [67] Rawal LB, Tapp RJ, Williams ED, et al. (2012) Prevention of type 2 diabetes and its complications in developing countries: A review. Int J Behav Med 19: 121-133. doi: 10.1007/s12529-011-9162-9
    [68] Rathmann W, Giani G (2004) Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047-1053. doi: 10.2337/diacare.27.10.2568
    [69] Zhang BB, Moller DE (2000) New approaches in the treatment of type 2 diabetes. Curr Opin Chem Biol 4: 461-467. doi: 10.1016/S1367-5931(00)00103-4
    [70] Buse JB (2011) Type 2 diabetes mellitus in 2010: Individualizing treatment targets in diabetes care. Nat Rev Endocrinol 7: 67-68. doi: 10.1038/nrendo.2010.230
    [71] Sivakumar S, Palsamy P, Subramanian SP (2010) Impact of D-pinitol on the attenuation of proinflammatory cytokines, hyperglycemia-mediated oxidative stress and protection of kidney tissue ultrastructure in streptozotocin-induced diabetic rats. Chem Biol Interact 188: 237-245. doi: 10.1016/j.cbi.2010.07.014
    [72] Geethan PK, Prince PS (2008) Antihyperlipidemic effect of D-pinitol on streptozotocin-induced diabetic Wistar rats. J Biochem Mol Toxicol 22: 220-224. doi: 10.1002/jbt.20218
    [73] WHO Expert Committee on Diabetes Mellitus: Second Report (1980) World Health Organ Tech Rep Ser 646: 1-80.
    [74] Bates SH, Jones RB, Bailey CJ (2000) Insulin like effect of pinitol. Br J Pharmacol 130: 1944-1948. doi: 10.1038/sj.bjp.0703523
    [75] Narayanan CR, Joshi DD, Mujumdar AM, et al. (1987) Pinitol, a new antidiabetic compound from the leaves of Bougainvillea pectabilis. Curr Sci 56: 139-141.
    [76] Rastegar S, Soltani S, Roohipoor A, et al. (2017) Study of plants with D-chiro-inositol and its derivatives on diabetes. Int J Pharmacogn 4: 43-53.
    [77] Nascimento N, Cortez LU, Sousa LG, et al. (2014) Pinitol ameliorates impaired pressurenatriuresis in experimental diabetes. FASEB J 28: 1063-1065. doi: 10.1096/fasebj.28.1_supplement.1063.5
    [78] Sivakumar S, Palsamy P, Subramanian SP (2010) Attenuation of oxidative stress and alteration of hepatic tissue ultrastructure by D-pinitol in streptozotocin-induced diabetic rats. Free Radic Res 44: 668-678. doi: 10.3109/10715761003733901
    [79] Sivakumar S, Subramanian SP (2009) Pancreatic tissue protective nature of D-pinitol studied in streptozotocin-mediated oxidative stress in experimental diabetic rats. Eur J Pharmacol 622: 65-70. doi: 10.1016/j.ejphar.2009.09.021
    [80] Davis A, Christiansen M, Horowitz JF, et al. (2000) Effect of pinitol treatment on insulin action in subjects with insulin resistance. Diabetes Care 23: 1000-1005. doi: 10.2337/diacare.23.7.1000
    [81] Ortmeyer HK, Huang LC, Zhang L, et al. (1993) Chiroinositol deficiency and insulin resistance. Ⅱ. Acute effects of D-chiroinositol administration in streptozotocin diabetic rats, normal rats given a glucose load, and spontaneously insulin-resistant rhesus monkeys. Endocrinology 132: 646-651. doi: 10.1210/endo.132.2.8425484
    [82] Fonteles MC, Huang LC, Larner J (1996) Infusion of pH 2.0 D-chiroinositol glycan insulin putative mediator normalizes plasma glucose in streptozotocin diabetic rats at a dose equivalent to insulin without inducing hypoglycaemia. Diabetologia 39: 731-734. doi: 10.1007/BF00418546
    [83] Fonteles MC, Almeida MQ, Larner J (2000) Antihyperglycemic effects of 3-O-methyl-D-chiro-inositol and D-chiro-inositol associated with manganese in sterptozotocin diabetic rats. Horm Metab Res 32: 129-132. doi: 10.1055/s-2007-978606
    [84] Ortmeyer HK, Larner J, Hansen BC (1995) Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys. Obes Res 3: 605S-608S. doi: 10.1002/j.1550-8528.1995.tb00232.x
    [85] Kang MJ, Kim JI, Yoon SY, et al. (2006) Pinitol from soybeans reduces postprandials blood glucose in patients with type 2 diabetes mellitus. J Med Food 9: 182-186. doi: 10.1089/jmf.2006.9.182
    [86] Dang NT, Mukai R, Yoshida K, et al. (2010) D-pinitol and myo-inositol stimulate translocation of glucose transporter 4 in skeletal muscle of C57BL/6 mice. Biosci Biotechnol Biochem 74: 1062-1067. doi: 10.1271/bbb.90963
    [87] Yu J, Choi S, Park ES, et al. (2012) D-chiro-inositol negatively regulates the formation of multinucleated osteoclasts by down-regulating NFATc1. J Clin Immunol 32: 1360-1371. doi: 10.1007/s10875-012-9722-z
    [88] Kim JI, Kim JC, Kang MJ, et al. (2005) Effects of pinitol isolated from soybeans on glycemic control and cardiovascular risk factors in patients with type 2 diabetes mellitus: A randomized controlled study. Eur J Clin Nutr 59: 456-458. doi: 10.1038/sj.ejcn.1602081
    [89] Kim MJ, Yoo KH, Kim JH, et al. (2007) Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes. Diabetes Res Clin Pract 77: S247-S251. doi: 10.1016/j.diabres.2007.01.066
    [90] Kim HJ, Park KS, Lee SK, et al. (2012) Effects of pinitol on glycemic control, insulin resistance and adipocytokine levels in patients with type 2 diabetes mellitus. Ann Nutr Metab 60: 1-5. doi: 10.1159/000334834
    [91] Yap A, Nishiumi S, Yoshida KI, et al. (2007) Rat L6 myotubes as an in vitro model system to study GLUT4-dependent glucose uptake stimulated by inositol derivatives. Cytotechnology 55: 103-108. doi: 10.1007/s10616-007-9107-y
    [92] Larner J (2002) D-chiro-inositol its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res 3: 47-60. doi: 10.1080/15604280212528
    [93] Yamashita Y, Yamaoka M, Hasunuma T, et al. (2013) Detection of orally administered inositol stereoisomers in mouse blood plasma and their effects on translocation of glucose trasporter 4 in skeletal muscle cells. J Agric Food Chem 61: 4850-4854. doi: 10.1021/jf305322t
    [94] Hernández-Mijares A, Bañuls C, Peris JE, et al. (2013) A single acute dose of pinitol from a naturally-occurring food ingredient decreases hyperglycaemia and circulating insulin levels in healthy subjects. Food Chem 141: 1267-1272. doi: 10.1016/j.foodchem.2013.04.042
    [95] Martin-Lomas M, Rademacher TW, Caro HN, et al. (2001) Alkylated inositolglycans and their use. Worldwide patent WO 0185747(A1).
    [96] Ostlund RE, Sherman WR (1998) Pinitol and derivatives thereof for the treatment of metabolic disorders. United States patent US 5827896(A).
    [97] Larner J, Price J, Picariello T, et al. (1997) Method of treating defective glucose metabolism using synthetic insulin substances. United States patent US 5652221(A).
    [98] Koon MH (2013) Combination of pinitol and natural product for treating diabetes mellitus. Korean patent KR 20130017864(A).
    [99] Koon MH (2013) Combination of pinitol and drug for treating diabetes mellitus. Korean patent KR 20130017859(A).
    [100] Jun JG, Jun YJ, Kim JJ, et al. (2004) Use of chiro-inositol or pinitol for prevention of oxidative damage and prophylaxis composition for diabetic complications containing the chiro-inositol or pinitol. Korean patent KR 20040051455(A).
    [101] Holman GD, Kasuga M (1997) From receptor to transporter: Insulin signalling to glucose transport. Diabetologia 40: 991-1003. doi: 10.1007/s001250050780
    [102] White MF (1997) The insulin signaling system and IRS proteins. Diabetologia 40: S2-S17. doi: 10.1007/s001250051387
    [103] Huang LC, Fonteles MC, Houston DB, et al. (1993) Chiroinositol deficiency and insulin resistance. Ⅲ. Acute glycogenic and hypoglycemic effects of two inositol phospsoglycan insulin mediators in normal and streptozotocin diabetic rats. Endocrinology 132: 652-657. doi: 10.1210/endo.132.2.8425485
    [104] PI3 Kinase/Akt Signaling Pathway, In: Cell Signaling Technology. Available from: https://www.cellsignal.com/contents/science-pathway-research-pi3k-akt-signaling-resources/pi3k-akt-signaling-pathway/pathways-akt-signaling.
    [105] Rahal A, Kumar A, Singh V, et al. (2014) Oxidative stress, pro-oxidants, and antioxidants: The interplay. Biomed Res Int 2014: 761264. doi: 10.1155/2014/761264
    [106] Shin YC, Jeon YJ, Kim JJ (2007) Use of pinitol or chiroinositol for protecting the liver. United States patent US 2007098826 (A1).
    [107] Magielse J, Arcoraci T, Breynaert A, et al. (2013) Antihepatotoxic activity of a quantified desmodium adscendens decoction and D-pnitol against chemically-induced liver in rats. J Ethnopharmacol 146: 250-256. doi: 10.1016/j.jep.2012.12.039
    [108] Keppler D, Lesch R, Reutter W, et al. (1968) Experimental hepatitis induced by D-galactosamine. Exp Mol Pathol 9: 279-290. doi: 10.1016/0014-4800(68)90042-7
    [109] Beck G, Habicht GS (1996) Immunity and the invertebrates. Sci Am 275: 60-66. doi: 10.1038/scientificamerican1196-60
    [110] Alexander P (1975) Tumour immunology in perspective, In: Schcultz J, Leiff RC. Eds., Critical factors in cancer immunology, New York: Academic Press, 213-222.
    [111] Katz A (1983) Immunobiologic staging of patients with carcinoma of the nad and neck. Laryngoscope 93: 445-463. doi: 10.1002/lary.1983.93.4.445
    [112] Gleich GJ, kita H (1997) Bronchial asthma: Lessons from murine models. Proc Natl Acad Sci USA 94: 2101-2102. doi: 10.1073/pnas.94.6.2101
    [113] Chauhan PS, Gupta KK, Bani S (2011) The immunosuppressive effects of Agyrolobium roseum and pinitol in experimental animals. Int Immunopharmacol 11: 286-291. doi: 10.1016/j.intimp.2010.11.028
    [114] Kim JC, Shin JY, Shin DH, et al. (2005) Synergistic anti-inflammatory effects of pinitol and glucosamine in rats. Phytother Res 19: 1048-1051. doi: 10.1002/ptr.1788
    [115] Lee JS, Lee CM, Jeong YI, et al. (2007) D-pinitol regulates Th1/Th2 balance via suppressing Th2 immune response in ovalbumin-induced asthma. FEBS Lett 581: 57-64. doi: 10.1016/j.febslet.2006.11.077
    [116] Lee JS, Jung ID, Jeong YI, et al. (2007) D-pinitol inhibits Th1 polarization via the suppression of dendritic cells. Int Immunopharmacol 7: 79-804.
    [117] Heo JC, Lee SH, Hwang YH, (2011) Extract of immuno-suppressive activities of pinitol isolated from soybean. Korean patent KR 20110116627(A).
    [118] Yun YC, Choi CM, Jeon YJ, (2007) Composition for preventing and treating inflammatory disease comprising glucosamine and Pinitol. Korean patent KR 20070002401(A).
    [119] Goltzman D (2002) Discoveries, drugs and skeletal disorders. Nat Rev Drug Discov 1: 784-796. doi: 10.1038/nrd916
    [120] Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289: 1508-1514. doi: 10.1126/science.289.5484.1508
    [121] Jaerang R, Hyeon-Koon M (2010) Composition for prevention or treatment of bone metabolism disorder comprising d-pinitol as an active ingredient. Chinese patent CN 101808628(A).
    [122] Kirkwood TB, Austad SN (2000) Why do we age? Nature 408: 233-238. doi: 10.1038/35041682
    [123] Hada B, Yoo MR, Seong KM, et al. (2013) D-chiro-inositol and pinitol extend the life span of Drosophila Melanogaster. J Gerontol 68: 226-234. doi: 10.1093/gerona/gls156
    [124] Fontana L, Partridge L, Longo V (2010) Science 328: 321-326.
    [125] Bartke A, Chandrashekar V, Dominici F, et al. (2003) Insulin-like growth fact 1 (IGF-1) and aging: Controversies and new insights. Biogerontology 4: 1-8. doi: 10.1023/A:1022448532248
    [126] Van-Heemst D (2010) Insulin, IGF-1 and logevity. Aging Dis 1: 147-157.
    [127] Chung HY, Kim HJ, Kim JW, et al. (2001) The inflammation hypothesis of aging: Molecular modulation by calorie restriction. Ann N Y Acad Sci 928: 327-335. doi: 10.1111/j.1749-6632.2001.tb05662.x
    [128] Ishida M, Suzuki T, Tsuji A (2015) Biological clock adjusting agent. Japanese patent JP 2015140305(A).
    [129] Choi SK, Park KD, Kim DA, et al. (2013) Preparation method for Ceratonia siliqua fruit extract and cosmetic composition for anti-aging comprising the same. Korean patent KR 101339915(B1).
    [130] Choi SK, Park KD, Kim DA, et al. (2015) Cosmetic composition for anti-aging comprising Ceratonia siliqua fruit extract. Korean patent KR 20150060004(A).
    [131] Barcelos RP, Stefanello ST, Mauriz JL, et al. (2016) Creatine and the liver: Metabolism and possible interactions. Mini Rev Med Chem 16: 12-18. doi: 10.2174/1389557515666150722102613
    [132] Cooper R, Naclerio F, Allgrove J, et al. (2012) Creatine supplementation with specific view to exercise/sports performance: An update. J Int Soc Sports Nutr 9: 1-11. doi: 10.1186/1550-2783-9-33
    [133] Greenwood M, Kreider RB, RasMussen C, et al. (2001) D-pinitol augments whole body creatine retention in man. J Exerc Physiol Online 4: 41-47.
    [134] Cooke MB, Cribb PJ (2015) Effective nutritional supplement combinations, In: Greenwood M, Cooke MC, Ziegenfuss T, Kalman DS, Jose-Antonio Eds., Nutritional Supplements in Sports and Exercise, 2nd ed., Switzerland: Springer.
    [135] Chantler S, Smit K (2015) Pinitol, In: Castell LM, Stear SJ, Burke LM Eds., Nutritional Supplements in Sport, Exercise and Health: An A-Z Guide, London and New York: Routledge-Taylor & Francis Group.
    [136] Kerksick CM, Wilborn CD, Campbell WI, et al. (2009) The effects of creatine monohydrate supplementation with and without D-pinitol on resistance training adaptations. J Strength Cond Res 23: 2673-2682. doi: 10.1519/JSC.0b013e3181b3e0de
    [137] Dykstra JC (2001) A combination of pinitol and creatine to enhance uptake and retention of creatine. Worldwide patent WO 0180853(A1).
    [138] Heuer MA, Clement K, Chaudhuri S (2008) Composition and method for enhancing or promoting the activity of insulin, enhancing skeletal muscle growth, reducing skeletal muscle loss, and increasing the energy supply to skeletal muscle. Worldwide patent WO 2008025116(A1).
    [139] Weeks C (2003) Stimulating transport of glucose into animal administration of pinitol. United States patent US 6518318.
    [140] Ferrante RM, Cunnigham CK (2012) Performance enhancing composition and method of delivering nutrients. United States patent US 2012100247(A1).
    [141] Ferrante RM, Cunnigham CK (2012) Performance enhancing compositions and method of delivering nutrients. United States patent US 2012100120(A1).
    [142] Ferrante RM, Cunnigham CK (2015) Performance enhancing composition and method of delivering nutrients. United States patent US 2015196579(A1).
    [143] Heuer MA, Clement K, Chaudhuri S (2008) Composition and method for enhancing or promoting the activity of insulin, enhancing skeletal muscle growth, reducing skeletal muscle loss, and increasing the energy supply to skeletal muscle. United States patent US 2008058254(A1).
    [144] Dykstra JC, Prairie E (2003) Combination of pinitol and creatine to enhance uptake and retention of creatine. United States patent US 2003212134(A1).
    [145] Heuer MA, Clement K, Chaudhuri S (2008) Composition and method for enhancing or promoting the activity of insulin, enhancing skeletal muscle growth, reducing skeletal muscle loss, and increasing the energy supply to skeletal muscle. Canadian patent CA 2558110(A1).
    [146] Folch J, Petrov D, Ettcheto M, et al. (2016) Current research therapeutic strategies for Alzheimer's disease treatment. Neural Plast 2016: 1-15. doi: 10.1155/2016/8501693
    [147] Pitt J, Thorner M, Brautigan D, et al. (2013) Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols. FASEB J 27: 199-207. doi: 10.1096/fj.12-211896
    [148] Wischik CM, Harrington CR, Storey JMD (2014) Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 88: 529-539. doi: 10.1016/j.bcp.2013.12.008
    [149] Shea TB, Remington R (2015) Nutritional supplementation for Alzheimer's disease? Curr Opin Psychiatry 28: 141-147. doi: 10.1097/YCO.0000000000000138
    [150] Amirrad F, Bousoik E, Shamloo K, et al. (2017) Alzheimer's disease: Dawm of a new era? J Pharm Pharm Sci 20: 184-225. doi: 10.18433/J3VS8P
    [151] Hung SY, Fu WM (2017) Drug candidates in clinical trials for Alzheimer's disease. J Biomed Sci 24: 1-12. doi: 10.1186/s12929-016-0310-z
    [152] Acton QA (2013) Therapies and treatments, In: Neurodegenerative diseases: New insights for the healthcare professional, Georgia: ScholarlyEditions, 203-204.
    [153] Yates P, Woodward M (2017) Drug treatments in development for Alzheimer's disease, In: Ames D, O'Brien JT, Burns A. Editors, Dementia, 5 Eds., New York: CRC Press, 559.
    [154] Pasinetti GM (2006) Compositions and methods for treating Alzheimer's disease and related disorders and promoting a healthy nervous system. United States patent US 2006/0111450A1.
    [155] Pasinetti GM (2013) Compositions and methods for treating Alzheimer's disease and related disorders and promoting a healthy nervous system. United States patent US 2013/0123370A1.
    [156] McLaurin J (2010) Methods of preventing, treating and diagnosing disorders of protein aggregation. European patent EU 2153829A1.
    [157] Available from: a) https://clinicaltrials.gov/ct2/show/NCT00470418. b) Available from: https://clinicaltrials.gov/ct2/show/NCT01928420.
    [158] Falshaw A, Hart JB, Tyler PC (2000) New synthesis of 1 d-and 1 L-1, 2-anhydro-myo-inositol and assessment of their glycosidase inhibitory activities. Carbohydr Res 329: 301-308. doi: 10.1016/S0008-6215(00)00192-0
    [159] Zhan T, Lou H (2007) Synthesis of azole nucleoside analogues of D-pinitol as potential antitumor agents. Carbohydr Res 342: 865-869. doi: 10.1016/j.carres.2007.01.004
    [160] Li M, Wu A, Zhou P (2006) A concise synthesis of (+)-pancratistatin using pinitol as a chiral building blog. Tetrahedron Lett 47: 3707-3710. doi: 10.1016/j.tetlet.2006.03.138
    [161] Tegge W, Ballou CE (1989) Chiral synthesis of D-and L-myo-inositol 1, 4, 5-triphosphate. Proc Natl Acad Sci USA 86: 94-98. doi: 10.1073/pnas.86.1.94
    [162] Ballou CE, Fischer HOL (1953) Derivatives of D-mannohexodialdose (6-aldo-D-Mannose). J Am Chem Soc 75: 3673-3675. doi: 10.1021/ja01111a020
  • This article has been cited by:

    1. Marina Sánchez-Hidalgo, Antonio J. León-González, Marina Gálvez-Peralta, Nuria H. González-Mauraza, Carmen Martin-Cordero, d-Pinitol: a cyclitol with versatile biological and pharmacological activities, 2021, 20, 1568-7767, 211, 10.1007/s11101-020-09677-6
    2. Nurul Husna Ibrahim, Mohamad Fairuz Yahaya, Wael Mohamed, Seong Lin Teoh, Chua Kien Hui, Jaya Kumar, Pharmacotherapy of Alzheimer’s Disease: Seeking Clarity in a Time of Uncertainty, 2020, 11, 1663-9812, 10.3389/fphar.2020.00261
    3. Ana M. Zuluaga, Adal Mena-García, Ana C. Soria Monzón, Maite Rada-Mendoza, Diana M. Chito, Ana I. Ruiz-Matute, Maria L. Sanz, Microwave assisted extraction of inositols for the valorization of legume by-products, 2020, 133, 00236438, 109971, 10.1016/j.lwt.2020.109971
    4. Laura Siracusa, Cristina Occhiuto, Maria Sofia Molonia, Francesco Cimino, Marco Palumbo, Antonella Saija, Antonio Speciale, Concetta Rocco, Giuseppe Ruberto, Mariateresa Cristani, A pinitol-rich Glycyrrhiza glabra L. leaf extract as functional supplement with potential in the prevention of endothelial dysfunction through improving insulin signalling, 2020, 1381-3455, 1, 10.1080/13813455.2020.1764046
    5. Tomasz Antonowski, Adam Osowski, Lesław Lahuta, Ryszard Górecki, Andrzej Rynkiewicz, Joanna Wojtkiewicz, Health-Promoting Properties of Selected Cyclitols for Metabolic Syndrome and Diabetes, 2019, 11, 2072-6643, 2314, 10.3390/nu11102314
    6. Tadashi Yoshida, Christiaan J. Malherbe, Kazunobu Okon, Yutaka Miura, Makoto Hattori, Hiroshi Matsuda, Christo J.F. Muller, Elizabeth Joubert, Enhanced production of Th1- and Th2-type antibodies and induction of regulatory T cells in mice by oral administration of Cyclopia extracts with similar phenolic composition to honeybush herbal tea, 2020, 64, 17564646, 103704, 10.1016/j.jff.2019.103704
    7. Magdalena Ligor, Ileana-Andreea Rațiu, Hossam Al-Suod, Agnieszka Owczarczyk-Saczonek, Lesław Lahuta, Ryszard Górecki, Bogusław Buszewski, 2021, Chapter 7, 978-3-030-61878-0, 163, 10.1007/978-3-030-61879-7_7
    8. Il-Sup Kim, Cheorl-Ho Kim, Woong-Suk Yang, Physiologically Active Molecules and Functional Properties of Soybeans in Human Health—A Current Perspective, 2021, 22, 1422-0067, 4054, 10.3390/ijms22084054
    9. Özge ŞENER, Bengi HAKGÜDER TAZE, Carob As A Functional Food Ingredient: Properties and Food Applications, 2022, 2636-879X, 10.47137/usufedbid.1130043
    10. José Ignacio López-Sánchez, Diego A. Moreno, Cristina García-Viguera, Correction: D-pinitol, a highly valuable product from carob pods: Health-promoting effects and metabolic pathways of this natural super-food ingredient and its derivatives, 2021, 6, 2471-2086, 752, 10.3934/agrfood.2021044
    11. Esther García-Díez, Helena Sánchez-Ayora, María Blanch, Sonia Ramos, María Ángeles Martín, Jara Pérez-Jiménez, Exploring a cocoa–carob blend as a functional food with decreased bitterness: Characterization and sensory analysis, 2022, 165, 00236438, 113708, 10.1016/j.lwt.2022.113708
    12. Elif Yaver, Novel crackers incorporated with carob and green lentil flours: Physicochemical, textural, and sensory attributes, 2022, 46, 0145-8892, 10.1111/jfpp.16911
    13. Danko Jeremic, Lydia Jiménez-Díaz, Juan D. Navarro-López, Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review, 2021, 72, 15681637, 101496, 10.1016/j.arr.2021.101496
    14. Joanna Płonka, Joanna Szablińska-Piernik, Bogusław Buszewski, Irena Baranowska, Lesław B. Lahuta, Analyses of Antioxidative Properties of Selected Cyclitols and Their Mixtures with Flavanones and Glutathione, 2021, 27, 1420-3049, 158, 10.3390/molecules27010158
    15. María Emilia Brassesco, Teresa R.S. Brandão, Cristina L.M. Silva, Manuela Pintado, Carob bean (Ceratonia siliqua L.): A new perspective for functional food, 2021, 114, 09242244, 310, 10.1016/j.tifs.2021.05.037
    16. Aristea Gioxari, Charalampia Amerikanou, Irini Nestoridi, Eleni Gourgari, Harris Pratsinis, Nick Kalogeropoulos, Nikolaos K. Andrikopoulos, Andriana C. Kaliora, Carob: A Sustainable Opportunity for Metabolic Health, 2022, 11, 2304-8158, 2154, 10.3390/foods11142154
    17. Aamir Khan, Ashif Iqubal, Mohd Wasim, Mansoor Ali Syed, Syed Ehtaishamul Haque, D‐pinitol attenuates isoproterenol‐induced myocardial infarction by alleviating cardiac inflammation, oxidative stress and ultrastructural changes in Swiss albino mice, 2022, 49, 0305-1870, 1232, 10.1111/1440-1681.13703
    18. Maria Derkaczew, Piotr Martyniuk, Adam Osowski, Joanna Wojtkiewicz, Cyclitols: From Basic Understanding to Their Association with Neurodegeneration, 2023, 15, 2072-6643, 2029, 10.3390/nu15092029
    19. Xinxin Liu, Tomoyuki Koyama, D-Pinitol Improved Glucose Metabolism and Inhibited Bone Loss in Mice with Diabetic Osteoporosis, 2023, 28, 1420-3049, 3870, 10.3390/molecules28093870
    20. Xinxin LIU, Chuan HE, Tomoyuki KOYAMA, D-Pinitol Ameliorated Osteoporosis via Elevating D-chiro-Inositol Level in Ovariectomized Mice, 2023, 69, 0301-4800, 220, 10.3177/jnsv.69.220
    21. Irit Schwartz Nadam, Aouatef Bellamine, Rafael Salom, Sonia Guilera, A. M. Inarejos‐Garcia, Giora Pillar, Effects of the active botanical blend “WKUP GT” on attention and cognitive functions after lunch in healthy volunteers, 2024, 0885-6222, 10.1002/hup.2895
    22. Nur Intan Saidaah Mohamed Yusof, Fazlin Mohd Fauzi, Nature's Toolbox for Alzheimer's Disease: A Review on the Potential of Natural Products as Alzheimer's Disease Drugs, 2024, 01970186, 105738, 10.1016/j.neuint.2024.105738
    23. Peter A. Thomas, Xavier Garcia‐Martí, Tarek A. Mukassabi, Joan Tous, International Biological Flora: Ceratonia siliqua, 2024, 0022-0477, 10.1111/1365-2745.14325
    24. Manfred Choo-Yong Ku, Shao-Quan Liu, Unveiling the cocoa-carob flavour gap in dark chocolates via instrumental and descriptive sensory analyses, 2024, 195, 09639969, 114992, 10.1016/j.foodres.2024.114992
    25. Adrienne M. Lambert, Cade M. Christensen, Megan M. McRee, Vaios Moschos, Markiesha H. James, Janica N. D. Gordon, Haley M. Royer, Marc N. Fiddler, Barbara J. Turpin, Solomon Bililign, Jason D. Surratt, Chemical Characterization of Organic Aerosol Tracers Derived from Burning Biomass Indigenous to Sub-Saharan Africa: Fresh Emissions versus Photochemical Aging, 2024, 2837-1402, 10.1021/acsestair.4c00206
    26. Nurul Husna Ibrahim, Jaya Kumar, Wael M.Y. Mohamed, 2025, 9780443157028, 437, 10.1016/B978-0-443-15702-8.00027-0
    27. Mohamad Ali El Chami, Guillermo Palacios-Rodríguez, José L. Ordóñez-Díaz, Raquel Rodríguez-Solana, Rafael M. Navarro-Cerrillo, José M. Moreno-Rojas, Proximate Analysis, Total Phenolic Content, and Antioxidant Activity of Wild Carob Pulp from Three Mediterranean Countries, 2025, 15, 2076-3417, 1340, 10.3390/app15031340
    28. Kadir Aksu, Melek Çol Ayvaz, Ömer Faruk Çelik, Goncagül Serdaroğlu, Elvan Üstün, Latif Kelebekli, Synthesis, Biological Activities, DFT Calculations, and Molecular Docking Studies of O‐Methyl‐Inositols, 2025, 1612-1872, 10.1002/cbdv.202402346
  • Reader Comments
  • © 2018 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(13132) PDF downloads(3187) Cited by(25)

Article outline

Figures and Tables

Figures(9)  /  Tables(2)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog