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Nutraceuticals Synergistically Promote Proliferation of Human Stem Cells

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Abstract

A viable alternative to stem cell transplantation is to design approaches that stimulate endogenous stem cells to promote healing and regenerative medicine. Many natural compounds have been shown to promote healing; however, the effects of these compounds on stem cells have not been investigated. We report here the effects of several natural compounds on the proliferation of human bone marrow and human CD34(+) and CD133(+) cells. A dose-related effect of blueberry, green tea, catechin, carnosine, and vitamin D(3) was observed on proliferation with human bone marrow as compared with human granulocyte-macrophage colony-stimulating factor (hGM-CSF). We further show that combinations of nutrients produce a synergistic effect to promote proliferation of human hematopoietic progenitors. This demonstrates that nutrients can act to promote healing via an interaction with stem cell populations.

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... This formulation was chosen specifically based upon a study of hundreds of potential ingredients where top candidates were tested for the ability to promote stem cell proliferation in vitro, and this combination was found to be more than additive [26]. Follow-up studies demonstrated that the administration of this supplement to mice protects cells from oxidative insults during ischemic stroke [27]. ...
... NT-20 is a proprietary formulation that contains green tea extract which is a minimum of 95% polyphenols and 45% EGCG, blueberry powder from fruit, carnosine, 2000 IU Vitamin D3, and 40 mg grape seed extract. Initial studies describing the formulation described the process for choosing the formulation based upon screening many individual ingredients followed by targeted combinations; the choice of the final formulation showed more than additive effects of the four ingredients on stimulating the proliferation of stem cells in culture [26]. The dose of NT-020 used is based upon the recommended daily dose of NT-020 for humans. ...
... We performed gene ontology on differentially expressed proteins (p < 0.05) in the AGING and OLD-NT-020 comparisons using the GOplot package in R [26]. Circle plots generated with the GOCircle script integrated functional enrichment analysis on dataset proteins based on z-score using g: Profiler output [27]. ...
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Microglial activity in the aging neuroimmune system is a central player in aging-related dysfunction. Aging alters microglial function via shifts in protein signaling cascades. These shifts can propagate neurodegenerative pathology. Therapeutics require a multifaceted approach to understand and address the stochastic nature of this process. Polyphenols offer one such means of rectifying age-related decline. Our group used mass spectrometry (MS) analysis to explicate the complex nature of these aging microglial pathways. In our first experiment, we compared primary microglia isolated from young and aged rats and identified 197 significantly differentially expressed proteins between these groups. Then, we performed bioinformatic analysis to explore differences in canonical signaling cascades related to microglial homeostasis and function with age. In a second experiment, we investigated changes to these pathways in aged animals after 30-day dietary supplementation with NT-020, which is a blend of polyphenols. We identified 144 differentially expressed proteins between the NT-020 group and the control diet group via MS analysis. Bioinformatic analysis predicted an NT-020 driven reversal in the upregulation of age-related canonical pathways that control inflammation, cellular metabolism, and proteostasis. Our results highlight salient aspects of microglial aging at the level of protein interactions and demonstrate a potential role of polyphenols as therapeutics for age-associated dysfunction.
... ChiCTR2200061216 investigates if hAD-MSC derived exosomes loaded with circcol elns (a circular RNA, circRNA) can promote collagen and elastin synthesis in skin samples from 6 to 10 photoaged patients (55-75 years). The study compares samples of facial skin tissue (part exposed to light), with skin tissue of the hip or upper arm (part protected from light) ( Bickford et al. (2006) reported that these agents (as well as catechin) synergistically stimulated the in vitro proliferation of human bone marrow and human CD34 + and CD133+ cells. CD34 + are often used clinically to quantify H-SC numbers in H-SC transplantation (Remberger et al., 2020). ...
... Frontiers in Aging frontiersin.org Some nutraceuticals (carnosine, catechin, vitamin D3, spirulina) promote SC proliferation in vitro (Bickford et al., 2006;Bachstetter et al., 2010), and are candidates to be repurposed for aging frailty (Figure 4). Before entering clinical trials for aging frailty, these compounds should show their ability to increase SC blood levels in animal models (using GM-CSF as active comparator). ...
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Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions). Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed. With regard to facial skin aging, positive results have been obtained with an autologous preparation of adipose-derived stem cells. A further sixteen clinical trials for physical frailty and facial skin aging are currently underway. Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system. However, intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns). In addition to aesthetic purposes, clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods. Therefore, research on both conditions is complementary, which facilitates a global vision.
... A 2006 study [13] found a dose-related effect of blueberries, L-carnosine and vitamin D3 on the proliferation of human bone marrow related stem cells (as compared with an FDA approved drug, recombinant human granulocyte-macrophage colony stimulating factor, GM-CSF). Compounds such as L-Carnosine and vitamin D3 have been shown to support stem cell proliferation [13]. ...
... A 2006 study [13] found a dose-related effect of blueberries, L-carnosine and vitamin D3 on the proliferation of human bone marrow related stem cells (as compared with an FDA approved drug, recombinant human granulocyte-macrophage colony stimulating factor, GM-CSF). Compounds such as L-Carnosine and vitamin D3 have been shown to support stem cell proliferation [13]. Vitamin D3 has also been shown to be essential for intestinal absorption of calcium and for the regulation of calcium in bones, muscles, and nerves [14]. ...
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Stout et al. (Amer Surg. 73:1106‐1110, 2007) reported base‐line levels of primitive stem cells circulating in adult porcine peripheral blood, which increased dramatically after just 90 minutes of trauma. Ongoing studies have shown similar stem cells in adult equine blood and that base‐line levels varied according to breed of the horse. The current study was undertaken to determine whether these stem cells would increase in number in the peripheral blood following stress in the same horse. Stress was defined as moderate exercise, i.e., 10 minutes of cantering. Blood withdrawal followed the guidelines of FVSU‐IACUC. Adult horses had 8 ml of blood withdrawn by venipuncture immediately prior to and immediately after exercising. After gravity separation, the plasma was withdrawn and 15 microliters of plasma from each sample was mixed with 15 microliters of 0.4% Trypan blue. The resultant solution was mixed, placed onto a hemocytometer and photographed: blastomere‐like stem cells (BLSCs) were Trypan blue positive and < 2.0 microns in size; transitional‐BLSCs (Tr‐BLSCs) were both Trypan blue positive & negative and 2‐5 microns in size; and epiblast‐like stem cells (ELSCs) were Trypan blue negative and 6‐8 microns in size (Young and Black, Minerva Biotech 17:55‐63, 2005). This study demonstrates that moderate exercise will increase the level of these primitive pluripotent stem cells in the blood of adult equines.
... These antioxidants could also push normal HSC stem cells into desired phenotypes specific for certain disorders [46][47][48][49]. The synergic effect between antioxidants (such as blueberry, green tea, catechin, carnosine, and vitamin D3) can act to promote healing via an interaction with CD34+ from human hematopoietic stem cells in vitro [50]. ...
... The optimal concentration of the nutraceutical required is a crucial factor for inducing hematopoietic stem cells mobilization in patients. These active principles from plants could have a great potential for broad clinical applications of HSC [35] in diabetes, Alzheimer, and age-related disorders; these pathologies are associated with low HSC cell numbers [48][49][50]. ...
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Several active principles from plants could trigger the release of stem cells from the bone marrow. Stem cell mobilizers have shown side effects in patients. Thus, the purpose of this paper is to find the natural products from plants (curcuminoids, glycosinolate of sulforaphane, AFA bluegreen algae), which could be potential stem mobilizes without adverse side effects. The antioxidant curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-2,5-dione], glycosinolate of sulforaphane (broccoli) or AFA (Aphanizomenon flos) extract promote beneficial effects in patients. The number of circulating stem cells were monitored by HSC marker-CD34 by flow cytometry in peripheral blood from healthy subjects. CD34 is a hematological stem cells (HSC) marker. A double-blind study was conducted in 22 healthy subjects. We have evaluated whether short-term AFA—Aphanizomenon flos aquae—algae or curcuminoids consumption (powder or liquid formulation) over 48 consecutive hours could increase the total number of peripheral CD34+ blood cells (n = 22, n = 5 subjects/group). The total number of circulating CD34+ cells were quantified after short-term and long-term nutritional supplementation; their levels were compared with their own basal levels (n = 5/group, controls: before taking any supplement) or placebo-treated patients (n = 7); their average age was 54 years old. We also evaluated whether long-term nutritional supplementation with several nutraceuticals could enhance HSC mobilization by increasing the total number of peripheral CD-34+ cell after seven or 38 consecutive days of administration (n = 5, with seven placebo-treated patients). The long-term administration take place with these doses/day [curcuminoids: 2000 mg/day, equivalent to 120 mg of curcuminoids/day), glycosinolate of sulforaphane (66 mg/day), plus AFA Algae bluegreen extract (400 mg/day)]. On the last day (10 A.M.) of treatment, blood samples were collected six hours after taking these supplements; the average age was 54 years old. Notably, the blue green AFA algae extract consumption over 48 h enhances HSC mobilization by increasing the total number of peripheral CD34+ cells. The long-term administration with curcuminoids, glycosinolate of sulforaphane, and AFA bluegreen algae extract also increased the total number of CD34-HSC cells after seven or 38 days of consecutive of administration in healthy subjects.
... In light of recent failures in clinical trials of more than a dozen single-target antiamyloidogenic drugs for the treatment of AD, recent studies have focused on the potential effectiveness of nutritional supplements, or nutraceuticals, with multiple therapeutic targets [12,13,14,15]. NT-020, a propriety blend of blueberry, green tea extract, carnosine and vitamin D3 [16,17], has previously been shown to reduce cognitive decline in aged rats and humans, by enhancing mitochondrial function, as well as enhancing neural stem cell proliferation and reducing oxidative injury [17,18,19]. In the present study, we tested the therapeutic effectiveness of NT-020 on AD-related mitochondrial dysfunction, neuropathology and behavioral impairment in the 5XFAD transgenic mouse model [20]. ...
... Therefore, NT020 can reduce cognitive impairment, possibly by exerting anti-inflammatory and neurogenic actions related to enhanced proliferation of neural stem cells. In vitro studies indicate that NT020 stimulates the proliferation of human stem cells derived from bone marrow, bone marrow-derived CD34 + cells and CD133+ progenitor cells derived from peripheral blood [16]. NT020 also reduced the oxidative stress-induced apoptosis of microglia cells and neurons in vitro and cultured bone marrow cells removed from mice given NT020 orally for 2 weeks exhibited a dose-related reduction of oxidative stress induced cell death. ...
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Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP) proteolysis, tau hyperphosphorylation and the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT). A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore, in the present study, we tested the beneficial effect of a nutraceutical formulation Nutrastem II (Nutra II), containing NT020 (a mitochondrial restorative and antioxidant proprietary formulation) and pyrroloquinolinequinone (PQQ, a stimulator of mitochondria biogenesis) in 5XFAD transgenic mice. Animals were fed Nutra II for 12 weeks, starting at 3 months of age, after which behavioral and neuropathological endpoints were determined. The data from behavioral test batteries clearly revealed that dietary supplementation of Nutra II effectively ameliorated the motor deficiency and cognitive impairment of 5XFAD mice. In addition, Nutra II also protected mitochondrial function in 5XFAD mice brain, as evidenced by declined ROS levels and membrane hyperpolarization, together with elevated ATP levels and respiratory states. Interestingly, while Nutra II treatment only slightly reduced soluble Aβ42 levels, this formulation significantly impacted tau metabolism, as shown by reduced total and phosphorylated tau levels of 5XFAD mouse brain. Taken together, these preclinical findings confirm that mitochondrial function may be a key treatment target for AD and that Nutra II should be further investigated as a potential candidate for AD therapy.
... Because aging is a phenomenon that affects all self-renewing tissues in the body and may result from defects in the local microenvironment, studies aimed at prolonging male fertility are needed in the fields of clinical and preventive medicine [8]. Recently, a few studies have investigated various plant extracts that may modulate the proliferation of many tissue and cell types, including insulinoma, skin, bone marrow, and hematopoietic cells [10][11][12][13][14][15]. Other studies have shown that dietary fatty acids, particularly oleic acid and linolenic acid, actively promote the proliferation of hematopoietic stem cells [10,16,17] and modulate the self-renewal of intestinal epithelial cells [18]. ...
... Recently, a few studies have investigated various plant extracts that may modulate the proliferation of many tissue and cell types, including insulinoma, skin, bone marrow, and hematopoietic cells [10][11][12][13][14][15]. Other studies have shown that dietary fatty acids, particularly oleic acid and linolenic acid, actively promote the proliferation of hematopoietic stem cells [10,16,17] and modulate the self-renewal of intestinal epithelial cells [18]. The potential of natural plant extracts to support the growth of many cell types has been confirmed as reported above. ...
... Ellagic acid belongs to the group of hydrolysable tannins and has antioxidant, antiapoptotic, antimutagenic, antifibrosis, anti-inflammatory, antiatherosclerotic, antibacterial, and HIV-replicating properties. Ellagic acid acts on the proliferation of human bone marrow stem cells, as well as on the viability of osteoblasts and fibroblasts in vitro, in a dose-dependent manner [45,46]. ...
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Severe loss of bone mass may require grafting, and, among the alternatives available, there are natural biomaterials that can act as scaffolds for the cell growth necessary for tissue regeneration. Collagen and elastin polymers are a good alternative due to their biomimetic properties of bone tissue, and their characteristics can be improved with the addition of polysaccharides such as chitosan and bioactive compounds such as jatoba resin and pomegranate extract due to their antigenic actions. The aim of this experimental protocol was to evaluate bone neoformation in experimentally made defects in the mandible of rats using polymeric scaffolds with plant extracts added. Thirty rats were divided into group 1, with a mandibular defect filled with a clot from the lesion and no graft implant (G1-C, n = 10); group 2, filled with collagen/chitosan/jatoba resin scaffolds (G2-CCJ, n = 10); and group 3, with collagen/nanohydroxyapatite/elastin/pomegranate extract scaffolds (G3-CHER, n = 10). Six weeks after surgery, the animals were euthanized and samples from the surgical areas were submitted to macroscopic, radiological, histological, and morphometric analysis of the mandibular lesion repair process. The results showed no inflammatory infiltrates in the surgical area, indicating good acceptance of the scaffolds in the microenvironment of the host area. In the control group (G1), there was a predominance of reactive connective tissue, while in the grafted groups (G2 and G3), there was bone formation from the margins of the lesion, but it was still insufficient for total bone repair of the defect within the experimental period standardized in this study. The histomorphometric analysis showed that the mean percentage of bone volume formed in the surgical area of groups G1, G2, and G3 was 17.17 ± 2.68, 27.45 ± 1.65, and 34.07 ± 0.64 (mean ± standard deviation), respectively. It can be concluded that these scaffolds with plant extracts added can be a viable alternative for bone repair, as they are easily manipulated, have a low production cost, and stimulate the formation of new bone by osteoconduction.
... The economic production and availability of nutraceutical foods are highly desirable objective to improve the health of people in the country especially that of the poor [9]. Now, the nutraceuticals related research for improving its quality and quantity is an important area for ongoing biotechnological investigations [12]. Moreover, the Covid 19 pandemic has proven that in Africa and especially in Cameroon, due to the strong ethnobotanical potential, it is possible to overcome many diseases such as type 2 diabetes. ...
Article
Many modes of action have been explored in the fight against type 2 diabetes, including the use of drugs. But these drugs, in addition to their relatively high cost, are not without side effects. As an alternative to these difficulties, traditional pharmacopoeia use several nutraceutic plants in the treatment of type 2 diabetes including: Vernonia amygdalina, Tetrapleura tetraptera, Leptadenia lancifolia decne and Gum Arabic (Acacia Senegal sap). The fact that these plants are used for the same treatment means that they contain bioactive contents, which can be different depending on the plant. For this reason production of formulated powders (JE1 and JE2) of these plants with good anti-diabetic effects can help in the treatment of some chronic diseases. To assess the efficacy of the formulated powders a study of antioxidant activity of two formulated powders was evaluated. Formulation of powders and comparative analyses of bioactive compounds of different formulated powders obtained was done by using classical methods. The results revealed some difference in the phytochemical contents of the both formulated powders. JE1 is rich in mineral and anti-nutrition contents and JE2 is rich in vitamin C. JE1 and JE2 possess strong antiradical activities, but in general JE1 has the better free radical scavenging efficacy and antiradical activity compared to JE2. Indeed the results reveal that JE1 and JE2 can have an impact on the control of oxidative stress on patients suffering from type 2 diabetes and this explains why Vernonia amygdalina, Tetrapleura tetraptera, Leptadenia lancifolia decne and Gum Arabic (Acacia Senegal sap) are used in the traditional pharmacopoeia for treatment of type 2 diabetes. For this reason consumption of these plants need to be encouraged.
... They can recruit stem cells, increase their proliferation and promote their differentiation. Several natural compounds and their combinations can promote the proliferation and differentiation of iPSCs in vitro (Bickford et al., 2006). Propolis, a natural compound increased the proliferation rate of bone marrow-derived mesenchymal stem cells (BMMSCs), enhanced the chondrogenic and adipogenic differentiation processes. ...
Article
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The effect of stingless bee propolis on the proliferation and differentiation of human stem cells is reported for the first time. Cells (hPSCs) treated with the propolis extracted from Lisotrigona sp., Tetragonula calophyllae and T. travancorica displayed a remarkable difference in their morphology. Gene expression analysis revealed pluripotency markers OCT4 and NANOG to be down-regulated upon treatment with propolis, which confirmed early differentiation of hPSCs. Further investigation on the gene expression of early differentiation markers revealed that propolis supports mesendoderm differentiation, which is a novel finding. The propolis obtained from stingless bees Tetragonula spp. probably has more therapeutic value in terms of its effect on hPSCs viz., more tendency of the cells to differentiate into mesoderm and endoderm lineages, compared to the propolis obtained from Lisotrigona sp.
... They can recruit stem cells, increase their proliferation and promote their differentiation. Several natural compounds and their combinations can promote the proliferation and differentiation of iPSCs in vitro (Bickford et al., 2006). Propolis, a natural compound increased the proliferation rate of bone marrow-derived mesenchymal stem cells (BMMSCs), enhanced the chondrogenic and adipogenic differentiation processes. ...
Article
The effect of stingless bee propolis on the proliferation and differentiation of human stem cells is reported for the first time. Cells (hPSCs) treated with the propolis extracted from Lisotrigona sp., Tetragonula calophyllae and T. travancorica displayed a remarkable difference in their morphology. Gene expression analysis revealed pluripotency markers OCT4 and NANOG to be down-regulated upon treatment with propolis, which confirmed early differentiation of hPSCs. Further investigation on the gene expression of early differentiation markers revealed that propolis supports mesendoderm differentiation, which is a novel finding. The propolis obtained from stingless bees Tetragonula spp. probably has more therapeutic value in terms of its effect on hPSCs viz., more tendency of the cells to differentiate into mesoderm and endoderm lineages, compared to the propolis obtained from Lisotrigona sp.
... They can recruit stem cells, increase their proliferation and promote their differentiation. Several natural compounds and their combinations can promote the proliferation and differentiation of iPSCs in vitro (Bickford et al., 2006). Propolis, a natural compound increased the proliferation rate of bone marrow-derived mesenchymal stem cells (BMMSCs), enhanced the chondrogenic and adipogenic differentiation processes. ...
Article
Full-text available
The effect of stingless bee propolis on the proliferation and differentiation of human stem cells is reported for the first time. Cells (hPSCs) treated with the propolis extracted from Lisotrigona sp., Tetragonula calophyllae and T. travancorica displayed a remarkable difference in their morphology. Gene expression analysis revealed pluripotency markers OCT4 and NANOG to be down-regulated upon treatment with propolis, which confirmed early differentiation of hPSCs. Further investigation on the gene expression of early differentiation markers revealed that propolis supports mesendoderm differentiation, which is a novel finding. The propolis obtained from stingless bees Tetragonula spp. probably has more therapeutic value in terms of its effect on hPSCs viz., more tendency of the cells to differentiate into mesoderm and endoderm lineages, compared to the propolis obtained from Lisotrigona sp.
... In addition to the decrease in the survival of neural stem cells, one of the most notifiable impacts of aging, stress, and neurodegeneration on adult neural stem cells is the progressive reduction in proliferation [5]. Similar to a previous study using human hematopoietic stem cells [43], we showed that BB was able to reverse the decrease in proliferation of human neural stem/progenitor cells induced by a cellular stressor. Decreased hippocampal neurogenesis due to reduced proliferation is an important mechanism underlying age-related cognitive decline as well as neurodegeneration and various types of dementia [44]. ...
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The aging process impacts neural stem cells and causes a significant decline in neurogenesis that contributes to neuronal dysfunction leading to cognitive decline. Blueberries are rich in polyphenols and have been shown to improve cognition and memory in older humans. While our previous studies have shown that blueberry supplementations can increase neurogenesis in aged rodents, it is not clear whether this finding can be extrapolated to humans. We thus investigated the effects of blueberry treatments on adult hippocampal human neural progenitor cells (AHNPs) that are involved in neurogenesis and potentially in memory and other brain functions. Cultured AHNPs were treated with blueberry extract at different concentrations. Their viability, proliferation, and differentiation were evaluated with and without the presence of a cellular oxidative stressor, dopamine, and potential cellular mechanisms were also investigated. Our data showed that blueberry extract can significantly increase the viability and proliferation rates of control hippocampal AHNPs and can also reverse decreases in viability and proliferation induced by the cellular stressor dopamine. These effects may be associated with blueberry’s anti-inflammatory, antioxidant, and calcium-buffering properties. Polyphenol-rich berry extracts thus confer a neuroprotective effect on human hippocampal progenitor cells in vitro.
... Perhaps most interesting regarding the clinical use is the ability to assist with stem cells mobilization. In 2006, the effects of nutraceuticals compounds on stem cells as a viable alternative to induce the proliferation and mobilization of human bone marrow and human CD34+ and CD133+ cells were explored [132]. Another study evaluated human stem cells in vitro and in vivo of an extract from the edible cyanobacterium Aphanizomenon flos-aqua (AFA) [133]. ...
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Spirulina is the most studied cyanobacterium species for both pharmacological applications and the food industry. The aim of the present review is to summarize the potential benefits of the use of Spirulina for improving healthcare both in space and on Earth. Regarding the first field of application, Spirulina could represent a new technology for the sustainment of long-duration manned missions to planets beyond the Lower Earth Orbit (e.g., Mars); furthermore, it could help astronauts stay healthy while exposed to a variety of stress factors that can have negative consequences even after years. As far as the second field of application, Spirulina could have an active role in various aspects of medicine, such as metabolism, oncology, ophthalmology, central and peripheral nervous systems, and nephrology. The recent findings of the capacity of Spirulina to improve stem cells mobility and to increase immune response have opened new intriguing scenarios in oncological and infectious diseases, respectively.
... The most usual nutraceuticals are nutrients, herbs, dietary supplements, functional food, and natural chemical derived from different medicinal plants. 14 The global market for nutraceuticals is expected to touch USD 722.49 Billion by 2027 with a CAGR (COMPOUND ANNUAL GROWTH RATE) of over 8%. ...
Article
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Nutraceuticals are products used as medicines in addition to nutrition. Nutraceuticals can be defined as substances that have physiological benefits or provide protection against chronic disease. Nutraceuticals can be used to improve health, slow down the aging process, prevent chronic diseases, increase life expectancy or support body structure or function. Nutraceuticals are getting a lot of attention these days because of their potential nutritional, safety and therapeutic benefits. Recent studies have shown that these compounds have promising results in various complications. In this review, we have made a great effort in proposing new concepts for nutraceuticals based on disease indications. Highlights herbal remedies that are effective for harsh therapeutic conditions associated with oxidative stress, including allergies, Alzheimer's disease, cardiovascular disease, cancer, diabetes, eye, immunity, inflammation, and Parkinson's disease and obesity. These nutraceuticals are used in various diseases, their application, and current market demand. Examples of fish oil preparations, prebiotics and probiotics reviewed. KEYWORDS: Nutraceutical, Dietary supplements, Antioxidants, Probiotics, Health benefits
... Their multifunctional roles in skeletal muscles have been well addressed through intracellular pH buffering, moderating the energy metabolism, intracellular Ca 2+ level regulation, and antioxidant activity [49]. Although there is limited information regarding their roles in muscle satellite cells, there is some evidence suggesting their potential role in the proliferation of human stem cells and the prevention of senescence in human skeletal myoblasts [50][51][52]. A recent study demonstrated that vitamin B6 and carnosine metabolisms were highly upregulated during myogenic progression of primary human skeletal muscle cells [39]. ...
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Emerging research in human studies suggests an association among vitamin B6, sarcopenia, and muscle strength. However, very little is known regarding its potential role at the cellular level, especially in muscle satellite cells. Therefore, to determine whether vitamin B6 affects the satellite cells, we isolated single myofibers from muscles of vitamin B6-deficient and vitamin B6-supplemented mice. Subsequently, we subjected them to single myofiber culture and observed the number and function of the satellite cells, which remained in their niche on the myofibers. Prior to culture, the vitamin B6-deficient myofibers exhibited a significantly lower number of quiescent satellite cells, as compared to that in the vitamin B6-supplemented myofibers, thereby suggesting that vitamin B6 deficiency induces a decline in the quiescent satellite cell pool in mouse muscles. After 48 and 72 h of culture, the number of proliferating satellite cells per cluster was similar between the vitamin B6-deficient and -supplemented myofibers, but their numbers decreased significantly after culturing the myofibers in vitamin B6-free medium. After 72 h of culture, the number of self-renewing satellite cells per cluster was significantly lower in the vitamin B6-deficient myofibers, and the vitamin B6-free medium further decreased this number. In conclusion, vitamin B6 deficiency appears to reduce the number of quiescent satellite cells and suppress the proliferation and self-renewal of satellite cells during myogenesis.
... A potential nutraceutical is one that holds a promise of a particular health or medical benefit; such a potential nutraceutical only becomes an established one after there are sufficient clinical data to demonstrate such a benefit. It is disappointing to note that the overwhelming majority of nutraceutical products are in the 'potential' category, waiting to become established [27]. The food products used as nutraceutical are categorized as [28]. ...
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Nutraceuticals provides medical and health benefits including the prevention and treatment of a disease. Nutraceuticals are naturally derived bioactive compounds that are found in foods, dietary supplements and herbal products, and have health promoting, disease preventing and medicinal properties. Nutraceuticals are the substances which are not traditionally recognized nutrients but which have positive physiological effects on the human body. Nutraceutical has advantage over the medicine because they avoid side effects. Nutraceuticals are classifying on the basis of their natural source, chemical grouping, nutrients, herbals, dietary supplements and dietary fiber. Herbal nutraceutical is used in maintaining health and act against nutritionally induced acute and chronic diseases, thereby promoting optimal health, longevity, and quality of life. The nutraceutical revolution will lead us into a new era of medicine and health, in which the food industry will become research oriented to the pharmaceutical industry. The present review has been devoted towards understanding of the nutraceuticals from different medicinal plants based on their disease specific indications.
... Therefore, strategies to prevent diseases related to vitamin D status are of great interest. CD34+ cell number could be negatively affected by low levels of vitamin D. In fact, vitamin D could contribute to the proliferation and differentiation of stem cells by interacting with phospholipase C, VEGF1, and 2 and pro-MMP2 activity [28,72]. In addition, it was also proposed that vitamin D protects progenitor cells against oxidative stress [30]; RA patients with higher vitamin D levels presented with higher CD34+ cell number [18], while reduced CD34+ cells were characterized by increased intracellular ROS levels and imbalanced antioxidant enzymes [20]. ...
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Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud's phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. Methods: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). Results: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: -0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: -0.311, p < 0.01), and E/A ratio (r: -0.487, p < 0.001), but not with ejection fraction (r: -0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: -0.619, p < 0.001), sPAP (r: -0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. Conclusion: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.
... For example, in a study carried out by Sanberg et al. was found that certain combinations of blueberry, green tea, catechin, carnosine, and vitamin D3 had a positive effect on the proliferation of HSCs in a dose-dependent manner. 128 Although many studies have been conducted to elucidate the effect of plant derivatives on SCs proliferation, more studies are needed to fully understand all signaling pathways involved. In summary, it can be established that cell proliferation is mediated mostly by the Wnt-⊎ catenin, PI-3K and JAK-STAT pathways, whilst apoptosis is regulated predominantly by the PCK-Bax/Bcl-2 and Cas pathways, as can be observed in Fig. 1. ...
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Stem cells are characterized by their self‐renewal and differentiation potential, emerging as a promising strategy for developing cell therapies to treat degenerative diseases. Stem cell culture under in vitro conditions involves the addition of growth factors to the media to stimulate their proliferation. However, most of these growth factors are of animal origin, hindering the implementation of the cultured cells into the clinic. Therefore, the replacement of animal‐derived growth factors for plant‐derived compounds has been proposed to accomplish the guidelines of good manufacturing practices. Plants are rich sources of bioactive compounds implicated in mainly anti‐inflammatory, anti‐oxidative and immunomodulatory mechanisms. Thus, for many years they have been used to prevent and treat many human diseases. Regarding stem cell culture, plant‐derived compounds act as regulators of signaling pathways involved in proliferation; therefore, their use as supplements in culture media represents a lower cost alternative with greater reproducibility to potentialize cell proliferation under in vitro conditions. Hence, this review aims to discuss plant‐derivative effects on the proliferation of stem cells with special interest in three main mechanisms of actions: (i) growth factors and their proliferation signaling effect, (ii) mitogens and their cell‐cycle regulation effect, and (iii) survival factors and their anti‐apoptotic effect. © 2021 Society of Chemical Industry (SCI).
... It was known that NT-020 is able to stimulate the proliferation of human BMSCs, bone marrow-derived CD34+, and progenitor cells from peripheral blood (CD133+) in vitro [142]. Moreover, NT-020 supplementation protects male Sprague-Dawley rats against ischemic stroke, decreasing by 75% mean glial scarring at the infarction area, increasing the proliferation of SCs in the SVZ of hippocampus, and the migration of SCs to the area of injury [143]. ...
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Cellular senescence plays a very important role in organismal aging increasing with age and in age-related diseases (ARDs). This process involves physiological, structural, biochemical, and molecular changes of cells, leading to a characteristic trait referred to "senescence-associated secretory phenotype (SASP)." In particular, with aging, stem cells (SCs) in situ exhibit a diminished capacity of self-renewal and show a decline in their functionality. The identification of interventions able to prevent the accumulation of senescent SCs in the organism or to pretreat cultured multipotent mesenchymal stromal cells (MSCs) prior to employing them for cell therapy is a main purpose of medical research. Many approaches have been investigated and resulted effective to prevent or counteract SC senescence in humans, as well as other animal models. In this work, we have reviewed the chance of using a number of herb-derived products as novel tools in the treatment of cell senescence, highlighting the efficacy of these agents, often still far from being clearly understood.
... Normally, we lose resilience as we grow old. The authors conducted their studies in rats (Bickford et al. 2015) and human stem cells (Bickford et al. 2006). But, as the authors concluded that researchers need to be aware that not all the phenomena that happens in mice will similarly occur in humans. ...
... Normally, we lose resilience as we grow old. The authors conducted their studies in rats (Bickford et al. 2015) and human stem cells (Bickford et al. 2006). But, as the authors concluded that researchers need to be aware that not all the phenomena that happens in mice will similarly occur in humans. ...
... EA has a stimulatory effect on the proliferation of osteoblasts and fibroblasts and is not toxic to bone-forming cells. 25 It also increases the proliferation of human bone marrow stromal cells (osteoblast progenitor cells) and 26 inhibits osteoclastogenesis by decreasing the expression of tartrate-resistant acid phosphatase, reducing the amount of RANKL that binds to osteoclasts, and inhibiting resorption by preventing the release of helix peptide chains. 27 The reduction in RANKL expression by EA-HA effectively increases the expression of OPG. ...
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Objective Ellagic acid (EA), a phenolic antioxidant, has benefits in bone health and wound healing. The combination of EA and hydroxyapatite (HA) (EA-HA) is expected to increase osteogenesis. The aim of this study was to analyze osteogenesis after application of EA-HA according to the number of osteoblasts and osteoclasts in the bone and the expression of the receptor activator of nuclear factor kappa- ligand (RANKL), osteoprotegerin (OPG), and osteocalcin (OCN) protein. Materials and Methods Thirty Wistar rats were assessed with bone defects created in the left femur. The defects were filled with EA-HA and then sutured. Control groups were filled with polyethylene glycol (PEG) or HA. Each group was sacrificed either 7 or 14 days after treatment. Results The defects filled with EA-HA exhibited the highest number of osteoblasts and the greatest expression of OPG and OCN at both day 7 and day 14 (p = 0.000). Conversely, treatment with EA-HA resulted in lower numbers of osteoclasts and reduced RANKL staining at both time points (p = 0.000). Conclusions EA-HA can increase osteogenesis in bone defects by increasing the number of osteoblasts and the expression of OPG and OCN.
... Nutraceuticals or functionalfoods can be classified based on their natural sources, pharmacological parameters or according to their chemical constitution. The most usual nutraceuticals are nutrients, herbals, dietary supplements, functional food and natural chemicals derived from different medicinal plants (Bickford et al. 2006).The chemical characteristics can be used for grouping nutraceuticals based upon their chemical nature. This approach allows nutraceuticals to be categorized under different molecular/elemental groups and subgroups. ...
Chapter
Wild plants have a great role in the lives of tribal peoples living in and around the world by way of providing products for both food and medicine. Such herbal plants are the core of research, which can solve several health issues as well as nutritional supplements. Keeping on the view we have presented a summary of medicinal plants used as nutraceuticals collected from various regions of India. This communication describes 35 herbal plants used as a medicine against different diseases as well as their nutritional applicability.
... In a rat model of stroke, rats given an NT-020supplemented diet showed increased neurogenesis compared with vehicle-treated rats (Yasuhara et al. 2008). In in vitro studies, NT-020 and the blue-green algae spirulina were shown to synergistically increase proliferation of human adult stem cells (Bickford et al. 2006;Bachstetter et al. 2010;Shytle et al. 2010). Furthermore, when rat mesenchymal stem cells (MSCs) or neural progenitor cells (NPCs) were cultured in serum derived from old rats, decreased proliferation was observed. ...
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Aging is associated with many pathophysiological changes that could lead to the onset of degenerative disease. Some of the physiological changes that occur with aging include increased inflammation and decreased stem cell proliferation, leading to decreased capacity for tissue regeneration and loss of function. In previous studies, we and others have found nutraceutical intervention to ameliorate some of the deleterious effects associated with aging. In particular, we have previously shown that NT-020, a supplement composed of a proprietary blend of blueberries, green tea, vitamin D3, and carnosine, is able to rescue age-related cognitive deficits, impaired neurogenesis, and inflammation in rats. We have also previously demonstrated that stem cells cultured with old serum showed decreased proliferation; however, when stem cells were cultured in serum from old rats given a diet supplemented with NT-020, proliferation did not differ from that of cells cultured with serum from young rats. While it is clear that NT-020 is exerting a therapeutic, anti-aging effect, the mechanisms of action were yet to be fully elucidated.To that end, in the present study, we conducted a bioinformatics experiment to examine the rat proteome of serum from young and old control rats and young and old rats given a diet supplemented with NT-020. Serum from old rats showed an increase in some inflammatory and pro-aging factors while serum from old rats given a diet supplemented with NT-020 showed an increase in some anti-aging factors, most notably proteins associated with the complement system and autophagy. A number of immune functions that increase with age were shown to be downregulated with NT-020 treatment.
... stem cell proliferation, which is the reason they were studied initially. However, NT-020 has been shown to be more than additive to promote stem cell proliferation when the individual ingredients are combined together [8]. ...
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Purpose: Evaluate the effectiveness of a commercially available nutraceutical product on levels of exercise-related energy, fatigue, and exertion before and after 4 weeks of supplementation. Primary ingredients within the product include a proprietary blend of blueberry extract, green tea extract, L-carnosine, Vitamin D3 (NT-020; 920mg), and rhodiola rosea, a plant that purports to boost energy and hold antioxidant and anti-inflammatory properties. Methods: Twenty-seven participants (13 females, 14 males, mean BMI = 23, mean age ± SD = 24 + 6 years) completed a baseline assessment of aerobic fitness (mean VO2 peak = 40 mL x kg-1 x min-1) before being randomized into a placebo or supplement group for four weeks. All participants were involved in regular physical activity three or more days per week. Assessment of energy, fatigue, and perceived exertion responses during and immediately following moderately intense cycle ergometry exercise was conducted before and after the 4-week ingestion period during which participants were instructed to maintain existing exercise activities. Results: Data were analyzed by way of repeated measures ANOVA and dependent t-tests to determine the presence of significant differences across time and between the supplement and placebo conditions. Participants receiving the supplement reported: greater levels of energy and lower levels of fatigue during the initial moments after completing the exercise trial (p < 0.05), greater levels of energy at the midpoint of the exercise trial (p < 0.05) but not at the end of the exercise session (p > 0.05), and lower perceived exertion at four of the six measurement points during exercise (p < 0.05). No differences were observed from pre to post intervention within the placebo condition (p > 0.05). Conclusions: Findings indicate that a commercially available supplement marketed to boost energy and reduce fatigue can deliver the purported benefits at least in part. Related findings that supplementation for a 4-week period can allow for equal work at a lower rating of perceived exertion provides further, though limited support that this product may have efficacy. Keywords: fatigue; perceived exertion; energy; rhodiola rosea; NT-020
... Blue berry, green tea, catechin, carnosine, and vitamin D3 were proved to have cell proliferation potential on human bone marrow as compared with human granulocyte macrophage colony-stimulating factor (h GM-CSF). Further studies showed that an interaction of nutrients with stem cell populations can promote rejuvenation (Bickford et al., 2006). There are several other natural compounds such as betulin and betulinic acid, which had previously been reported for cell proliferative potential and exhibited mitogenic activity with the ability to induce and modulate cytokine production in human blood leucocyte cells (Zdzisiń ska et al., 2003). ...
Article
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Using different chromatographic methods, four new compounds were isolated from the aerial parts of Suaeda monoica (Chenopodiaceae) along with 2-hydroxy-1-naphthoic acid (SCM-3). The structures of the new compounds were established as 6'-hydroxy-10'-geranilanyl naphtha-1-oate (SMC-1), 4,4,8β,10β-Tetramethyl-9β-isobutanyl decalin-13-ol-13-O-β-D-xylopyranoside (SCM-2), 6'-(2-hydroxynaphthalen-3-yl) hexanoic acid (SCM-4) and 1'-(2-Methoxy-3-naphthyl)-4'-(2''-methylbenzoyl)-n-butane (SMC-5) by IR, EIMS and NMR (1 & 2D) analyses. All compounds (50 μg/mL) were tested for cell proliferative potential on cultured human liver cell HepG2 cells by MTT assay. The results revealed a marked cell proliferative potential of all compounds (1.42-1.48 fold) as compared to untreated control. The results of molecular docking and binding with specific proteins such as PTEN (Phosphatase and Tensin homolog) and p53 also justify the cell proliferative potential of the isolated compounds. Glide program with Schrodinger suit 2018 was used to evaluate the binding between SMC compounds and proteins (PTEN and p53). The binding affinity of all compounds was in order of 104-105 M-1 towards both PTEN and p53. All the SMC compounds have been found to bind at the active site of PTEN, thereby may prevent the binding of phosphatidylinositiol 3,4,5-triphosphate (PI3P). In the locked position, PTEN would not be able to hydrolyze PI3P and hence the PI3P regulated signaling pathway remains active. Similarly, SMC molecules were found to interact with the amino acid residues (Ser99, Thr170, Gly199, and Asp224) which are critically involved in the formation of tetrameric p53. The blockage of p53 to attain its active conformation thus may prevent the recruitment of p53 on DNA and hence may promote cell proliferation.
... Many natural compounds have been shown to promote healing. Bickford et al. (2006) reported about the effects of several natural compounds on the proliferation of human bone marrow and human CD34(+) and CD133(+) cells. A dose-related effect of blueberry, green tea, catechin, carnosine, and vitamin D was observed on proliferation with human bone marrow as compared with human granulocyte-macrophage colony-stimulating factor (hGM-CSF). ...
Article
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This study aimed to investigate the ameliorative role of curcumin or green tea on gasoline-induced hematotoxicity. Green tea extract and powdered curcumin were chosen as antioxidant and antihematoxicity natural products. CD1 mice were taken as experimental model. Mice were exposed to gasoline vapor 2hours/day for 3 weeks in inhalation chamber. The concentration of gasoline is 9375 ppm and the concentration of benzene is 100 fold less than gasoline in equilibrium with pure benzene being 93.75 ppm. Hematological parameters in bone marrow and peripheral blood were measured and histopathological investigations were done. The results of this study were concluded as follow: 1-Bone marrow depression was occurred by gasoline as reduction in bone marrow cellularity and slow rate of cells maturation. Apptosis appeared in bone marrow cells by histopathological examination for biopsies. All these were improved in the groups provided with green tea and curcumin in the diet. 2-Reduction in blood cell counts was occurred, in RBCs, WBCs, platelets, and hemoglobin. Lymphocytes percentages in blood were depressed and neutrophils percentages were elevated ingasoline inhalation group. All these changes returned to the normal levels by green tea extract and curcumin. (13) (PDF) Ameliorative effects of curcumin and green tea against gasoline inhalation hematotoxicity. Available from: https://www.researchgate.net/publication/335727313_Ameliorative_effects_of_curcumin_and_green_tea_against_gasoline_inhalation_hematotoxicity [accessed Oct 17 2019].
... One of the first study that took into account the possibility to use a combination of natural antioxidant compounds to stimulate the proliferation of stem cells was conducted by Bickford et al. 146 Human hematopoietic stem cells derived from bone marrow were supplemented with different concentrations of catechin, carnosine, blueberry extract, green tea extract, and vitamin D 3 alone or in combination. All the tested compounds exhibited a positive effect on cell proliferation, although the combined treatments showed a stronger effect with respect to the single treatments. ...
Article
The efficient use of stem cells for transplantation is often limited by the relatively low number of stem cells collected. The ex vivo expansion of human stem cells for clinical use is a potentially valuable approach to increase stem cell number. Currently, most of the procedures used to expand stem cells are carried out using a 21% oxygen concentration, which is about 4- to 10-fold greater than the concentration characteristic of their natural niches. Hyperoxia might cause oxidative stress with a deleterious effect on the physiology of cultured stem cells. In this review, we investigate and critically examine the available information on the ability of natural compounds to counteract hyperoxia-induced damage in different types of stem cells ex vivo. In particular, we focused on proliferation and stemness maintenance in an attempt to draw up useful indications to define new culture media with a promoting activity on cell expansion in vitro.
... [2][3][4][5] These observations were obtained when stem cells was treated in the presence of common chemical reagents.Interestingly, several studies had reported that natural product from plants could promote stem cell growth. [6][7][8] Therefore; it would be a huge advantage to identify certain natural product that is non-toxic and can maintain or promote the growth of SHED. ...
Article
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Previous study reported that plant natural product promotes stem cell growth. Flaxseed (Linum usitatissimum) contains numerous compounds recognized for its health benefits. This study aimed to investigate the biological effects of flaxseed crude extract on stem cells obtained from human exfoliated deciduous teeth (SHED). Whole flaxseeds were ground and extracted with absolute ethanol using soxhlet extractor. The effects of flaxseed crude extract on SHED were assessed at concentration 1, 2, 4, 8 and 16 mg/ml for cell viability using MTT assay, cell morphology using inverted microscope and proliferative activity describe as population doubling time (PDT) using alamarBlue assay. The fatty acid composition of flaxseed was analysed using gas chromatography-mass spectrometry (GCMS) instrumental technique.Although insignificant, flaxseed at concentration up to 4 mg/ml slightly increased SHED proliferation activity while maintaining cell viability and morphology. However, 8 mg/ml of flaxseed inhibited cell viability and proliferation activity, and changed the cell morphology. GCMS analysis revealed the presence of linolenic acid, linoleic acid, palmitic acid and stearic acid. Overall, ethanolic crude extract of flaxseed at concentration up to 4 mg/ml slightly enhanced the growth and maintained the morphology of SHED. Clinical article (J Int Dent Med Res 2018; 11(2): pp. 643-649)
... Natural extracts represent a promising source of alternative medicine for many degenerative diseases. Their effect is mediated by different factors, including their capacity to recruit stem cells, to increase their proliferation, to migrate, and to enhance the differentiation of endogenous stem cells [1][2][3]. Propolis is classified as a natural extract from honeybee glue. It has been proven to have several positive biological effects, such as being anti-inflammatory, anti-ulcerative, antibacterial, anti-oxidant, anti-tumor, and immunomodulatory, which favors its use in alternative medicine [4][5][6][7][8][9][10][11][12][13]. ...
Article
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Background: Propolis is a resinous material extracted from bee glue with a complex chemical composition. The unique biological properties of propolis have led to its use in alternative medicine and as a nutritional supplement. Recent research shows that propolis could affect the immune system by decreasing the production of inflammatory cytokines and potentiating an effect on resident stem cells. The exact mechanism, however, is unknown. The goal of this study was to demonstrate whether green propolis extract affects any characteristic properties of mesenchymal stromal cells (MSCs)in vitro. Methods: The cytocompatibility of propolis extract and the proliferation of bone marrow mesenchymal stromal cells (BMMSCs) in the presence of propolis was evaluated by live/dead cell staining and MTS viability assay over a period of 3 days. Also, we evaluated the effect of propolis extract on trilineage differentiation and migration capacity of undifferentiated and differentiated BMMSCs. Results: Relative to the control, propolis extract resulted in a significant and linear increase in the proliferation of MSCs and inhibited the osteogenic differentiation of BMMSCs, while there was a potentiation of chondrogenesis and adipogenesis. Finally, in relevance to wound healing, an in vitro scratch assay demonstrated that the migratory potential of differentiated BMMSCs was enhanced in the presence of propolis. Conclusion: We have demonstrated that propolis extract was not toxic to BMMSCs (<400 μg/ml), supported their proliferation, potentiated chondrogenic and adipogenic differentiation processes, and supported cell migrationin vitro. Most interestingly, there was a down-regulation of osteogenesis. These data support the use of propolis extract for enhanced cell proliferation and tissue regeneration; however, it warrants further investigation.
... What is that built-in transforming power that terminates our body-state of 10 12 -10 16 united cells (22), and now replicated in some 7•10 9 human beings living around the world today, remains to be elucidated. Our life span may be related to apoptosis (23), free radicals (24), telomere shortening (25), failure of stem cell regeneration (26), lack of caloric intake restriction (so that the body metabolism operates at an enhanced rate) (27), or something else. Apparently, these undetermined factors affect our lives more than we think. ...
Article
Full-text available
Background. We have studied human life expectancy in Croatia. Materials and Methods. Local daily papers reported obituaries for 447 men and 366 women who died in a month period. The data were analyzed with the median derivative power function model. Results. The median age of death was 76 and 81 years for men and women, respectively. Cumulative mortality increases at a constant rate after the age 60 y and 65 y for men and women, respectively (r2 = 0.99 and 0.98). Conclusions. Individual life span is a stochastic (random) biological event within the deterministic frame of cumulative mortality.
... A study by Kim and colleagues showed that Aconiti Lateralis Preparata Radix (ALR) promoted mouse bone marrow-derived mesenchymal stem cell proliferation by more than 100% compared to controls [318]. Several studies also showed that blueberry and catechin all have a dose-dependent effect on human bone marrow proliferation compared to the granulocyte-macrophage colony-stimulating factor [319][320][321]. Several plant extracts were shown to increase the healing of scratch wounds in several assays compared to controls [322,323]. Polysaccharides and hyperforin from the medicinal plant Hypericum perforatum also known as St John's wort stimulated the differentiation of keratinocytes in several studies [324,325]. ...
Article
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Humans and animals lose tissues and organs due to congenital defects, trauma, and diseases. The human body has a low regenerative potential as opposed to the urodele amphibians commonly referred to as salamanders. Globally, millions of people would benefit immensely if tissues and organs can be replaced on demand. Traditionally, transplantation of intact tissues and organs has been the bedrock to replace damaged and diseased parts of the body. The sole reliance on transplantation has created a waiting list of people requiring donated tissues and organs, and generally, supply cannot meet the demand. The total cost to society in terms of caring for patients with failing organs and debilitating diseases is enormous. Scientists and clinicians, motivated by the need to develop safe and reliable sources of tissues and organs, have been improving therapies and technologies that can regenerate tissues and in some cases create new tissues altogether. Tissue engineering and/or regenerative medicine are fields of life science employing both engineering and biological principles to create new tissues and organs and to promote the regeneration of damaged or diseased tissues and organs. Major advances and innovations are being made in the fields of tissue engineering and regenerative medicine and have a huge impact on three-dimensional bioprinting (3D bioprinting) of tissues and organs. 3D bioprinting holds great promise for artificial tissue and organ bioprinting, thereby revolutionizing the field of regenerative medicine. This review discusses how recent advances in the field of regenerative medicine and tissue engineering can improve 3D bioprinting and vice versa. Several challenges must be overcome in the application of 3D bioprinting before this disruptive technology is widely used to create organotypic constructs for regenerative medicine.
... What is that built-in transforming power that terminates our body-state of 10 12 -10 16 united cells (22), and now replicated in some 7•10 9 human beings living around the world today, remains to be elucidated. Our life span may be related to apoptosis (23), free radicals (24), telomere shortening (25), failure of stem cell regeneration (26), lack of caloric intake restriction (so that the body metabolism operates at an enhanced rate) (27), or something else. Apparently, these undetermined factors affect our lives more than we think. ...
Article
Full-text available
Background. We have studied human life expectancy in Croatia. Materials and Methods. Local daily papers reported obituitairies for 447 men and 366 women who died in a month period. The data were analyzed with the median derivative power function model. Results. The median age of death was 76 and 81 years for men and women, respectively. Cummulative mortality increases at a constant rate after the age 60 y and 65 y for men and women, respectively (r² = 0.99 and 0.98). Conclusions. Individual life span is a stochastic (random) biological event within the deterministic frame of cumulative mortality. © 2018, Croatian Society of Natural Sciences. All rights reserved.
... Indeed, Radix aconiti lateralis preparata has been found to increase 20% the proliferation rate of mouse bone marrow mesenchymal stem cells compared to untreated cells 23 . In addition, blueberry and green tea extracts promote an approximately 30% proliferation rate of human bone marrow cells 24 . Both RAD288 and RAD289 promoted OEC viability and proliferation by 25% and 40% respectively over 24 h. ...
Article
Full-text available
Olfactory ensheathing cells (OECs) are being trialled for cell transplantation therapies for neural repair as they have unique properties which can enhance neuron regeneration. However, improvements in cell viability, proliferation and migration are needed to enhance therapeutic outcomes. Growth factors can enhance cell activity, but they can also induce side effects as they can act on numerous cell types. An alternative approach is to identify natural products (NPs) that more selectively activate specific cell functions. We have examined two pure NPs, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (RAD288) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid (RAD289) isolated from the Australian plant Eremophila microtheca. We determined that RAD288 and RAD289 stimulated the viability and proliferation of OECs in two-dimensional cultures and increased cell viability in three-dimensional spheroids. Both compounds also enhanced OEC-mediated phagocytosis of neural debris. However, only RAD288 stimulated migration of OECs, demonstrating that key structural changes to the compound can dramatically affect the resultant cellular action. In addition, cell-type specific action is highlighted by the result that neither compound stimulated the viability of Schwann cells which are a closely-related glial cell type. Therefore, these small molecules may have high potential for selective activation of specific therapeutically-useful activities of OECs for transplantation therapies to repair the nervous system.
... Calcitriol treatment increased EPC counts in vitro and promoted an improvement in their functionality, these effects being associated with a decreasing IL-6 production by EPC from SLE patients [150]. These results may be caused by the positive effect of vitamin D on the proliferation of human stem cells previously reported [151]. On the other hand, the restoration in EPC functionality was related to a down-regulation of CXCL10 production by EPC [150]. ...
Article
From the discovery of Endothelial Progenitor Cells (EPC), these bone marrow-derived precursors have been placed as crucial mediators of the endothelial repair. Accordingly, altered levels and function of EPC have been found in different scenarios of CV risk. Despite the fact that EPC exhibit important characteristics which support a link of this cell subset with a number of inflammatory and immune networks, little is known on the actual mediators involved and the clinical relevance of these features. Systemic diseases are generally hallmarked by a vascular repair failure and increased cardiovascular disease occurrence, EPC impairment having a pivotal role. Because of their immune-mediated etiology, this group of conditions represents an invaluable scenario to unravel the connections between immune dysregulation and EPC dysfunction. In the present review, we summarize the current knowledge regarding the cutting-edge area of the modulation of EPC levels and function by inflammatory cytokines in systemic diseases. We also address the possibility of the available immunomodulatory drugs to counteract this situation. Finally, due to the emerging role of the vitamin D as a common mediator in the immune system and the cardiovascular axis, we cover the topic of the role of vitamin D as a potential player in the inflammatory-mediated EPC dysfunction in systemic diseases.
... Many natural compounds have been shown to promote healing. Bickford et al. (2006) reported about the effects of several natural compounds on the proliferation of human bone marrow and human CD34(+) and CD133(+) cells. A dose-related effect of blueberry, green tea, catechin, carnosine, and vitamin D was observed on proliferation with human bone marrow as compared with human granulocyte-macrophage colony-stimulating factor (hGM-CSF). ...
Article
Full-text available
This study aimed to investigate the ameliorative role of curcumin or green tea on gasoline-induced hematotoxicity. Green tea extract and powdered curcumin were chosen as antioxidant and antihematoxicity natural products. CD1 mice were taken as experimental model. Mice were exposed to gasoline vapor 2hours/day for 3 weeks in inhalation chamber. The concentration of gasoline is 9375 ppm and the concentration of benzene is 100 fold less than gasoline in equilibrium with pure benzene being 93.75 ppm. Hematological parameters in bone marrow and peripheral blood were measured and histopathological investigations were done. The results of this study were concluded as follow: 1-Bone marrow depression was occurred by gasoline as reduction in bone marrow cellularity and slow rate of cells maturation. Apptosis appeared in bone marrow cells by histopathological examination for biopsies. All these were improved in the groups provided with green tea and curcumin in the diet. 2-Reduction in blood cell counts was occurred, in RBCs, WBCs, platelets, and hemoglobin. Lymphocytes percentages in blood were depressed and neutrophils percentages were elevated ingasoline inhalation group. All these changes returned to the normal levels by green tea extract and curcumin.
... The aims of this research were to investigate the effect of Dex administration toward expression of population number of hematopoietic stem cells and blood progenitor cells, which abundant and produced on bone marrow [5]. We used several parameters in this research, they are hematopoietic stem cells, CD34 + , chemokines, SDF-1 + , erythroid lineage cells, Gr-1 -TER-119 + , granulocytes, Gr-1 + , and B lineage cells, B220 + . ...
... 12 NT-020 was shown to stimulate the proliferation of human stem cells derived from bone marrow, bone marrow-derived CD34 þ , and progenitor cells from peripheral blood (CD133 þ ) in vitro. 20 NT-020 reduced the oxidative stress-induced apoptosis of microglia cells and neurons in vitro. Furthermore, cultured bone mar-row cells removed from mice given NT-020 orally for 2 weeks exhibited a dose-related reduction of oxidative stressinduced cell death. ...
Article
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Abstract Endogenous stem cell (ESC) exploration refers to an increase in the number of stem cells residing in the human body. This can be achieved by administering natural substances, such as honey, which can activate stem cells. Numerous studies have explored the potential of honey for animal and human health, including its antibacterial, antifungal, antiparasitic, anti-inflammatory, immunomodulatory, antioxidant, anti-osteoporosis, anti-malnutrition, and anti-fertility properties. Here, we review the scientific data on the importance of honey as a potential natural substance, and how its ability to activate endogenous stem cells can lead to new therapeutic strategies for different diseases. Honey majorly contributes to stem cell proliferation and differentiation and consequently tissue repair via mobilization and homing of endogenous stem cells toward damaged tissues. Altogether, bioactive compounds in honey or phytochemicals are potential compounds for enhancing stem cell therapeutics for several degenerative diseases.
Chapter
Bioresources are the biologically generated materials that support life on the earth. They include plants, animals, microorganisms, and the total biogenic products. The purposeful use of these resources involves the preparation of food, the discovery of value-added bio-products, and the generation of energy. So these resources have a significant role in agriculture, pharmacological industries, and the production of bioactive molecules with pharmaceutical and industrial potential, thus, contributing to the nation’s overall economic development. Bioresources are generally diverse and abundant in nature. Due to this rich diversity, people depend on these resources to get enough goods and services to meet their needs. Microbial diversity is very vast and can have a wide range of applications in the agriculture, environment, and pharmaceutical industries. Legumes provide food security to millions of populations, and climate-smart agriculture can enhance sustainable utilization. Medicinal plants are storehouses of bioactive molecules with antimicrobial, anticancer, antidiabetic, and hepatoprotective potential. Validation of the ethnomedicinal properties of such plants can lead to the identification of many drug leads, which will be beneficial to mankind. The purposeful over-use of natural resources will lead to socio-economic and environmental issues. The conservation and sustainable consumption of biological resources are very critical for maintaining the balance of our ecosystem. There are many strategies to be followed for the prevention of overexploitation of these resources. A strong focus should be given to improving the resource efficiency of the available biomass to develop novel products with reduced costs. In this aspect, the multidisciplinary research studies on the utilization of different resources would be beneficial for the advancements in health systems and industrial areas through scientific and technological innovation.
Article
Nutraceuticals are essential for healthcare which is an alternative medicine that has gained popularity in recent years. Nutraceuticals consist of nutrients, herbals, and dietary supplements, which make them useful in preserving and promoting health, fighting illness, and improving overall quality of life. Its success or failure will be determined by its rapid expansion, research advances, lack of standards, marketing enthusiasm, quality assurance, and regulations. Nutraceuticals have been used in different regions under different names/categories. however, globally there are no stringent pharmaceutical standards for nutraceutical health products till date, but slowly regulators are paying attention on it. Nutraceuticals can be broadly classified according to it clinical significance, source and therapeutic effects. Nutraceuticals and functional foods have grown to be a multibillion-dollar business worldwide in recent years and personalization is the emerging approach to deliver the best therapeutic effect in future. This review carries extensive information about nutraceutical history, classification, regulatory aspects and industrial perspective.
Article
Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.
Chapter
Tissue damage caused by disease or trauma necessitates a substitution of the damaged tissue through tissue engineering and regenerative medicine. It is a multidisciplinary research in the field of tissue engineering that deals with the synthesis of various kinds of human tissue equivalents, such as heart muscle, bone, cartilage, blood vessels, and nerves. It potentially leads to entire organ replacement by employing principles from the biology (molecular, cell biology, physiology, immunology, chemical) and engineering (electrical, materials science, mechanical) domains. The development of stem cells has opened a vast realm for regenerative medicines, tissue, and organs. Tissue engineering and regenerative medicines adopt the evaluation of biomaterial performance and behavior. The evaluation of properties also includes its drug delivery nature and biomimetic properties. The condemnatory hurdle in tissue engineering and regenerative medicine lies in understanding the interaction between the cells and engineered tissues, the influence of physical and chemical stimuli on cell growth, and cell function, migration, and differentiation. This chapter is a comprehensive discussion on interdisciplinary involvement in tissue engineering and regenerative medicines.
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The ageing trajectory is plastic and can be slowed down by lifestyle factors, including good nutrition, adequate physical activity and avoidance of smoking. In humans, plant-based diets such as the Mediterranean dietary pattern are associated with healthier ageing and lower risk of age-related disease, whereas obesity accelerates ageing and increases the likelihood of most common complex diseases including CVD, T2D, dementia, musculoskeletal diseases and several cancers. As yet, there is only weak evidence in humans about the molecular mechanisms through which dietary factors modulate ageing but evidence from cell systems and animal models suggest that it is probable that better dietary choices influence all 9 hallmarks of ageing. It seems likely that better eating patterns retard ageing in at least two ways including (i) by reducing pervasive damaging processes such as inflammation, oxidative stress/redox changes and metabolic stress and (ii) by enhancing cellular capacities for damage management and repair. From a societal perspective, there is an urgent imperative to discover, and to implement, cost-effective lifestyle (especially dietary) interventions which enable each of us to age well, i.e. to remain physically and socially active and independent and to minimise the period towards the end of life when individuals suffer from frailty and multi-morbidity.
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Nutraceutical is a term coined to describe substances which are not traditionally recognized nutrients but which have positive physiological effects on the human body. Nutraceuticals are derived from various sources such as medicinal plants, marine organisms, vegetables and fruits. Since ancient times mankind has believed in the role played by the appropriate amount of nutrition in maintaining proper health. In the past few years the increasing interest is seen among the consumers, as they feel that it is a relatively safer way to good health. The potential of nutraceuticals/functional foods/food supplements in mitigating hea lth problems. Nutraceuticals are alternative to modern medicine. Development of better characterized and research proven products will help enhance consumer confidence in nutraceuticals. In this review, an attempt has been made to discuss all aspects of nutraceuticals-definition, categories, classification their use in various diseases.
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Aging is the primary risk factor for many neurodegenerative diseases. Thus, understanding the basic biological changes that take place with aging that lead to the brain being less resilient to disease progression of neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease or insults to the brain such as stroke or traumatic brain injuries. Clearly this will not cure the disease per se, yet increasing the ability of the brain to respond to injury could improve long term outcomes. The focus of this review is examining changes in microglia with age and possible therapeutic interventions involving the use of polyphenol rich dietary supplements.
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It was believed since last three decades that anthocyanins have healthy effects on human organs and organs systems. There are now many evidenced-based nutrition studies including epidemiological surveys, animal studies and randomized controlled trials that have elucidated the mechanism behind the positive influence of anthocyanins on various tissues, organs and organ systems of human beings. Anthocyanins in nature mainly exist as heterosides and are not listed and recognized as essential nutrients. Their health benefits are mainly associated with their antioxidant properties, which clearly are influenced by the molecular mechanism related to the expression and modulation of key genes. The present chapter highlights the various studies indicating the co-relation between consumption of anthocyanins and well-being of various parts of human body.
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Cyanobacteria are prokaryotes which can perform photosynthesis like higher plants. Their genomic organisation is very simple and thus is suitable for the study of detailed photosynthesis mechanism at a molecular level also for many other genomic manipulations relevant to benefit of living organisms. This unicellular alga, Spirulina has a thin thread like elongated structure and classified under Cyanobacteriaceae which is blue green in colour. Under microscope it looks like bunch of bright helical threads (Fig. 11.1).
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We have previously found that TJ-48 has the capacity to accelerate recovery from hematopoietic injury induced by radiation and the anti-cancer drug mitomycin C (MMC). The effects are found to be due to its stimulation of spleen colony-forming unit (CFU-S) counts on day 14. In the present study, we attempt to isolate and purify the active components in TJ-48 extracts using a new in vitro hematopoietic stem cell (HSC) assay method. n-Hexane extract from TJ-48 shows a significant stimulatory activity. The extract is further fractionated by silica gel chromatography and HPLC in order to identify its active components. 1H-NMR and GC-EI-MS indicate that the active fraction is composed of free fatty acids (oleic acid and linolenic acid). When 27 kinds of free fatty acids (commercially available) are tested using the HSC proliferating assay, oleic acid, elaidic acid, and linolenic acid are found to have potent activity. The administration of oleic acid to MMC-treated mice enhances CFU-S counts on days 8 and 14 to twice the control group. These findings strongly suggest that fatty acids contained in TJ-48 actively promote the proliferation of HSCs. Although many mechanisms seem to be involved in the stimulation of HSC proliferation, we speculate that at least one of the signals is mediated by stromal cells, rather than any direct interaction with the HSCs.
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CD34(+)-selected hematopoietic progenitor cells are being increasingly used for autotransplantation, and recent evidence indicates that these cells can be expanded ex vivo. Of 15 patients with solid tumors undergoing a phase I/II clinical trial using CD34(+)-selected peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy, we analyzed the frequency of long-term culture-initiating cells (LTCIC) as a measure of transplantation potential before and after ex vivo expansion of CD34+ cells. PBPCs were mobilized by combination chemotherapy and granulocyte colony-stimulating factor (G-CSF). The original unseparated leukapheresis preparations, the CD34(+)-enriched transplants, as well as nonabsorbed fractions eluting from the CD34 immunoaffinity columns (Ceprate; CellPro, Bothell, WA) were monitored for their capacity to repopulate irradiated allogeneic stroma in human long-term bone marrow cultures. We found preservation of more than three quarters of fully functional LTCIC in the CD34(+)-selected fractions. Quantitation of LTCIC by limiting dilution analysis showed a 53-fold enrichment of LTCIC from 1/9,075 in the unseparated cells to an incidence of 1/169 in the CD34+ fractions. Thus, in a single apheresis, it was possible to harvest a median of 1.65 x 10(4) LTCIC per kg body weight (range, 0.71 to 3.72). In addition, in six patients, large-scale ex vivo expansions were performed using a five-factor cytokine combination consisting of stem cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (EPO), previously shown to expand committed progenitor cells. LTCIC were preserved, but not expanded during the culture period. Optimization of ex vivo expansion growth factor requirements using limiting dilution assays for LTCIC estimation indicated that the five-factor combination using SCF, IL-1, IL-3, IL-6, and EPO together with autologous plasma was the most reliable combination securing both high progenitor yield and, at the same time, optimal preservation of LTCIC. Our data suggest that ex vivo-expanded CD34+ PBPCs might be able to allow long-term reconstitution of hematopoiesis.
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Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress that may be ameliorated by antioxidants. Our previous study had shown that rats given dietary supplements of fruit and vegetable extracts with high antioxidant activity for 8 months beginning at 6 months of age retarded age-related declines in neuronal and cognitive function. The present study showed that such supplements (strawberry, spinach, or blueberry at 14.8, 9.1, or 18.6 gm of dried aqueous extract per kilogram of diet, respectively) fed for 8 weeks to 19-month-old Fischer 344 rats were also effective in reversing age-related deficits in several neuronal and behavioral parameters including: oxotremorine enhancement of K(+)-evoked release of dopamine from striatal slices, carbachol-stimulated GTPase activity, striatal Ca(45) buffering in striatal synaptosomes, motor behavioral performance on the rod walking and accelerod tasks, and Morris water maze performance. These findings suggest that, in addition to their known beneficial effects on cancer and heart disease, phytochemicals present in antioxidant-rich foods may be beneficial in reversing the course of neuronal and behavioral aging.
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Tea catechins and other flavonoids have been shown to potentially protect against chronic cardiovascular diseases such as coronary heart disease and atherosclerosis. In this study, 6-month-old female Sprague-Dawley rats were fed green tea extract (50 mg/100 ml in drinking water) up to the age of 22 months, and the age-associated changes in Maillard-type fluorescence and carbonyl groups in the aortic and skin collagen were compared with those occurring in the water-fed control animals. Collagen-linked Maillard-type fluorescence was found to increase in both the aortic and skin tissues as animals aged. The age-associated increase in the fluorescence in the aortic collagen was remarkably inhibited by the green tea extract treatment, while that occurring in the skin collagen was not significantly inhibited by the treatment. The collagen carbonyl content also increased in both the aortic and skin tissues as animals aged. In contrast with the case of Maillard-type fluorescence, however, the age-associated increase in the carbonyl content was not inhibited by the green tea extract treatment either in the aortic or skin collagen. These results suggest that the inhibition of AGE formation in collagen is an important mechanism for the protective effects of tea catechins against cardiovascular diseases.
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Juzen-taiho-to (a Japanese herbal medicine) has been traditionally administered to patients with anemia, neutropenia, or wasting syndrome. We previously attempted to isolate and purify the hemopoiesis-stimulatory components in Juzen-taiho-to extracts using an in vitro hemopoietic stem cell (HSC) assay method in which mouse HSCs can proliferate on a stromal cell line (MS-5). We have found that fatty acids (particularly oleic acid and linolenic acid) actively promote the proliferation of HSCs, and that the effect is mediated by stromal cells, rather than by any direct action on the HSCs. In the present study, we show, using human normal bone marrow cells (BMCs) and umbilical cord blood cells, that similar stimulatory effects are due to the presence of oleic acid and linolenic acid, which stimulate the proliferation of HSCs in stroma-based culture systems. Furthermore, a marked stimulatory effect was noted on BMCs from patients with Shwachman syndrome, which shows pancreatic and bone marrow dysfunctions. We also show the data on hemopoietic recovery after the administration of Juzen-taiho-to to a patient with Shwachman syndrome. These findings suggest that decreased fatty acid levels in the blood, caused by exocrine pancreatic insufficiency, induce bone marrow dysfunction in Shwachman syndrome.
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Antioxidants and diets supplemented with foods high in oxygen radical absorbance capacity (ORAC) reverse age-related decreases in cerebellar beta-adrenergic receptor function. We examined whether this effect was related to the antioxidant capacity of the food supplement and whether an antioxidant-rich diet reduced the levels of proinflammatory cytokines in the cerebellum. Aged male Fischer 344 rats were given apple (5 mg dry weight), spirulina (5 mg), or cucumber (5 mg) either in 0.5 ml water by oral gavage or supplied in the rat chow daily for 14 d. Electrophysiologic techniques revealed a significant decrease in beta-adrenergic receptor function in aged control rats. Spirulina reversed this effect. Apple (a food with intermediate ORAC) had an intermediate effect on cerebellar beta-adrenergic receptor physiology, and cucumber (low ORAC) had no effect, indicating that the reversal of beta-adrenergic receptor function decreases might be related to the ORAC dose. The mRNA of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and TNFbeta was also examined. RNase protection assays revealed increased levels of these cytokines in the aged cerebellum. Spirulina and apple significantly downregulated this age-related increase in proinflammatory cytokines, whereas cucumber had no effect, suggesting that one mechanism by which these diets work is by modulation of an age-related increase in inflammatory responses. Malondialdehyde (MDA) was measured as a marker of oxidative damage. Apple and spirulina but not cucumber decreased MDA levels in the aged rats. In summary, the improved beta-adrenergic receptor function in aged rats induced by diets rich in antioxidants is related to the ORAC dose, and these diets reduce proinflammatory cytokine levels.
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Erythropoiesis is the process in which new erythrocytes are produced. These new erythrocytes replace the oldest erythrocytes (normally about one percent) that are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have crucial roles in erythropoiesis. Erythroblasts require folate and vitamin B12 for proliferation during their differentiation. Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anemia from ineffective erythropoiesis. Erythroblasts require large amounts of iron for hemoglobin synthesis. Large amounts of iron are recycled daily with hemoglobin breakdown from destroyed old erythrocytes. Many recently identified proteins are involved in absorption, storage, and cellular export of nonheme iron and in erythroblast uptake and utilization of iron. Erythroblast heme levels regulate uptake of iron and globin synthesis such that iron deficiency causes anemia by retarded production rates with smaller, less hemoglobinized erythrocytes.
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Carnosine is a naturally occurring dipeptide (β-alanyl-l-histidine) found in brain, innervated tissues, and the lens at concentrations up to 20 mM in humans. In 1994 it was shown that carnosine could delay senescence of cultured human fibroblasts. Evidence will be presented to suggest that carnosine, in addition to antioxidant and oxygen free-radical scavenging activities, also reacts with deleterious aldehydes to protect susceptible macromolecules. Our studies show that, in vitro, carnosine inhibits nonenzymic glycosylation and cross-linking of proteins induced by reactive aldehydes (aldose and ketose sugars, certain triose glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation product). Additionally we show that carnosine inhibits formation of MDA-induced protein-associated advanced glycosylation end products (AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde. At the cellular level 20 mM carnosine protected cultured human fibroblasts and lymphocytes, CHO cells, and cultured rat brain endothelial cells against the toxic effects of formaldehyde, acetaldehyde and MDA, and AGEs formed by a lysine/deoxyribose mixture. Interestingly, carnosine protected cultured rat brain endothelial cells against amyloid peptide toxicity. We propose that carnosine (which is remarkably nontoxic) or related structures should be explored for possible intervention in pathologies that involve deleterious aldehydes, for example, secondary diabetic complications, inflammatory phenomena, alcoholic liver disease, and possibly Alzheimer's disease.
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The anemia of chronic renal failure can now be effectively treated with recombinant human erythropoietin when given in adequate doses. This hormone replacement therapy is associated with significant clinical benefits but it requires adequate iron stores for maximal effectiveness, it may result in elevation in diastolic blood pressure, and the response may be blunted by the presence of infection or inflammation.
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Available evidence indicates that qualitative changes in hematopoietic stem cells and progenitors, such as the decision of stem cells to self-renew or differentiate, or selection of lineage potentials by the multipotential progenitors during differentiation (commitment), are intrinsic properties of the progenitors and are stochastic in nature. In-contrast, proliferative kinetics of the progenitors, namely survival and expansion of the progenitors, appear to be controlled by a number of interacting cytokines. While proliferation and maturation of committed progenitors is controlled by late-acting lineage-specific factors such as Ep, M-CSF, G-CSF, and IL-5, progenitors at earlier stages of development are controlled by a group of several overlapping cytokines. IL-3, GM-CSF, and IL-4 regulate proliferation of multipotential progenitors only after they exit from G0 and begin active cell proliferation. Triggering of cycling by dormant primitive progenitors and maintenance of B-cell potential of the primitive progenitors appears to require interactions of early acting cytokines including IL-6, G-CSF, IL-11, IL-12, LIF, and SF. Currently, this simple model fits our understanding of the interactions of growth factors with hematopoietic progenitors. Naturally the model risks oversimplification of a very complex process. However, because the model is testable, it will hopefully challenge investigators to design new experiments to examine its validity.
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Fruit extracts of four Vaccinium species (lowbush blueberry, bilberry, cranberry, and lingonberry) were screened for anticarcinogenic compounds by a combination of fractionation and in vitro testing of their ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA). The crude extracts, anthocyanin and proanthocyanidin fractions were not highly active in QR induction whereas the ethyl acetate extracts were active QR inducers. The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of lowbush blueberry, cranberry, lingonberry, and bilberry were 4.2, 3.7, 1.3, and 1.0 microgram tannic acid equivalents (TAE), respectively, Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction (CDqr = 0.07 microgram TAE). In contrast to their effects on QR, crude extracts of lowbush blueberry, cranberry, and lingonberry were active inhibitors of ODC activity. The concentrations of these crude extracts needed to inhibit ODC activity by 50% (designated IC50) were 8.0, 7.0, and 9.0 micrograms TAE, respectively. The greatest activity in these extracts appeared to be contained in the polymeric proanthocyanidin fractions of the lowbush blueberry, cranberry, and lingonberry fruits (IC50 = 3.0, 6.0, and 5.0 micrograms TAE, respectively). The anthocyanidin and ethyl acetate extracts of the four Vaccinium species were either inactive or relatively weak inhibitors of ODC activity. Thus, components of the hexane/chloroform fraction of bilberry and of the proanthocyanidin fraction of lowbush blueberry, cranberry, and lingonberry exhibit potential anticarcinogenic activity as evaluated by in vitro screening tests.
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Elucidation of mechanisms that regulate hematopoietic stem cell self-renewal and differentiation would be facilitated by the identification of defined culture conditions that allow these cells to be amplified. We now demonstrate a significant net increase (3-fold, P < 0.001) in vitro of cells that are individually able to permanently and competitively reconstitute the lymphoid and myeloid systems of syngeneic recipient mice when Sca-1(+)lin- adult marrow cells are incubated for 10 days in serum-free medium with interleukin 11, flt3-ligand, and Steel factor. Moreover, the culture-derived repopulating cells continued to expand their numbers in the primary hosts at the same rate seen in recipients of noncultured stem cells. In the expansion cultures, long-term culture-initiating cells increased 7- +/- 2-fold, myeloid colony-forming cells increased 140- +/- 36-fold, and total nucleated cells increased 230- +/- 62-fold. Twenty-seven of 100 cultures initiated with 15 Sca-1(+)lin- marrow cells were found to contain transplantable stem cells 10 days later. This frequency of positive cultures is the same as the frequency of transplantable stem cells in the original input suspension, suggesting that most had undergone at least one self-renewal division in vitro. No expansion of stem cells was seen when Sca-1+TER119- CD34+ day 14.5 fetal liver cells were cultured under the same conditions. These findings set the stage for further investigations of the mechanisms by which cytokine stimulation may elicit different outcomes in mitotically activated hematopoietic stem cells during ontogeny and in the adult.
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Intestinal-fatty acid binding protein (I-FABP) has been proposed to target long chain fatty acids (LCFA) to triglyceride synthesis pathways in the intestinal epithelium. In the present studies hBRIE 380i cells, which endogenously express I-FABP only when fully differentiated, were used to investigate the role of I-FABP in LCFA incorporation and targeting by examining the relative distribution of [3H]-oleic acid in cellular lipids in these cells. [3H]-oleic acid incorporation into triglyceride was significantly higher in hBRIE 380i cells expressing I-FABP than in cells not expressing I-FABP. After 15 min, 1 and 4 h of incubation, cells expressing I-FABP incorporated 24.0%, 34.0% and 43.9% of [3H]-oleic acid into triglyceride, while newly confluent cells (no I-FABP expression) incorporated 15.6%, 18.3% and 31.9%. An I-FABP negative cell line, hBRIE 380i-neg cells, was stably transfected to investigate the effect of adding I-FABP to small intestinal epithelial cell lines. No measurable differences in [3H]-oleic acid incorporation into triglyceride was detected in these transfectants. Additionally I-FABP expression had no effect on [3H]-oleic acid incorporation or distribution within phospholipid subclasses in hBRIE 380i or transfected hBRIE 380i-neg fabpi cells. Our data from hBRIE 380i cells suggest that I-FABP can target LCFA to triglyceride synthesis pathway. However, endogenous I-FABP expression was also correlated to cellular differentiation and therefore raises the possibility that other differentiation-dependent factors may have a role in LCFA targeting. Because no effects of I-FABP were detected in the transfected hBRIE 380i-neg fabpi cells, it is concluded that factors in addition to I-FABP play a major role in determining the metabolic fate of LCFA in small intestinal epithelial cells. (c) 1998 Elsevier Science B.V.
Article
(-)-Epigallocatechin gallate (EGCG), a catechin polyphenol compound, represents the main ingredient of green tea extract. Although EGCG has been shown to be growth inhibitory in a number of tumor cell lines, it is not clear whether the effect is cancer-specific. In this study we compared the effect of EGCG on the growth of SV40 virally transformed WI38 human fibroblasts (WI38VA) with that of normal WI38 cells. The IC50 value of EGCG was estimated to be 120 and 10 microM for WI38 and WI38VA cells, respectively. Thus, EGCG at 40 microM completely inhibited the growth of WI38VA cells, but had little or no inhibitory effect on the growth of WI38 cells. Similar differential growth inhibition was also observed between a human colorectal cancer cell line (Caco-2), a breast cancer cell line (Hs578T) and their respective normal counterparts. EGCG at a concentration range of 40-200 microM induced a significant amount of apoptosis in WI38VA cultures, but not in WI38 cultures, as determined by terminal deoxynucleotidyl transferase assay. After exposure to EGCG at 200 microM for 8 h, more than 50% of WI38VA cells in a confluent culture became apoptotic. In contrast, less than 1% of WI38 cells displayed apoptotic labeling under the same condition. EGCG did not affect the serum-induced expression of c-fos and c-myc genes in normal WI38 cells. However, it significantly enhanced their expression in transformed W138VA cells. It is possible that differential modulation of certain genes, such as c-fos and c-myc, may cause differential effects of EGCG on the growth and death of cancer cells.
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The understanding of molecular mechanisms regulating the formation, growth and differentiation of haemopoietic stem cells has advanced considerably recently. Particular progress has been made in defining the cytokines, chemokines and extracellular matrix components which retain and maintain primitive haemopoietic cell populations in bone marrow. Furthermore, signal transduction pathways that are critical for haemopoiesis, both in vivo and in vitro, and that are activated by cytokines have also been identified and further characterised. The importance of these processes has, this year, been exemplified by the phenotypes of mice deficient in key signal transduction proteins and the discovery that mutations in the component proteins of some signalling pathways are linked to human diseases. Significant advances in understanding the molecular mechanisms for mobilisation of stem cells from bone marrow have also been made this year; this has potential importance for bone marrow transplantation.
Article
This chapter outlines the role of cytokine receptor signaling in the regulation and maturation of myeloid cells: erythrocytes, macrophages, granulocytes, megakaryocytes, and eosinophils. Some cytokine receptors are involved in unique and lineage-specific effects, whereas others appear to have multiple, overlapping, or redundant effects. The biochemical events following receptor activation are identified. Each receptor activates a number of signaling molecules, and in many cases the same molecules are activated by a number of different receptors. Experiments with mutant mice demonstrate that growth factors with overlapping cellular functions nevertheless do have specific unique roles under certain circumstances. The chapter also describes experimental models available for the study, the principal ways in which cytokine receptors are thought to contribute to hematopoietic cell differentiation and survival, and the pathological effects of aberrant cytokine receptor function. Alterations in cytokine receptor structure and function can induce severe pathologies, including immunodeficiency, severe congenital neutropenia and leukemia, dwarfism, or obesity.
Article
Carnosine is a naturally occurring dipeptide (beta-alanyl-L-histidine) found in brain, innervated tissues, and the lens at concentrations up to 20 mM in humans. In 1994 it was shown that carnosine could delay senescence of cultured human fibroblasts. Evidence will be presented to suggest that carnosine, in addition to antioxidant and oxygen free-radical scavenging activities, also reacts with deleterious aldehydes to protect susceptible macromolecules. Our studies show that, in vitro, carnosine inhibits nonenzymic glycosylation and cross-linking of proteins induced by reactive aldehydes (aldose and ketose sugars, certain triose glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation product). Additionally we show that carnosine inhibits formation of MDA-induced protein-associated advanced glycosylation end products (AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde. At the cellular level 20 mM carnosine protected cultured human fibroblasts and lymphocytes, CHO cells, and cultured rat brain endothelial cells against the toxic effects of formaldehyde, acetaldehyde and MDA, and AGEs formed by a lysine/deoxyribose mixture. Interestingly, carnosine protected cultured rat brain endothelial cells against amyloid peptide toxicity. We propose that carnosine (which is remarkably nontoxic) or related structures should be explored for possible intervention in pathologies that involve deleterious aldehydes, for example, secondary diabetic complications, inflammatory phenomena, alcoholic liver disease, and possibly Alzheimer's disease.
Article
The dipeptide L-carnosine has beneficial effects on cultured human fibroblasts. Physiological concentrations in standard media prolong their in vitro lifespan and strongly reduce the normal features of senescence. Late passage cells in normal medium are rejuvenated when transferred to medium containing carnosine, and become senescent when carnosine is removed. In the absence of pyruvate, carnosine is cytotoxic to neoplastic and transformed human and rodent cells. None of these effects are seen with its optical isomer, D-carnosine.
Article
The effect of the green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG) was tested in cultures of normal and transformed NIH-pATM ras fibroblasts. In this system transformation can be induced at will by the addition of dexamethasone, which induces the expression of H- ras by activating the mammary tumor virus long terminal repeat (MMTV-LTR) promoter. This facilitates a reliable comparison of the susceptibility of normal and transformed cells to EGCG. It has been shown that EGCG inhibited the growth of transformed but not of the normal fibroblasts. In an attempt to elucidate the mode of the preferential inhibitory activity of EGCG, its effect on growth promoting factors has been examined. The level of ornithine decarboxylase (ODC, EC 4.1.1.17), which is a signal for cellular proliferation, was reduced by EGCG in the transformed but not in the normal cells. EGCG also showed strong inhibition of tyrosine kinase and mitogen-activated protein kinase (MAPK) activities, without affecting the kinases in the normal cells. Similarly, EGCG also preferentially decreased the levels of the oncogenes Ras and Jun in transformed cell. EGCG preferentially induced apoptosis in the transformed fibroblasts. In vitro chemosensitivity tests demonstrated that EGCG inhibited the proliferation of leukemic cells. These findings suggest that EGCG has a therapeutic potential in the combat against cancer.
Article
It is now well established that the active metabolite of vitamin D3, 1α,25(OH)2D3, regulates cell growth and differentiation in various in vitrocancer models. However, its clinical use is precluded due to its hypercalcemicactivity in vivo. Hence, several less calcemic vitamin D analogs have been synthesizedand evaluated for their chemopreventive and therapeutic efficacy inexperimental carcinogenesis models. A novel analog of vitamin D3, 1α-hydroxy-24-ethyl-cholecalciferol (1α[OH]D5), has currently been under investigationin our laboratory for its application in breast cancer prevention andtherapy. 1α(OH)D5 had been shown to inhibit development of estrogen-andprogesterone-dependent ductal lesions as well as steroid hormone-independentalveolar lesions in a mammary gland organ culture (MMOC) model. Moreover, the inhibitory effect was more significant if 1α(OH)D5 was presentduring the promotional phase of the lesion development. The growth inhibitoryeffect of 1α(OH)D5 has also been manifested in several breast cancer celllines, including BT-474 and MCF-7. Breast cancer cell lines that responded to1a(OH)D5 treatment were vitamin D receptor positive (VDR+). Vitamin D receptor-negative (VDR_) cell lines, such as MDA-MB-231 and MDA-MB-435, did not show growth inhibition upon incubation with 1α(OH)D5.
Article
Treatment from weaning until old age with 1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) prevents diabetes in NOD mice. It is mainly through its actions on dendritic cells (DCs), that 1,25(OH)(2)D(3) changes the function of potentially autoreactive T lymphocytes. In contrast, early life treatment (from 3 to 70 days of age) of NOD mice with vitamin D or 1,25(OH)(2)D(3) did not influence final diabetes incidence at 200 days of age. Also in spontaneous diabetic BB rats, diabetes could not be prevented by early life treatment (from 3 to 50 days of age) with vitamin D (1000 IU per day) or 1,25(OH)(2)D(3) (0.2 microg/kg per day or 1 microg/kg per 2 days). However, when NOD mice were made vitamin D deficient in early life (until 100 days of age), diabetes onset occurred earlier and final incidence was increased. These data further support a role for vitamin D and its metabolites in the pathogenesis of type 1 diabetes in NOD mice.
Article
During aging, reductions in hippocampal neurogenesis are associated with memory decline indicating a causal relationship. Indeed, insulin-like growth factor-1 (IGF-1), a major activator of the extracellular receptor kinase pathway that is central in learning and memory processes, is also a key modulator of hippocampal neurogenesis. Previously, we showed that age-related declines in spatial memory tasks can be improved by antioxidant-rich diets containing blueberries. In this study, to begin to understand the mechanisms responsible for the beneficial effects of blueberries, we assessed changes in hippocampal plasticity parameters such as hippocampal neurogenesis, extracellular receptor kinase activation, and IGF-1 and IGF-1R levels in blueberry-supplemented aged animals. Our results show that all these parameters of hippocampal neuronal plasticity are increased in supplemented animals and aspects such as proliferation, extracellular receptor kinase activation and IGF-1 and IGF-1R levels correlate with improvements in spatial memory. Therefore, cognitive improvements afforded by polyphenolic-rich fruits such as blueberries appear, in part, to be mediated by their effects on hippocampal plasticity.
Article
Many studies are accumulating that report the neuroprotective, cardioprotective, and chemopreventive actions of dietary flavonoids. While there has been a major focus on the antioxidant properties, there is an emerging view that flavonoids, and their in vivo metabolites, do not act as conventional hydrogen-donating antioxidants but may exert modulatory actions in cells through actions at protein kinase and lipid kinase signalling pathways. Flavonoids, and more recently their metabolites, have been reported to act at phosphoinositide 3-kinase (PI 3-kinase), Akt/protein kinase B (Akt/PKB), tyrosine kinases, protein kinase C (PKC), and mitogen activated protein kinase (MAP kinase) signalling cascades. Inhibitory or stimulatory actions at these pathways are likely to affect cellular function profoundly by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of flavonoids, either as antioxidants or modulators of cell signalling, and the influence of their metabolism on these properties are key to the evaluation of these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors of neurodegeneration
Cytokines in hematopoiesis: specificity and redundancy in receptor function Role of cytokines and extracellular matrix in the regulation of haemopoietic stem cells
  • M Socolovsky
  • S Constantinescu
  • A Bergelson
  • Sirotkin
  • Lodish
Socolovsky M, SN Constantinescu, S Bergelson, A Sirotkin and HF Lodish. (1998). Cytokines in hematopoiesis: specificity and redundancy in receptor function. Adv Protein Chem 52:141–198. NUTRACEUTICAL INTERACTION WITH HUMAN STEM CELLS 123 3. Whetton AD and E Spooncer. (1998). Role of cytokines and extracellular matrix in the regulation of haemopoietic stem cells. Curr Opin Cell Biol 10:721–726.
Efficacy and mechanism of action of
  • Hussain Ea
  • Mehta
  • Ray
  • Tk Das Gupta
  • Mehta
Hussain EA, RR Mehta, R Ray, TK Das Gupta and RG Mehta. (2003). Efficacy and mechanism of action of