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Review of literature: Role of 5-aminolevulinic acid and sleep  [PDF]
Michael H. Perez, Beatriz L. Rodriguez, Terry T. Shintani, Terry T. Shintani, Rosanne C. Harrigan
World Journal of Neuroscience (WJNS) , 2013, DOI: 10.4236/wjns.2013.34042

Objective: To determine if current peer-reviewed literature supports the existence of a relationship between the administration of dietary supplements containing 5-Aminolevulinic Acid (5-ALA) and sleep. Methods: Conceptual analysis of a systematically defined group of data is based on publications in referred journals. Constant comparative analyses were used to analyze the data. Detailed analyses were used to identify trends that led to qualifying relationships between the use of 5-ALA and heme. In addition, the relationship among heme, melatonin, and sleep were explored. Since there were no published data related to 5-ALA and sleep, an analysis of what is known about 5-ALA and heme was undertaken. Results: Currently, within the scope of this review, no literature available directly connecting 5-ALA and sleep was found. Research indicates that 5-ALA has an indirect relationship with intra-cellular energy production, which could result in a wide range of effects fromcellular to endocrine to neurologic to behavioral. In addition, there is evidence that 5-ALA may influence tryptophan and serotonin levels. Conclusion: While there are no studies on 5-ALA and sleep were found, current research suggests several potential mechanisms by which 5-ALA could influence sleep. The mechanisms suggest the potential for 5-ALA to assist in the adjustment of a person’s circadian cycle, endocrine function, or neurologic function in order to allow for better sleep in a natural way. In doing so, it may provide for a safer alternative to currently available sleep medication. Further research is needed to explore this possibility.

5-Aminolevulinic Acid (5-ALA): Analysis of Preclinical and Safety Literature  [PDF]
Michael H. Perez, Beatriz L. Rodriguez, Terry T. Shintani, Keitaro Watanabe, Setsuko Miyanari, Rosanne C. Harrigan
Food and Nutrition Sciences (FNS) , 2013, DOI: 10.4236/fns.2013.410131

Problem: 5-ALA has been used for many years at relatively high dose amounts in single doses for photodynamic therapy and immunofluorescence of tumors. An analysis of compiled data relating to safety and any side-effects about the use of 5-ALA at low doses has not yet been published. Purpose: This report analyzes data about the safety of the use of 5-Aminolevulinic Acid (5-ALA) in low doses as a supplement over an extended period of time. Methods: This investigation is a systematic analysis of the current literature ((Medline, and SBI) and snowballing techniques) related to the safety and efficacy of 5-ALA in animals and humans. Clinical trials in progress using 5-ALA were also analyzed. Constant comparative analyses were used to synthesize the findings. Results: The safety of low-dose 5-ALA as a supplement has been demonstrated by animal and human studies. The results suggest that none of the investigations document the presence of symptoms or abnormal laboratory results of clinical significance. The minor laboratory changes documented were judged not clinically significant.

Promotive Effects of 5-Aminolevulinic Acid (5-ALA) on Fruit Yield and Quality of Date Palm cv., Khalas  [PDF]
A.A. Al-Khateeb,S.A. Al-Khateeb,R. Okawara,I.A. Al-Abdoulhady
Journal of Biological Sciences , 2006,
Abstract: The effects of spraying 5-ALA on date palm in relation to chlorophyll biosynthesis and fruits yield an quality during 1998/1999 seasons had been investigated. Fruits of Khalas cv. were sprayed with 5-ALA aqueous solutions of 0, 50 and 100 ppm two weeks after fruit setting. Spraying was applied biweekly for six weeks duration. Fruits chlorophyll content in Khalal stage was significantly increased with 5-ALA treatments. Fruit weight, fruit volume and fruit flesh percentage of rutab stage were significantly increased with 100 ppm 5-ALA. On tamer stage, fruit volume was significantly increased with 5-ALA treatment, while fruit weight was not. Total and reducing sugars were significantly increased with 5-ALA treatment in rutab stage, but not in tamer stage.
Photodynamic Therapy with 5-Aminolevulinic acid (ALA) Impairs Tumor Initiating and Chemo-Resistance Property in Head and Neck Cancer-Derived Cancer Stem Cells  [PDF]
Chuan-Hang Yu, Cheng-Chia Yu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087129
Abstract: Background Head and neck cancer (HNC) ranks the fourth leading malignancy and cancer death in male population in Taiwan. Despite recent therapeutic advances, the prognosis for HNC patients is still dismal. New strategies are urgently needed to improve the chemosensitization to conventional chemotherapeutic drugs and clinical responses of HNC patients. Studies have demonstrated that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is being used in the treatment of various human premalignant and malignant lesions with some encouraging clinical outcomes. However, the molecular mechanisms of ALA-PDT in the therapeutic effect in HNC tumorigenesis and whether ALA-PDT as chemosensitizer for HNC treatment remain unclear. Accumulating data support cancer stem cells (CSCs) contributes chemo-resistance in HNC. Based on the previous studies, the purpose of the study is to investigate the effect of ALA-PDT on CSCs and chemosensitization property in HNC. Methodology/Principal Finding CSCs marker ALDH1 activity of HNC cells with ALA-PDT treatment as assessed by the Aldefluor assay flow cytometry analysis. Secondary Sphere-forming self-renewal, stemness markers expression, and invasiveness of HNC-CSCs with ALA-PDT treatment were presented. We observed that the treatment of ALA-PDT significantly down-regulated the ALDH1 activity and CD44 positivity of HNC-CSCs. Moreover, ALA-PDT reduced self-renewal property and stemness signatures expression (Oct4 and Nanog) in sphere-forming HNC-CSCs. ALA-PDT sensitized highly tumorigenic HNC-CSCs to conventional chemotherapies. Lastly, synergistic effect of ALA-PDT and Cisplatin treatment attenuated invasiveness/colongenicity property in HNC-CSCs. Conclusion/Significance Our results provide insights into the clinical prospect of ALA-PDT as a potential chemo-adjuvant therapy against head and neck cancer through eliminating CSCs property.
Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA)-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors  [PDF]
Toshihisa Ishikawa,Kenkichi Takahashi,Naokado Ikeda,Yoshinaga Kajimoto,Yuichiro Hagiya,Shun-ichiro Ogura,Shin-ichi Miyatake,Toshihiko Kuroiwa
Pharmaceutics , 2011, DOI: 10.3390/pharmaceutics3030615
Abstract: Photodynamic diagnosis (PDD) is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX) exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA) or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new?approach of quantitative structure-activity relationship (QSAR) analysis to design potent ABCG2-inhibitors.
Stabilization of 5-aminolevulinic acid by the zinc(II) ion in an aqueous solution  [cached]
Hiroshi Sakiyama,Hidetatsu Inoue,Md.Kudrat-E-Zahan Md.Kudrat-E-Zahan,Shoichi Hueki
European Journal of Chemistry , 2010, DOI: 10.5155/eurjchem.1.4.373-376.101
Abstract: It is known that 5-aminolevulinic acid (5-ALA) is not stable in an aqueous solution because of the auto-condensation reaction between two 5-ALA molecules; however, in this study, 5-ALA was stabilized by the zinc(II) ion in an aqueous solution of neutral pH. This stabilization effect was ascertained by UV-Vis Spectroscopy and 1H and 13C NMR Spectroscopy.
Derivatives of 5-Aminolevulinic Acid for Photodynamic Therapy
Ryan F. Donnelly, Paul A. McCarron and A. David Woolfson
Perspectives in Medicinal Chemistry , 2012,
Abstract: Photodynamic therapy (PDT) is a clinical treatment that combines the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitising drug (possessing no dark toxicity) to cause destruction of selected cells. Today, the most common agent used in dermatological PDT is 5-aminolevulinic acid (ALA). As a result of its hydrophilic character, ALA penetrates skin lesions poorly when applied topically. Its systemic bioavailability is limited and it is known to cause signifi cant side effects when given orally or intravenously. Numerous chemical derivatives of ALA have been synthesised with the aims of either improving topical penetration or enhancing systemic bioavailability, while reducing side effects. In vitro cell culture experiments with ALA derivatives have yielded promising results. However, if ALA derivatives are to demonstrate meaningful clinical benefi ts, a rational approach to topical formulation design is required, along with a systematic study aimed at uncovering the true potential of ALA derivatives in photodynamic therapy. With respect to systemic ALA delivery, more study is required in the developing area of ALA-containing dendrons and dendrimers.
The possibility of using 5-aminolevulinic acid in lead phytoextraction process  [PDF]
Zbigniew Jarosz,Katarzyna Dzida,Karolina Pitura,Joanna Konopińska
Modern Phytomorphology , 2013,
Abstract: Studies conducted in the greenhouse involving a sunflower (Helianthus annuus L.) grown in medium containing 200 mg Pb dm -3 which were designed to evaluate the impact of foliar nutrition with 5-aminolevulinic acid (5-ALA) on the chemical composition of sunflower in reference to possible use of this plant in the process of induced phytoextraction. The study revealed from 4.8% to 34.1% increase in aboveground matter of sunflower which was sprayed by 5-ALA solution at concentrations of 0.01-0.1 ppm in comparison with plants grown in a medium containing 200 mg Pb dm -3 with no 5-ALA spraying. The sunflower leaves sprayed by 5-ALA solution contained from 3.78% to 27.1% more lead in comparison to plants not sprayed by this agent. As well as remarkable decrease in lead content from 17.4 to 33.4% was recorded in the roots of sunflower sprayed by 5-ALA solution. The lead content in plant shoots was independent from foliar application of 5-aminolevulinic acid
Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer  [PDF]
Ma?gorzata Wachowska,Angelika Muchowicz,Ma?gorzata Firczuk,Magdalena Gabrysiak,Magdalena Winiarska,Ma?gorzata Wańczyk,Kamil Bojarczuk,Jakub Golab
Molecules , 2011, DOI: 10.3390/molecules16054140
Abstract: Aminolevulinic acid (ALA) is an endogenous metabolite normally formed in the mitochondria from succinyl-CoA and glycine. Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme. Conversion of PpIX to its downstream substrates requires the activity of a rate-limiting enzyme ferrochelatase. When ALA is administered externally the abundantly produced PpIX cannot be quickly converted to its final product - heme by ferrochelatase and therefore accumulates within cells. Since PpIX is a potent photosensitizer this metabolic pathway can be exploited in photodynamic therapy (PDT). This is an already approved therapeutic strategy making ALA one of the most successful prodrugs used in cancer treatment.
δ-Aminolevulinic Acid (ALA) as a Potential Feed Additive in Pig: A Review
J.H. Cho,I.H. Kim
Journal of Animal and Veterinary Advances , 2012, DOI: 10.3923/javaa.2011.1627.1631
Abstract: Delta-Aminolevulinic Acid (ALA) which is the precursor of is synthesized by the condensation of glycine and succinyl-CoA with ALA synthetase as a coenzyme. This reaction is a mandatory step in heme synthesis and is rate-determining for the pathway. After several intermediate reactions, ALA is transformed into protoporphyrin IX. Subsequently, an iron atom is inserted into the porphyrin ring of protoporphyrin IX with the help of ferrochelatase forming heme. According to this reaction mechanism, supplementation of ALA in livestock can affect heme synthesis, positively influence the iron contentor hemoglobin status of animals. By increasing iron transfer efficiency from sow to piglets, through elevated milk iron concentrations immune system response could improve during inflammatory challenge.
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