Case Reports: Safety, Tolerability, and Efficacy of 5-Aminolevulinic Acid Phosphate, an Inducer of Heme Oxygenase 1, in Combination with Sodium Ferrous Citrate for the Treatment of COVID-19 Patients

Abstract Background and Aims A growing number of evidence indicates the association with dyslipidemia and the progression of chronic kidney disease. Endoplasmic reticulum (ER) stress and apoptosis in renal tubule are suggested to be linked to the pathophysiology of toxic lipid-induced kidney injury. 5-aminolevulinic acid (ALA) is a precursor of heme oxygenase (HO)-1, which plays an important role in protecting cells from various stresses. In the present study, we aimed to investigate the therapeutic effect of ALA, on toxic lipid-induced ER stress and apoptosis in the renal tubule. Method Renal proximal tubular epithelial cells (RPTECs) were treated with palmitic acid to induce ER stress and apoptosis. ALA was also added with palmitic acid (PA). The gene and protein expressions of NF E2-related factor 2, HO-1, glucose-regulated protein (GRP)78, and C/EBP-homologous protein (CHOP) were quantified. Apoptotic cells were evaluated by caspase-3/7 assay. An HO-1 inhibitor, Zn-protoporphyrin IX, was added to investigate the involvement of HO-1 in ALA-mediated therapeutic effect on the ER stress and apoptosis. Results The expressions of GRP78 and CHOP increased in cells treated with PA. Apoptotic signals also increased with PA treatment. ALA induced a significant increase in the HO-1 expression and that led to the suppression of ER stress response. Apoptotic signals in PA-treated cells also decreased with ALA and the effect of ALA disappeared when combined with Zn-protoporphyrin IX. Conclusion PA-induced ER stress and apoptosis in RPTECs. ALA has a therapeutic effect by suppressing ER stress, possibly through HO-1 induction.

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5-Aminolevulinic acid combined with sodium ferrous citrate ameliorates H2O2-induced cardiomyocyte hypertrophy via activation of the MAPK/Nrf2/HO-1 pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00369.2014 ◽

2015 ◽

Vol 308 (8) ◽

pp. C665-C672 ◽

Cited By ~ 20

Author(s):

Mingyi Zhao ◽

Huiming Guo ◽

Jimei Chen ◽

Masayuki Fujino ◽

Hidenori Ito ◽

...

Keyword(s):

Oxidative Stress ◽

Natriuretic Peptide ◽

Aminolevulinic Acid ◽

Cardiomyocyte Hypertrophy ◽

Marker Genes ◽

Heme Oxygenase 1 ◽

Dependent Manner ◽

Ros Production ◽

Ferrous Citrate ◽

Atrial Natriuretic

Hydrogen peroxide (H2O2) causes cell damage via oxidative stress. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that can protect cardiomyocytes against oxidative stress. In this study, we investigated whether the heme precursor 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) could protect cardiomyocytes from H2O2-induced hypertrophy via modulation of HO-1 expression. HL-1 cells pretreated with/without 5-ALA and SFC were exposed to H2O2 to induce a cardiomyocyte hypertrophy model. Hypertrophy was evaluated by planar morphometry, 3H-leucine incorporation, and RT-PCR analysis of hypertrophy-related gene expressions. Reactive oxygen species (ROS) production was assessed by 5/6-chloromethyl-2′,7′-ichlorodihydrofluorescein diacetate acetylester. HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expressions were analyzed by Western blot. In our experiments, HL-1 cells were transfected with Nrf2 siRNA or treated with a signal pathway inhibitor. We found several results. 1) ROS production, cell surface area, protein synthesis, and expressions of hypertrophic marker genes, including atrial natriuretic peptide, brain natriuretic peptide, atrial natriuretic factor, and β-myosin heavy chain, were decreased in HL-1 cells pretreated with 5-ALA and SFC. 2) 5-ALA and SFC increased HO-1 expression in a dose- and time-dependent manner, associated with upregulation of Nrf2. Notably, Nrf2 siRNA dramatically reduced HO-1 expression in HL-1 cells. 3) ERK1/2, p38, and SAPK/JNK signaling pathways were activated and modulate 5-ALA- and SFC-enhanced HO-1 expression. SB203580 (p38 kinase), PD98059 (ERK), or SP600125 (JNK) inhibitors significantly reduced this effect. In conclusion, our data suggest that 5-ALA and SFC protect HL-1 cells from H2O2-induced cardiac hypertrophy via activation of the MAPK/Nrf2/HO-1 signaling pathway.

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Safety test of a supplement, 5-aminolevulinic acid phosphate with sodium ferrous citrate, in diabetic patients treated with oral hypoglycemic agents

Functional Foods in Health and Disease ◽

10.31989/ffhd.v4i9.151 ◽

2014 ◽

Vol 4 (9) ◽

pp. 415 ◽

Cited By ~ 2

Author(s):

Naohide Yamashita ◽

Atai Watanabe ◽

Hikaru Kondo ◽

Satofumi Kawata ◽

Tohru Tanaka ◽

...

Keyword(s):

Blood Glucose ◽

Adverse Events ◽

Hemoglobin A1c ◽

Aminolevulinic Acid ◽

Fasting Blood Glucose ◽

Hypoglycemic Agents ◽

Diabetic Patients ◽

Oral Hypoglycemic Agents ◽

Acid Phosphate ◽

Ferrous Citrate

Objective: This study aimed to examine the safety of 5-aminolevulinic acid phosphate (5-ALA) with sodium ferrous citrate (SFC) in diabetic patients treated with one or more oral hypoglycemic agents (OHAs).Background: Recent intervention studies performed in the USA and Japan have shown that a nutritional supplement of 5-ALA with SFC efficiently reduced blood glucose levels in pre-diabetic population without any adverse events. Thus, it was anticipated that 5-ALA with SFC may potentially be taken as a beneficial supplement by diabetic patients who were being treated with OHA therapy. Nevertheless, it is important to examine its safety and efficacy in diabetic population.Methods: This study was a prospective single-blinded, randomized, placebo-controlled and parallel-group comparison study. Medically treated diabetic patients between the ages of 30 and 75 were recruited from the Tokyo metropolitan area of Japan and 45 subjects were selected after screening. These subjects were randomly assigned to three groups: daily intake of 15mg 5-ALA, 50mg 5-ALA, and a placebo (n=15, respectively). The supplement or placebo was administered for 12 weeks followed by a four week washout period. The primary endpoint was safety and occurrence of hypoglycemic attack, while the secondary endpoint was changes of fasting blood glucose (FBG) and hemoglobin A1c (HbA1c). Results: Adverse events related to 5-ALA with SFC were not observed in all the groups. Abnormalities in blood and urine tests were not observed either. Significant decrease in FBG was not detected in all the groups. However, there was a small but significant decrease in HbA1c at 4 and 8 week in the 15 mg 5-ALA group. Significant decrease in HbA1c was not observed in the 50 mg 5-ALA group, although a tendency to decrease after 4 weeks was apparent.Conclusion: 5-ALA with SFC is a safe and potentially beneficial supplement if taken by diabetic patients treated with OHAs.Trial registration: UMIN 000008038Key words: type 2 diabetes, 5-aminolevulinic acid (5-ALA), sodium ferrous citrate (SFC), oral hypoglycemic agent (OHA), hemoglobin A1c (HbA1c), fasting blood glucose (FBG)

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5-Aminolevulinic Acid as a Novel Therapeutic for Inflammatory Bowel Disease

Biomedicines ◽

10.3390/biomedicines9050578 ◽

2021 ◽

Vol 9 (5) ◽

pp. 578

Author(s):

Vipul Yadav ◽

Yang Mai ◽

Laura E. McCoubrey ◽

Yasufumi Wada ◽

Motoyasu Tomioka ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Heme Oxygenase ◽

Bowel Disease ◽

Aminolevulinic Acid ◽

Heme Oxygenase 1 ◽

Aminosalicylic Acid ◽

Colonic Tissue ◽

Inflammatory Bowel ◽

Anti Inflammatory

5-Aminolevulinic acid (5-ALA) is a naturally occurring nonprotein amino acid licensed as an optical imaging agent for the treatment of gliomas. In recent years, 5-ALA has been shown to possess anti-inflammatory and immunoregulatory properties through upregulation of heme oxygenase-1 via enhancement of porphyrin, indicating that it may be beneficial for the treatment of inflammatory conditions. This study systematically examines 5-ALA for use in inflammatory bowel disease (IBD). Firstly, the ex vivo colonic stability and permeability of 5-ALA was assessed using human and mouse fluid and tissue. Secondly, the in vivo efficacy of 5-ALA, in the presence of sodium ferrous citrate, was investigated via the oral and intracolonic route in an acute DSS colitis mouse model of IBD. Results showed that 5-ALA was stable in mouse and human colon fluid, as well as in colon tissue. 5-ALA showed more tissue restricted pharmacokinetics when exposed to human colonic tissue. In vivo dosing demonstrated significantly improved colonic inflammation, increased local heme oxygenase-1 levels, and decreased concentrations of proinflammatory cytokines TNF-α, IL-6, and IL-1β in both plasma and colonic tissue. These effects were superior to that measured concurrently with established anti-inflammatory treatments, ciclosporin and 5-aminosalicylic acid (mesalazine). As such, 5-ALA represents a promising addition to the IBD armamentarium, with potential for targeted colonic delivery.

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5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction

International Journal of Molecular Sciences ◽

10.3390/ijms222111405 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11405

Author(s):

Takaaki Hashimoto ◽

Takaaki Sugihara ◽

Tsutomu Kanda ◽

Tomoaki Takata ◽

Hajime Isomoto

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Heme Oxygenase ◽

Caspase 3 ◽

Aminolevulinic Acid ◽

Therapeutic Potential ◽

B Cell Lymphoma ◽

Heme Oxygenase 1 ◽

Glucose Regulated Protein

Endoplasmic reticulum (ER) stress plays a pivotal role in the progression of steatohepatitis. 5-aminolevulinic acid (5-ALA), a precursor in the heme biosynthetic pathway, has recently been reported to induce heme oxygenase (HO)-1. HO-1 exerts important cytoprotective actions. In this study, we aimed to explore the therapeutic potential of 5-ALA on palmitate-induced ER stress and lipoapoptosis. Huh-7 cells were treated with palmitic acid (PA) (800 μM) to induce steatosis for eight hours. Steatosis was evaluated by Lipi-green staining. 5-ALA (200 μM) was added with PA. The gene expression levels of the nuclear factor erythroid 2–related factor 2 (NRF2), HO-1, Glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), C/EBP homologous protein (CHOP), and B-cell lymphoma 2 (BCL-2) were evaluated by RT-PCR. Caspase-3/7 activity was evaluated by fluorescein active Caspase-3/7 staining. Cell death was evaluated by Annexin V/SYTOX green staining. PA significantly induced steatosis and increased GRP78 expression in Huh-7 cells. 5-ALA significantly induced HO-1 and decreased GRP78 expression. ATF6 was subsequently decreased. However, NRF2 and CHOP expression were not altered. Anti-apoptotic BCL-2 expression significantly increased, and Caspase 3/7 activity and cell death also decreased. 5-ALA has a therapeutic potential on hepatic steatosis by suppressing ER stress and lipoapoptosis by attenuating GRP78 via HO-1 induction.

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