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Molecular Cancer Therapeutics Sep 2020Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with...
Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA ( = 0.0079). SDs for core and margin regions of interest in 5-ALA-treated tissues were significantly higher than those found in panitumumab-IRDye800CW-treated tissues ( = 0.0240 and = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.
Topics: Aminolevulinic Acid; Animals; Antineoplastic Agents, Immunological; Female; Glioblastoma; Humans; Mice; Mice, Nude; Optical Imaging; Panitumumab; Photosensitizing Agents
PubMed: 32606015
DOI: 10.1158/1535-7163.MCT-19-0819 -
Tomography (Ann Arbor, Mich.) Aug 2023Recent advances in tumor visualization have improved the extent of resection (EOR) of primary and secondary tumors of the central nervous system, while limiting the... (Meta-Analysis)
Meta-Analysis Review
Intraoperative Fluorophores: An Update on 5-Aminolevulinic Acid and Sodium Fluorescein in Resection of Tumors of the Central Nervous System and Metastatic Lesions-A Systematic Review and Meta-Analysis.
INTRODUCTION
Recent advances in tumor visualization have improved the extent of resection (EOR) of primary and secondary tumors of the central nervous system, while limiting the morbidity and mortality of the surgery. One area of recent interest has been the use of intraoperative fluorophores for tumor visualization such as 5-aminolevulinic acid (5-ala) and sodium fluorescein. We performed a systematic review and meta-analysis on the utility of fluorophore administration and EOR with each fluorophore to update the current literature.
METHODS
We conducted a systematic review and meta-analysis on the use of intraoperative 5-ala or fluorescein between 2021 and 2023 using the PubMed, SCOPUS, and WOS databases. The initial search yielded 8688 results. After inclusion and exclusion criteria were met, 44 studies remained for review. A meta-analysis was performed to compare the EOR between studies for each fluorophore and to compare the presence of intraoperative fluorescence by tumor type. Odds ratios (OR) were calculated for gross total resection (GTR), and two-way ANOVA tests were performed to compare rates of intraoperative fluorescence by fluorophore and tumor type.
RESULTS
In all groups except low-grade glioma, fluorescence was present after 5-ala administration; fluorescence was present for all groups after fluorescein administration. Two-way ANOVA analysis for both fluorophores demonstrated no statistically significant difference in presence of fluorescence between type of tumor resected. Meta-analysis of EOR did show a higher, but not significant, rate of GTR in the 5-ala group compared to controls (OR = 1.29, 95% CI = 0.49; 3.37). In the fluorescein group, there were statistically significant higher odds of GTR compared to the control group (OR = 2.10, 95% CI = 1.43; 3.10, I = 0%).
CONCLUSIONS
Both 5-ala and sodium fluorescein demonstrated intraoperative fluorescence among various tumor types in both cranial and spinal tumors, as well as efficacy in improving EOR. Both fluorophores merit further investigation for use in surgery of CNS tumors.
Topics: Humans; Fluorescein; Aminolevulinic Acid; Levulinic Acids; Glioma
PubMed: 37736977
DOI: 10.3390/tomography9050124 -
Frontiers in Bioscience (Scholar... Dec 2023Mitochondrial dysfunction is considered an important mechanism in the pathogenesis of various diseases. Therefore, mitochondria are currently being considered as...
BACKGROUND
Mitochondrial dysfunction is considered an important mechanism in the pathogenesis of various diseases. Therefore, mitochondria are currently being considered as subjects for targeted therapies, particularly, phototherapy using 5-aminolevulinic acid. This study aimed to investigate the activity of mitochondria in cells with different mutation loads.
MATERIALS AND METHODS
The study was conducted using 11 cybrid lines obtained from the THP-1 cell line (a human monocytic leukemia cell line) and platelets of patients with different mitochondrial mutations.
RESULTS
Our results illustrate that 5-aminolevulinic acid was metabolized equally in all cell lines, however, there was a significant decrease in mitochondrial potential, which differed among lines.
CONCLUSIONS
The results of this study can be used to develop a personalized therapeutic approach based on different mitochondrial activities.
Topics: Humans; Aminolevulinic Acid; Photosensitizing Agents; Mitochondria; Cell Line; THP-1 Cells; Cell Line, Tumor
PubMed: 38163956
DOI: 10.31083/j.fbs1504017 -
Journal of Diabetes Research 20195-Aminolevulinic acid (5-ALA) is a delta amino acid naturally present in every living cell of the human body. 5-ALA is produced in the mitochondria as the first product... (Review)
Review
5-Aminolevulinic acid (5-ALA) is a delta amino acid naturally present in every living cell of the human body. 5-ALA is produced in the mitochondria as the first product of the porphyrin synthesis pathway and composes heme; exogenously supplemented 5-ALA helps in upregulating mitochondrial functions. Mitochondrial dysfunction has been associated with the pathophysiology of diabetes mellitus. Thus, in this review, we evaluate the mechanisms of action and adverse effects of common medications used to treat type 2 diabetes mellitus as well as 5-ALA including its mechanism and possible use in diabetes management.
Topics: Aminolevulinic Acid; Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Mitochondria; Patient Safety; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 31781665
DOI: 10.1155/2019/4267357 -
The Journal of Biological Chemistry Mar 2022Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule,... (Review)
Review
Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule, defects in heme biosynthesis underlie several blood disorders in humans. Aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in α-proteobacteria and nonplant eukaryotes. Debilitating and painful diseases such as X-linked sideroblastic anemia and X-linked protoporphyria can result from one of more than 91 genetic mutations in the human erythroid-specific enzyme ALAS2. This review will focus on recent structure-based insights into human ALAS2 function in health and how it dysfunctions in disease. We will also discuss how certain genetic mutations potentially result in disease-causing structural perturbations. Furthermore, we use thermodynamic and structural information to hypothesize how the mutations affect the human ALAS2 structure and categorize some of the unique human ALAS2 mutations that do not respond to typical treatments, that have paradoxical in vitro activity, or that are highly intolerable to changes. Finally, we will examine where future structure-based insights into the family of ALA synthases are needed to develop additional enzyme therapeutics.
Topics: 5-Aminolevulinate Synthetase; Aminolevulinic Acid; Anemia, Sideroblastic; Animals; Genetic Diseases, X-Linked; Heme; Humans; Structure-Activity Relationship
PubMed: 35093382
DOI: 10.1016/j.jbc.2022.101643 -
International Journal of Molecular... May 2023Cancer is the leading cause of death worldwide and several anticancer therapies take advantage of the ability of reactive oxygen species to kill cancer cells. Added to... (Review)
Review
Cancer is the leading cause of death worldwide and several anticancer therapies take advantage of the ability of reactive oxygen species to kill cancer cells. Added to this is the ancient hypothesis that light alone can be used to kill cancer cells. 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT) is a therapeutic option for a variety of cutaneous and internal malignancies. PDT uses a photosensitizer that, activated by light in the presence of molecule oxygen, forms ROS, which are responsible for the apoptotic activity of the malignant tissues. 5-ALA is usually used as an endogenous pro-photosensitizer because it is converted to Protoporphyrin IX (PpIX), which enters into the process of heme synthesis and contextually becomes a photosensitizer, radiating a red fluorescent light. In cancer cells, the lack of the ferrochelatase enzyme leads to an accumulation of PpIX and consequently to an increased production of ROS. PDT has the benefit of being administered before or after chemotherapy, radiation, or surgery, without impairing the efficacy of these treatment techniques. Furthermore, sensitivity to PDT is unaffected by the negative effects of chemotherapy or radiation. This review focuses on the studies done so far on 5-ALA-PDT and its efficacy in the treatment of various cancer pathologies.
Topics: Humans; Aminolevulinic Acid; Photosensitizing Agents; Reactive Oxygen Species; Photochemotherapy; Neoplasms; Protoporphyrins; Cell Line, Tumor
PubMed: 37240309
DOI: 10.3390/ijms24108964 -
Ecotoxicology and Environmental Safety Oct 2022Food availability represents a major worldwide concern due to climate change and population growth. Low-temperature stress (LTS) severely restricts the growth of tomato...
Food availability represents a major worldwide concern due to climate change and population growth. Low-temperature stress (LTS) severely restricts the growth of tomato seedlings. Exogenous 5-aminolevulinic acid (ALA) can alleviate the harm of abiotic stress including LTS; however, data on its protective mechanism on tomato seedling roots, the effects of organelle structure, and the regulation of metabolic pathways under LTS are lacking. In this study, we hope to fill the above gaps by exploring the effects of exogenous ALA on morphology, mitochondrial ultrastructure, reactive oxygen species (ROS) enrichment, physiological indicators, related gene expression, and metabolic pathway in tomato seedlings root under LTS. Results showed that ALA pretreatment could increase the activity of antioxidant enzymes and the content of antioxidant substances in tomato seedlings roots under LTS to scavenge the massively accumulated ROS, thereby protecting the mitochondrial structure of roots and promoting root development under LTS. Combined transcriptomic and metabolomic analysis showed that exogenous ALA pretreatment activated the glutathione metabolism and β-alanine metabolism of tomato seedling roots under LTS, further enhanced the scavenging ability of tomato seedling roots to ROS, and improved the low-temperature tolerance of tomato seedlings. The findings provide a new insight into the regulation of the low-temperature tolerance of tomato by exogenous ALA.
Topics: Aminolevulinic Acid; Antioxidants; Glutathione; Solanum lycopersicum; Reactive Oxygen Species; Seedlings; Stress, Physiological; Temperature; beta-Alanine
PubMed: 36155340
DOI: 10.1016/j.ecoenv.2022.114112 -
Microbial Biotechnology Nov 2021Gamma-aminobutyric acid (GABA) and delta-aminolevulinic acid (ALA), playing important roles in agriculture, medicine and other fields, are multifunctional non-protein... (Review)
Review
Gamma-aminobutyric acid (GABA) and delta-aminolevulinic acid (ALA), playing important roles in agriculture, medicine and other fields, are multifunctional non-protein amino acids with similar and comparable properties and biosynthesis pathways. Recently, microbial synthesis has become an inevitable trend to produce GABA and ALA due to its green and sustainable characteristics. In addition, the development of metabolic engineering and synthetic biology has continuously accelerated and increased the GABA and ALA yield in microorganisms. Here, focusing on the current trends in metabolic engineering strategies for microbial synthesis of GABA and ALA, we analysed and compared the efficiency of various metabolic strategies in detail. Moreover, we provide the insights to meet challenges of realizing industrially competitive strains and highlight the future perspectives of GABA and ALA production.
Topics: Aminolevulinic Acid; Biosynthetic Pathways; Metabolic Engineering; Synthetic Biology; gamma-Aminobutyric Acid
PubMed: 33675575
DOI: 10.1111/1751-7915.13783 -
Photodiagnosis and Photodynamic Therapy Jun 2024Actinic keratosis (AK) is a precancerous lesion that occurs in areas that are chronically exposed to sunlight and has the potential to develop into invasive cutaneous...
BACKGROUND
Actinic keratosis (AK) is a precancerous lesion that occurs in areas that are chronically exposed to sunlight and has the potential to develop into invasive cutaneous squamous cell carcinoma (cSCC). We investigated the efficacy of 20 % 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) with LED red light for the treatment of AK in Chinese patients by examining changes in dermoscopic features, histopathology and fluorescence after treatment.
METHODS
Twenty-eight patients with fourty-six AK lesions from March 2022 to September 2023 were treated with 20 % ALA, and 3 h later, they were irradiated with LED red light (80-100 mW/cm) for 20 min. A session of 20 % ALA-PDT was performed once a week for three consecutive weeks, and the dermoscopic, histopathological, fluorescent and photoaging outcomes were measured one week after the treatment.
RESULTS
One week after ALA-PDT, complete remission (CR) was reached in 53.6 % of patients. The CR of Grade I AK lesions was 100 %, that of Grade II lesions was 71.4 %, and that of Grade III lesions was 38.1 %. There was a significant improvement in the dermoscopic features, epidermal thickness and fluorescence of the AK lesions. The presence of red fluorescence decreased, and there was an association between CR and post-PDT fluorescence intensity. ALA-PDT also exhibited efficacy in treating photoaging, including fine lines, sallowness, mottled pigmentation, erythema, and telangiectasias, and improved the global score for photoaging. There were no serious adverse effects during or after ALA-PDT, and 82.1 % of the patients were satisfied with the treatment.
CONCLUSION
AK lesions can be safely and effectively treated with 20 % ALA-PDT with LED red light, which also alleviates photoaging in Chinese patients, including those with multiple AKs. This study highlights the possibility that fluorescence could be used to diagnose AK with peripheral field cancerization and evaluate the efficacy of ALA-PDT.
Topics: Keratosis, Actinic; Aminolevulinic Acid; Humans; Photochemotherapy; Photosensitizing Agents; Female; Male; Aged; Middle Aged; Dermoscopy; Aged, 80 and over; Fluorescence
PubMed: 38663488
DOI: 10.1016/j.pdpdt.2024.104100 -
International Journal of Molecular... Jan 2022Priming is an adaptive strategy that improves plant defenses against biotic and abiotic stresses. Stimuli from chemicals, abiotic cues, and pathogens can trigger the... (Review)
Review
Priming is an adaptive strategy that improves plant defenses against biotic and abiotic stresses. Stimuli from chemicals, abiotic cues, and pathogens can trigger the establishment of priming state. Priming with 5-aminolevulinic acid (ALA), a potential plant growth regulator, can enhance plant tolerance to the subsequent abiotic stresses, including salinity, drought, heat, cold, and UV-B. However, the molecular mechanisms underlying the remarkable effects of ALA priming on plant physiology remain to be elucidated. Here, we summarize recent progress made in the stress tolerance conferred by ALA priming in plants and provide the underlying molecular and physiology mechanisms of this phenomenon. Priming with ALA results in changes at the physiological, transcriptional, metabolic, and epigenetic levels, and enhances photosynthesis and antioxidant capacity, as well as nitrogen assimilation, which in turn increases the resistance of abiotic stresses. However, the signaling pathway of ALA, including receptors as well as key components, is currently unknown, which hinders the deeper understanding of the defense priming caused by ALA. In the future, there is an urgent need to reveal the molecular mechanisms by which ALA regulates plant development and enhances plant defense with the help of forward genetics, multi-omics technologies, as well as genome editing technology.
Topics: Aminolevulinic Acid; Plant Development; Plants; Stress, Physiological
PubMed: 35054887
DOI: 10.3390/ijms23020702