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Simple Summary: This study investigated the circadian rhythm of intracellular protoporphyrin IX (PPIX) accumulation in bladder cancer cells exposed to 5-aminolevulinic acid to understand the variability in red fluorescence intensity observed during photodynamic diagnosis-assisted transurethral resection among different tumors and patients. We identified the circadian rhythm of the clock genes PER2 and BMAL1 and their impact on PPIX accumulation in bladder cancer cell lines UM-UC-3 and J82, as well as in mouse xenograft models. Additionally, enzymes involved in heme synthesis, including coproporphyrinogen oxidase and ferrochelatase, were found to follow circadian rhythms. When red fluorescence intensity was quantified and compared among the four groups based on surgery start times, from 9 a.m. to 5 p.m., it peaked in surgeries performed between 3 and 5 p.m. These findings suggest that optimizing surgery timing based on circadian rhythms may improve the efficacy of photodynamic diagnosis in bladder cancer. Background/Objectives: The standard recommendation for patients with non-muscle invasive bladder cancer is 5-aminolevulinic acid-mediated photodynamic diagnosis. The intensity of the fluorescence caused by the intracellular accumulation of protoporphyrin IX (PPIX) varies among tumors and patients. This study investigated the circadian rhythm of intracellular PPIX accumulation in bladder urothelial cancer cells exposed to 5-aminolevulinic acid. Methods: The expression of two clock genes, PER2 and BMAL1, and their impact on intracellular PPIX accumulation were evaluated in two bladder cancer cell lines, UM-UC-3 and J82, and mouse xenograft models. We evaluated the enzymes involved in the heme synthesis pathway that potentially affect the circadian rhythm of intracellular PPIX accumulation. The red fluorescence intensity of the images captured during photodynamic diagnosis-assisted transurethral resection of bladder tumors was quantified and compared among the four groups according to surgery start time: 9 a.m.–11 a.m., 11 a.m.–1 p.m., 1–3 p.m., and 3–5 p.m. Results: We observed the circadian rhythm of intracellular PPIX accumulation, which was potentially regulated by the clock genes PER2 and BMAL1. Two enzymes involved in the heme synthesis pathway, coproporphyrinogen oxidase and ferrochelatase, exhibit a circadian rhythm. The fluorescence intensity started gradually increasing at 12 p.m., and the highest level was observed in patients who underwent surgery between 3 and 5 p.m. Conclusions: Our findings suggest that it may be possible to optimize the timing of the photodynamic diagnosis in photodynamic diagnosis-assisted transurethral resection of bladder cancer based on the circadian rhythm to improve tumor detection and treatment outcomes. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effects of blue light and 5-aminolevulinic acid (5-ALA) co-treatment on B16F1 melanoma cells and HaCaT keratinocytes. We focused on cellular responses, including mitochondrial function, DNA integrity, and gene expression. Co-treatment significantly damaged the mitochondria, altered their morphology, induced mitochondrial membrane depolarization, increased intracellular reactive oxygen species, and led to cardiolipin peroxidation in both cell types. This approach promoted DNA fragmentation and apoptosis. However, blue light and co-treatment with 5-ALA did not enhance the formation of cyclobutane pyrimidine dimers, 6–4 photoproducts, or Dewar photoproducts. Moreover, it triggered complex, time-dependent changes in gene expression, particularly the upregulation of MMP-1 and p21 in HaCaT cells. Our findings revealed that blue light and 5-ALA co-treatment caused substantial cellular stress and damage, suggesting their therapeutic potential against melanoma and highlighting the need for caution and precision in their application to avoid harming normal cells. This underscores the necessity for further research to refine therapeutic approaches. [ABSTRACT FROM AUTHOR]

5-Aminolevulinic acid (5-ALA) is an endogenous non-protein amino acid and has been used as a new type of growth promoter in aquaculture feed. This study explored the effects of 5-ALA on growth and intestinal health in juvenile shrimp, Litopenaeus vannamei. Shrimps were fed diets containing five different 5-ALA levels (0, 15, 30, 45, and 60 g/t) for 90 days. A concentration of 45 g/t 5-ALA significantly improved growth metrics, including the specific growth rate, protein efficiency, and feed conversion (P < 0.05). The optimal concentration of 5-ALA was 38.3 g/t, as indicated by broken-line regression. Dietary supplementation with 5-ALA increased the crude protein content of whole shrimp, but had no significant effect on the moisture, ash, or crude lipid content (P > 0.05). Suitable supplementation of 5-ALA (45 g/t, 60 g/t) improved the activities of the digestive enzymes alpha-amylase, pepsin, trypsin, and lipase, thus promoting digestion and absorption. Shrimp fed with 45 g/t 5-ALA had increased levels of essential amino acids in the muscles and a higher proportion of polyunsaturated fatty acids in the hepatopancreas. Supplementation with 45 or 60 g/t 5-ALA upregulated the expression of genes related to growth and molting, including chitinase, ecdysone receptor, retinoic X receptor, calcium/calmodulin-dependent protein kinase I, heat shock protein 60, and heat shock protein 70. Moreover, dietary supplementation with 5-ALA affected the abundance of intestinal flora, increased the number of beneficial bacteria, and improved intestinal health. These results indicated that 5-ALA may significantly benefit shrimp health and aquaculture productivity, providing a novel theoretical basis for further research into 5-ALA as a dietary supplement. [ABSTRACT FROM AUTHOR]

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Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes undergo Ca2+-induced phase separation and assembly, accelerating α-synuclein sol-gel phase transition. In α-synuclein preformed fibril-treated neurons, RNA G-quadruplex assembly comprising synaptic mRNAs co-aggregates with α-synuclein upon excess cytoplasmic Ca2+ influx, eliciting synaptic dysfunction. Forced RNA G-quadruplex assembly using an optogenetic approach evokes α-synuclein aggregation, causing neuronal dysfunction and neurodegeneration. The administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevents RNA G-quadruplex phase separation, thereby attenuating α-synuclein aggregation, neurodegeneration, and progressive motor deficits in α-synuclein preformed fibril-injected synucleinopathic mice. Therefore, Ca2+ influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation, potentially contributing to synucleinopathies. [Display omitted] • RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation • Cytoplasmic Ca2+ influx induces RNA G-quadruplex assembly • RNA G-quadruplex assembly accelerates α-synuclein phase transition and aggregation • RNA G-quadruplex assembly may contribute to synucleinopathy pathogenesis Calcium influx-induced RNA G-quadruplex assembly accelerates α-synuclein phase transition and neuropathological aggregation. [ABSTRACT FROM AUTHOR]

Objective: To compare effectiveness of topical 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA PDT) and loop electrosurgical excision procedure (LEEP) among patients with cervical intraepithelial neoplasia (CIN). Methods: We retrospectively identified patients who underwent either 5-ALA PDT or LEEP from Sep. 2012 to Dec. 2019 in Chinese PLA general hospital. Patients' outcomes were compared according to the HPV genotyping, cytological tests within 3–6-month follow-up post-treatment, the pathological examination would be performed if the cytological results indicated the risk of CIN. Propensity score matching (PSM) was adapted to pair the baseline. Complete remission (CR), partial remission (PR) and the remission rate of HPV infections were used to evaluate the efficacy of 5-ALA PDT versus LEEP. Results: In total, 30 pairs were matched as the matching tolerance was set as 0.03. There was no significant difference about the CR and PR between 5-ALA PDT and LEEP group (73.33% vs 84.00%, P = 0.340; 3.33% vs 4.00%, P = 1.000). Among different CIN group, there was no statistic difference between 5-ALA PDT and LEEP. Moreover, in terms of HPV remission rate, 5-ALA PDT showed the same efficacy as LEEP (59.26% vs 53.85%, P = 0.691). Conclusions: In essence, topical 5-ALA PDT emerges as a non-invasive, repeatable procedure with minimal side effects for cervical lesions, preserving cervical structure. Overall, the efficacy of 5-ALA PDT is comparable to LEEP in achieving successful outcomes. [ABSTRACT FROM AUTHOR]

Abstract5-aminolevulinic acid (ALA) is a non-protein amino acid that has been widely used in the fields of medicine and agriculture. This study aims to engineer the C5 pathway of the ALA biosynthesis in Escherichia coli BL21 to enhance ALA production. The ALA synthase genes gltX, hemA, and hemL were overexpressed in E. coli BL21 to lead to the increase in the production of ALA. The sRNA RyhB was also overexpressed to downregulate the expression of ALA dehydratase to reduce the downstream bioconversion of ALA to porphobilinogen. Next, the gene arcA was knocked out by CRISPR-Cas9 technology to open the TCA cycle to promote the respiratory metabolism of the strain to reduce the feedback inhibition of heme to ALA. The fermentation conditions of the engineered strain were optimized by response surface experiments. The time-course analysis of the ALA production was carried out in a 1 L shake flask. Through these efforts, the production of ALA in engineered strain reached 2953 mg/L in a 1 L shake flask. This study contributes to the industrial production of ALA by the engineered E. coli in the future. [ABSTRACT FROM AUTHOR]

Aminolevulinic acid (5-ALA) and dihydroporphyrin iron chelates (DHFe) play roles in plant growth regulation under normal and stressful conditions. However, definitive data on their roles in regulating chlorophyll synthesis in wheat are lacking. In this study, the optimal concentrations for foliar-spray application of 5-ALA and DHFe to promote wheat seedling growth and leaf chlorophyll content were assessed. The optimal concentrations of 5-ALA or DHFe (50 mg/L and 0.01 mg/L, respectively) were applied as foliar sprays to seedlings of wheat 'Bainong 4199' (high light efficient) and 'Zhoumai No. 18' (average light efficient) under different light intensities. Chlorophyll precursor contents and activities of three chlorophyll synthesis-related enzymes were altered, and the combined application of 5-ALA and DHFe more strongly increased the leaf chlorophyll content. 5-ALA significantly increased the contents of the chlorophyll precursors porphobilinogen, uroporphyrinogen III, protoporphyrin IX, and magnesium-protoporphyrin IX, and the activities of 5-amino-ketovalerate dehydratase and uroporphyrinogen III synthase. DHFe resulted in an increase in chlorophyll content but a significant decrease in chlorophyllase activity and protochlorophyllide content. 5-ALA promoted the synthesis of chlorophyll precursors by regulating the activities of 5-amino-ketovalerate dehydratase and uroporphyrinogen III synthase. DHFe decreased chlorophyllase activity, thereby slowing chlorophyll degradation and increasing the chlorophyll content. [ABSTRACT FROM AUTHOR]

5‐Aminolevulinic acid (ALA) is a prodrug for protoporphyrin IX (PpIX)‐mediated photodynamic therapy (PDT) and fluorescence‐guided tumor surgery. We previously reported that lapatinib, a repurposed ABCG2 inhibitor, enhanced ALA‐induced PpIX fluorescence and PDT by blocking ABCG2‐mediated PpIX efflux. In the present study, we evaluated how the variation in ABCG2 activities/protein levels affected tumor cell response to the enhancement of PpIX/PDT by lapatinib and Ko143, an ABCG2 tool inhibitor. ABCG2 activities and protein levels were determined in a panel of human cancer cell lines. Effects of lapatinib and Ko143 on enhancing ALA‐PpIX fluorescence and PDT were evaluated and correlated with tumor cell ABCG2 activities. We found that both lapatinib and Ko143 enhanced ALA‐PpIX fluorescence and PDT in a dose‐dependent manner, although lapatinib exhibited lower efficacy and potency than Ko143 in nearly all cancer cell lines. The EC50 of ABCG2 inhibitors for enhancing ALA‐PpIX and PDT had a positive correlation with tumor cell ABCG2 activities, indicating that tumor cell lines with lower ABCG2 activities were more sensitive to ABCG2 inhibitors for PpIX/PDT enhancement. Our results suggest that, for optimal therapeutic enhancement, the dose of ABCG2 inhibitors needs to be tailored based on the ABCG2 expression/activity in tumors. [ABSTRACT FROM AUTHOR]

Establishment of a highly efficient cell factory is imperative for 5-aminolevulinic acid (5-ALA) biomanufacturing. A streamlined workflow is described that enables highly efficient 5-ALA synthase mining. Genome-scale model-guided identification and combination of multiplex targets are reported. An artificial homeostasis was designed for dynamically responding to, and fine-tuning, redox status. Final collaborative optimization resulted in the highest 5-ALA biomanufacturing performance achieved to date. The versatile applications of 5-aminolevulinic acid (5-ALA) across the fields of agriculture, livestock, and medicine necessitate a cost-efficient biomanufacturing process. In this study, we achieved the economic viability of biomanufacturing this compound through a systematic engineering framework. First, we obtained a 5-ALA synthase (ALAS) with superior performance by exploring its natural diversity with divergent evolution. Subsequently, using a genome-scale model, we identified and modified four key targets from distinct pathways in Escherichia coli , resulting in a final enhancement of 5-ALA titers up to 21.82 g/l in a 5-l bioreactor. Furthermore, recognizing that an imbalance of redox equivalents hindered further titer improvement, we developed a dynamic control system that effectively balances redox status and carbon flux. Ultimately, we collaboratively optimized the artificial redox homeostasis system at the transcription level with other cofactors at the feeding level, demonstrating the highest recorded performance to date with a titer of 63.39 g/l for the biomanufacturing of 5-ALA. Graphical abstract [Display omitted] The economic viability of biomanufacturing 5-aminolevulinic acid (5-ALA) was successfully demonstrated in this study, showcasing excellent production performance. The titer reached a record-breaking 63.39 g/l at 44 h, representing the highest reported value to date, with the productivity of 1.44 g/l/h. Although the yield (0.384 mol/mol glucose) was lower than theoretically expected, the significant value of 5-ALA positions our developed cell factory competitively for efficient industrial-scale biomanufacturing. Therefore, no challenges unique to this compound can be identified for full-scale fermentation, particularly considering that our 5-ALA cell factory was derived from a widely utilized Escherichia coli strain. Currently, two primary approaches are used to produce 5-ALA: chemical synthesis and biomanufacturing. Microbial biosynthesis of 5-ALA presents a more facile, environmentally benign, and low-cost alternative. Given that 5-ALA is a non-protein amino acid, we anticipated that the entire biomanufacturing process would be analogous to the biomanufacturing of canonical amino acids. Therefore, although a separation process was not implemented in this study, we believe that our developed 5-ALA cell factory exhibits excellent parameters and represents a highly cost-efficient biomanufacturing process. Within NASA's Technology Readiness Level (TRL) system, we propose that this 5-ALA cell factory has reached TRL 6, indicating a fully functional prototype suitable for demonstration in real production scenarios. A systematic engineering framework was demonstrated to construct a 5-aminolevulinic acid (5-ALA) cell factory, achieving the economic viability of biomanufacturing this compound with an unprecedented production performance (63.39 g/l). This comprehensive framework encompasses enzyme mining, multitarget engineering, artificial homeostasis design, and collaborative optimization. [ABSTRACT FROM AUTHOR]

Simple Summary: In brain tumor surgery, increasing the extent of resection has been shown to improve patient outcomes and survival. 5-ALA serves as a tumor visualization adjunct and has been approved for use in adult high-grade gliomas. The purpose of this systematic review was to assess whether 5-ALA has similar utility and safety in pediatric patients. A total of 249 pediatric cases were identified from the relevant literature, confirming the safety of 5-ALA in this population. Overall, the fluorescence rates and utility were favorable, although there were some variations across different tumor grades and types. While our preliminary findings suggest that 5-ALA is both safe and effective in pediatric brain tumor surgery, further systematic clinical studies are needed to validate these results. Background: 5-Aminolevulinic acid-guided surgery for adult gliomas has been approved by the European Medicines Agency and the US Food and Drug Administration, becoming a reliable tool for improving gross total resection rates and patient outcomes. This has led several medical centers to explore the off-label use of 5-ALA in the resection of pediatric brain tumors, assessing its efficacy and safety across various tumor types. However, given the differences between children and adults, the appropriateness of 5-ALA use in pediatric populations has not yet been fully established. Methods: We collected eligible publications from Embase, Scopus, PubMed, and Proquest, ultimately selecting 27 studies. Data extraction and retrospective analysis of 249 surgical cases were conducted to determine the current efficacy and safety of 5-ALA in pediatric brain tumors. The fluorescence rate and utility stratified by several clinical features, including WHO grade, tumor classification, and tumor location, were analyzed. Results: Most studies suggest that 5-ALA can enhance tumor identification in high-grade tumors, including glioblastomas and anaplastic astrocytomas. Changes in survival or recurrence rates associated with 5-ALA-guided resection have not been reported. None of the cases reported significant postoperative complications related to the use of 5-ALA. Conclusions: 5-ALA can aid in the resection of high-grade gliomas in pediatric patients. The efficacy of 5-ALA in low-grade gliomas and other tumors may require enhancement with additional tools or modified administration protocols. The safety of 5-ALA has reached a preliminary consensus, although further randomized controlled trials and data on survival and molecular characteristics are needed. [ABSTRACT FROM AUTHOR]

Strawberry Fusarium wilt (SFW) is a systematic soil-borne disease caused by Fusarium oxysporum f. sp. fragaria (Fof), which infects the vascular bundles, blocking water and nutrient transport from roots to the aboveground. It is a severe pathogen which spreads rapidly and destroys strawberry production. Finding a way to control this disease is of great scientific value and practical importance. In this study, three fungi were isolated from the vascular tissues of sick strawberries in the field. After DNA sequencing, they were identified as Fof, Aspergillus fumigatus and Trichoderma harzianum, respectively, among which the first two are pathogens and the third is a probiotic. All fungi were controlled by thiophanate-methyl (TM), a commercial fungicide. On PDA medium, 20 mg•L-1 5-aminolevulinic acid (ALA), a natural non-protein amino acid, promoted T. harzianum proliferation, but inhibited Fof and A. fumigatus. In confrontation test, the growth of Fof or A. fumigatus was inhibited by T. harzianum and exogenous ALA promoted T. harzianum growth but significantly inhibited the pathogen growth. When three species of fungi were separately or combinedly inoculated on healthy strawberry plants, T. harzianum promoted plant growth and development while Fof or A. fumigatus caused growth retardation, where Fof directly caused leaf yellowing and plant wilting. When the plants inoculated with different fungus were treated with ALA, the results turned out that ALA alleviated SFW symptoms by bidirectionally promoting T. harzianum proliferation and inhibiting Fof and A. fumigatus. Thus, ALA might be used in comprehensively controlling SFW in strawberry industry. [ABSTRACT FROM AUTHOR]

Fusobacterium nucleatum (F. nucleatum), a key pathogen implicated in periodontal disease, contributes to oral biofilm maturation and is linked to development of systemic diseases like colorectal cancer and liver cirrhosis. Photodynamic therapy (PDT) combined with 5-aminolevulinic acid (5-ALA) treatment (ALA-PDT) selectively targets F. nucleatum by inducing porphyrin accumulation. The bactericidal effect of red light-based PDT on F. nucleatum has not been evaluated previously. This study investigates the effect of ALA-PDT using red light-emitting diode (LED) light on F. nucleatum subspecies and their porphyrin accumulation. F. nucleatum subspecies were cultured with varying concentrations of 5-ALA under anaerobic conditions. Porphyrin accumulation was measured via fluorescence spectroscopy, and colony-forming units were measured to determine bacterial viability post-treatment. Additionally, other subspecies responded well to 0.01% 5-ALA, and uroporphyrin I accumulation correlated with bacterial death, revealing optimal bactericidal conditions. These results suggest that optimizing light intensity and 5-ALA concentration can significantly enhance the therapeutic potential of ALA-PDT in oral healthcare. [ABSTRACT FROM AUTHOR]

Background/Aim: Radiotherapy is one of the most frequently used options for prostate cancer (PCa). However, adverse effects related to irradiation of surrounding normal organs are significant clinical concerns. Specifically, genitourinary toxicity can dramatically reduce the quality of life. This clinical trial investigated the efficacy of oral 5-aminolevulinic acid phosphate combined with sodium ferrous citrate (ALA-SFC) in patients treated with low-dose-rate brachytherapy (LDR-BT) using an iodine-125 seed source. Patients and Methods: The AMBER study was a prospective single-center trial involving patients with localized PCa who underwent LDR-BT without external-beam radiotherapy (jRCTs051190077). Fifty patients were included and instructed to take capsules of ALA-SFC twice a day (200 mg phosphate salt and 229.42 mg per day) for six months from the day of seed implantation (prescribed radiation dose of 160 Gy). Patient data were collected before implantation, during ALA-SFC treatment, and at 1, 3, 6, 9, and 12 months post-LDR-BT. The primary endpoint of this trial was urinary frequency at three months. Other patientreported outcomes, investigator-reported adverse events, and oncological outcomes were secondary endpoints. Results: Of 50 enrolled cases (45 in the per-protocol analysis, 49 in the safety analysis), urinary frequency and its increase from baseline did not differ from 141 historical controls at any time point, including at three months post-LDR-BT. Propensity score matched analysis confirmed no time-course differences in frequency, volume, or urinary symptom scores between groups. Biochemical failure-free and metastasis-free survival also remained similar. Conclusion: Oral supplementation of ALA-SFC to LDR-BT did not alleviate radiation-induced toxicity or improve oncological outcomes. [ABSTRACT FROM AUTHOR]

Different types of photosensitizers (PSs) have different dynamics and intensities of accumulation, depending on the type of tumor or different areas within the same tumor. This determines the effectiveness of fluorescence diagnostics and photodynamic therapy (PDT). This paper studies the processes of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) and chlorin e6 (Ce6) accumulation in the central and border zones of a tumor after combined administration of two PSs into the patient's body. Fluorescence diagnostic methods have shown that sublingual administration of 5-ALA leads to the more intense accumulation of PpIX in a tumor compared to oral administration. Differences have been identified in the dynamics of 5-ALA-induced PpIX and Ce6 accumulation in the central and border zones of the tumor, as well as normal tissues. Ce6 accumulates mainly in the central zone of the tumor while PpIX accumulates in the border zone of the tumor. All patients with combined PDT experienced complete therapeutic pathomorphosis and relapse-free observation. [ABSTRACT FROM AUTHOR]

Background: Spine grape (Vitis davidii) is a promising source of high-quality anthocyanins, with vast potential for application in food, pharmaceutical, and cosmetic industries. However, their availability is limited by resource constraints. Plant cell culture has emerged as a valuable approach for anthocyanin production and serves as an ideal model to investigate the regulation of anthocyanin biosynthesis. Elicitors are employed to achieve targeted enhancement of anthocyanin biosynthesis. The present study investigated the impact of 5-aminolevulinic acid (ALA) as an elicitor on the accumulation of anthocyanins and flavonoids during spine grape callus growth. Specifically, we examined the effects of ALA on anthocyanin and its component accumulation in callus, and biosynthetic anthocyanin gene expression. Results: ALA at 25 µg/L increased the biomass of spine grape callus. ALA induction enhanced the levels of flavonoids, anthocyanins and proanthocyanidins in callus, with maximum values reaching 911.11 mg/100 g DW, 604.60 mg/100 g DW, and 5357.00 mg/100 g DW, respectively, after callus culture for 45 days. Notably, those levels were 1.47-, 1.93- and 1.83-fold higher than controls. ALA induction modulated the flavonoid profile, and among 97 differential flavonoid metabolites differing from controls, 77 were upregulated and 20 were downregulated. Six kinds of anthocyanins, namely cyanidin (8), delphinidin (6), peonidin (5), malvidin (4), petunidin (3) and pelargonidin (3), were detected in callus, with peonidin most abundant. Compared with controls, anthocyanin components were increased in ALA-treated callus. The key genes PAL1, PAL2, PAL4, CHI, CHS3, F3'H, F3H, FLS, DFR, UFGT, MYBA1, LDOX, OMT3, GT1 and ACT involved in anthocyanin biosynthesis were upregulated following ALA treatment, resulting in anthocyanin accumulation. Conclusion: This study revealed a novel mode of ALA-mediated promotion of plant anthocyanin biosynthesis and accumulation at the cellular level, and a strategy for enhancing anthocyanin content in spine grape callus. The findings advance commercial-scale production of anthocyanins via spine grape callus culture. we also explored the accumulation patterns of flavonoids and anthocyanins under ALA treatment. Augmentation of anthocyanins coincided with elevated expression levels of most genes involved in anthocyanin biosynthesis within spine grape callus following ALA treatment. [ABSTRACT FROM AUTHOR]

Introduction: Acne vulgaris is a highly prevalent skin disorder, driving the ongoing search for innovative treatment modalities. While numerous studies have demonstrated the effectiveness of photodynamic therapy (PDT) in managing acne vulgaris, there remains a lack of clear guidlines regarding optimal treatment parameters. Aim: To assess the efficacy and safety of 10% concentration 5-aminolevulinic acid-(ALA) in comparison to 15% ALA PDT for treating facial acne vulgaris. Material and methods: A randomized, double-blind, split-face clinical trial was conducted on 25 patients with moderate to severe acne (Leeds grades 2–4). Patients were randomly assigned to two groups with different ALA concentrations applied on one cheek, while a placebo was applied on the other side. After a 1.5-hour incubation, illumination with 633 nm red light from a Light Emitting Diode (LED) lamp (96 J/cm2) was performed in three sessions with 7–10 days' intervals. Treatment effectiveness was assessed by the lesion reduction rate based on lesion counts before the study, after each session, and at 4 and 8 weeks after the last session. Results: Both 15% and 10% ALA-PDT treatments demonstrated significant reductions in inflammatory acne lesion counts compared to the placebo: 10% ALA-PDT showed a reduction of 27.36% versus 12.64% for the placebo (p = 0.04), while 15% ALA-PDT showed a reduction of 40.45% compared to 13.41% (p < 0.01). However, there was no significant difference between ALA-PDT and placebo in treating non-inflammatory lesions. Additionally, there was no difference between the effectiveness of 10% and 15% ALA in reducing any type of acne lesions. Conclusions: ALA-PDT is effective in treating acne vulgaris. However, ALA-PDT provides an advantage over red light only for inflammatory acne lesions. The study indicates that higher concentrations of ALA do not result in more significant reductions in acne lesions. [ABSTRACT FROM AUTHOR]

Objective To explore the application of ALA photodynamic fluorescence combined with dermatoscopy in the diagnosis of facial cancerization and precancerous lesions. Methods From March 2022 to March 2024, a total of 52 patients with actinic keratosis, BOWEN's disease, squamous cell carcinoma and basal cell carcinoma were enrolled at the dermatology clinic of the First Affiliated Hospital of Henan University of Science and Technology. Each patient was examined by naked eye and ALA photodynamic fluorescence, and the difference in area was compared between these two methods. The ALA photodynamic fluorescence area was divided into 8 equal sections, followed by examination with a dermatoscope to determine whether there were cancerization and precancerous lesions. The lesion area and severity were scored. Results The ALA photodynamic fluorescence area was larger than that observed by the naked eye (all P<0.001). Dermatoscopic examination of the ALA photodynamic fluorescence imaging area revealed precancerous features of various areas and severity, with cancerous area and severity scores of 4.55±1.21, 5.45±2.42, 6.64±2.84, and 5.27±1.95, respectively. Conclusions ALA-photodynamic fluorescence combined with dermatoscopy can find cancerization and precancerous lesions that can't be detected by naked eyes, providing a new method for early screening and early diagnosis of skin cancerization and precancerous lesions. [ABSTRACT FROM AUTHOR]

5-Aminolevulinic acid (5-ALA), a non-proteinogenic amino acid, is an intermediate in the biosynthesis of heme and exerts antiviral effects against feline coronavirus (FCoV); however, the underlying mechanisms remain unclear. In the biosynthesis of heme, 5-ALA is condensed and converted to protoporphyrin IX (PpIX), which is then transformed into heme by the insertion of ferrous iron. Previous research has suggested that the metabolites generated during heme biosynthesis contribute to the antiviral effects of 5-ALA. Therefore, the present study investigated the in vitro mechanisms responsible for the antiviral effects of 5-ALA. The results obtained revealed that 5-ALA and PpIX both effectively reduced the viral titer in the supernatant of FCoV-infected fcwf-4 cells. Moreover, PpIX exerted virucidal effects against FCoV. We also confirmed that 5-ALA increased PpIX levels in cells. While hemin induced heme oxygenase-1 gene expression, it did not reduce the viral titer in the supernatant. Sodium ferrous citrate decreased PpIX levels and suppressed the antiviral effects of 5-ALA. Collectively, these results suggest that the antiviral effects of 5-ALA against FCoV are dependent on PpIX. [ABSTRACT FROM AUTHOR]

Iron plays a crucial role in various metabolic processes. However, the impact of 5-aminolevulinic acid (ALA) in combination with iron chelators on iron metabolism and the efficacy of ALA-photodynamic therapy (PDT) remain inadequately understood. This study aimed to examine the effect of thiosemicarbazone derivatives during ALA treatment on specific genes related to iron metabolism, with a particular emphasis on mitochondrial iron metabolism genes. In our study, we observed differences depending on the cell line studied. For the HCT116 and MCF-7 cell lines, in most cases, the decrease in the expression of selected targets correlated with the increase in protoporphyrin IX (PPIX) concentration and the observed photodynamic effect, aligning with existing literature data. The Hs683 cell line showed a different gene expression pattern, previously not described in the literature. In this study, we collected an extensive analysis of the gene variation occurring after the application of novel thiosemicarbazone derivatives and presented versatile and effective compounds with great potential for use in ALA-PDT. [ABSTRACT FROM AUTHOR]

Background: Minimally-invasive 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is used for treating cervical high-grade squamous intraepithelial lesions (HSIL/CIN2). The purpose of this study was to analyze the factors affecting the efficacy of ALA-PDT in the treatment of cervical HSIL/CIN2 in order to guide physicians in making appropriate treatment decisions. Methods: A retrospective study including 69 female patients with pathologically diagnosed HSIL/CIN2 was conducted. Patients were given six doses of 20% ALA-PDT at 7–14-day intervals. Cytology, HPV testing, colposcopy, and pathology were performed before treatment and at 6-month follow-up after treatment to assess efficacy. The main outcome of this study was the regression of HSIL/CIN2 and the clearance of high-risk HPV (hrHPV) infection after ALA-PDT treatment. Clinicopathological characteristics were collected to analyze the factors affecting the effectiveness of ALA-PDT treatment for HSIL/CIN2. Results: Between the successful and failed lesion regression group, there was a significant difference in sleeping disorders (p < 0.05). Between the successful and failed hrHPV clearance group, no statistically significant factors were found. With sensitivity values of 0.556 and 0.778, respectively, multivariate analysis showed that current smoking and sleeping disorders were independent prognostics of failure in lesion regression after ALA-PDT treatment. Conclusions: Smoking and sleep disorders were independent risk factors for failure in HSIL/CIN2 regression following ALA-PDT, suggesting the need for careful consideration of ALA-PDT for patients with these conditions. [ABSTRACT FROM AUTHOR]

Abstract Objective To compare effectiveness of topical 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA PDT) and loop electrosurgical excision procedure (LEEP) among patients with cervical intraepithelial neoplasia (CIN). Methods We retrospectively identified patients who underwent either 5-ALA PDT or LEEP from Sep. 2012 to Dec. 2019 in Chinese PLA general hospital. Patients’ outcomes were compared according to the HPV genotyping, cytological tests within 3–6-month follow-up post-treatment, the pathological examination would be performed if the cytological results indicated the risk of CIN. Propensity score matching (PSM) was adapted to pair the baseline. Complete remission (CR), partial remission (PR) and the remission rate of HPV infections were used to evaluate the efficacy of 5-ALA PDT versus LEEP. Results In total, 30 pairs were matched as the matching tolerance was set as 0.03. There was no significant difference about the CR and PR between 5-ALA PDT and LEEP group (73.33% vs 84.00%, P = 0.340; 3.33% vs 4.00%, P = 1.000). Among different CIN group, there was no statistic difference between 5-ALA PDT and LEEP. Moreover, in terms of HPV remission rate, 5-ALA PDT showed the same efficacy as LEEP (59.26% vs 53.85%, P = 0.691). Conclusions In essence, topical 5-ALA PDT emerges as a non-invasive, repeatable procedure with minimal side effects for cervical lesions, preserving cervical structure. Overall, the efficacy of 5-ALA PDT is comparable to LEEP in achieving successful outcomes.

Objective To explore the application of ALA photodynamic fluorescence combined with dermatoscopy in the diagnosis of facial cancerization and precancerous lesions. Methods From March 2022 to March 2024, a total of 52 patients with actinic keratosis, BOWEN's disease, squamous cell carcinoma and basal cell carcinoma were enrolled at the dermatology clinic of the First Affiliated Hospital of Henan University of Science and Technology. Each patient was examined by naked eye and ALA photodynamic fluorescence, and the difference in area was compared between these two methods. The ALA photodynamic fluorescence area was divided into 8 equal sections, followed by examination with a dermatoscope to determine whether there were cancerization and precancerous lesions. The lesion area and severity were scored. Results The ALA photodynamic fluorescence area was larger than that observed by the naked eye (all P

Abstract Background Spine grape (Vitis davidii) is a promising source of high-quality anthocyanins, with vast potential for application in food, pharmaceutical, and cosmetic industries. However, their availability is limited by resource constraints. Plant cell culture has emerged as a valuable approach for anthocyanin production and serves as an ideal model to investigate the regulation of anthocyanin biosynthesis. Elicitors are employed to achieve targeted enhancement of anthocyanin biosynthesis. The present study investigated the impact of 5-aminolevulinic acid (ALA) as an elicitor on the accumulation of anthocyanins and flavonoids during spine grape callus growth. Specifically, we examined the effects of ALA on anthocyanin and its component accumulation in callus, and biosynthetic anthocyanin gene expression. Results ALA at 25 µg/L increased the biomass of spine grape callus. ALA induction enhanced the levels of flavonoids, anthocyanins and proanthocyanidins in callus, with maximum values reaching 911.11 mg/100 g DW, 604.60 mg/100 g DW, and 5357.00 mg/100 g DW, respectively, after callus culture for 45 days. Notably, those levels were 1.47-, 1.93- and 1.83-fold higher than controls. ALA induction modulated the flavonoid profile, and among 97 differential flavonoid metabolites differing from controls, 77 were upregulated and 20 were downregulated. Six kinds of anthocyanins, namely cyanidin (8), delphinidin (6), peonidin (5), malvidin (4), petunidin (3) and pelargonidin (3), were detected in callus, with peonidin most abundant. Compared with controls, anthocyanin components were increased in ALA-treated callus. The key genes PAL1, PAL2, PAL4, CHI, CHS3, F3’H, F3H, FLS, DFR, UFGT, MYBA1, LDOX, OMT3, GT1 and ACT involved in anthocyanin biosynthesis were upregulated following ALA treatment, resulting in anthocyanin accumulation. Conclusion This study revealed a novel mode of ALA-mediated promotion of plant anthocyanin biosynthesis and accumulation at the cellular level, and a strategy for enhancing anthocyanin content in spine grape callus. The findings advance commercial-scale production of anthocyanins via spine grape callus culture. we also explored the accumulation patterns of flavonoids and anthocyanins under ALA treatment. Augmentation of anthocyanins coincided with elevated expression levels of most genes involved in anthocyanin biosynthesis within spine grape callus following ALA treatment.

Abstract Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20–35 weeks (aged-A1 +/−s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1 +/−s and a sarcopenic phenotype in A1 +/−s at 75–95 weeks (senile-A1 +/−s). Senile-A1 +/−s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1 +/−s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1 +/−s and A1KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.

Features of the expression of membrane importers of 5-ALA, as well as transporters involved in the removal of photoactive precursors of protoporphyrin IX (PPIX) (uro-, copro- and protoporphyrinogens), may cause differences in the effectiveness of photodynamic therapy of malignant neoplasms using 5-aminolevulinic acid (5-ALA). Increased expression of ALA transporters is associated with an increase in the intensity of PPIX synthesis. When the expression of PPIX exporters increases, there is a decrease in PPIX concentration. The review describes the main transporters of 5-ALA, uro-, copro- and protoporphyrinogens, provides data on their expression in various tissues, and discusses the possibility of predicting the effectiveness of photodynamic therapy considering the expression of the corresponding transport proteins in malignant tissues.

5-Aminolevulinic acid (ALA), as a novel plant growth regulator, is a critical precursor for the biosynthesis of porphyrin compounds in all organisms. Many studies have reported that exogenous ALA treatment could improve fruit sweetness. However, the mechanism by which ALA promotes the increase in sugar content in fruit remains unclear. In this study, we found that ALA significantly promoted sucrose accumulation and SPS (sucrose phosphate synthase) activity in peach fruit. At 14, 28, 42, 50 and 60 days after ALA treatment, sucrose content of fruit was increased by 23%, 43%, 37%, 40% and 16%, respectively, compared with control treatment, and SPS enzyme activity was increased by 21%, 28%, 47%, 37% and 29%, respectively. Correlation analysis showed that the sucrose content of peach fruit under ALA treatment was significantly positively correlated with SPS activity. Subsequently, bioinformatics was used to identify SPS gene family members in peach fruit, and it was found that there were four members of the PpSPS gene family, distributed on chromosomes 1, 7 and 8, named PpSPS1, PpSPS2, PpSPS3 and PpSPS4, respectively. The results of qRT-PCR showed that PpSPS2 and PpSPS3 were highly expressed in response to ALA during fruit development, and the expression of PpSPS2 was positively correlated with SPS activity and sucrose accumulation in peach fruit. The results of tobacco subcellular localization showed that PpSPS2 was mainly distributed in the cytoplasm and nucleus, while PpSPS3 was mainly distributed in the nucleus. The results of this study will lay the foundation for further study on the functions of PpSPS and the regulation of sugar metabolism during the development and ripening of peach fruit by ALA.

Enhancing crop drought tolerance is crucial for food security amid climate change. This study examines how 5‐aminolevulinic acid (ALA) and hydrogen sulfide (H2S) can improve drought resilience in tomato plants, which are essential for sustainable food production. Drought stress was induced using 12% PEG‐6000. Plants were pre‐treated with 25 mg L−1 ALA and 0.1 mg L−1 hypotaurine (HT), followed by 0.2 mM sodium hydrosulfide (NaHS) treatment to assess the effects on plant physiological effects over 10 days. Drought stress reduced plant dry weight, chlorophylls (a and b), Fv/Fm, leaf water potential, and relative water content, while increasing glycine betaine (GB) and proline levels. Additionally, drought stress elevated NADPH oxidase (NOX) and glycolate oxidase (GOX) activities, inducing oxidative stress and membrane damage. ALA and NaHS enhanced plant growth, photosynthesis, proline, GB, ALA content, ATP synthase, and ATPase activities, while mitigating NOX and GOX activities, thereby reducing O2·−$$ {\mathrm{O}}_2^{\cdotp -} $$ and H2O2 radicals. ALA alone boosted L‐DES activity, promoting H2S accumulation. However, ALA + HT reduced H2S levels, compromising ALA's efficacy. NaHS with ALA + HT reinstated positive effects by restoring H2S levels. Biochemical assays confirmed ALA and NaHS promoted H2S accumulation, bolstering antioxidants, mitigating lipid peroxidation, suggesting their drought resilience potential in tomatoes. [ABSTRACT FROM AUTHOR]

BACKGROUND: In periprosthetic joint infections (PJIs), the surgeon's role becomes pivotal in addressing the infection locally, necessitating the surgical removal of infected and necrotic tissue. Opportunity to enhance the visualization of infected tissue during surgery could represent a game-changing innovation. OBJECTIVE: The aim of this narrative review is to delineate the application of intraoperative fluorescence imaging for targeting infected tissues in PJIs. METHODS: A systematic review, adhering to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, was carried out. The search included multiple online database; MEDLINE, Scopus, and Web of Science. For data extraction the following were evaluated: (i) diagnosis of musculoskeletal infection; (ii) use of intraoperative fluorescence imaging; (iii) infected or necrotic tissues as target. RESULTS: Initially, 116 studies were identified through online database searches and reference investigations. The search was narrowed down to a final list of 5 papers for in-depth analysis at the full-text level. Subsequently, 2 studies were included in the review. The study included a total of 13 patients, focusing on cases of fracture-related infections of the lower limbs. CONCLUSION: The primary and crucial role for orthopedic surgeons in PJIs is the surgical debridement and precise removal of necrotic and infected tissue. Technologies that enable clear and accurate visualization of the tissue to be removed can enhance the eradication of infections, thereby promoting healing. A promising avenue for the future involves the potential application of intraoperative fluorescence imaging in pursuit of this objective. [ABSTRACT FROM AUTHOR]

5-Aminolevulinic acid (5-ALA) is orally administered 2-4 hours before surgery to identify tumor location. Hypotension is sometimes observed after 5-ALA administration. Case reoprt We present a case of a patient with 5-ALA-induced hypotension that resulted in the development of cerebral infarction. An 83-year-old man with a bladder tumor was scheduled for photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) and right radical nephroureterectomy. 5-ALA was orally administered and his ordinary antihypertensive and antianginal agents were also administered an hour after 5-ALA administration. Following this, his blood pressure dropped, and he developed muscle weakness and paralysis in his left upper extremity. Magnetic resonance imaging showed evidence of cerebral infarction. Conclusions We cannot conclude definitively that our patient's cerebral infarction was solely caused by 5-ALAinduced hypotension because hypotension under these circumstances is not rare. We consider that additional factors, such as patient-specific doses of antihypertensive and antianginal agents may have played a role in the development of his cerebral infarction. [ABSTRACT FROM AUTHOR]

Objectives: In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis‐assisted transurethral resection of bladder tumor (PDD‐TURBT) using oral 5‐aminolevulinic acid hydrochloride reduced residual tumors in high‐risk non‐muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD‐TURBT for intravesical recurrence after a second transurethral resection for high‐risk NMIBC. Methods: High‐risk NMIBC patients initially treated with PDD‐TURBT (PDD group) were prospectively registered between 2018 and 2020. High‐risk patients with NMIBC who were initially treated with white‐light TURBT (WL group) were retrospectively registered. Intravesical recurrence‐free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis. Results: In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25–0.77). In subgroup analysis, PDD‐TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14–0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16–0.86), and no postoperative intravesical Bacillus Calmette‐Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13–0.58). Conclusions: PDD‐TURBT may reduce short‐term intravesical recurrence in patients with high‐risk NMIBC. [ABSTRACT FROM AUTHOR]

Objective: Intraoperative hypotension remains a serious adverse event of photodynamic diagnosis‐assisted transurethral resection of bladder tumor with oral administration of 5‐aminolevulinic acid. We conducted a re‐analysis of perioperative hypotension in photodynamic diagnosis‐assisted transurethral resection of the bladder tumor with oral 5‐aminolevulinic acid to ascertain its safety. Methods: A total of 407 cases who underwent transurethral resection of bladder tumors in our institution were reviewed (274 cases for the PDD group with photodynamic diagnosis and 133 for the white light (WL) group without). A classification of hypotension severity was devised to identify risk factors for clinically troublesome hypotension. The distribution of hypotension severity in each of the PDD and WL groups was compared. Additionally, the patient background and perioperative data by hypotension severity were compared only in the PDD group. Results: More patients with moderate and severe hypotension were noted in the PDD group. The renal function was lower with increasing hypotension severity in the PDD group. More patients on general anesthesia were included in the mild and moderate hypotension group, whereas more patients on spinal anesthesia were included in the severe hypotension group. Furthermore, the frequency of side effects other than hypotension tended to increase with hypotension severity. Conclusions: Renal function impairment and the other adverse effects of 5‐aminolevulinic acid may be risk factors for severe hypotension. Mild or moderate hypotension may be caused by general anesthesia and severe hypotension may be caused by spinal anesthesia. To elucidate specific risk factors, further case–control studies are warranted. [ABSTRACT FROM AUTHOR]

TiO2 nanoparticles (TiO2NPs) were directly conjugated with the phototherapeutic prodrug, 5‐aminolevulinic acid (ALA), using a mild and green approach. The resultant TiO2NPs‐ALA nanoconjugates were characterized by different techniques, including HPLC, UV‐Vis, FTIR‐ATR, 1H‐NMR, FESEM‐EDS, TEM, DLS, and synchrotron radiation‐induced XPS (SR‐XPS) to assess the successful loading of 15 % and the chemical stability of ALA on the TiO2NPs. More importantly, the SR‐XPS results showed the stabilizing effect of TiO2 nanosurface on the ALA molecules (against structural change) in neutral and alkaline pHs, which is of great significance in the potential therapeutic applications of ALA. The FESEM and TEM results exhibited the grain‐like TiO2NPs‐ALA particles with a 20–50 nm size distribution, indicating size‐controlling effect of ALA on the TiO2NPs during the conjugation process and the presence of the organic molecule layer onto the surface. TiO2NPs‐ALA represents a promising candidate for studies in photodynamic therapy considering the stabilization effect observed by spectroscopic characterizations. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC. The high risks of disease recurrence from residual tumor and progression after TURBT in NMIBC are well known. A new-generation photosensitizer, 5-Aminolevulinic acid (5-ALA), with a high tumor specificity, has been studied for detecting precise tumor areas. Moreover, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Thus, 5-ALA may contribute to the inclusive treatment of NMIBC. Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard of care in treating NMIBC and serves both diagnostic and therapeutic purposes despite the prevalent recurrence and progression among many patients. In particular, flat urothelial carcinoma in situ and urothelial carcinoma with lamina propria invasion are the major precursors of MIBC. A new-generation photosensitizer, 5-Aminolevulinic acid (5-ALA), demonstrates high tumor specificity by illuminating the tumor lesion with a specific wavelength of light to produce fluorescence and has been studied for photodynamic diagnosis to detect precise tumor areas by TURBT. Additionally, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Moreover, 5-ALA may contribute to screening before and after TURBT in NMIBC. Here, we summarize the updated evidence and ongoing research on photodynamic technology for NMIBC, providing insight into the potential for improving patient outcomes. [ABSTRACT FROM AUTHOR]

Vitiligo is an acquired chronic depigmentary skin disorder which results from the destruction of melanocytes. The clinical characteristic of vitiligo is the development of white macules due to the loss of functioning melanocytes in the skin or hair. Vitiligo in the genital area brings about a serious psychological impact on individuals. However, the choices of treatment for genital vitiligo are scarce. This study sheds light on the leverage of 5-ALA (5-Aminolevulinic Acid) Photodynamic Therapy (PDT) for the management of genital vitiligo. Nine patients with genital vitiligo who underwent 20 % ALA-PDT treatment were reported. The results revealed that the treatment protocol simulated melanocyte regeneration in the patients effectively. ALA-PDT exerts significant anti-inflammatory effects by reducing pro-inflammatory cytokines and inducing regulatory T cells, which may help suppress the autoimmune response involved in vitiligo pathogenesis. Notably, five patients who were defined as responders showed moderate to excellent improvement in repigmentation and the treatment was well tolerated in all cases. Our findings suggest that ALA-PDT is a potential treatment option for genital vitiligo.

Background: Herpes simplex virus (HSV) infections are prevalent worldwide, posing challenges due to asymptomatic carriage and recurrent outbreaks. Conventional treatments, including antiviral medications, are limited by drug resistance. Photodynamic therapy (PDT) offers a promising alternative, leveraging photosensitizers to induce viral inactivation via reactive oxygen species (ROS) generation upon light activation. Methods: This study investigates the efficacy of 5-aminolevulinic acid (5-ALA) as a photosensitizer in antiviral PDT against HSV-1. HSV-1 was treated with varying concentrations of 5-ALA and subjected to light irradiation at a 630 nm wavelength. Virus titers were assessed using the 50 % Tissue Culture Infectious dose (TCID50) assay. Six experimental groups were used: [1] Control (no 5-ALA or light), HSV-1 with 0.05 g/ml 5-ALA and 630 nm light, [2] HSV-1 with 0.05 g/ml 5-ALA (no light), [3] HSV-1 with 0.1 g/ml 5-ALA and light, [4] HSV-1 with 0.1 g/ml 5-ALA (no light), and [5] HSV-1 with light (no 5-ALA). Results: Virus treatment with 0.1 g/ml 5-ALA combined with light irradiation significantly reduced HSV-1 titer compared to control groups (p < 0.05). Specifically, the virus titer decreased from 10 6.3 TCID50/ml in the control group to 10 4.5 TCID50/ml in the treated group. However, lower concentrations of 5-ALA or light irradiation alone did not yield significant reductions in HSV-1 titer (p > 0.05). Group 4, receiving 0.1 g/ml 5-ALA with light irradiation, exhibited a significantly greater reduction in virus titer than group 2, receiving 0.05 g/ml 5-ALA with light irradiation (p < 0.05). Conclusions: 5-ALA-mediated PDT demonstrates selective antiviral efficacy against HSV-1, particularly at higher concentrations coupled with light irradiation. These findings underscore the potential of 5-ALA-based PDT as a promising approach for HSV-1 treatment, especially in cases of drug-resistant strains and immunocompromised individuals. Optimization of dosage and treatment protocols is essential for maximizing effectiveness in clinical applications, highlighting the need for further research in this area.

ABSTRACT Bacteria within the family Paracoccaceae show promising potential for applications in various fields, garnering significant research attention. Three Gram stain-negative bacteria, strains CPCC 101601T, CPCC 101403T, and CPCC 100767, were isolated from diverse environments: freshwater, rhizosphere soil of Broussonetia papyrifera, and the phycosphere, respectively. Analysis of their 16S rRNA gene sequences, compared with those in the GenBank database, indicated that they belong to the family Paracoccaceae, with nucleotide similarities of 92.5%–99.9% to all of the Paracoccaceae members with valid taxonomic names. Phylogenetic studies based on 16S rRNA gene and whole-genome sequences identified CPCC 101601T as a member of the genus Pseudogemmobacter, CPCC 101403T belonging to the genus Paracoccus, and CPCC 100767 as part of the genus Gemmobacter. Notably, genomic analysis using average nucleotide identity (ANI;

Background: Female vulvar lichen sclerosus (VLS) is a chronic inflammatory skin disease of the vulva and its etiology is unknown. The main clinical symptoms are itching, burning and dyspareunia, and there is a lack of effective treatment. Methods: Clinical and follow-up data of women with VLS who underwent 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) from January 2023 to December 2023 in the department of obstetrics and gynecology, Qilu Hospital of Shandong University, were retrospectively analyzed. According to the inclusion and exclusion criteria, 36 patients with VLS who received ineffective conventional treatment (intractable VLS) were enrolled. Objective signs and subjective symptoms of vulvar lesions were recorded before treatment and 6 months after the end of treatment according to corresponding scoring criteria. Quality of life was evaluated using the Dermatology Life Quality Index (DLQI). Results: All patients received six sessions of ALA-PDT treatment and follow-up visits. After ALA-PDT treatment, 24 of 36 (66.67 %) patients' itching symptoms completely disappeared, 10 of 36 (27.78 %) patients' itching symptoms were relieved from severe to mild, and only 2 of 36 (5.56 %) patients' symptoms were not significantly relieved. 16 of 36 (44.4 %) patients' itching symptoms completely disappeared, 9 of 36 (25 %) patients' itching symptoms were relieved from severe to mild, and only 2 of 36 (5.56 %) patients still had severe pain. Compared to 22 patients with dyspareunia before treatment, only 9 patients still had dyspareunia with varying degrees of dyspareunia relief after treatment. Clinical signs improved significantly in the patients after ALA-PDT treatment. The total scores of clinical signs were (5.31 ± 1.67 vs 3.67 ± 1.71) before and after treatment. All patients showed improvement in DLQI after treatment. The main side effects of ALA-PDT were pain, erythema and swelling which were transient and tolerable. All patients were “satisfied” or “very satisfied” with the results of the treatment. Conclusions: ALA-PDT is a safe and effective treatment for women with intractable vulva lichen sclerosus.

Background: Oral 5-aminolevulinic acid for transurethral resection of bladder tumor reduces bladder cancer recurrence compared with standard white-light transurethral resection of bladder tumor. However, data regarding risks of adverse events with this drug are unclear. The aim of the present study was to identify risk factors associated with oral 5-aminolevulinic acid induced adverse events in photodynamic diagnosis-transurethral resection of bladder tumor. Methods: We studied 104 cases of 5-aminolevulinic acid-photodynamic diagnosis-transurethral resection of bladder tumor from October 2021 to April 2023, administering 20 mg/kg 5-aminolevulinic acid orally at least 2 h pre-surgery. Four major adverse events associated with 5-aminolevulinic acid were selected to identify risk factors for their occurrence, including perioperative hypotension, nausea and/or vomiting, photosensitivity, and liver dysfunction. Univariate and multivariate analyses were conducted to identify the risk factors of those adverse events. Results: Perioperative hypotension (11.5 %), nausea and/or vomiting (37.5 %) photosensitivity (31.7 %), and liver dysfunction (51.9 %) were observed. Multivariate analyses revealed that spinal anesthesia was associated with hypotension (p = 0.02), whereas advanced age (p < 0.01) and higher body mass index (p < 0.01) were associated with nausea and/or vomiting. Also, male sex (p < 0.01) and longer operative time (p = 0.01) were associated with photosensitivity, and renin-angiotensin system inhibitors use was associated with postoperative liver dysfunction (p < 0.01). Conclusions: For elderly male obese patients taking renin-angiotensin system inhibitors, particular attention is needed during the perioperative period of photodynamic diagnosis-transurethral resection of bladder tumor under spinal anesthesia due to the higher risk of onset of the adverse events involved in oral administration of 5-aminolevulinic acid.

Candidiasis is a common fungal infection, with Candida tropicalis infections being relatively rare. These infections develop into skin fungal infections under conditions such as broad-spectrum antibiotic use, diabetes, and immunosuppression. Traditionally, antifungal drugs have been the primary treatment; however, issues like hepatotoxicity and the need for long-term use persist. Consequently, new treatment approaches are essential. Most previous reports have focused on Candida albicans, with fewer addressing Candida tropicalis. This study reports a case where a patient with a skin Candida tropicalis infection was treated with a combination of surgery and ALA photodynamic therapy(635 nm, 120 J/cm2, 177 mW/cm2). After just one session of this combined treatment, the patient achieved significant clinical remission. Therefore, the combination of surgery and ALA-PDT may offer a safe and effective treatment option.

Abstract Background 5-Aminolevulinic acid (ALA) recently received much attention due to its potential application in many fields such as medicine, nutrition and agriculture. Metabolic engineering is an efficient strategy to improve microbial production of 5-ALA. Results In this study, an ALA production strain of Escherichia coli was constructed by rational metabolic engineering and stepwise improvement. A metabolic strategy to produce ALA directly from glucose in this recombinant E. coli via both C4 and C5 pathways was applied herein. The expression of a modified hemA RS gene and rational metabolic engineering by gene knockouts significantly improved ALA production from 765.9 to 2056.1 mg/L. Next, we tried to improve ALA production by RGMS-directed evolution of eamA gene. After RGMS, the ALA yield of strain A2-ASK reached 2471.3 mg/L in flask. Then, we aimed to improve the oxidation resistance of cells by overexpressing sodB and katE genes and ALA yield reached 2703.8 mg/L. A final attempt is to replace original promoter of hemB gene in genome with a weaker one to decrease its expression. After 24 h cultivation, a high ALA yield of 19.02 g/L was achieved by 108-ASK in a 5 L fermenter. Conclusions These results suggested that an industrially competitive strain can be efficiently developed by metabolic engineering based on combined rational modification and optimization of gene expression.

Abstract Background Although 5-aminolevulinic acid is useful for the photodynamic diagnosis of bladder tumors, it often causes severe intraoperative hypotension. We report a case of postoperative cardiac arrest in addition to severe intraoperative hypotension, probably owing to the use of 5-aminolevulinic acid. Case presentation An 81-year-old Japanese man was scheduled to undergo transurethral resection of bladder tumor. The patient took 5-aminolevulinic acid orally 2 hours before entering the operating room. After the induction of anesthesia, his blood pressure decreased to 47/33 mmHg. The patient’s hypotension did not improve even after noradrenaline was administered. After awakening from anesthesia, the patient’s systolic blood pressure increased to approximately 100 mmHg, but approximately 5 hours after returning to the ward, cardiac arrest occurred for approximately 12 seconds. Conclusion We experienced a case of postoperative cardiac arrest in a patient, probably owing to the use of 5-aminolevulinic acid. Although the cause of cardiac arrest is unknown, perioperative hemodynamic management must be carefully performed in patients taking 5-aminolevulinic acid.

Background: Genital lichen sclerosus (GLS) is a chronic inflammatory skin disease affecting the genital and anal areas. Treatment of refractory remains a challenge in clinical practice. Objective: This study aimed to evaluate the efficacy and safety of 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) for refractory GLS. Methods: Thirty-five patients with histopathologically confirmed GLS (including 32 females and 3 males) were treated with 5-ALA PDT. Lesion pretreatment was performed to enhance photosensitizer penetration, and fluorescence diagnosis was used for precise point-to-point treatment. Efficacy and safety were systematically evaluated by assessing treatment outcomes, symptom improvement, side effects and maintenance of efficacy over a 6-month follow-up period. Results: After treatment, most patients experienced significant relief of pruritus, improved skin elasticity and color, and reduced lesion area. After 6 treatment sessions, 11 patients (31.43 %) achieved complete resolution of pruritus, with 3 patients (8.57 %) achieving complete remission after 3 sessions. Cattaneo scores decreased significantly after treatment and during follow-up (P < 0.05). Adverse reactions were mainly mild pain, which could be relieved by ice compression or oral analgesics. Conclusions: 5-ALA PDT shows significant efficacy and good safety for refractory GLS, improving the clinical symptoms and signs of patients, and warrants wider clinical application.

DescriptionThe acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15-50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options.MethodsThis expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Women aged 15-50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. BEST PRACTICE ADVICE 2: Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. BEST PRACTICE ADVICE 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. BEST PRACTICE ADVICE 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. BEST PRACTICE ADVICE 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. BEST PRACTICE ADVICE 6: Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. BEST PRACTICE ADVICE 7: Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). BEST PRACTICE ADVICE 8: Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. BEST PRACTICE ADVICE 9: Patients with AHP should be monitored annually for liver disease. BEST PRACTICE ADVICE 10: Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. BEST PRACTICE ADVICE 11: Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. BEST PRACTICE ADVICE 12: Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.

Background: 5-Aminolevulinic acid (ALA) recently received much attention due to its potential application in many fields such as medicine, nutrition and agriculture. Metabolic engineering is an efficient strategy to improve microbial production of 5-ALA. Results: In this study, an ALA production strain of Escherichia coli was constructed by rational metabolic engineering and stepwise improvement. A metabolic strategy to produce ALA directly from glucose in this recombinant E. coli via both C4 and C5 pathways was applied herein. The expression of a modified hemARS gene and rational metabolic engineering by gene knockouts significantly improved ALA production from 765.9 to 2056.1 mg/L. Next, we tried to improve ALA production by RGMS-directed evolution of eamA gene. After RGMS, the ALA yield of strain A2-ASK reached 2471.3 mg/L in flask. Then, we aimed to improve the oxidation resistance of cells by overexpressing sodB and katE genes and ALA yield reached 2703.8 mg/L. A final attempt is to replace original promoter of hemB gene in genome with a weaker one to decrease its expression. After 24 h cultivation, a high ALA yield of 19.02 g/L was achieved by 108-ASK in a 5 L fermenter. Conclusions: These results suggested that an industrially competitive strain can be efficiently developed by metabolic engineering based on combined rational modification and optimization of gene expression. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis (ECP) is a therapeutic modality used for T-cell-mediated disorders. This approach involves exposing isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light, aiming to induce apoptosis in T-cells and thereby modulate immune responses. However, conventional 8-MOP-ECP lacks cell selectivity, killing both healthy and diseased cells, and has shown limited treatment efficacy. An alternative approach under investigation involves the use of 5-aminolevulinic acid (ALA) in conjunction with light, referred to as ALA-based photodynamic therapy. Our previous ex vivo studies suggest that ALA-ECP exhibits greater selectivity and efficiency in killing T-cells derived from patients with T-cell-mediated disorders compared to those treated with 8-MOP-ECP. We have conducted a clinical phase I–(II) study evaluating ALA-ECP safety and tolerability in cutaneous T-cell lymphoma (CTCL). Here, 20 ALA-ECP treatments were administered to one CTCL patient, revealing no significant changes in vital signs. Two adverse events were reported; both evaluated by the Internal Safety Review Committee as non-serious. In addition, five conceivable events with mainly mild symptoms took place. During the study period, a 53% reduction in skin involvement and a 50% reduction in pruritus was observed. In conclusion, the results indicate that ALA-ECP treatment is safe and well tolerated. [ABSTRACT FROM AUTHOR]

Oral squamous-cell and pancreatic carcinomas are aggressive cancers with a poor outcome. Photodynamic therapy (PDT) consists of the use of photosensitizer-induced cell and tissue damage that is activated by exposure to visible light. PDT selectively acts on cancer cells, which have an accumulation of photosensitizer superior to that of the normal surrounding tissues. 5-aminolevulinic acid (5-ALA) induces the production of protoporphyrin IX (PpIX), an endogenous photosensitizer activated in PDT. This study aimed to test the effect of a new gel containing 5% v/v 5-ALA (ALAD-PDT) on human oral CAL-27 and pancreatic CAPAN-2 cancer cell lines. The cell lines were incubated in low concentrations of ALAD-PDT (0.05%, 0.10%, 0.20%, 0.40%, 0.75%, 1.0%) for 4 h or 8 h, and then irradiated for 7 min with 630 nm RED light. The cytotoxic effects of ALAD-PDT were measured using the MTS assay. Apoptosis, cell cycle, and ROS assays were performed using flow cytometry. PpIX accumulation was measured using a spectrofluorometer after 10 min and 24 and 48 h of treatment. The viability was extremely reduced at all concentrations, at 4 h for CAPAN-2 and at 8 h for CAL-27. ALAD-PDT induced marked apoptosis rates in both oral and pancreatic cancer cells. Elevated ROS production and appreciable levels of PpIX were detected in both cell lines. The use of ALA-PDT as a topical or intralesional therapy would permit the use of very low doses to achieve effective results and minimize side effects. ALAD-PDT has the potential to play a significant role in complex oral and pancreatic anticancer therapies. [ABSTRACT FROM AUTHOR]