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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]

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.

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: 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]

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. [ABSTRACT FROM AUTHOR]

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. The aim of this narrative review is to delineate the application of intraoperative fluorescence imaging for targeting infected tissues in PJIs. 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. 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. 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]

Persistent HPV infections may cause cervical and vaginal intraepithelial neoplasia (CIN and VaIN). Traditional methods might destroy the structure and function of the cervix. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive targeted therapy. This study aims to evaluate the efficacy and safety of ALA-PDT for CIN and VaIN and the clearance of HPV. A retrospective study of 303 patients who confirmed CIN or VaIN and received ALA-PDT was conducted. All the patients were followed up at six and twelve months after treatment and then annually thereafter. The effect was evaluated through HPV genotyping, a cytology test, and colposcopy-directed biopsy if necessary. After ALA-PDT, the remission rates for CIN 2, CIN 3, VaIN 2, and VaIN 3 were 90.6%, 88.5%, 87.3%, and 77.8%. For CIN 1, the remission rate at the six-month follow-up was 93.1%. The total HPV clearance rates were 72.5% at the six-month follow-up and 85.7% at the 12-month follow-up. The most common adverse event was vaginal discharge. No severe adverse effect was observed. ALA-PDT is an effective and safe treatment for all grades of CIN and VaIN and is helpful in clearing HPV with minimal side effects. This treatment may not influence fertility and delivery. [ABSTRACT FROM AUTHOR]

Shewanella oneidensis MR-1 has found widespread applications in pollutant transformation and bioenergy production, closely tied to its outstanding heme synthesis capabilities. However, this significant biosynthetic potential is still unexploited so far. Here, we turned this bacterium into a highly-efficient bio-factory for green synthesis of 5-Aminolevulinic Acid (5-ALA), an important chemical for broad applications in agriculture, medicine, and the food industries. The native C5 pathway genes of S. oneidensis was employed, together with the introduction of foreign anti-oxidation module, to establish the 5-ALA production module, resulting 87-fold higher 5-ALA yield and drastically enhanced tolerance than the wild type. Furthermore, the metabolic flux was regulated by using CRISPR interference and base editing techniques to suppress the competitive pathways to further improve the 5-ALA titer. The engineered strain exhibited 123-fold higher 5-ALA production capability than the wild type. This study not only provides an appealing new route for 5-ALA biosynthesis, but also presents a multi-dimensional modularized engineering strategy to broaden the application scope of S. oneidensis. • Efficient synthesis of 5-ALA solely relying on the S. oneidensis endogenous C5 pathway was achieved for the first time. • Employ a modular assembly strategy to build production, antioxidant, and inhibition modules for tuning the metabolic flux. • Rational metabolic engineering enhances the 5-ALA yield of S. oneidensis by 123 times. [ABSTRACT FROM AUTHOR]

Abstract5-Aminolevulinic acid (5-ALA) is a non-proteinogenic amino acid essential for synthesizing tetrapyrrole compounds, including heme, chlorophyll, cytochrome, and vitamin B12. As a plant growth regulator, 5-ALA is extensively used in agriculture to enhance crop yield and quality. The complexity and low yield of chemical synthesis methods have led to significant interest in the microbial synthesis of 5-ALA. Advanced strategies, including the: enhancement of precursor and cofactor supply, compartmentalization of key enzymes, product transporters engineering, by-product formation reduction, and biosensor-based dynamic regulation, have been implemented in bacteria for 5-ALA production, significantly advancing its industrialization. This article offers a comprehensive review of recent developments in 5-ALA production using engineered bacteria and presents new insights to propel the field forward. [ABSTRACT FROM AUTHOR]

Using beneficial microorganisms, such as purple non-sulfur bacteria (PNSB), has shown enormous potential for improving plant growth and agricultural production. However, the full extent of their benefits and interactions with agricultural practices is yet to be fully understood. The present study aimed to investigate the use of PNSB in crop rotation practice, focusing on its impact on rice growth and yield. The experiment was conducted over two rice cropping seasons, with djulis grown between the rice as a rotation crop. The study shows that PNSB treatment increased the concentration of 5-aminolevulinic acid (5-ALA) in plants, indicating enhanced photosynthesis. Moreover, when combined with crop rotation, PNSB remarkably improved soil fertility. These combined benefits resulted in substantial increases in tiller numbers (163%), leaf chlorophyll content (13%), and lodging resistance (66%), compared to the untreated plants. The combined treatment also resulted in higher productive tillers per hill (112%), average grain per hill (65%), and grain fertility (26%). This led to increased grain yield (65%), shoot dry weight (15%), and harvest index (37%). The findings clearly suggest that the incorporation of PNSB in crop rotation strategies can significantly augment the growth and yield of rice crops. These insights, pivotal for sustainable rice cultivation, hold the potential to simultaneously tackle the pressing issues of global food security and climate change. [ABSTRACT FROM AUTHOR]

Background: Typical treatments for cervical high-grade squamous intraepithelial lesion (HSIL) are invasive procedures. However, these procedures often come with several severe side effects, despite their positive effects on cervical HSIL. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive treatment that has been successfully used to treat cervical low-grade squamous intraepithelial lesion (LSIL). In this study, we aimed to further investigate the clinical efficacy and safety of ALA-PDT in the treatment of patients with cervical HSIL. Methods: A total of 40 patients aged 20 - 41 years with cervical HSIL and highrisk Human Papilloma Virus (HR-HPV) infections were enrolled in this retrospective study from January 2019 to December 2022. Patients were treated with six times of ALA-PDT at intervals of 7-14 days. Three months after the treatment, the efficacy was evaluated through HPV genotyping and cervical cytology examination. If the cytological result was worse than ASC -US, the patient underwent colposcopy-directed biopsy immediately. Otherwise, patients would receive rigorous follow-up observation. Results: Three months after receiving ALA-PDT treatment, 65% (26/40) of cervical HSIL patients at our center showed complete regression (cytological result: normal; HR-HPV: negative). This rate increased to 82.5% (33/40) at the 12-month follow-up. None of the patients experienced disease progression after ALA-PDT therapy. The risk of persistent HR-HPV infection was 32.5% (13/40) at the 3-month follow-up after ALA-PDT. Multivariate analyses identified cervical canal involvement as an independent risk factor for persistent HR-HPV infection at the 3-month follow-up after ALA-PDT treatment. During the treatment of the 40 patients with ALA-PDT, there were no reports of severe adverse reactions. Only a limited number of patients experienced slight discomfort symptoms. Conclusion: ALA-PDT is safe and effective noninvasive therapy for patients with cervical HSIL and HR-HPV infections. It is particularly suitable for young women, who have been confirmed with cervical HSIL and have demand for fertility protection. Three months after ALA-PDT treatment, if a patient still has either ASC-US cervical cytological result and/or HR-HPV infection, rigorous observation is considered safe for her. Cervical canal involvement is an independent risk factor for persistent HR-HPV infection at the 3-month follow-up after ALA-PDT treatment. [ABSTRACT FROM AUTHOR]

Antimicrobial photodynamic inactivation (aPDI) is a method that specifically kills target cells by combining a photosensitizer and irradiation with light at the appropriate wavelength. The natural amino acid, 5-aminolevulinic acid (5-ALA), is the precursor of endogenous porphyrins in the heme biosynthesis pathway. This review summarizes the recent progress in understanding the biosynthetic pathways and regulatory mechanisms of 5-ALA synthesis in biological hosts. The effectiveness of 5-ALA-aPDI in destroying various groups of pathogens (viruses, fungi, yeasts, parasites) was presented, but greater attention was focused on the antibacterial activity of this technique. Finally, the clinical applications of 5-ALA in therapies using 5-ALA and visible light (treatment of ulcers and disinfection of dental canals) were described. [ABSTRACT FROM AUTHOR]

The transition of active Mycolicibacterium smegmatis cells to a dormant state under acidification conditions is accompanied by the intracellular accumulation of tetramethyl ester of coproporphyrin (TMC). At the same time, the dormant forms of mycobacteria develop resistance to a number of damaging factors. The addition of 5-aminolevulinic acid (ALA), a precursor of porphyrin synthesis, into the bacterial culture medium leads to the accumulation of TMC in actively growing cells, which simulates the situation with dormant mycobacteria. Upon threefold increasing the concentration of TMC, the bacteria become sevenfold more resistant to the action of 40 mM hydrogen peroxide and 90-fold more resistant to heating up to 80°C. At the same time, in M. smegmatis cells with an increased concentration of TMC, the activity of dichlorophenolindophenol reductase that is a marker of respiratory chain activity decreases by 18%. The detected inhibition of activity can lead to a decrease in side oxidative reactions in the cell. Therefore, the accumulation of methylated coproporphyrin is possibly one of the mechanisms for the development of mycobacterium resistance at dormancy. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) has been utilized as a promising alternative cancer treatment due to its minimum invasiveness over the years. Exogenous 5-aminolevulinic acid (ALA) triggers protoporphyrin IX (PpIX) accumulation, which happens in cancer cells. However, certain types of cancer exhibit reduced effectiveness in the PpIX accumulation mechanism. This study aimed to determine the effect of ALA-PDT combination with hemin on gastric carcinoma TMK-1 cells. Methods: This study utilized TMK-1 gastric cancer cell line to evaluate PpIX, ROS, and Fe2+ accumulation following the administration of ALA, hemin, and a combination of ALA and hemin PDT. We also evaluate the mRNA expressions related to iron homeostasis and treatment impacts on cell viability. Results: The co-addition of ALA and hemin PDT for 4 h of treatment resulted in a significant decrease in cell viability by up to 18 %. While ALA-PDT enhanced PpIX metabolism, the addition of hemin influenced both the production of reactive oxygen species (ROS) and cellular iron homeostasis by inducing Fe2+ accumulation and affecting mRNA levels of IRP, Tfr1, Ferritin, NFS1, and SDHB. Conclusion: These findings suggest that the addition of ALA and hemin enhances phototoxicity in TMK-1 cells. The combination of ALA and hemin with PDT induces cell death, evidenced by increased cytotoxicity properties such as PpIX and ROS, along with significant changes in TMK-1 gastric cancer iron homeostasis. Therefore, the combination of ALA and hemin could be one of the alternatives in photodynamic therapy for cancer in the future.

Background: Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors. Methods: We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis. Results: In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients. Conclusions: PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors.

Background and Aim: The diagnostic accuracy for cholangiocarcinoma (CCA) is inadequate, necessitating the exploration of novel diagnostic approaches. Protoporphyrin IX (Pp IX), a metabolic product of 5-aminolevulinic acid (5-ALA), emits red fluorescence upon blue light exposure. Because it accumulates selectively in cancer cells, photodynamic diagnosis using 5-ALA (5-ALA-PDD) has been integrated into clinical practice for diverse cancer types. Nevertheless, there is currently no device capable of capturing Pp IX-derived fluorescence for real-time 5-ALA-PDD within the biliary tract, largely due to challenges in device miniaturization. Methods: To investigate the feasibility of real-time 5ALA-PDD in CCA, we developed two essential components of the cholangioscopy system: a small-diameter flexible camera and a light guide for emitting blue light. We evaluated the detectability of Pp IX fluorescence using these devices in experimental gels and animal models. Results: Our camera and light guide were smoothly inserted into the lumen of existing cholangioscopes. Incorporating a long-pass filter at the camera tip enabled efficient detection of red fluorescence without significantly impacting white-light observation. The integration of these devices facilitated clear visualization of red fluorescence from gels containing Pp IX at concentrations of 5 μM or higher. Additionally, when observing subcutaneous human CCA tumor models in nude mice treated with 5-ALA, we successfully demonstrated distinct red fluorescence from Pp IX accumulation in tumors compared to peritumoral subcutaneous areas. Conclusion: The integration of our device combination holds promise for real-time 5-ALA-PDD in human CCA, potentially enhancing the diagnostic accuracy for this complex condition.

Dermatosis papulosa nigra (DPN) is a type of benign epidermal hyperplasia that affects the appearance of patients and poses a threat to their physical and mental health. Photodynamic therapy (PDT) has been shown to have the advantages of non-invasiveness, efficacy, and low recurrence in the treatment of skin disorders. However, no studies have been reported on the use of PDT for the treatment of DPN. Therefore, we used PDT for the first time to treat DPN and monitor its efficacy. Forty-five patients with DPN diagnosed at the outpatient clinic of Changzhou First People's Hospital were treated with 10 % 5-aminolevulinic acid (ALA) once a week for four consecutive weeks and followed for 3 months. After four treatment sessions, the cure rate among the 45 patients was 71.1 %, and the overall efficacy rate was 93.3 %. The most common adverse reactions were mild erythema, edema, and temporary pigmentation. PDT is expected to become a new and effective treatment for DPN.

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.

An awake craniotomy's primary goal is to remove the tumor or damaged cells as much as possible without affecting the patient's capacity for clear thought or other crucial functions. This surgical procedure offers a better prognosis by balancing the maximum removal of lesions with the preservation of working zones. For patients with malignant gliomas, the current neurosurgical objective is for resection the large part of a tumor using contrast and not causing neurological deficits. Neurooncological patients are required to have further chemotherapy and radiotherapy, with a control MRI of the brain in 3 and 6 months. Real multidisciplinary work should be provided to improve each patient's quality of life and overall survival. This paper aims to report single case of successful awake craniotomy with fluorescence guidance and discuss the outcomes of the performed surgery.

Abstract Background Topical photodynamic therapy (PDT) has demonstrated encouraging results in the treatment of oral leukoplakia (OLK). However, data on the clinical efficacy of PDT in Chinese patients with OLK are still limited. Methods Fifty patients diagnosed with OLK were enrolled, including patients with various dysplastic tissues. All patients received topical PDT with 5-aminolevulinic acid (5-ALA) as a photosensitizer. Clinical efficacy was evaluated 4 weeks after treatment. Follow-up was performed every 3 months during the first year and every 6 months during the second year. Results The overall response rate was 68% (34/50): 12% (n = 6) complete and 56% (n = 28) partial responses. Aneuploidy was reduced in the patients with dysplastic lesions. Oral pain and local ulcers developed in 52% of the patients (n = 26). Patients with a long history of OLK including hyperplasia and dysplastic lesions, as well as those with non-homogenous lesions, were more likely to develop pain and ulcer. During follow-up, the recurrence rate of hyperplasia and dysplastic lesions was 32% (n = 16) and the malignant transformation rate of dysplastic lesions was 4% (n = 2). Lesions on the buccal mucosa were associated with recurrence (P = 0.044; OR: 0.108, 95% CI: 0.013–0.915). Conclusion Topical 5-ALA-mediated PDT is an effective treatment for OLK, particularly for homogenous leukoplakia, with few side effects. The buccal mucosa may be a protective factor that can reduce recurrence.

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.

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]

Heme enzyme dysfunction causes a group of diseases called porphyrias. Particularly, a decrease in porphobilinogen deaminase, involved in the third step of heme biosynthesis, leads to acute intermittent porphyria (AIP). Considering our previous works demonstrating the multiplicity of brain metabolisms affected by porphyrinogenic agents, this study aimed to elucidate whether they cause any alteration on the mitochondrial respiratory chain. The activities of respiratory chain complexes (I to IV) were measured in encephalon mitochondria of CF1 male mice receiving volatile anesthetics: isoflurane (2 mL/kg) and sevoflurane (1.5 mL/kg), ethanol (30%), allylisopropylacetamide (AIA) (350 mg/kg), and barbital (167 mg/kg). Moreover, they were compared versus animals with pathological levels of 5-aminolevulinic acid (ALA, 40 mg/kg). Complex I–III activity was induced by isoflurane and decreased by AIA, ethanol, and ALA. Complex II–III activity was increased by sevoflurane and decreased by isoflurane and AIA. Complex II activity was increased by sevoflurane and barbital and decreased by AIA, ethanol, and ALA. Complex IV activity was increased by barbital and ALA and decreased by sevoflurane. The damage to the respiratory chain by ALA could be reflecting the pathophysiological condition of patients with AIP. Better understanding the broad effect of porphyrinogenic drugs and the mechanisms acting on the onset of AIP is vital in translational medicine. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the incidence and risk factors of intraoperative hypotension related to photodynamic diagnosis‐assisted transurethral resection of bladder tumor (PDD‐TURBT) with oral 5‐aminolevulinic acid (5‐ALA). Methods: We retrospectively analyzed 487 patients with bladder tumors who underwent PDD‐TURBT (n = 184) or conventional TURBT (conv‐TURBT) (n = 303) between 2018 and 2021. Intraoperative hypotension was defined as hypotension requiring vasopressors during TURBT, and its incidence was compared between the two groups. Potential risk factors of intraoperative hypotension, including preoperative change in mean arterial pressure (MAP), were further investigated in patients receiving PDD‐TURBT. Results: The median age was 72 years, 392 patients (81%) were male, and 203 (42%) had hypertension. TURBT was performed under general and spinal anesthesia in 76 (16%) and 411 (84%) patients, respectively. The incidence of intraoperative hypotension was significantly higher in PDD‐TURBT compared to conv‐TURBT (43% vs. 17%, respectively). The median change in MAP until the induction of anesthesia was +6.5 mmHg (range: −29.0 to +46.3) in the PDD‐TURBT group and +14.7 mmHg (range: −35.3 to +67.7) in the conv‐TURBT group, showing a significantly smaller increase in the PDD‐TURBT group (p < 0.001). In the multivariable analysis for PDD‐TURBT patients, advanced age, general anesthesia, and lower MAP change (<+6.5 mmHg) until anesthesia induction were significantly associated with intraoperative hypotension (p = 0.0104, <0.001, and <0.001, respectively). Conclusions: Intraoperative hypotension occurred more frequently in patients who underwent PDD‐TURBT than in those who underwent conv‐TURBT. Using oral 5‐ALA decreases preoperative blood pressure elevation and may be responsible for intraoperative hypotension. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the efficacy and safety of 5-aminolevulinic acid ( ALA-photodynamic (PDT) combined with low-dose isotretinoin in the treatment of acne rosacea (AR). METHODS: A total of 86 patients with AR admitted into the Second Affiliated Hospital of Xinjiang Medical University from Jan. 2022 to Jan. 2023 were selected to be divided into combination group and control group via random number table method, with 43 cases in each group. The control group was treated with low-dose isotretinoin, the combination group was given ALA-PDT combined with low-dose isotretinoin. The clinical efficacy, the skin erythema indexes (EI), Acne Specific Quality of Life Scale (Acne-QOL) scores, skin physiological function [transdermal water loss (TEWL), water content of stratum corneum and pH], cuticle integrity indexes (serine protease activity, mucin content) and incidences of adverse drug reactions before and after treatment were compared between two groups. RESULTS: The total effective rate of the combination group was 95. 35% (41/ 43), higher than 79. 07% (34/ 43) in the control group, with statistically significant difference (P<0. 05). After treatment, the EI was lower and the Acne-QOL score was higher in the combination group than those in the control group; the TEWL and pH of the combination group were lower than those of the control group, the water content of stratum corneum of the combination group was higher than that of the control group; the serine protease activity and mucin content of the combination group were lower than those of the control group, with statistically significant differences (P < 0. 05). The incidences of adverse drug reactions of the combination group and control group were respectively 9. 30% ( 4/ 43 ) and 11. 63% ( 5/ 43 ), the difference was not statistically significant ( P > 0. 05 ). CONCLUSIONS: The combination of ALA-PDT with low-dose isotretinoin in the treatment of AR can repair skin barrier function, improve EI and promote patients’ quality of life, with significant efficacy and high safety. [ABSTRACT FROM AUTHOR]

Cutaneous alternariosis is a rare condition, more frequently presented in immunocompromised patients, which usually requires long courses of systemic antifungals that may interact with other medications. The presented series shows three cases of cutaneous alternariosis in immunocompromised patients and organ transplant recipients that were successfully treated with photodynamic therapy and oral antifungals, allowing a reduction in the systemic treatment duration and therefore decreasing the risk of side effects and drug interactions. [ABSTRACT FROM AUTHOR]

Redox-dependent thiol-disulfide switches of cysteine residues are one of the significant posttranslational modifications of proteins to control rapidly their stability, activity, and protein interaction. Redox control also modulates the tetrapyrrole biosynthesis (TBS). Among the redox-dependent TBS enzymes, 5-aminolevulinic acid dehydratase (ALAD) was previously recognized to interact with reductants, such a thioredoxins or NADPH-dependent thioredoxin reductase C. In this report, we aim to verify the redox sensitivity of ALAD and identify the redox-reactive cysteine residues among the six cysteines of the mature protein form Arabidopsis. Based on structural modelling and comparative studies of wild-type ALAD and ALAD mutants with single and double Cys➔Ser substitutions under oxidizing and reducing conditions, we aim to predict the dimerization and oligomerisation of ALAD as well as the crucial Cys residues for disulfide bridge formation and enzyme activity. The Cys404Ser mutation led to a drastic inactivation of ALAD and redox-dependent properties of ALAD were severely impaired, when Cys71 was simultaneously mutated with Cys152 or Cys251. Cys71 is located in a flexible N-terminal arm of ALAD, which could allow intramolecular disulfide bridges with Cys residues at the surface of the remaining globule ALAD structure. As a result, we propose different roles of Cys residues for redox control, catalytic activity and Mg2+-dependent assembly. [ABSTRACT FROM AUTHOR]

Objectives: To determine the utility of 5‐aminolevulinic acid (5‐ALA) fluorescence for resection of head and neck carcinoma. Methods: In this prospective pilot trial, 5‐ALA was administered as an oral suspension 3–5 h prior to induction of anesthesia for resection of head and neck squamous cell carcinoma (HNSCC). Following resection, 405 nm blue light was applied, and fluorescence of the tumor as well as the surgical bed was recorded. Specimen fluorescence intensity was graded categorically as none (score = 0), mild (1), moderate (2), or robust (3) by the operating surgeon intraoperatively and corroborated with final pathologic diagnosis. Results: Seven patients underwent resection with 5‐ALA. Five (83%) were male with an age range of 33–82 years (mean = 60). Sites included nasal cavity (n = 3), oral cavity (n = 3), and the larynx (n = 1). All specimens demonstrated robust fluorescence when 5‐ALA was administered 3–5 h preoperatively. 5‐ALA fluorescence predicted the presence of perineural invasion, a positive margin, and metastatic lymphadenopathy. Two patients had acute photosensitivity reactions, and one patient had a temporary elevation of hepatic enzymes. Conclusions: 5‐ALA induces robust intraoperative fluorescence of HNSCC, capable of demonstrating a positive margin, perineural invasion, and metastatic nodal disease. Although no conclusions are there about the safety of this drug in the head and neck cancer population, our study parallels the extensive safety data in the neurosurgical literature. Future applications may include intraoperative assessment of margin status, diagnostic accuracy, and impacts on survival. Level of Evidence: 4 Laryngoscope, 134:741–748, 2024 [ABSTRACT FROM AUTHOR]

Simple Summary: Although 5-aminolevulinic acid (ALA) is commonly used in glioma surgery to identify cell infiltration, recent studies have shown its successful use in brain metastasis (BM) surgery due to its ability to infiltrate adjacent brain tissue. Several studies have proven the histopathological relationship between tumor infiltration and positive fluorescence of 5-ALA; however, few comprehensive studies have shown the role of genetic alterations in the fluorescent activity of 5-ALA, especially in BM. The present study illustrates the causal relationship between certain genetic alterations (i.e., cell cycle regulation and cell proliferation) and the fluorescent activity of 5-ALA in BM. In addition, these alterations were associated with clinical outcomes of BM of lung adenocarcinoma. As the results were achieved through the clinical practice of BM surgery, such as intraoperative 5-ALA and next-generation sequencing (NGS) analysis, it is mandatory for basic researchers to examine the pathophysiology in more detail. The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM of lung adenocarcinoma at our institute for five years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Topical photodynamic therapy (PDT) has demonstrated encouraging results in the treatment of oral leukoplakia (OLK). However, data on the clinical efficacy of PDT in Chinese patients with OLK are still limited. Methods: Fifty patients diagnosed with OLK were enrolled, including patients with various dysplastic tissues. All patients received topical PDT with 5-aminolevulinic acid (5-ALA) as a photosensitizer. Clinical efficacy was evaluated 4 weeks after treatment. Follow-up was performed every 3 months during the first year and every 6 months during the second year. Results: The overall response rate was 68% (34/50): 12% (n = 6) complete and 56% (n = 28) partial responses. Aneuploidy was reduced in the patients with dysplastic lesions. Oral pain and local ulcers developed in 52% of the patients (n = 26). Patients with a long history of OLK including hyperplasia and dysplastic lesions, as well as those with non-homogenous lesions, were more likely to develop pain and ulcer. During follow-up, the recurrence rate of hyperplasia and dysplastic lesions was 32% (n = 16) and the malignant transformation rate of dysplastic lesions was 4% (n = 2). Lesions on the buccal mucosa were associated with recurrence (P = 0.044; OR: 0.108, 95% CI: 0.013–0.915). Conclusion: Topical 5-ALA-mediated PDT is an effective treatment for OLK, particularly for homogenous leukoplakia, with few side effects. The buccal mucosa may be a protective factor that can reduce recurrence. [ABSTRACT FROM AUTHOR]

Plant growth and production can be adversely affected by high temperature stress, which is defined as an increase in temperature over a threshold level. 5-aminolevulinic acid (ALA) can be used as a beneficial growth regulator in agriculture, particularly for plants experiencing abiotic stress. The efficacy of exogenous two form ALA application (bulk and nanoencapsulated) was investigated in a factorial experiment based on a completely randomized block design with 12 replications. In this study, different temperatures (optimal temperature 25 °C, and high temperature 35 °C) and different ALA treatments were used (control, 1 mM of ALA, and 1 mM Nano-encapsulated N-ALA). The study revealed that elevated temperatures of 35 °C had an adverse impact on the majority of bell pepper growth characteristics. Nevertheless, the application of ALA and N-ALA significantly enhanced the growth characteristics under these conditions. In contrast to the conditions at 25 °C, the concentrations of potassium (K), proline, electrolyte leakage (EL), glucose, and fructose exhibited an increase at 35 °C. However, both forms of ALA were effective in mitigating these adverse effects. Comparatively, the control treatment showed elevated levels of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) enzymes, along with increased malondialdehyde (MDA) levels compared to the ALA treatment. The treatment with ALA resulted in the highest fresh weight and shoot length at 35 °C compared to N-ALA. Conversely, at the same temperature, N-ALA led to a 17 % increase in chlorophyll fluorescence and a 32 % increase in DPPH compared to ALA. In summary, the application of both ALA and Nano-encapsulated N-ALA effectively mitigates the adverse effects of exposure to 35 °C on bell pepper growth and biochemical parameters.

Purpose: Gadolinium-enhancing necrosis in glioblastoma multiforme (GBM), as an occasionally occurring false positive in contrast enhancement (CE) imaging, leads to trouble for segmentation of GBM and treatment. Therefore, the investigation of complementary detection way to identify the metabolically active volume of the tumor with high reliability is very worth to be addressed. Here, we reported on a case of GBM with gadolinium-enhancing necrosis in an experimental CE imaging study in mice and evaluated the discrimination of the necrosis and metabolically active parts of the GBM using conventional and state-of-the-art susceptibility-based MRI. Methods: In this study, following 5-aminolevulinic acid (ALA) and iron supplements (FAC, 6 h after ALA, intra-tumoral injection) to animal, T2*-W imaging and quantitative susceptibility mapping (QSM) were performed, and compared with CE imaging. Results: The signal intensity (SI) of the active and necrosis areas of the case in the CE image demonstrated no significant difference while the SI on the T2*-W images and susceptibility value in QSM changed 24 and 150%, respectively. Conclusion: The preclinical case report provides valuable insights into the potential of susceptibility-based MRI using ALA + FAC to apply as a robust discriminator between necrotic and viable tumors.

Purpose: Extent of resection (EOR) predicts progression-free survival (PFS) and may impact overall survival (OS) in patients with glioblastoma. We recently demonstrated that 5-aminolevulinic acid-(5-ALA)-fluorescence-enhanced endoscopic surgery increase the rate of gross total resection. However, it is hitherto unknown whether fluorescence-enhanced endoscopic resection affects survival. Methods: We conducted a retrospective single-center analysis of a consecutive series of patients who underwent surgery for non-eloquently located glioblastoma between 2011 and 2018. All patients underwent fluorescence-guided microscopic or fluorescence-guided combined microscopic and endoscopic resection. PFS, OS, EOR as well as clinical and demographic parameters, adjuvant treatment modalities, and molecular characteristics were compared between microscopy-only vs. endoscopy-assisted microsurgical resection. Results: Out of 114 patients, 73 (65%) were male, and 57 (50%) were older than 65 years. Twenty patients (18%) were operated on using additional endoscopic assistance. Both cohorts were equally distributed in terms of age, performance status, lesion location, adjuvant treatment modalities, and molecular status. Gross total resection was achieved in all endoscopy-assisted patients compared to about three-quarters of microscope-only patients (100% vs. 75.9%, p=0.003). The PFS in the endoscope-assisted cohort was 19.3 months (CI95% 10.8–27.7) vs. 10.8 months (CI95% 8.2–13.4; p=0.012) in the microscope-only cohort. OS in the endoscope-assisted group was 28.9 months (CI95% 20.4–34.1) compared to 16.8 months (CI95% 14.0–20.9), in the microscope-only group (p=0.001). Conclusion: Endoscope-assisted fluorescence-guided resection of glioblastoma appears to substantially enhance gross total resection and OS. The strong effect size observed herein is contrasted by the limitations in study design. Therefore, prospective validation is required before we can generalize our findings. [ABSTRACT FROM AUTHOR]

Cerenkov radiation induced photodynamic therapy (CR-PDT) can tackle the tissue penetration limitation of traditional PDT. However, co-delivery of radionuclides and photosensitizer may cause continuous phototoxicity in normal tissues during the circulation. 5-aminolevulinic acid (ALA) which can intracellularly transform into photosensitive protoporphyrin IX (PpIX) is a cancer-selective photosensitizer with negligible side effect. However, the hydrophilic nature of ALA and the further conversion of PpIX to photoinactive Heme severely hinder the therapeutic benefits of ALA-based PDT. Herein, we developed an 89Zr-labeled, pH responsive ALA and artemisinin (ART) co-loaded liposome (89Zr-ALA-Liposome-ART) for highly selective cancer therapy. 89Zr can serve as the internal excitation source to self-activate PpIX for CR-PDT, and the photoinactive Heme can activate the chemotherapeutic effect of ART. The 89Zr-ALA-Liposome-ART exhibited excellent tumor inhibition capability in subcutaneous 4T1-tumor-bearing Balb/c mice via CR-PDT and chemotherapy. Combined with anti-PD-L1, the 89Zr-ALA-Liposome-ART elicited strong antitumor immunity to against tumor recurrence. A radiolabeled dual drug-loaded responsive liposome was designed to achieve tumor-selective Cerenkov radiation induced photodynamic therapy and combined chemotherapy. [Display omitted] • 89Zr labeled self-illuminated liposome facilitates PDT for deep tumors. • pH responsive release of prodrug ALA reduces the phototoxicity to normal tissue. • Heme generated from exogenous ALA activates the ART for combined chemotherapy. [ABSTRACT FROM AUTHOR]

Modified 5-aminolevulinic acid photodynamic therapy (M-PDT) and isotretinoin (ISO) are effective treatments for moderate to severe acne vulgaris. To evaluate the efficacy and adverse effects of M-PDT and ISO for moderate to severe acne vulgaris. A multicenter, randomized clinical trial was conducted with participants randomly assigned to the M-PDT group (up to 5 weekly sessions following manual comedone extraction) or the ISO group (oral ISO, 0.5 mg/kg/d for 6 months) and followed up to 6-months after therapy. A total of 152 patients were allocated. The overall effective rates in the M-PDT group were significantly higher than the ISO group at 1 month (67.74% vs 10.26%), whereas the opposite was the case 1 month after treatment (75.81% vs 97.44%). Time to achieve 50% lesion improvement in the M-PDT group was significantly less than the ISO group (1 vs 8 weeks). Overall, 70.67% of the ISO group patients experienced systemic side effects such as hepatotoxicity, whereas side effects were skin-limited in the M-PDT group. Limitations of this study included relatively low numbers of participants and high withdrawal rate. M-PDT offers a more rapid onset of improvement, comparable overall efficacy, good tolerability, and comparable durability of response compared with ISO. [ABSTRACT FROM AUTHOR]

This study investigated the preventive effect of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) on blood–aqueous barrier (BAB) breakdown induced after anterior chamber paracentesis (ACP) in beagles. 5-ALA/SFC (1/0.64 mg/kg or 3/1.92 mg/kg) or carprofen (4.0 mg/kg) was orally administered daily for 7 days prior to ACP. Then, a sample of the aqueous humor (AH) was collected from one eye via ACP (first sample) and again 60 min later (second sample). The protein and prostaglandin E2 (PGE2) concentrations in both samples were measured. Compared with the control group, high-dose 5-ALA/SFC and carprofen significantly reduced the AH protein and PGE2 concentrations in the second sample. Our findings suggest that 5-ALA/SFC suppresses BAB breakdown in dogs. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to observe the fluorescence characteristics of acne inflammatory skin lesions in 5‐aminolevulinic acid‐based photodynamic diagnosis (ALA‐PDD), and discuss the viability of using ALA‐PDD to evaluate acne inflammatory skin lesions and explore the advantages of predicting subclinical skin lesions. Methods: The OBSERV facial skin detector collected photographs of 20 patients before and after optical intra‐tissue fiber irradiation photodynamic therapy (OFI‐ALA‐PDT) in both ALA‐PDD and white light patterns. The patients were treated once a week for four consecutive weeks in order to analyze the correlation between the two patterns in recognizing inflammatory skin lesions. Results: Before and after treatment, there was no significant difference between the two patterns for recognizing acne inflammatory skin lesions (p > 0.05). Both patterns demonstrated a strong correlation (r > 0.90) for the recognition of various types of inflammatory skin lesions at different treatment stages. Conclusion: ALA‐PDD is a feasible method for evaluating acne inflammatory lesions, guiding treatment and judging efficacy. It has advantages in predicting subclinical skin lesions and deserves further study. [ABSTRACT FROM AUTHOR]

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Conventional 5‐aminolevulinic acid-photodynamic (ALA-PDT) therapy (10–20%) has been widely applied for moderate-to-severe acne. The aim of this study is to investigate the effects of non-ablative Q-switched 1064-nm Nd:YAG laser-assisted ALA-PDT with low concentration (2%) on the treatment of acne vulgaris. Enrolled patients were randomly assigned to 2 groups. One group received combined therapy of 2% ALA-PDT and non-ablative Q-switched 1064-nm Nd:YAG laser, and the other received only 2% ALA-PDT. Patients in each group had received 3-session treatments with 4-week intervals (week 0, 4, and 8). Sebum secretion, melanin index, erythema index, and transepidermal water loss (TEWL) were assessed at week 2, 8, 12, and 24. VISIA® skin image system score and global esthetic improvement scale (GAIS) were also evaluated. Twenty-four participants were enrolled and evenly randomized to two groups. Significant improvement in sebum secretion was noted in combined therapy group compared to the monotherapy group at week 12 (37.5% versus 16.3%), and the improvement would still be noted until week 24 (18.3% versus 17.4%). Combined group also showed more severe melanin index and erythema index after treatment. For VISIA® skin analysis, patients in combined group had better percentile ranking in porphyrins and red-light images. There were no significant differences in GAIS at the end of the follow-up between each group, whereas higher proportion of satisfaction was noted in combined group at week 2. With the assistance of laser, low concentrations (2%) of 5-ALA can provide effective phototoxic reactions in treating acne vulgaris. The satisfaction of patients is high with acceptable adverse effects. [ABSTRACT FROM AUTHOR]