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European Journal of Dermatology : EJD Oct 2023This article reviews the 2022 European Society for Photodynamic Therapy (Euro-PDT) Annual Congress. PDT has been investigated for the treatment of a broad number of... (Review)
Review
This article reviews the 2022 European Society for Photodynamic Therapy (Euro-PDT) Annual Congress. PDT has been investigated for the treatment of a broad number of oncologic, infectious and inflammatory indications. New studies confirm the potential for wider use of topical PDT for acne and photoaging, as well as several uncommon conditions including tinea capitis, Mycobacterium marinum, cutaneous alternariosis, resistant acral warts, eyelid Bowen's disease, mycosis fungoides, pseudolymphoma, and graft-versus-host disease. Hidradenitis suppurativa patients may also benefit from intra-lesional PDT. Several methods of delivering PDT have been validated, including conventional, daylight and artificial daylight PDT. Light-emitting fabrics have emerged as an innovative solution to the delivery of uniform light over the scalp as well as anatomically-challenging sites, with opportunities now to control and monitor these devices via mobile phone applications. Pre-treatment of patients with thicker, more difficult-to-treat actinic keratoses (AK) with calcitriol appears to be a practical approach to increasing efficacy, although this is associated with increased local skin reactions. Sequential treatment of AK and photoaging with daylight-PDT and injectable NASHA gel indicates that these two therapeutic approaches offer complementary effects. Potential biomarkers may help predict responsiveness of patients with field cancerization and AK receiving daylight PDT. Over-expression of the proto-oncogene, Myc, has been observed in poor responders, whilst the tumour suppressor gene, PTEN, showed under-expression. The potential for use and methods of delivery of topical PDT for dermatological indications continue to expand the enhanced choice of treatment offered to patients.
Topics: Humans; Photosensitizing Agents; Photochemotherapy; Keratosis, Actinic; Skin Neoplasms; Skin; Aminolevulinic Acid; Treatment Outcome
PubMed: 38297922
DOI: 10.1684/ejd.2023.4562 -
MSystems Feb 2024Tuberculosis remains the most pervasive infectious disease and the recent emergence of drug-resistant strains emphasizes the need for more efficient drug treatments. A...
Tuberculosis remains the most pervasive infectious disease and the recent emergence of drug-resistant strains emphasizes the need for more efficient drug treatments. A key feature of pathogenesis, conserved between the human pathogen and the model pathogen is the metabolic switch to lipid catabolism and altered expression of virulence genes at different stages of infection. This study aims to identify genes involved in sustaining viable intracellular infection. We applied transposon sequencing (Tn-Seq) to , an unbiased genome-wide strategy combining saturation insertional mutagenesis and high-throughput sequencing. This approach allowed us to identify the localization and relative abundance of insertions in pools of transposon mutants. Gene essentiality and fitness cost of mutations were quantitatively compared between growth and different stages of infection in two evolutionary distinct phagocytes, the amoeba and the murine BV2 microglial cells. In the genome, 57% of TA sites were disrupted and 568 genes (10.2%) were essential, which is comparable to previous Tn-Seq studies on and . Major pathways involved in the survival of during infection of are related to DNA damage repair, lipid and vitamin metabolism, the type VII secretion system (T7SS) ESX-1, and the Mce1 lipid transport system. These pathways, except Mce1 and some glycolytic enzymes, were similarly affected in BV2 cells. These differences suggest subtly distinct nutrient availability or requirement in different host cells despite the known predominant use of lipids in both amoeba and microglial cells.IMPORTANCEThe emergence of biochemically and genetically tractable host model organisms for infection studies holds the promise to accelerate the pace of discoveries related to the evolution of innate immunity and the dissection of conserved mechanisms of cell-autonomous defenses. Here, we have used the genetically and biochemically tractable infection model system / to apply a genome-wide transposon-sequencing experimental strategy to reveal comprehensively which mutations confer a fitness advantage or disadvantage during infection and compare these to a similar experiment performed using the murine microglial BV2 cells as host for to identify conservation of virulence pathways between hosts.
Topics: Animals; Mice; Humans; Virulence; Microglia; Mycobacterium marinum; Amoeba; Dictyostelium; Tuberculosis; Mycobacterium tuberculosis; Lipids
PubMed: 38270456
DOI: 10.1128/msystems.01326-23 -
Journal of Biotechnology Feb 2024Mycobacterium marinum CAR (MmCAR) is one of the most widely used CARs as the key enzyme for the synthesis of aldehydes, alcohols and further products from the respective...
Mycobacterium marinum CAR (MmCAR) is one of the most widely used CARs as the key enzyme for the synthesis of aldehydes, alcohols and further products from the respective carboxylic acids. Herein, we describe the first functionally secreted 131 kDa CAR and its isolated A-domain using Komagataella phaffii and a methanol-free constitutive expression strategy. Precipitated and lyophilized MmCAR (500 µg) was isolated from the culture supernatant and showed no decrease in activity for piperonylic acid (80% conversion), even when stored for up to 3 weeks at 4°C. Lyophilized MmCAR precipitate gave 48% yield of E/Z-nonanal-4-nitrobenzoyloxime from the reduction of nonanoic acid and in-situ derivatization with O-4-nitrobenzoyl-hydroxylamine. Furthermore, K. phaffii could successfully secrete the MmCAR adenylation domain. Its activity was confirmed by the amidation of benzoic acid with n-hexylamine. Neither enzyme variant was glycosylated by the yeast. In summary, functional CAR can be secreted by K. phaffii and used for cell free conversion of carboxylic acids to various products.
Topics: Carboxylic Acids; Oxidoreductases; Alcohols
PubMed: 38266924
DOI: 10.1016/j.jbiotec.2024.01.008 -
Frontiers in Cellular and Infection... 2023Anti-bacterial autophagy, also known as xenophagy, is a crucial innate immune process that helps maintain cellular homeostasis by targeting invading microbes. This...
Anti-bacterial autophagy, also known as xenophagy, is a crucial innate immune process that helps maintain cellular homeostasis by targeting invading microbes. This defense pathway is widely studied in the context of infections with mycobacteria, the causative agents of human tuberculosis and tuberculosis-like disease in animal models. Our previous work in a zebrafish tuberculosis model showed that host defense against (Mm) is impaired by deficiencies in xenophagy receptors, optineurin (Optn) or sequestome 1 (p62), and Damage-regulated autophagy modulator 1 (Dram1). However, the interdependency of these receptors and their interaction with Dram1 remained unknown. In the present study, we used single and double knockout zebrafish lines in combination with overexpression experiments. We show that Optn and p62 can compensate for the loss of each other's function, as their overexpression restores the infection susceptibility of the mutant phenotypes. Similarly, Dram1 can compensate for deficiencies in Optn and p62, and, vice versa, Optn and p62 compensate for the loss of Dram1, indicating that these xenophagy receptors and Dram1 do not rely on each other for host defense against Mm. In agreement, Dram1 overexpression in double mutants restored the interaction of autophagosome marker Lc3 with Mm. Finally, double mutants displayed more severe infection susceptibility than the single mutants. Taken together, these results suggest that Optn and p62 do not function downstream of each other in the anti-mycobacterial xenophagy pathway, and that the Dram1-mediated defense against Mm infection does not rely on specific xenophagy receptors.
Topics: Animals; Autophagy; Macroautophagy; Mycobacterium marinum; Tuberculosis; Zebrafish; Zebrafish Proteins
PubMed: 38264729
DOI: 10.3389/fcimb.2023.1331818 -
BioRxiv : the Preprint Server For... Jan 2024The mycobacterial cell envelope is a major virulence determinant in pathogenic mycobacteria. Specific outer lipids play roles in pathogenesis, modulating the immune...
The mycobacterial cell envelope is a major virulence determinant in pathogenic mycobacteria. Specific outer lipids play roles in pathogenesis, modulating the immune system and promoting the secretion of virulence factors. ESX-1 (ESAT-6 system-1) is a conserved protein secretion system required for mycobacterial pathogenesis (1, 2). Previous studies revealed that mycobacterial strains lacking the outer lipid PDIM have impaired ESX-1 function during laboratory growth and infection (3-5). The mechanisms underlying changes in ESX-1 function are unknown. We used a proteo-genetic approach to measure PDIM and PGL-dependent protein secretion in , a non-tubercular mycobacterial pathogen that causes tuberculosis-like disease in ectothermic animals (6, 7). Importantly, is a well-established model for mycobacterial pathogenesis (8, 9). Our findings showed that strains without PDIM and PGL showed specific, significant reductions in protein secretion compared to the WT and complemented strains. We recently established a hierarchy for the secretion of ESX-1 substrates in four (I-IV) groups (10). Loss of PDIM differentially impacted secretion of Groups III and IV ESX-1 substrates, which are likely the effectors of pathogenesis. Our data suggests that the altered secretion of specific ESX-1 substrates is responsible for the observed ESX-1-related effects in PDIM-deficient strains.
PubMed: 38260599
DOI: 10.1101/2024.01.09.574891 -
The Journal of Antibiotics Apr 2024Tunicamycins (TUN) are well-defined, Streptomyces-derived natural products that inhibit protein N-glycosylation in eukaryotes, and by a conserved mechanism also block...
Tunicamycins (TUN) are well-defined, Streptomyces-derived natural products that inhibit protein N-glycosylation in eukaryotes, and by a conserved mechanism also block bacterial cell wall biosynthesis. TUN inhibits the polyprenylphosphate-N-acetyl-hexosamine-1-phospho-transferases (PNPT), an essential family of enzymes found in both bacteria and eukaryotes. We have previously published the development of chemically modified TUN, called TunR1 and TunR2, that have considerably reduced activity on eukaryotes but that retain the potent antibacterial properties. A mechanism for this reduced toxicity has also been reported. TunR1 and TunR2 have been tested against mammalian cell lines in culture and against live insect cells but, until now, no in vivo evaluation has been undertaken for vertebrates. In the current work, TUN, TunR1, and TunR2 are investigated for their relative toxicity and antimycobacterial activity in zebrafish using a well-established Mycobacterium marinum (M. marinum) infection system, a model for studying human Mycobacterium tuberculosis infections. We also report the relative ability to activate the unfolded protein response (UPR), the known mechanism for the eukaryotic toxicity observed with TUN treatment. Importantly, TunR1 and TunR2 retained their antimicrobial properties, as evidenced by a reduction in M. marinum bacterial burden, compared to DMSO-treated zebrafish. In summary, findings from this study highlight the characteristics of recently developed TUN derivatives, mainly TunR2, and its potential for use as a novel anti-bacterial agent for veterinary and potential medical purposes.
Topics: Animals; Humans; Anti-Bacterial Agents; Mammals; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Tunicamycin; Zebrafish; Phosphotransferases
PubMed: 38238588
DOI: 10.1038/s41429-023-00694-z -
Computational and Structural... Dec 2024The exposure of ethanol increases the risk of head and neck inflammation and tumor progression. However, limited studies have investigated the composition and...
UNLABELLED
The exposure of ethanol increases the risk of head and neck inflammation and tumor progression. However, limited studies have investigated the composition and functionality of laryngeal microbiota under ethanol exposure. We established an ethanol-exposed mouse model to investigate the changes in composition and function of laryngeal microbiota using Metagenomic shotgun sequencing. In the middle and late stages of the experiment, the laryngeal microbiota of mice exposed to ethanol exhibited obvious distinguished from that of the control group on principal-coordinate analysis (PCoA) plots. Among the highly abundant species, and were likely to be most impacted. Our findings indicated that the exposure to ethanol significantly increased their abundance in larynxes in mice of the same age, which has been confirmed through FISH experiments. Among the species-related functions and genes, metabolism is most severely affected by ethanol. The difference was most obvious in the second month of the experiment, which may be alleviated later because the animal established tolerance. Notable enrichments concerning energy, amino acid, and carbohydrate metabolic pathways occurred during the second month under ethanol exposure. Finally, based on the correlation between species and functional variations, a network was established to investigate relationships among microbiota, functional pathways, and related genes affected by ethanol. Our data first demonstrated the continuous changes of abundance, function and their interrelationship of laryngeal microbiota under ethanol exposure by Metagenomic shotgun sequencing.
IMPORTANCE
Ethanol may participate in the inflammation and tumor progression by affecting the composition of the laryngeal microbiota. Here, we applied the metagenomic shotgun sequencing instead of 16 S rRNA sequencing method to identify the laryngeal microbiota under ethanol exposure. and are two dominant species that may play a role in the reconstruction of the laryngeal microenvironment, as their local abundance increases following exposure to ethanol. The metabolic function is most evidently impacted, and several potential metabolic pathways could be associated with alterations in microbiota composition. These findings could help us better understand the impact of prolonged ethanol exposure on the microbial composition and functionality in the larynx.
PubMed: 38235358
DOI: 10.1016/j.csbj.2023.12.022 -
Journal of Veterinary Diagnostic... Mar 2024An adult male captive diamondback water snake () was found dead after a 1-d history of lethargy and cutaneous ulcers. The snake had eaten 2 sunfish ( spp.) 5 d before...
An adult male captive diamondback water snake () was found dead after a 1-d history of lethargy and cutaneous ulcers. The snake had eaten 2 sunfish ( spp.) 5 d before death. Gross examination revealed white-to-tan nodules in the lung and liver and segmental intestinal impactions with digested fish. Histopathology confirmed disseminated granulomas with numerous intrahistiocytic acid-fast bacteria in the skin, skeletal muscle, lung, liver, and intestines. and were identified by culture of the hepatic granuloma, followed by PCR and gene sequencing. To our knowledge, this is the first description of and coinfection in this species. Although has been isolated from reptiles, lesions associated with its presence in tissues have not been described previously. Interestingly, the mineralization within granulomas that we observed in our case is not reported in mycobacterial infection in reptiles, whereas this finding is common in mammals.
Topics: Male; Animals; Mycobacterium marinum; Mycobacterium Infections, Nontuberculous; Colubridae; Coinfection; Granuloma; Mammals
PubMed: 38205524
DOI: 10.1177/10406387231224465 -
Vaccine Jan 2024Based on previous evidence demonstrating the efficacy of inactivated mycobacteria for the control of fish mycobacteriosis, we explored the protective efficacy of two...
Based on previous evidence demonstrating the efficacy of inactivated mycobacteria for the control of fish mycobacteriosis, we explored the protective efficacy of two inactivated Mycobacterium bovis administered via parenteral and mucosal routes against Mycobacterium marinum infection mimicking natural conditions in the zebrafish model of tuberculosis. Although we did not observe a clear effect of any of the immunostimulants on mycobacterial burden, the results showed a significant increase in TLR2 and TLR4 gene expression levels in fishes parenterally immunized with inactivated Bacillus Calmette-Guérin (BCG). Our findings demonstrated that the TLR2 and the TLR4 signaling pathways are involved in the immune response elicited by inactivated mycobacteria in the zebrafish model of tuberculosis and support the use of inactivated mycobacteria in vaccine formulations for the control of mycobacteriosis.
Topics: Animals; Toll-Like Receptor 2; Zebrafish; Toll-Like Receptor 4; Hot Temperature; Tuberculosis; Mycobacterium bovis; BCG Vaccine
PubMed: 38184390
DOI: 10.1016/j.vaccine.2023.12.085 -
Molecular Biology Reports Jan 2024Investigate the role of COX signaling in activating the PGE2-EP2 pathway.
PURPOSE
Investigate the role of COX signaling in activating the PGE2-EP2 pathway.
METHODS
Utilized a marine Mycobacterium infection model in zebrafish. Marine mycobacteria were stained with fluorescein isothiocyanate. The COX inhibitor indomethacin, EP2 receptor inhibitor AH6809, EP4 receptor inhibitor AH23848 and clodronate Liposomes were used to investigate the role of COX, EP2, EP4 and macrophage whether participating in combat marine mycobacterial infection. The expression level of the target gene was detected using real-time fluorescence quantitative PCR instrument.
RESULTS
The findings revealed that larvae exposed to the COX inhibitor indomethacin or the EP2 receptor inhibitor AH6809 demonstrated a significantly higher mortality rate due to marine mycobacterium infection than those in the control group. Administration of exogenous prostaglandin E2 (PGE2) rescued the survival of zebrafish infected with marine mycobacteria and treated with indomethacin. Additionally, a significant reduction in survival rate was noted in macrophage-depleted zebrafish infected with marine mycobacteria.
CONCLUSION
The host may combat marine mycobacterium infection via COX signaling, which activates the PGE2-EP2 pathway and mediates macrophage resistance.
Topics: Animals; Mycobacterium marinum; Dinoprostone; Prostaglandin-Endoperoxide Synthases; Zebrafish; Indomethacin; Mycobacterium Infections
PubMed: 38183522
DOI: 10.1007/s11033-023-09015-x