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1.
Free Radic Biol Med ; 221: 98-110, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-38754743

ABSTRACT

Photodynamic therapy is a noninvasive treatment in which specific photosensitizers and light are used to produce high amounts of reactive oxygen species (ROS), which can be employed for targeted tissue destruction in cancer treatment or antimicrobial therapy. However, it remains unknown whether lower amounts of ROS produced by mild photodynamic therapy increase lifespan and stress resistance at the organism level. Here, we introduce a novel photodynamic treatment (PDTr) that uses 20 µM hypericin, a photosensitizer that originates from Hypericum perforatum, and orange light (590 nm, 5.4 W/m2, 1 min) to induce intracellular ROS formation (ROS), thereby resulting in lifespan extension and improved stress resistance in C. elegans. The PDTr-induced increase in longevity was abrogated by N-acetyl cysteine, suggesting the hormetic response was driven by prooxidative mechanisms. PDTr activated the translocation of SKN-1/NRF-2 and DAF-16/FOXO, leading to elevated expression of downstream oxidative stress-responsive genes, including ctl-1, gst-4, and sod-3. In summary, our findings suggest a novel PDTr method that extends the lifespan of C. elegans under both normal and oxidative stress conditions through the activation of SKN-1 and DAF-16 via the involvement of many antioxidant genes.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Longevity , Oxidative Stress , Perylene , Photochemotherapy , Photosensitizing Agents , Reactive Oxygen Species , Transcription Factors , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Oxidative Stress/drug effects , Longevity/drug effects , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Reactive Oxygen Species/metabolism , Transcription Factors/metabolism , Transcription Factors/genetics , Perylene/analogs & derivatives , Perylene/pharmacology , Anthracenes/pharmacology , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase/genetics , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Gene Expression Regulation/drug effects , Light , Acetylcysteine/pharmacology
2.
J Vis Exp ; (154)2019 12 03.
Article in English | MEDLINE | ID: mdl-31868179

ABSTRACT

In living organisms, intestinal hyperpermeability is a serious symptom that leads to many inflammatory bowel diseases (IBDs). Caenorhabditis elegans is a nonmammalian animal model that is widely used as an assay system due to its short lifespan, transparency, cost-effectiveness, and lack of animal ethics issues. In this study, a method was developed to investigate the effects of different bacteria and 3,3'-diindolylmethane (DIM) on the intestinal permeability of C. elegans with a high-throughput image analysis system. The worms were infected with different gut bacteria or cotreated with DIM for 48 h and fed with fluorescein isothiocyanate (FITC)-dextran overnight. Then, the intestinal permeability was examined by comparing the fluorescence images and the fluorescence intensity inside the worm bodies. This method may also have the potential to identify probiotic and pathogenic intestinal bacteria that affect intestinal permeability in the animal model and is effective for examining the effects of harmful or health-promoting chemicals on intestinal permeability and intestinal health. However, this protocol also has some considerable limitations at the genetic level, especially for determining which genes are altered to control illness, because this method is mostly used for phenotypic determination. In addition, this method is limited to determining exactly which pathogenic substrates cause inflammation or increase the permeability of the worms' intestines during infection. Therefore, further in-depth studies, including investigation of the molecular genetic mechanism using mutant bacteria and nematodes as well as chemical component analysis of bacteria, are required to fully evaluate the function of bacteria and chemicals in determining intestinal permeability.


Subject(s)
Bacteria/pathogenicity , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Intestines/physiopathology , Animals , Disease Models, Animal
3.
Pharmaceutics ; 11(12)2019 Dec 01.
Article in English | MEDLINE | ID: mdl-31805742

ABSTRACT

Bacterial antibiotic resistance is an alarming global issue that requires alternative antimicrobial methods to which there is no resistance. Antimicrobial photodynamic therapy (APDT) is a well-known method to combat this problem for many pathogens, especially Gram-positive bacteria and fungi. Hypericin and orange light APDT efficiently kill Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and the yeast Candida albicans. Although Gram-positive bacteria and many fungi are readily killed with APDT, Gram-negative bacteria are difficult to kill due to their different cell wall structures. Pseudomonas aeruginosa is one of the most important opportunistic, life-threatening Gram-negative pathogens. However, it cannot be killed successfully by hypericin and orange light APDT. P. aeruginosa is ampicillin resistant, but we hypothesized that ampicillin could still damage the cell wall, which can promote photosensitizer uptake into Gram-negative cells. Using hypericin and ampicillin cotreatment followed by orange light, a significant reduction (3.4 log) in P. aeruginosa PAO1 was achieved. P. aeruginosa PAO1 inactivation and gut permeability improvement by APDT were successfully shown in a Caenorhabditis elegans model.

4.
J Agric Food Chem ; 67(33): 9277-9285, 2019 Aug 21.
Article in English | MEDLINE | ID: mdl-31353906

ABSTRACT

3,3'-Diindolylmethane (DIM), a digestive metabolite originating from cruciferous vegetables, has dietary potential for the treatment of various human intestinal diseases. Although intestinal permeability dysfunction is closely related to the initiation and progression of human intestinal inflammatory diseases (IBDs), the effect of DIM on intestinal permeability is unclear. We evaluated the effect of DIM on the intestinal permeability of human intestinal cell monolayers and the animal model Caenorhabditis elegans, which were treated with IL-1ß and Pseudomonas aeruginosa, respectively, to mimic IBD conditions. DIM substantially restored the intestinal permeability of differentiated Caco-2 cells by enhancing the expression of tight junction proteins (including occludin and ZO-1). Compared to the IL-1ß single treatment (551.0 ± 49.0 Ω·cm2), DIM (10 µM) significantly increased the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers (919.0 ± 66.4 Ω·cm2, p < 0.001). DIM also ameliorated the impaired intestinal permeability and extended the lifespan of C. elegans fed P. aeruginosa. The mean lifespan of DIM-treated worms (10.8 ± 1.3 days) was higher than that of control-treated worms (9.7 ± 1.1 days, p < 0.01). Thus, DIM is a potential nutraceutical candidate for the treatment of leaky gut syndrome by improving intestinal permeability.


Subject(s)
Indoles/administration & dosage , Inflammatory Bowel Diseases/drug therapy , Intestinal Mucosa/drug effects , Animals , Caco-2 Cells , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Disease Models, Animal , Female , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Intestinal Mucosa/metabolism , Intestines , Male , Occludin/genetics , Occludin/metabolism , Permeability/drug effects , Zonula Occludens-1 Protein/genetics , Zonula Occludens-1 Protein/metabolism
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