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Scientific Reports Oct 2023Prodigiosin, a red pigment produced by Hahella chejuensis, a marine-derived microorganism, has several biological functions, including antimicrobial activity and...
Prodigiosin, a red pigment produced by Hahella chejuensis, a marine-derived microorganism, has several biological functions, including antimicrobial activity and inflammatory relief. In this study, the antibacterial activity of prodigiosin against skin microorganisms was explored. Paper disc assay on skin bacterial cells revealed that Cutibacterium acnes related to acne vulgaris highly susceptible to prodigiosin. MIC (Minimal Inhibitory Concentration) and MBC (Minimal Bactericidal Concentration) were determined on Cutibacterium species. The RNA-seq analysis of prodigiosin-treated C. acnes cells was performed to understand the antibacterial mechanism of prodigiosin. Among changes in the expression of hundreds of genes, the expression of a stress-responsive sigma factor encoded by sigB increased. Conversely, the gene expression of cell wall biosynthesis and energy metabolism was inhibited by prodigiosin. Specifically, the expression of genes related to the metabolism of porphyrin, a pro-inflammatory metabolite, was significantly reduced. Therefore, prodigiosin could be used to control C. acnes. Our study provided new insights into the antimicrobial mechanism of prodigiosin against C. acnes strains.
Topics: Humans; Prodigiosin; Transcriptome; Anti-Bacterial Agents; Acne Vulgaris; Microbial Sensitivity Tests; Propionibacterium acnes
PubMed: 37833344
DOI: 10.1038/s41598-023-44612-7 -
Journal of the American Chemical Society Jan 2024We report on porphyrin-flavonol hybrids consisting of a porphyrin antenna and four covalently bound 3-hydroxyflavone (flavonol) groups, which act as highly efficient...
We report on porphyrin-flavonol hybrids consisting of a porphyrin antenna and four covalently bound 3-hydroxyflavone (flavonol) groups, which act as highly efficient photoactivatable carbon monoxide (CO)-releasing molecules (photoCORMs). These bichromophoric systems enable activation of the UV-absorbing flavonol chromophore by visible light up to 650 nm and offer precise spatial and temporal control of CO administration. The physicochemical properties of the porphyrin antenna system can also be tuned by inserting a metal cation. Our computational study revealed that the process occurs via endergonic triplet-triplet energy transfer from porphyrin to flavonol and may become feasible thanks to flavonol energy stabilization upon intramolecular proton transfer. This mechanism was also indirectly supported by steady-state and transient absorption spectroscopy techniques. Additionally, the porphyrin-flavonol hybrids were found to be biologically benign. With four flavonol CO donors attached to a single porphyrin chromophore, high CO release yields, excellent uncaging cross sections, low toxicity, and CO therapeutic properties, these photoCORMs offer exceptional potential for their further development and future biological and medical applications.
PubMed: 38157303
DOI: 10.1021/jacs.3c11426 -
PLoS Pathogens Sep 2023Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, poses a great threat to human health. With the emergence of drug resistant Mtb strains, new...
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, poses a great threat to human health. With the emergence of drug resistant Mtb strains, new therapeutics are desperately needed. As iron is critical to the growth and survival of Mtb, mechanisms through which Mtb acquires host iron represent attractive therapeutic targets. Mtb scavenges host iron via Mtb siderophore-dependent and heme iron uptake pathways. While multiple studies describe the import of heme and ferric-siderophores and the export of apo-siderophores across the inner membrane, little is known about their transport across the periplasm and cell-wall environments. Mtb FecB and FecB2 are predicted periplasmic binding proteins implicated in host iron acquisition; however, their precise roles are not well understood. This study sought to differentiate the roles FecB and FecB2 play in Mtb iron acquisition. The crystallographic structures of Mtb FecB and FecB2 were determined to 2.0 Å and 2.2 Å resolution, respectively, and show distinct ligand binding pockets. In vitro ligand binding experiments for FecB and FecB2 were performed with heme and bacterial siderophores from Mtb and other species, revealing that both FecB and FecB2 bind heme, while only FecB binds the Mtb sideophore ferric-carboxymycobactin (Fe-cMB). Subsequent structure-guided mutagenesis of FecB identified a single glutamate residue-Glu339-that significantly contributes to Fe-cMB binding. A role for FecB in the Mtb siderophore-mediated iron acquisition pathway was corroborated by Mycobacterium smegmatis and Mtb pull-down assays, which revealed interactions between FecB and members of the mycobacterial siderophore export and import machinery. Similarly, pull-down assays with FecB2 confirms its role in heme uptake revealing interactions with a potential inner membrane heme importer. Due to ligand preference and protein partners, our data suggest that Mtb FecB plays a role in siderophore-dependent iron and heme acquisition pathways; in addition, we confirm that Mtb FecB2 is involved in heme uptake.
Topics: Humans; Iron; Siderophores; Mycobacterium tuberculosis; Ligands; Bacterial Proteins; Heme
PubMed: 37747938
DOI: 10.1371/journal.ppat.1011650 -
Cellular and Molecular Life Sciences :... Dec 2023MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to...
MFSD7b belongs to the Major Facilitator Superfamily of transporters that transport small molecules. Two isoforms of MFSD7b have been identified and they are reported to be heme exporters that play a crucial role in maintaining the cytosolic and mitochondrial heme levels, respectively. Mutations of MFSD7b (also known as FLVCR1) have been linked to retinitis pigmentosa, posterior column ataxia, and hereditary sensory and autonomic neuropathy. Although MFSD7b functions have been linked to heme detoxification by exporting excess heme from erythroid cells, it is ubiquitously expressed with a high level in the kidney, gastrointestinal tract, lungs, liver, and brain. Here, we showed that MFSD7b functions as a facilitative choline transporter. Expression of MFSD7b slightly but significantly increased choline import, while its knockdown reduced choline influx in mammalian cells. The influx of choline transported by MFSD7b is dependent on the expression of choline metabolizing enzymes such as choline kinase (CHKA) and intracellular choline levels, but it is independent of gradient of cations. Additionally, we showed that choline transport function of Mfsd7b is conserved from fly to man. Employing our transport assays, we showed that missense mutations of MFSD7b caused reduced choline transport functions. Our results show that MFSD7b functions as a facilitative choline transporter in mammalian cells.
Topics: Animals; Humans; Choline; Heme; Mammals; Mutation, Missense; Membrane Transport Proteins
PubMed: 38055060
DOI: 10.1007/s00018-023-05048-4 -
Pharmaceuticals (Basel, Switzerland) Dec 2023In order to select for further development novel photosensitizers for photodynamic therapy in cutaneous disorders, three unsymmetrical porphyrins, namely...
In order to select for further development novel photosensitizers for photodynamic therapy in cutaneous disorders, three unsymmetrical porphyrins, namely 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2), 5-(2-hydroxy-5-methoxyphenyl)-10,15,20-tris-(4-carboxymethylphenyl) porphyrin (P3.2), and 5-(2,4-dihydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P4.2), along with their fully symmetrical counterparts 5,10,15,20-tetrakis-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.1) and 5,10,15,20-tetrakis-(4-carboxymethylphenyl) porphyrin (P3.1) were comparatively evaluated. The absorption and fluorescence properties, as well as atomic force microscopy measurements were performed to evaluate the photophysical characteristics as well as morphological and textural properties of the mentioned porphyrins. The cellular uptake of compounds and the effect of photodynamic therapy on the viability, proliferation, and necrosis of human HaCaT keratinocytes, human Hs27 skin fibroblasts, human skin SCL II squamous cell carcinoma, and B16F10 melanoma cells were assessed in vitro, in correlation with the structural and photophysical properties of the investigated porphyrins, and with the predictions regarding diffusion through cell membranes and ADMET properties. All samples were found to be isotropic and self-similar, with slightly different degrees of aggregability, had a relatively low predicted toxicity (class V), and a predicted long half-life after systemic administration. The in vitro study performed on non-malignant and malignant skin-relevant cells highlighted that the asymmetric P2.2 porphyrin qualified among the five investigated porphyrins to be a promising photosensitizer candidate for PDT in skin disorders. P2.2 was shown to accumulate well within cells, and induced by PDT a massive decrease in the number of metabolically active skin cells, partly due to cell death by necrosis. P2.2 had in this respect a better behavior than the symmetric P.2.1 compound and the related asymmetric compound P4.2. The strong action of P2.2-mediated PDT on normal skin cells might be an important drawback for further development of this compound. Meanwhile, the P3.1 and P3.2 compounds were not able to accumulate well in skin cells, and did not elicit significant PDT in vitro. Taken together, our experiments suggest that P2.2 can be a promising candidate for the development of novel photosensitizers for PDT in skin disorders.
PubMed: 38256895
DOI: 10.3390/ph17010062 -
ChemistryOpen Dec 2023Dye-sensitized solar cells (DSSCs) are a feasible alternative to traditional silicon-based solar cells because of their low cost, eco-friendliness, flexibility, and... (Review)
Review
Dye-sensitized solar cells (DSSCs) are a feasible alternative to traditional silicon-based solar cells because of their low cost, eco-friendliness, flexibility, and acceptable device efficiency. In recent years, solid-state DSSCs (ss-DSSCs) have garnered much interest as they can overcome the leakage and evaporation issues of liquid electrolyte systems. However, the poor morphology of solid electrolytes and their interface with photoanodes can minimize the device performance. The photosensitizer/dye is a critical component of ss-DSSCs and plays a vital role in the device's overall performance. In this review, we summarize recent developments and performance of photosensitizers, including mono- and co-sensitization of ruthenium, porphyrin, and metal-free organic dyes under 1 sun and ambient/artificial light conditions. We also discuss the various requirements that efficient photosensitizers should satisfy and provide an overview of their historical development over the years.
PubMed: 37874016
DOI: 10.1002/open.202300170 -
PLoS Pathogens Aug 2023Epstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain...
Epstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain unknown. A major hallmark of malarial disease is hemolysis and bystander eryptosis of red blood cells, which causes release of free heme in large quantities into peripheral blood. We hypothesized that heme released during malaria infection drives differentiation of latently infected EBV-positive B cells, resulting in viral reactivation and release of infectious virus. To test this hypothesis, we used the EBV-positive Mutu I B-cell line and treated with hemin (the oxidized form of heme) and evaluated evidence of EBV reactivation. Hemin treatment resulted in the expression of EBV immediate early, early and late lytic gene transcripts. In addition, expression of CD138, a marker of plasma cells was co-expressed with the late lytic protein gp350 on hemin treated Mutu I cells. Finally, DNase-resistant EBV DNA indicative of virion production was detected in supernatant. To assess the transcriptional changes induced by hemin treatment, RNA sequencing was performed on mock- and hemin-treated Mutu I cells, and a shift from mature B cell transcripts to plasma cell transcripts was identified. To identify the mechanism of hemin-induced B cell differentiation, we measured levels of the plasma cell transcriptional repressor, BACH2, that contains specific heme binding sites. Hemin treatment caused significant degradation of BACH2 by 24 hours post-treatment in four BL cell lines (two EBV positive, two EBV negative). Knockdown of BACH2 in Mutu I cells using siRNAs significantly increased CD138+gp350+ cells to levels similar to treatment with hemin. This suggested that hemin induced BACH2 degradation was responsible for plasma cell differentiation and viral reactivation. Together, these data support a model where EBV reactivation can occur during malaria infection via heme modulation, providing a mechanistic link between malaria and EBV.
Topics: Humans; Hemin; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Heme; Cell Differentiation; Basic-Leucine Zipper Transcription Factors
PubMed: 37639483
DOI: 10.1371/journal.ppat.1011561 -
IUCrData Dec 2023The structure of the title solvated porphyrin, CHNO·CH, is reported. Two porphyrin mol-ecules, one ordered and one disordered -hexane solvate mol-ecules are present in...
The structure of the title solvated porphyrin, CHNO·CH, is reported. Two porphyrin mol-ecules, one ordered and one disordered -hexane solvate mol-ecules are present in its asymmetric unit. The porphyrin macrocycle shows a characteristic saddle-shaped distortion, and the maximum deviation from the mean plane for non-hydrogen atoms is 0.48 Å. N-H⋯N, N-H⋯O, and C-H⋯O hydrogen bonds, as well as ππ inter-actions, are observed in the crystal structure.
PubMed: 38313206
DOI: 10.1107/S2414314623010854 -
Photodiagnosis and Photodynamic Therapy Dec 2023To conduct a retrospective analysis of Hemoporfin photodynamic therapy (HMME-PDT) in the treatment of port-wine stains (PWS).
OBJECTIVE
To conduct a retrospective analysis of Hemoporfin photodynamic therapy (HMME-PDT) in the treatment of port-wine stains (PWS).
METHOD
A retrospective analysis was conducted based on the clinical data from March 2017 to December 2022, so as to summarize the demographic characteristics, clinical efficacy and adverse reactions. The effectiveness of HMME-PDT was examined with respect to treatment times, age, gender, subtype, and location of PWS lesions.
RESULT
The age of the 2952 cases ranged from 8 months to 56 years old (median, 2.8 years), with 1419 males (48.07 %), and 1533 females (51.93 %). There were 669 cases of pink type (22.66 %), 2184 cases of purplish red type (73.98 %), and 99 cases of nodular thickening type (3.35 %). The prevalence location was face (88.04 %), neck (14.94 %), limbs and trunk. 1602 cases (54.27 %) had never received treatment, 661 cases (22.39 %) had been treated by pulse dye laser (PDL), 229 cases (7.76 %) had previously been treated by PDT, 296 cases (10.03 %) had received both the modalities. The 2952 cases completed totally 7996 HMME-PDT times. Cure rate and effective rate increased continuously with the number of treatments. The pink type has the highest cure rate and effective rate, followed by the purplish red type and the last was the nodular thickening type. The therapeutic effects are considerably influenced by age, subtype, and treatment site (P < 0.05). However, there was no significant difference in the effectiveness of HMME-PDT between both genders. The local adverse reactions after the first treatment included edema (97.73 %), itching (82.62 %), purpura-like change (79.51 %), crusts (24.59 %), infection (4.07 %), scars (1.08 %), hyperpigmentation (0.61 %), and depigmentation (0.41 %). Nausea and vomiting occurred in 2 juveniles and 1 young adult (5, 6 and 22 years old respectively) immediately after treatment, and did not interfere with the administration of the treatment. Patients aged 21-30 were found to have a 3.4-fold higher likelihood of undergoing HMME-PDT under general anesthesia compared to those aged 15 or younger. There was no distinct systemic adverse reaction, such as allergic responses, cardiovascular effects, neurological symptoms, hematological abnormalities, respiratory symptoms, or musculoskeletal issues.
CONCLUSION
HMME-PDT is preferred in treating PWS, with relatively high effective rate and cure rate, mild local reactions and no distinct systemic adverse reaction.
Topics: Young Adult; Humans; Male; Female; Child; Adolescent; Adult; Photosensitizing Agents; Port-Wine Stain; Photochemotherapy; Retrospective Studies; Hematoporphyrins; Treatment Outcome
PubMed: 37827224
DOI: 10.1016/j.pdpdt.2023.103837 -
Journal of Investigative Surgery : the... Dec 2023The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy...
OBJECTIVE
The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells.
METHODS
We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent hybridization (FISH) assays to assess the interaction between mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated . Finally, the effect of VP on glycolysis was determined by using F-FDG uptake, glucose consumption, and lactate production assays.
RESULTS
Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUV) determined by F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells.
CONCLUSION
VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.
Topics: Female; Humans; Breast Neoplasms; Fluorodeoxyglucose F18; Glycolysis; In Situ Hybridization, Fluorescence; Positron Emission Tomography Computed Tomography; Verteporfin; YAP-Signaling Proteins
PubMed: 37828756
DOI: 10.1080/08941939.2023.2266732