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Journal of Photochemistry and... Jul 2024Emerging antibiotic resistance among bacterial pathogens has forced an urgent need for alternative non-antibiotic strategies development that could combat drug...
INTRODUCTION
Emerging antibiotic resistance among bacterial pathogens has forced an urgent need for alternative non-antibiotic strategies development that could combat drug resistant-associated infections. Suppression of virulence of ESKAPE pathogens' by targeting multiple virulence traits provides a promising approach.
OBJECTIVES
Here we propose an iron-blocking antibacterial therapy based on a cationic heme-mimetic gallium porphyrin (GaCHP), which antibacterial efficacy could be further enhanced by photodynamic inactivation.
METHODS
We used gallium heme mimetic porphyrin (GaCHP) excited with light to significantly reduce microbial viability and suppress both the expression and biological activity of several virulence traits of both Gram-positive and Gram-negative ESKAPE representatives, i.e., S. aureus and P. aeruginosa. Moreover, further improvement of the proposed strategy by combining it with routinely used antimicrobials to resensitize the microbes to antibiotics and provide enhanced bactericidal efficacy was investigated.
RESULTS
The proposed strategy led to substantial inactivation of critical priority pathogens and has been evidenced to suppress the expression and biological activity of multiple virulence factors in S. aureus and P. aeruginosa. Finally, the combination of GaCHP phototreatment and antibiotics resulted in promising strategy to overcome antibiotic resistance of the studied microbes and to enhance disinfection of drug resistant pathogens.
CONCLUSION
Lastly, considering high safety aspects of the proposed treatment toward host cells, i.e., lack of mutagenicity, no dark toxicity and mild phototoxicity, we describe an efficient alternative that simultaneously suppresses the functionality of multiple virulence factors in ESKAPE pathogens.
Topics: Photosensitizing Agents; Gallium; Porphyrins; Pseudomonas aeruginosa; Staphylococcus aureus; Heme; Anti-Bacterial Agents; Virulence; Microbial Sensitivity Tests; Light; Drug Resistance, Bacterial
PubMed: 38723545
DOI: 10.1016/j.jphotobiol.2024.112928 -
Molecular Phylogenetics and Evolution Jul 2024Dinoflagellates are diverse and ecologically important protists characterized by many morphological and molecular traits that set them apart from other eukaryotes. These...
Dinoflagellates are diverse and ecologically important protists characterized by many morphological and molecular traits that set them apart from other eukaryotes. These features include, but are not limited to, massive genomes organized using bacterially-derived histone-like proteins (HLPs) and dinoflagellate viral nucleoproteins (DVNP) rather than histones, and a complex history of photobiology with many independent losses of photosynthesis, numerous cases of serial secondary and tertiary plastid gains, and the presence of horizontally acquired bacterial rhodopsins and type II RuBisCo. Elucidating how this all evolved depends on knowing the phylogenetic relationships between dinoflagellate lineages. Half of these species are heterotrophic, but existing molecular data is strongly biased toward the photosynthetic dinoflagellates due to their amenability to cultivation and prevalence in culture collections. These biases make it impossible to interpret the evolution of photosynthesis, but may also affect phylogenetic inferences that impact our understanding of character evolution. Here, we address this problem by isolating individual cells from the Salish Sea and using single cell, culture-free transcriptomics to expand molecular data for dinoflagellates to include 27 more heterotrophic taxa, resulting in a roughly balanced representation. Using these data, we performed a comprehensive search for proteins involved in chromatin packaging, plastid function, and photoactivity across all dinoflagellates. These searches reveal that 1) photosynthesis was lost at least 21 times, 2) two known types of HLP were horizontally acquired around the same time rather than sequentially as previously thought; 3) multiple rhodopsins are present across the dinoflagellates, acquired multiple times from different donors; 4) kleptoplastic species have nucleus-encoded genes for proteins targeted to their temporary plastids and they are derived from multiple lineages, and 5) warnowiids are the only heterotrophs that retain a whole photosystem, although some photosynthesis-related electron transport genes are widely retained in heterotrophs, likely as part of the iron-sulfur cluster pathway that persists in non-photosynthetic plastids.
Topics: Dinoflagellida; Phylogeny; Photosynthesis; Heterotrophic Processes; Biological Evolution; Evolution, Molecular; Plastids
PubMed: 38677354
DOI: 10.1016/j.ympev.2024.108086 -
Pharmaceutics Apr 2024Cutaneous leishmaniasis (CL) is a neglected tropical disease. The treatment is restricted to drugs, such as meglumine antimoniate and amphotericin B, that exhibit toxic...
Combination of the Topical Photodynamic Therapy of Chloroaluminum Phthalocyanine Liposomes with Fexinidazole Oral Self-Emulsifying System as a New Strategy for Cutaneous Leishmaniasis Treatment.
Cutaneous leishmaniasis (CL) is a neglected tropical disease. The treatment is restricted to drugs, such as meglumine antimoniate and amphotericin B, that exhibit toxic effects, high cost, long-term treatment, and limited efficacy. The development of new alternative therapies, including the identification of effective drugs for the topical and oral treatment of CL, is of great interest. In this sense, a combination of topical photodynamic therapy (PDT) with chloroaluminum phthalocyanine liposomes (Lip-ClAlPc) and the oral administration of a self-emulsifying drug delivery system containing fexinidazole (SEDDS-FEX) emerges as a new strategy. The aim of the present study was to prepare, characterize, and evaluate the efficacy of combined therapy with Lip-ClAlPc and SEDDS-FEX in the experimental treatment of . Lip-ClAlPc and SEDDS-FEX were prepared, and the antileishmanial efficacy study was conducted with the following groups: 1. Lip-ClAlPc (0.05 mL); 2. SEDDS-FEX (50 mg/kg/day); 3. Lip-ClAlPc (0.05 mL)+SEDDS-FEX (50 mg/kg/day) combination; 4. FEX suspension (50 mg/kg/day); and 5. control (untreated). BALB/c mice received 10 sessions of topical Lip-ClAlPc on alternate days and 20 consecutive days of SEDDS-FEX or FEX oral suspension. Therapeutical efficacy was evaluated via the parasite burden (limiting-dilution assay), lesion size (mm), healing of the lesion, and histological analyses. Lip-ClAlPc and SEDDS-FEX presented physicochemical characteristics that are compatible with the administration routes used in the treatments. Lip-ClAlPc+SEDDS-FEX led to a significant reduction in the parasitic burden in the lesion and spleen when compared to the control group ( < 0.05) and the complete healing of the lesion in 43% of animals. The Lip-ClAlPc+SEDDS-FEX combination may be promising for the treatment of CL caused by
PubMed: 38675171
DOI: 10.3390/pharmaceutics16040509 -
Nutrients Apr 2024Vitamin D synthesis in human skin is initiated by solar ultraviolet radiation (UVR) exposure of precursor 7-dehydrocholesterol (7DHC), but influence of age on the early... (Comparative Study)
Comparative Study
Comparative Study of Healthy Older and Younger Adults Shows They Have the Same Skin Concentration of Vitamin D Precursor, 7-Dehydrocholesterol, and Similar Response to UVR.
Vitamin D synthesis in human skin is initiated by solar ultraviolet radiation (UVR) exposure of precursor 7-dehydrocholesterol (7DHC), but influence of age on the early stage of vitamin D metabolism is uncertain. We performed a prospective standardised study in healthy ambulant adults aged ≥65 and ≤40 years examining (1) if baseline skin 7DHC concentration differs between younger and older adults and (2) the impact of older age on serum vitamin D response to solar simulated UVR. Eleven younger (18-40 years) and 10 older (65-89 years) adults, phototype I-III, received low-dose UVR (95% UVA, 5% UVB, 1.3 SED) to ~35% of the body surface area. Biopsies were taken for 7DHC assay from unexposed skin, skin immediately and 24 h post-UVR, and blood sampled at baseline, 24 h and 7 d post-UVR for vitamin D assay. Samples were analysed by HPLC-MS/MS. Baseline skin 7DHC (mean ± SD) was 0.22 ± 0.07 and 0.25 ± 0.08 µg/mg in younger versus older adults (no significant difference). Baseline serum vitamin D concentration was 1.5 ± 1.5 and 1.5 ± 1.7 nmol/L in younger versus older adults, respectively, and showed a significant increase in both groups post-UVR (no significant differences between age groups). Thus, skin 7DHC concentration was not a limiting factor for vitamin D production in older relative to younger adults. This information assists public health guidance on sun exposure/vitamin D nutrition, with particular relevance to the growing populations of healthy ambulant adults ≥65 years.
Topics: Humans; Dehydrocholesterols; Adult; Aged; Ultraviolet Rays; Cholecalciferol; Skin; Male; Young Adult; Female; Aged, 80 and over; Adolescent; Prospective Studies; Age Factors
PubMed: 38674838
DOI: 10.3390/nu16081147 -
Frontiers in Plant Science 2024In our earlier works, we have shown that the rate-limiting steps, associated with the dark-to-light transition of Photosystem II (PSII), reflecting the photochemical...
In our earlier works, we have shown that the rate-limiting steps, associated with the dark-to-light transition of Photosystem II (PSII), reflecting the photochemical activity and structural dynamics of the reaction center complex, depend largely on the lipidic environment of the protein matrix. Using chlorophyll- fluorescence transients (ChlF) elicited by single-turnover saturating flashes, it was shown that the half-waiting time (Δ ) between consecutive excitations, at which 50% of the fluorescence increment was reached, was considerably larger in isolated PSII complexes of () than in the native thylakoid membrane (TM). Further, it was shown that the addition of a TM lipid extract shortened Δ of isolated PSII, indicating that at least a fraction of the 'missing' lipid molecules, replaced by detergent molecules, caused the elongation of Δ . Here, we performed systematic experiments to obtain information on the nature of TM lipids that are capable of decreasing Δ . Our data show that while all lipid species shorten Δ , the negatively charged lipid phosphatidylglycerol appears to be the most efficient species - suggesting its prominent role in determining the structural dynamics of PSII reaction center.
PubMed: 38576791
DOI: 10.3389/fpls.2024.1381040 -
Nature Communications Mar 2024Photoreceptor proteins utilise chromophores to sense light and trigger a biological response. The discovery that adenosylcobalamin (or coenzyme B) can act as a...
Photoreceptor proteins utilise chromophores to sense light and trigger a biological response. The discovery that adenosylcobalamin (or coenzyme B) can act as a light-sensing chromophore heralded a new field of B-photobiology. Although microbial genome analysis indicates that photoactive B-binding domains form part of more complex protein architectures, regulating a range of molecular-cellular functions in response to light, experimental evidence is lacking. Here we identify and characterise a sub-family of multi-centre photoreceptors, termed photocobilins, that use B and biliverdin (BV) to sense light across the visible spectrum. Crystal structures reveal close juxtaposition of the B and BV chromophores, an arrangement that facilitates optical coupling. Light-triggered conversion of the B affects quaternary structure, in turn leading to light-activation of associated enzyme domains. The apparent widespread nature of photocobilins implies involvement in light regulation of a wider array of biochemical processes, and thus expands the scope for B photobiology. Their characterisation provides inspiration for the design of broad-spectrum optogenetic tools and next generation bio-photocatalysts.
Topics: Photochemistry; Bile Pigments; Biliverdine; Bacterial Proteins; Photoreceptors, Microbial; Light
PubMed: 38548733
DOI: 10.1038/s41467-024-46995-1 -
International Journal of Molecular... Mar 2024Photobiology is a challenging research area that aims to explore the interactions between light and living organisms and their biological consequences, with applications...
Photobiology is a challenging research area that aims to explore the interactions between light and living organisms and their biological consequences, with applications in the fields of photomedicine, photo(nano)technology, photosynthesis, and photosensory biology [...].
Topics: Photobiology; Photosynthesis; Light
PubMed: 38542185
DOI: 10.3390/ijms25063209 -
PloS One 2024Photoreceptor cell death can cause progressive and irreversible visual impairments. Still, effective therapies on retinal neuroprotection are not available....
Photoreceptor cell death can cause progressive and irreversible visual impairments. Still, effective therapies on retinal neuroprotection are not available. Hypoxia-inducible factors (HIFs) are transcriptional factors which strongly regulate angiogenesis, erythropoiesis, intracellular metabolism, and programed cell death under a hypoxic or an abnormal metabolic oxidative stress condition. Therefore, we aimed to unravel that inhibition of HIFs could prevent disease progression in photoreceptor cell death, as recent studies showed that HIFs might be pathologic factors in retinal diseases. Adult male balb/cAJcl (8 weeks old; BALB/c) were used to investigate preventive effects of a novel HIF inhibitor halofuginone (HF) on a murine model of light-induced retinopathy. After intraperitoneal injections of phosphate-buffered saline (PBS) or HF (0.4 mg/kg in PBS) for 5 days, male BALB/c mice were subjected to a dark-adaption to being exposed to a white LED light source at an intensity of 3,000 lux for 1 hour in order to induce light-induced retinal damage. After extensive light exposure, retinal damage was evaluated using electroretinography (ERG), optical coherence tomography (OCT), and TUNEL assay. Light-induced retinal dysfunction was suppressed by HF administration. The amplitudes of scotopic a-wave and b-wave as well as that of photopic b-wave were preserved in the HF-administered retina. Outer retinal thinning after extensive light exposure was suppressed by HF administration. Based on the TUNEL assay, cell death in the outer retina was seen after light exposure. However, its cell death was not detected in the HF-administered retina. Halofuginone was found to exert preventive effects on light-induced outer retinal cell death.
Topics: Mice; Male; Animals; Retinal Degeneration; Disease Models, Animal; Retina; Electroretinography; Piperidines; Quinazolinones
PubMed: 38536853
DOI: 10.1371/journal.pone.0300045 -
Antimicrobial Agents and Chemotherapy May 2024Primaquine is the mainstream antimalarial drug to prevent relapses. However, this drug can induce hemolysis in patients with glucose-6-phosphate dehydrogenase...
Primaquine is the mainstream antimalarial drug to prevent relapses. However, this drug can induce hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Nanostructure formulations of primaquine loaded with D-galactose were used as a strategy to target the drug to the liver and decrease the hemolytic risks. Nanoemulsion (NE-Pq) and nanochitosan (NQ-Pq) formulations of primaquine diphosphate containing D-galactose were prepared and characterized by their physicochemistry properties. Pharmacokinetic and biodistribution studies were conducted using Swiss Webster mice. A single dose of 10 mg/kg of each nanoformulation or free primaquine solution was administered by gavage to the animals, which were killed at 0.5, 1, 2, 4, 8, and 24 hours. Blood samples and tissues were collected, processed, and analyzed by high-performance liquid chromatography. The nanoformulation showed sizes around 200 nm (NE-Pq) and 400 nm (NQ-Pq) and physicochemical stability for over 30 days. Free primaquine solution achieved higher primaquine Cmax in the liver than NE-Pq or NQ-Pq at 0.5 hours. However, the half-life and mean residence time (MRT) of primaquine in the liver were three times higher with the NQ-Pq formulation than with free primaquine, and the volume distribution was four times higher. Conversely, primaquine's half-life, MRT, and volume distribution in the plasma were lower for NQ-Pq than for free primaquine. NE-Pq, on the other hand, accumulated more in the lungs but not in the liver. Galactose-coated primaquine nanochitosan formulation showed increased drug targeting to the liver compared to free primaquine and may represent a promising strategy for a more efficient and safer radical cure for vivax malaria.
Topics: Primaquine; Animals; Mice; Liver; Galactose; Chitosan; Antimalarials; Nanoparticles; Tissue Distribution; Nanostructures; Male
PubMed: 38517190
DOI: 10.1128/aac.00915-23 -
The Journal of Biological Chemistry Apr 2024High sensitivity of scotopic vision (vision in dim light conditions) is achieved by the rods' low background noise, which is attributed to a much lower thermal...
High sensitivity of scotopic vision (vision in dim light conditions) is achieved by the rods' low background noise, which is attributed to a much lower thermal activation rate (k) of rhodopsin compared with cone pigments. Frogs and nocturnal geckos uniquely possess atypical rods containing noncanonical cone pigments that exhibit low k, mimicking rhodopsin. Here, we investigated the convergent mechanism underlying the low k of rhodopsins and noncanonical cone pigments. Our biochemical analysis revealed that the k of canonical cone pigments depends on their absorption maximum (λ). However, rhodopsin and noncanonical cone pigments showed a substantially lower k than predicted from the λ dependency. Given that the λ is inversely proportional to the activation energy of the pigments in the Hinshelwood distribution-based model, our findings suggest that rhodopsin and noncanonical cone pigments have convergently acquired low frequency of spontaneous-activation attempts, including thermal fluctuations of the protein moiety, in the molecular evolutionary processes from canonical cone pigments, which contributes to highly sensitive scotopic vision.
Topics: Animals; Evolution, Molecular; Light; Night Vision; Rhodopsin; Vertebrates; Cone Opsins
PubMed: 38499150
DOI: 10.1016/j.jbc.2024.107175