-
BioRxiv : the Preprint Server For... May 2024In response to environmental stress, chloroplasts generate reactive oxygen species, including singlet oxygen ( O ), which regulates nuclear gene expression (retrograde...
In response to environmental stress, chloroplasts generate reactive oxygen species, including singlet oxygen ( O ), which regulates nuclear gene expression (retrograde signaling), chloroplast turnover, and programmed cell death (PCD). Yet, the central signaling mechanisms and downstream responses remain poorly understood. The ( ) mutant conditionally accumulates O and involves Plant U-Box 4 (PUB4), a cytoplasmic E3 ubiquitin ligase, in propagating these signals. To gain insights into O signaling pathways, we compared transcriptomes of and mutants. The accumulation of O in plants broadly repressed genes involved in chloroplast function and photosynthesis, while O induced genes and transcription factors involved in abiotic and biotic stress, the biosynthesis of jasmonic acid (JA), and Salicylic acid (SA). Elevated JA and SA levels were observed in stressed plants, but were not responsible for PCD. reversed the majority of O -induced gene expression in and reduced the JA content, but maintained elevated levels of SA even in the absence of O stress. Reducing SA levels in restored O signaling and light sensitivity. Together, this work demonstrates that SA plays a protective role during photo-oxidative stress and that PUB4 mediates O signaling by modulating its levels.
PubMed: 38798329
DOI: 10.1101/2024.05.13.593788 -
Molecules (Basel, Switzerland) May 2024Photodynamic therapy (PDT) is a non-invasive anticancer treatment that uses special photosensitizer molecules (PS) to generate singlet oxygen and other reactive oxygen...
Photodynamic therapy (PDT) is a non-invasive anticancer treatment that uses special photosensitizer molecules (PS) to generate singlet oxygen and other reactive oxygen species (ROS) in a tissue under excitation with red or infrared light. Though the method has been known for decades, it has become more popular recently with the development of new efficient organic dyes and LED light sources. Here we introduce a ternary nanocomposite: water-soluble star-like polymer/gold nanoparticles (AuNP)/temoporfin PS, which can be considered as a third-generation PDT system. AuNPs were synthesized in situ inside the polymer molecules, and the latter were then loaded with PS molecules in an aqueous solution. The applied method of synthesis allows precise control of the size and architecture of polymer nanoparticles as well as the concentration of the components. Dynamic light scattering confirmed the formation of isolated particles (120 nm diameter) with AuNPs and PS molecules incorporated inside the polymer shell. Absorption and photoluminescence spectroscopies revealed optimal concentrations of the components that can simultaneously reduce the side effects of dark toxicity and enhance singlet oxygen generation to increase cancer cell mortality. Here, we report on the optical properties of the system and detailed mechanisms of the observed enhancement of the phototherapeutic effect. Combinations of organic dyes with gold nanoparticles allow significant enhancement of the effect of ROS generation due to surface plasmonic resonance in the latter, while the application of a biocompatible star-like polymer vehicle with a dextran core and anionic polyacrylamide arms allows better local integration of the components and targeted delivery of the PS molecules to cancer cells. In this study, we demonstrate, as proof of concept, a successful application of the developed PDT system for in vitro treatment of triple-negative breast cancer cells under irradiation with a low-power LED lamp (660 nm). We consider the developed nanocomposite to be a promising PDT system for application to other types of cancer.
Topics: Gold; Photochemotherapy; Metal Nanoparticles; Photosensitizing Agents; Humans; Acrylic Resins; Cell Line, Tumor; Singlet Oxygen; Reactive Oxygen Species; Porphyrins; Cell Survival; Polymers; Antineoplastic Agents
PubMed: 38792086
DOI: 10.3390/molecules29102224 -
Organic Process Research & Development May 2024We describe the optimization and scale-up of two consecutive reaction steps in the synthesis of bio-derived alkoxybutenolide monomers that have been reported as...
We describe the optimization and scale-up of two consecutive reaction steps in the synthesis of bio-derived alkoxybutenolide monomers that have been reported as potential replacements for acrylate-based coatings (Sci. Adv.2020, 6, eabe0026). These monomers are synthesized by (i) oxidation of furfural with photogenerated singlet oxygen followed by (ii) thermal condensation of the desired 5-hydroxyfuranone intermediate product with an alcohol, a step which until now has involved a lengthy batch reaction. The two steps have been successfully telescoped into a single kilogram-scale process without any need to isolate the 5-hydroxyfuranone between the steps. Our process development involved FTIR reaction monitoring, FTIR data analysis 2D visualization, and two different photoreactors: (i) a semicontinuous photoreactor based on a modified rotary evaporator, where FTIR and 2D correlation spectroscopy (2D-COS) revealed the loss of the methyl formate coproduct, and (ii) our fully continuous Taylor Vortex photoreactor, which enhanced the mass transfer and permitted the use of near-stoichiometric equivalents of O. The use of in-line FTIR monitoring and modeling greatly accelerated process optimization in the Vortex reactor. This led to scale-up of the photo-oxidation in 85% yield with a projected productivity of 1.3 kg day and a space-time yield of 0.06 mol day mL. Higher productivities could be achieved while sacrificing yield (, 4 kg day at 40% yield). The use of superheated methanol at 200 °C in a pressurized thermal flow reactor accelerated the second step, the thermal condensation of 5-hydroxyfuranone, from a 20 h batch reflux reaction (0.5 L, 85 g) to a space time of <1 min in a reactor only 3 mL in volume operating with projected productivities of >700 g day. Proof of concept for telescoping the two steps was established with an overall two-step yield of 67%, producing a process with a projected productivity of 1.1 kg day for the methoxybutenolide monomer without any purification of the 5-hydroxyfuranone intermediate.
PubMed: 38783853
DOI: 10.1021/acs.oprd.3c00462 -
Nature Communications May 2024The reactive singlet state of oxygen (O) can decay to the triplet ground state nonradiatively in the presence of a solvent. There is a controversy about whether...
The reactive singlet state of oxygen (O) can decay to the triplet ground state nonradiatively in the presence of a solvent. There is a controversy about whether tunnelling is involved in this nonadiabatic spin-crossover process. Semiclassical instanton theory provides a reliable and practical computational method for elucidating the reaction mechanism and can account for nuclear quantum effects such as zero-point energy and multidimensional tunnelling. However, the previously developed instanton theory is not directly applicable to this system because of a branch-point singularity which appears in the flux correlation function. Here we derive a new instanton theory for cases dominated by the singularity, leading to a new picture of tunnelling in nonadiabatic processes. Together with multireference electronic-structure theory, this provides a rigorous framework based on first principles that we apply to calculate the decay rate of singlet oxygen in water. The results indicate a new reaction mechanism that is 27 orders of magnitude faster at room temperature than the classical process through the minimum-energy crossing point. We find significant heavy-atom tunnelling contributions as well as a large temperature-dependent HO/DO kinetic isotope effect of approximately 20, in excellent agreement with experiment.
PubMed: 38773078
DOI: 10.1038/s41467-024-48463-2 -
Journal of Colloid and Interface Science Sep 2024The clinical translation of photosensitizers based on ruthenium(II) polypyridyl complexes (RPCs) in photodynamic therapy of cancer faces several challenges. To address...
The clinical translation of photosensitizers based on ruthenium(II) polypyridyl complexes (RPCs) in photodynamic therapy of cancer faces several challenges. To address these limitations, we conducted an investigation to assess the potential of a cubosome formulation stabilized in water against coalescence utilizing a polyphosphoester analog of Pluronic F127 as a stabilizer and loaded with newly synthesized RPC-based photosensitizer [Ru(dppn)(bpy-morph)](PF) (bpy-morph = 2,2'-bipyridine-4,4'-diylbis(morpholinomethanone)), PS-Ru. The photophysical characterization of PS-Ru revealed its robust capacity to induce the formation of singlet oxygen (O). Furthermore, the physicochemical analysis of the PS-Ru-loaded cubosomes dispersion demonstrated that the encapsulation of the photosensitizer within the nanoparticles did not disrupt the three-dimensional arrangement of the lipid bilayer. The biological tests showed that PS-Ru-loaded cubosomes exhibited significant phototoxic activity when exposed to the light source, in stark contrast to empty cubosomes and to the same formulation without irradiation. This promising outcome suggests the potential of the formulation in overcoming the drawbacks associated with the clinical use of RPCs in photodynamic therapy for anticancer treatments.
Topics: Photochemotherapy; Photosensitizing Agents; Lung Neoplasms; Humans; Ruthenium; Coordination Complexes; Adenocarcinoma of Lung; Antineoplastic Agents; Particle Size; Singlet Oxygen; Nanoparticles; Cell Survival; Poloxamer; Drug Screening Assays, Antitumor; Surface Properties; A549 Cells
PubMed: 38761576
DOI: 10.1016/j.jcis.2024.05.088 -
Colloids and Surfaces. B, Biointerfaces May 2024Breast cancer, the predominant malignancy afflicting women, continues to pose formidable challenges despite advancements in therapeutic interventions. This study...
Breast cancer, the predominant malignancy afflicting women, continues to pose formidable challenges despite advancements in therapeutic interventions. This study elucidates the potential of phototherapy, comprising both photothermal and photodynamic therapy (PTT/PDT), as a novel and promising modality. To achieve this goal, we devised liposomes coated with macrophage cell membranes including macrophage-associated membrane proteins, which have demonstrated promise in biomimetic delivery systems for targeting tumors while preserving their inherent tumor-homing capabilities. This integrated biomimetic delivery system comprised IR780, NONOate, and perfluorocarbon. This strategic encapsulation aims to achieve a synergistic combination of photodynamic therapy (PDT) and reactive nitrogen species (RNS) therapy. Under near-infrared laser irradiation at 808 nm, IR780 demonstrates its ability to prolifically generate reactive oxygen species (ROS), including superoxide anion (O), singlet oxygen, and hydroxyl radical (·OH). Simultaneously, NONOate releases nitric oxide (NO) gas upon the same laser irradiation, thereby engaging with IR780-induced ROS to facilitate the formation of peroxynitrite anion (ONOO-), ultimately inducing programmed cell death in cancer cells. Additionally, the perfluorocarbon component of our delivery system exhibits a notable affinity for oxygen and demonstrates efficient oxygen-carrying capabilities. Our results demonstrate that IR780-NO-PFH-Lip@M significantly enhances breast cancer cell toxicity, reducing proliferation and in vivo tumor growth through simultaneous heat, ROS, and RNS production. This study contributes valuable insights to the ongoing discourse on innovative strategies for advancing cancer therapeutics.
PubMed: 38749169
DOI: 10.1016/j.colsurfb.2024.113961 -
Inorganic Chemistry May 2024Phlorins have long remained underexplored relative to their fully conjugated counterparts, such as porphyrins, hydroporphyrins, and corroles. Herein, we have attempted...
Phlorins have long remained underexplored relative to their fully conjugated counterparts, such as porphyrins, hydroporphyrins, and corroles. Herein, we have attempted to bridge that knowledge gap with a scalar-relativistic density functional theory (DFT) study of unsubstituted iridium and gold phlorin derivatives and a multitechnique experimental study of iridium-bispyridine and gold complexes of 5,5-dimethyl-10,15,20-tris(pentafluorophenyl)phlorin. Theory and experiments concur that the phlorin derivatives exhibit substantially smaller HOMO-LUMO gaps, as reflected in a variety of observable properties. Thus, the experimentally studied Ir and Au complexes absorb strongly in the near-infrared (NIR), with absorption maxima at 806 and 770 nm, respectively. The two complexes are also weakly phosphorescent with emission maxima at 950 and 967 nm, respectively. They were also found to photosensitize singlet oxygen formation, with quantum yields of 40 and 28%, respectively. The near-infrared (NIR) absorption and emission are consonants with smaller electrochemical HOMO-LUMO gaps of ∼1.6 V, compared to values of ∼2.1 V, for electronically innocent porphyrins and corroles. Interestingly, both the first oxidation and reduction potentials of the Ir complex are some 600 mV shifted to more negative potentials relative to those of the Au complex, indicating an exceptionally electron-rich macrocycle in the case of the Ir complex.
PubMed: 38743029
DOI: 10.1021/acs.inorgchem.4c00483 -
RSC Advances May 2024Massive hemorrhage caused by injuries and surgical procedures is a major challenge in emergency medical scenarios. Conventional means of hemostasis often fail to rapidly...
Massive hemorrhage caused by injuries and surgical procedures is a major challenge in emergency medical scenarios. Conventional means of hemostasis often fail to rapidly and efficiently control bleeding, especially in inaccessible locations. Herein, a type of smart nanoliposome with ultrasonic responsiveness, loaded with thrombin (thrombin@liposome, named TNL) was developed to serve as an efficient and rapid hemostatic agent. Firstly, the hydrophilic cavities of the liposomes were loaded onto the sono-sensitive agent protoporphyrin. Secondly, a singlet oxygen-sensitive chemical bond was connected with the hydrophobic and hydrophilic ends of liposomes in a chemical bond manner. Finally, based on the host guest effect between ultrasound and the sono-sensitizer, singlet oxygen is continuously generated, which breaks the hydrophobic and hydrophilic ends of liposome fragments, causing spatial collapse of the TNL structure, swiftly releases thrombin loaded in the hydrophilic capsule cavity, thereby achieving accurate and rapid local hemostasis (resulted in a reduction of approximately 67% in bleeding in the rat hemorrhage model). More importantly, after thorough assessments of biocompatibility and biodegradability, it has been confirmed that TNL possesses excellent biosafety, providing a new avenue for efficient and precise hemostasis.
PubMed: 38741972
DOI: 10.1039/d3ra08445k -
Photodiagnosis and Photodynamic Therapy May 2024Efflux pumps are active transporters, which allow the cell to remove toxic substances from within the cell including antibiotics and photosensitizer complexes. Efflux...
Efflux pumps are active transporters, which allow the cell to remove toxic substances from within the cell including antibiotics and photosensitizer complexes. Efflux pump inhibitors (EPIs), chemicals that prevent the passage of molecules through efflux pumps, play a crucial role in antimicrobial effectiveness against pathogen. In this work, we studied the effect of EPI, namely, reserpine, on photodeactivation rate of pathogens when used with Ag NPs and methylene blue (MB). Our results show that using reserpine led to a higher deactivation rate than Ag NPs and MB alone. The mechanism of this observation was investigated with singlet oxygen generation amount. Additionally, different sizes of Ag NPs were tested with reserpine. Molecular docking calculation shows that reserpine had higher affinity toward AcrB than MB. The improvement in bacterial deactivation rate is attributed to blockage of the AcrAB-TolC efflux pump preventing the removal of MB rather than enhanced singlet oxygen production. These results suggest that using reserpine with nanoparticles and photosynthesize is a promising approach in photodynamic therapy.
PubMed: 38740317
DOI: 10.1016/j.pdpdt.2024.104212 -
The Journal of Physical Chemistry. A May 2024Reactions of singlet oxygen are numerous, some of which are desired but many are unwanted. Therefore, the ability to correctly predict and interpret this reactivity for...
Reactions of singlet oxygen are numerous, some of which are desired but many are unwanted. Therefore, the ability to correctly predict and interpret this reactivity for complex molecular systems is essential to our understanding of singlet oxygen reactions. DFT is widely used for predicting many reactions but is not suited to degenerate electronic structures; application to isolated singlet oxygen often uses the spin-unrestricted formalism, which results in severe spin contamination. In this work, we demonstrate that spin-restricted DFT can correctly describe the reaction pathway for four prototypical singlet oxygen reactions. By careful benchmarking with XMS-CASPT2, we show that, from the first transition state onward, the degeneracy of the Δ state is broken due to differing interactions of the (degenerate) π* orbitals with the organic substrate; this result is well replicated with DFT. These findings demonstrate the utility of using spin-restricted DFT to explore reactions, opening the way to confidently use this computationally efficient method for molecular systems of medium to large organic molecules.
PubMed: 38739627
DOI: 10.1021/acs.jpca.4c00744