High Concentrations Of Reactive Oxygen Species Research Articles

Novel 131-iodine labeled and ultrasound-responsive nitric oxide and reactive oxygen species controlled released nanoplatform for synergistic sonodynamic/nitric oxide/chemodynamic/radionuclide therapy

Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO–, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In −vitro and −vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.

"Cicada Out of the Shell" Deep Penetration and Blockage of the HSP90 Pathway by ROS-Responsive Supramolecular Gels to Augment Trimodal Synergistic Therapy.

Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small-molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)-responsive supramolecular gels co-loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo- photodynamic therapy (PDT) - photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAsunder high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP-related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA-regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).

Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal preimplantation embryogenesis.

Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, andtheir oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.

Reactive oxygen species (ROS) modulate nitrogen signaling using temporal transcriptome analysis in foxtail millet.

Reactive oxygen species (ROS) is a chemically reactive chemical substance containing oxygen and a natural by-product of normal oxygen metabolism. Excessive ROS affect the growth process of crops, which will lead to the decrease of yield. Nitrogen, as a critical nutrient element in plants and plays a vital role in plant growth and crop production. Nitrate is the primary nitrogen source available to plants in agricultural soil and various natural environments. However, the molecular mechanism of ROS-nitrate crosstalk is still unclear. In this study, we used the foxtail millet (Setaria italica L.) as the material to figure it out. Here, we show that excessive NaCl inhibits nitrate-promoted plant growth and nitrogen use efficiency (NUE). NaCl induces ROS accumulation in roots, and ROS inhibits nitrate-induced gene expression in a short time. Surprisingly, low concentration ROS slight promotes and high concentration of ROS inhibits foxtail millet growth under long-term H2O2 treatment. These results may open a new perspective for further exploration of ROS-nitrate signaling pathway in plants.

Insight into the Antioxidant Activity of Ascorbic Acid-Containing Gelatin Nanoparticles in Simulated Chronic Wound Conditions.

Chronic wounds differ from acute wounds by remaining in the inflammatory phase for a long time. This chronic inflammation confers a high concentration of inflammatory cytokines, proteases, and ROS. Likewise, the pH environment of chronic wounds has been recorded within the range of 7.2-8.9 due to the alkaline by-products of bacterial proliferation. In this work, differences in pH between healthy skin and chronic cutaneous wounds have been used for the design and development of pH-responsive gelatin-based nanoparticles (NPs). Ascorbic acid (AA), as an antioxidant compound that can neutralize reactive oxygen species (ROS), has been the therapeutic model compound included in these NPs. The goal of the present work has been the preparation and characterization (physicochemical and biological properties) of NPs for the effective release of AA under simulated chronic wound conditions. In vitro experiments demonstrated total AA release at pH corresponding to the chronic wounds. The biocompatible character of these gelatin-based NPs based on their hemolytic and cytotoxicity responses has been highlighted under in vitro conditions. The reversible and protective antioxidant properties of the AA-including NPs in erythrocytes and skin cell lines, respectively, have been confirmed to be modulated by the gelatin A gel strength.

Tumor Microenvironment-Responsive Drug Delivery Based on Polymeric Micelles for Precision Cancer Therapy: Strategies and Prospects.

In clinical practice, drug therapy for cancer is still limited by its inefficiency and high toxicity. For precision therapy, various drug delivery systems, including polymeric micelles self-assembled from amphiphilic polymeric materials, have been developed to achieve tumor-targeting drug delivery. Considering the characteristics of the pathophysiological environment at the drug target site, the design, synthesis, or modification of environmentally responsive polymeric materials has become a crucial strategy for drug-targeted delivery. In comparison to the normal physiological environment, tumors possess a unique microenvironment, characterized by a low pH, high reactive oxygen species concentration, hypoxia, and distinct enzyme systems, providing various stimuli for the environmentally responsive design of polymeric micelles. Polymeric micelles with tumor microenvironment (TME)-responsive characteristics have shown significant improvement in precision therapy for cancer treatment. This review mainly outlines the most promising strategies available for exploiting the tumor microenvironment to construct internal stimulus-responsive drug delivery micelles that target tumors and achieve enhanced antitumor efficacy. In addition, the prospects of TME-responsive polymeric micelles for gene therapy and immunotherapy, the most popular current cancer treatments, are also discussed. TME-responsive drug delivery via polymeric micelles will be an efficient and robust approach for developing clinical cancer therapies in the future.

Molecular Mechanism of Natural Food Antioxidants to Regulate ROS in Treating Cancer: A Review.

Cancer is the second-highest mortality rate disease worldwide, and it has been estimated that cancer will increase by up to 20 million cases yearly by 2030. There are various options of treatment for cancer, including surgery, radiotherapy, and chemotherapy. All of these options have damaging adverse effects that can reduce the patient's quality of life. Cancer itself arises from a series of mutations in normal cells that generate the ability to divide uncontrollably. This cell mutation can happen as a result of DNA damage induced by the high concentration of ROS in normal cells. High levels of reactive oxygen species (ROS) can cause oxidative stress, which can initiate cancer cell proliferation. On the other hand, the cytotoxic effect from elevated ROS levels can be utilized as anticancer therapy. Some bioactive compounds from natural foods such as fruit, vegetables, herbs, honey, and many more have been identified as a promising source of natural antioxidants that can prevent oxidative stress by regulating the level of ROS in the body. In this review, we have highlighted and discussed the benefits of various natural antioxidant compounds from natural foods that can regulate reactive oxygen species through various pathways.

Seasonal patterns of oxidative stress markers in captive Asian elephants in Thailand and relationships to elephant endotheliotropic herpesvirus shedding.

Oxidative stress refers to an imbalance between oxidant and antioxidant activity and accumulation of reactive oxygen species, which can have detrimental effects on animal health. Annual fluctuations in oxidative stress status can occur, increasing disease susceptibility during certain time periods. However, a full understanding of factors related to oxidative stress in Asian elephants and how to mitigate the negative consequences is lacking. This study measured six serum oxidative stress markers [reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), albumin, glutathione peroxidase (GPx), and catalase] and two stress markers [serum cortisol and fecal glucocorticoid metabolites (fGCM)] in 23 captive Asian elephants in Thailand over a 12 months period to examine relationships with age and season. Seasonal variations were observed, with several markers exhibiting significantly higher concentrations in the summer (ROS, MDA, 8-OHdG, albumin) and lower values during the rainy/winter seasons (MDA, 8-OHdG, albumin, catalase). By contrast, GPx was the only marker to be highest during the rainy season. For the stress markers, higher fGCM concentrations were noted during the rainy season, which contrasts with earlier studies showing more activity in the winter (tourist season). Positive correlations were found between the temperature-humidity index and ROS, GPx, and fGCM, while a negative correlation was observed with serum albumin. Elephant endotheliotropic herpesvirus (EEHV) shedding events were associated with higher concentrations of ROS and MDA. A moderate negative correlation was observed between 8-OHdG and the PCR threshold cycle of EEHV shedding (Ct), indicating DNA damage may be involved in EEHV shedding in elephants. Results revealed significant age and seasonal effects on several oxidative stress markers, indicating those factors should be considered in study design and data interpretation. There also may be physiological adaptations in oxidative stress conditions in relation to environmental changes that could impact health outcomes.

An oviduct glycan increases sperm lifespan by diminishing the production of ubiquinone and reactive oxygen species†.

Sperm storage by females after mating for species-dependent periods is used widely among animals with internal fertilization to allow asynchrony between mating and ovulation. Many mammals store sperm in the lower oviduct where specific glycans on oviduct epithelial cells retain sperm to form a reservoir. Binding to oviduct cells suppresses sperm intracellular Ca2+ and increases sperm longevity. We investigated the mechanisms by which a specific oviduct glycan, 3-O-sulfated Lewis X trisaccharide (suLeX), prolongs the lifespan of porcine sperm. Using targeted metabolomics, we found that binding to suLeX diminishes the abundance of 4-hydroxybenzoic acid, the precursor to ubiquinone (also known as Coenzyme Q), 30min after addition. Ubiquinone functions as an electron acceptor in the electron transport chain (ETC). 3-O-sulfated Lewis X trisaccharide also suppressed the formation of fumarate. A component of the citric acid cycle, fumarate is synthesized by succinate-coenzyme Q reductase, which employs ubiquinone and is also known as Complex II in the ETC. Consistent with the reduced activity of the ETC, the production of harmful reactive oxygen species (ROS) was diminished. The enhanced sperm lifespan in the oviduct may be because of suppressed ROS production because high ROS concentrations have toxic effects on sperm.

Selenium deficiency-induced high concentration of reactive oxygen species restricts hypertrophic growth of skeletal muscle in juvenile zebrafish by suppressing TORC1-mediated protein synthesis.

Se deficiency causes impaired growth of fish skeletal muscle due to the retarded hypertrophy of muscle fibres. However, the inner mechanisms remain unclear. According to our previous researches, we infer this phenomenon is associated with Se deficiency-induced high concentration of reactive oxygen species (ROS), which could suppress the target of rapamycin complex 1 (TORC1) pathway-mediated protein synthesis by inhibiting protein kinase B (Akt), an upstream protein of TORC1. To test this hypothesis, juvenile zebrafish (45 d post-fertilisation) were fed a basal Se-adequate diet or a basal Se-deficient diet or them supplemented with an antioxidant (DL-α-tocopherol acetate, designed as VE) or a TOR activator (MHY1485) for 30 d. Zebrafish fed Se-deficient diets exhibited a clear Se-deficient status in skeletal muscle, which was not influenced by dietary VE and MHY1485. Se deficiency significantly elevated ROS concentrations, inhibited Akt activity and TORC1 pathway, suppressed protein synthesis in skeletal muscle, and impaired hypertrophy of skeletal muscle fibres. However, these negative effects of Se deficiency were partly (except that on ROS concentration) alleviated by dietary MHY1485 and completely alleviated by dietary VE. These data strongly support our speculation that Se deficiency-induced high concentration of ROS exerts a clear inhibiting effect on TORC1 pathway-mediated protein synthesis by regulating Akt activity, thereby restricting the hypertrophy of skeletal muscle fibres in fish. Our findings provide a mechanistic explanation for Se deficiency-caused retardation of fish skeletal muscle growth, contributing to a better understanding of the nutritional necessity and regulatory mechanisms of Se in fish muscle physiology.

Phenylboronic acid-functionalized chitosan for enabling transmucosal delivery for cancer therapy

Mucosa administration and transmucosal polymeric carriers demonstrate specific advantages in locoregional therapy, which, however, suffer from unsatisfactory transmucosal delivery efficiency and limited hydrophobic or bio-macromolecular drug loading. Herein, we demonstrate several phenylboronic acid-modified chitosan derivatives to screen out a self-assembly nano-system. The phenylboronic acid unit synthesized in chitosan skeleton (CS) afforded donor–acceptor coordination with amidogen of pirarubicin (THP) and aPD-1[1–3],the drug loading content was increased from 18.2 ± 0.4% to 37.0 ± 1.0% compared with CS. Besides, the phenylboronic acid modification provided an additional transmucosal advantage for cationic CS via non-covalent binding with mucosal glycosaminoglycans and enhanced the penetration ability of drugs through the endocytosis, Golgi-endoplasmic reticulum and exocytosis pathway. Furthermore, the encapsulated agents can be selectively released in response to the high reactive oxygen species concentration in tumor tissues, which combined with enhanced transmucosal capacity extremely contribute to improving the therapeutic efficacy and biosafety of BCS@THP and BCS@aPD-1 NPs in bladder cancer perfusion therapy as well as lung cancer inhalation treatment. Even more exciting is that in addition to THP and aPD-1, our platform could be easily extended to other chemotherapeutics and bio-macromolecular agents with electron-donating groups, rendering a simple and robust strategy for enabling highly efficient mucosal administration-based cancer therapy.

Expression levels of ROS and Atg proteins in the vitreous in rhegmatogenous retinal detachment.

To detect the concentrations of reactive oxygen species (ROS), transient receptor potential mucin-1 (TRPML1), and autophagy-related (Atg) proteins (LC3-I, LC3-II, and Beclin1) in vitreous humor of patients with simple rhegmatogenous retinal detachment (RRD). RRD patients enrolled as the RRD group, and patients with idiopathic macular hole (IMH) and idiopathic macular epiretinal membrane (IMEM) were enrolled as control group. The levels of ROS, TRPML1, LC3-I, LC3-II, and Beclin1 in vitreous humor of patients in the RRD and control groups were detected by enzyme-linked immunosorbent assay (ELISA). The RRD group included 28 eyes 28 patients and had a higher concentration of ROS in vitreous humor (631.86±18.05 vs 436.34±108.22 IU/mL, P<0.05). The ROS level in patients with a wide retinal detachment (RD) extent (RD range ≥1/2) was higher than that with a narrow RD extent (RD range<1/2, P<0.05). ROS concentration was negatively correlated with RD time (r=-0.46, P=0.01). The expression levels of LC3-I and Beclin1 significantly decreased in RRD (P<0.05), but there were no correlations with the RD time, RD extent, or macular involvement. In eyes with RRD, the concentration of ROS in vitreous humor increases and the expression levels of Atg proteins decrease, reflecting possibly that autophagy is inhibited.

Potential Anti-Candida albicans Mechanism of Trichoderma Acid from Trichoderma spirale

Candida albicans is the main causal pathogen of fungal infections in human beings. Although diverse anti-C. albicans drugs have been explored, the drug resistance and side effects of these drugs are intensifying. Thus, it is urgent to explore new anti-C. albicans compounds from natural products. In this study, we identified trichoderma acid (TA), a compound from Trichoderma spirale with a strong inhibitory effect on C. albicans. Transcriptomic and iTRAQ-based proteomic analyses of TA-treated C. albicans in combination with scanning electronic microscopy and reactive oxygen species (ROS) detection were performed to investigate the potential targets of TA. The most significant differentially expressed genes and proteins after TA treatment were verified through Western blot analysis. Our results revealed that mitochondrial membrane potential, endoplasmic reticulum, ribosomes in the mitochondria, and cell walls were disrupted in TA-treated C. albicans, leading to the accumulation of ROS. The impaired enzymatic activities of superoxide dismutase further contributed to the increase in ROS concentration. The high concentration of ROS led to DNA damage and cell skeleton destruction. The expression levels of Rho-related GTP-binding protein RhoE (RND3), asparagine synthetase (ASNS), glutathione S-transferase, and heat shock protein 70 were significantly up-regulated in response to apoptosis and toxin stimulation. These findings suggest that RND3, ASNS, and supereoxide dismutase 5 are the potential targets of TA, as further demonstrated through Western blot analysis. The combination of transcriptomic, proteomic, and cellular analyses would provide clues for the anti-C. albicans mechanism of TA and the defensive response mechanism of C. albicans. TA is thus recognized as a promising new anti-C. albicans leading compound that alleviates the hazard of C. albicans infection in human beings.

Role of Aryl Hydrocarbon Receptor and Oxidative Stress in the Regioselective Toxicities of Hydroxychrysenes in Embryonic Japanese Medaka (Oryzias latipes).

Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are environmental contaminants that can be created through oxidation of parent PAHs. Previous studies have found that 2-hydroxychrysene (2-OHCHR) caused anemia in embryonic Japanese medaka whereas 6-hydroxychrysene (6-OHCHR) did not, an example of regioselective toxicity. Anemia was prevented by cytochrome P450 (CYP) inhibition, which reduced the formation of the potential oxidatively active metabolite, 1,2-catechol, from 2-OHCHR. 2-OHCHR has also been found to be a four-fold more potent aryl hydrocarbon receptor (AhR) agonist compared with 6-OHCHR. These findings led us to hypothesize that AhR activation and/or oxidative stress play an important role in 2-OHCHR toxicity. Although treatments with the AhR agonists polychlorinated biphenyl (PCB)126 and 2-methoxychrysene (2-MeOCHR) did not cause significant toxicity, pretreatments with the AhR antagonist, CH-223191, reduced anemia by 97.2 ± 0.84% and mortality by 96.6 ± 0.69%. Aryl hydrocarbon receptor inhibition by the antagonist was confirmed by significant reductions (91.0 ± 9.94%) in induced ethoxyresorufin-O-deethylase activity. Thiobarbituric acid reactive substances concentrations were 32.9 ± 3.56% higher (p < 0.05) in 2-OHCHR treatments at 100 hours postfertilization compared with controls. Staining 2-OHCHR-treated embryos with the reactive oxygen species (ROS) scavenger 2',7'-dichlorofluorescin diacetate revealed 32.6 ± 2.69% of 2-OHCHR-treated embryos exhibiting high concentrations of ROS in caudal tissues, which is a site for embryonic hematopoiesis in medaka. Pretreatment with antioxidants, N-acetylcysteine (NAC)or vitamin E (Vit E) significantly reduced 2-OHCHR-induced anemia (NAC: 80.7 ± 1.12% and Vit E: 99.1 ± 0.43%) and mortality (NAC: 67.1 ± 1.69% and Vit E: 98.9 ± 0.66%). These results indicate that AhR may mediate 2-OHCHR toxicity through canonical signaling by up-regulating CYP1, enhancing the formation of reactive metabolites of 2-OHCHR that generate ROS within caudal hematopoietic tissues, potentially disrupting hematopoiesis, leading to anemia and subsequent mortality. Environ Toxicol Chem 2023;42:698-706. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Hybrid peptide NTP-217 triggers ROS-mediated rapid necrosis in liver cancer cells by induction of mitochondrial leakage.

Liver cancer is the third leading cause of cancer-associated mortality globally, and >830,000 patients with liver cancer undergoing treatment succumbed to the disease in 2020, which indicates the urgent need to develop a more effective anti-liver cancer drug. In our previous study, nucleus-targeting hybrid peptides obtained from the fusion of LTX-315 and the rhodamine B group possessed potent anti-adherent cancer cell activity. Hybrid peptides accumulated in the cell nucleus and damaged the nuclear membrane, resulting in the transfer of reactive oxygen species (ROS) from the cytoplasm to the nucleus and the induction of apoptosis. However, the source of the high concentration of ROS within the cytoplasm is unclear. Moreover, although our previous study demonstrated that hybrid peptides possessed potent anticancer activity against adherent cancer cells, their efficacy on liver cancer remained unexplored. The current study found that the hybrid peptide NTP-217 killed liver cancer cells after 4-h treatment with a half-maximal inhibitory concentration of 14.6-45.7 μM. NTP-217 could stably accumulate in the liver tumor tissue and markedly inhibited liver tumor growth in mice. Furthermore, NTP-217 destroyed mitochondria and induced the leakage of mitochondrial contents, resulting in the generation of a substantial quantity of ROS. Unlike the apoptosis induced by 24h of treatment by NTP-217, 4h of treatment caused ROS-mediated necrotic cell death. These findings suggested that short-time treatment with hybrid peptides could trigger ROS-mediated rapid necrosis in liver cancer cells, and provided a basis for the future development of hybrid peptides as anti-liver cancer agents.

Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy.

Reactive oxygen species (ROS) play a crucial role in physiological and pathological processes, emerging as a therapeutic target in cancer. Owing to the high concentration of ROS in solid tumor tissues, ROS-based treatments, such as photodynamic therapy and chemodynamic therapy, and ROS-responsive drug delivery systems have been widely explored to powerfully and specifically suppress tumors. However, their anticancer efficacy is still hampered by the heterogeneous ROS levels, and thus comprehensively upregulating the ROS levels in tumor tissues can ensure an enhanced therapeutic effect, which can further sensitize and/or synergize with other therapies to inhibit tumor growth and metastasis. Herein, we review the recently emerging drug delivery strategies and technologies for increasing the H2O2, ˙OH, 1O2, and ˙O2- concentrations in cancer cells, including the efficient delivery of natural enzymes, nanozymes, small molecular biological molecules, and nanoscale Fenton-reagents and semiconductors and neutralization of intracellular antioxidant substances and localized input of mechanical and electromagnetic waves (such as ultrasound, near infrared light, microwaves, and X-rays). The applications of these ROS-upregulating nanosystems in enhancing and synergizing cancer therapies including chemotherapy, chemodynamic therapy, phototherapy, and immunotherapy are surveyed. In addition, we discuss the challenges of ROS-upregulating systems and the prospects for future studies.

Lack of Self-Medication by Fungus Infected Lasius platythorax (Formicidae, Formicinae) Ants in a Multitrophic Experiment

In laboratory conditions, ants can combat a pathogen infection by means of the medicinal use of reactive oxygen species (ROS). However, it is still unknown where they obtain medicinal compounds in the wild and how they use them. Due to an upregulation of ROS in response to herbivory, aphid-infested plants have been suggested to be a potential source of ROS for ants in the wild. We investigated whether infection would cause Lasius platythorax ants to change their foraging on extrafloral nectar on aphid-infested plants. We found no clear evidence for the ants significantly changing their foraging behaviour in response to the pathogen, nor for the extrafloral nectar to contain ROS. The aphids in our experiment had a relatively high concentration of ROS and future research should determine whether predation on aphids could be a potential source of both protein and ROS needed to combat a disease.

Intelligent triggering of nanomicelles based on a ROS-activated anticancer prodrug and photodynamic therapy (PDT)-synergistic therapy for lung cancers

The intelligent triggering of drug release at targeted sites is essential for the safety and efficacy of cancer therapies. This study aimed to design and synthesize a novel prodrug (DHA-S-CA) using a reactive oxygen species (ROS)-responsive moiety, thioacetal, to bridge cinnamaldehyde (CA) and dihydroartemisinin (DHA). As ROS are highly expressed in tumor tissues, the design uses the ROS-responsive moiety as an effective target for the nanodrug delivery system. Furthermore, the near-infrared dye IR808 and the prodrug were adopted to prepare co-loaded Soluplus®/TPGS nanomicelles (IR808/DHA-S-CA NMs). The photosensitized agent IR808 exhibited both tumor accumulation and cancer imaging properties while generating ROS during laser irradiation. Intracellular ROS detection indicated that the prodrug DHA-S-CA could degrade via the high concentration of ROS in cancer cells induced by laser irradiation, and the released CA stimulated mitochondria to regenerate additional ROS to further improve the antitumor effect of DHA. Combined with photodynamic therapy (PDT), IR808/DHA-S-CA (+) NMs outperformed free DHA, DHA NMs, and IR808/DHA-S-CA (−) in a comparison of their pharmacokinetic profiles because it had a longer circulation time and a greater area under the curve (AUC). Compared with other DHA groups, the ROS-responsive IR808/DHA-S-CA (+) micelles had comparable cytotoxic activity. Furthermore, the ROS-responsive IR808/DHA-S-CA (+) micelles exhibited markedly higher anticancer efficiency on lung cancer cells than the other DHA groups. Overall, these results indicated that the therapeutic strategy of our novel small-molecule prodrug combined with PDT has great potential for the treatment of tumors.

Tissue Engineering and Photodynamic Therapy: A New Frontier of Science for Clinical Application -An Up-To-Date Review.

Tissue engineering (TE) connects principles of life sciences and engineering to develop biomaterials as alternatives to biological systems and substitutes that can improve and restore tissue function. The principle of TE is the incorporation of cells through a 3D matrix support (scaffold) or using scaffold-free organoid cultures to reproduce the 3D structure. In addition, 3D models developed can be used for different purposes, from studies mimicking healthy tissues and organs as well as to simulate and study different pathologies. Photodynamic therapy (PDT) is a non-invasive therapeutic modality when compared to conventional therapies. Therefore, PDT has great acceptance among patients and proves to be quite efficient due to its selectivity, versatility and therapeutic simplicity. The PDT mechanism consists of the use of three components: a molecule with higher molar extinction coefficient at UV-visible spectra denominated photosensitizer (PS), a monochromatic light source (LASER or LED) and molecular oxygen present in the microenvironment. The association of these components leads to a series of photoreactions and production of ultra-reactive singlet oxygen and reactive oxygen species (ROS). These species in contact with the pathogenic cell, leads to its target death based on necrotic and apoptosis ways. The initial objective of PDT is the production of high concentrations of ROS in order to provoke cellular damage by necrosis or apoptosis. However, recent studies have shown that by decreasing the energy density and consequently reducing the production of ROS, it enabled a specific cell response to photostimulation, tissues and/or organs. Thus, in the present review we highlight the main 3D models involved in TE and PS most used in PDT, as well as the applications, future perspectives and limitations that accompany the techniques aimed at clinical use.

Visual Monitoring of Nucleic Acid Dynamic Structures during Cellular Ferroptosis Using Rationally Designed Carbon Dots with Robust Anti-Interference Ability to Reactive Oxygen Species.

Ferroptosis triggered by an iron-dependent accumulation of lipid reactive oxygen species (ROS) has drawn widespread attention. Directly visualizing the dynamic structures of nucleic acids during the ferroptosis of cells is of great importance considering their vital roles in numerous biological functions. However, direct imaging remains challenging, largely due to the extremely high concentrations of ROS generated during ferroptosis, which can affect the imaging of nucleic acid targeted fluorescent probes. To overcome this challenge, nucleic acid-responsive carbon dots (CDs) providing favorable optical properties together with high chemical stability were synthesized. Furthermore, the CDs penetrated the cell membrane quickly and accumulated in the nuclei of cells. The robust anti-interference ability to ROS allows the CDs to visualize the dynamic structures of nucleic acids during ferroptosis. Moreover, the CDs were successfully employed in the imaging of nucleic acids during cell division. The nuclei-targeting CDs show great potential as a powerful tool for imaging nuclei in ferroptosis-related biological and clinical research.