Triggered ROS Generation Research Articles

Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis.

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.

Dose-dependent effects of silver nanoparticles on cell death modes in mouse blastocysts induced via endoplasmic reticulum stress and mitochondrial apoptosis.

In view of the rapidly expanding medical and commercial applications of silver nanoparticles (AgNPs), their potential health risks and environmental effects are a significant growing concern. Earlier research by our group uncovered the embryotoxic potential of AgNPs, showing detrimental impacts of these nanoparticles on both pre- and post-implantation embryonic development. In the current study, we showed that low (50-100μM) and high (200-400μM) dose ranges of AgNPs trigger distinct cell death programs affecting mouse embryo development and further explored the underlying mechanisms. Treatment with low concentrations of AgNPs (50-100μM) triggered ROS generation, in turn, inducing mitochondria-dependent apoptosis, and ultimately, harmful effects on embryo implantation, post-implantation development, and fetal development. Notably, high concentrations of AgNPs (200-400μM) evoked more high-level ROS generation and endoplasmic reticulum (ER) stress-mediated necrosis. Interestingly, pre-incubation with Trolox, a strong antioxidant, reduced ROS generation in the group treated with 200-400μM AgNPs to the level induced by 50-100μM AgNPs, resulting in switching of the cell death mode from necrosis to apoptosis and a significant improvement in the impairment of embryonic development. Our findings additionally indicate that activation of PAK2 is a crucial step in AgNP-triggered apoptosis and sequent detrimental effects on embryonic development. Based on the collective results, we propose that the levels of ROS generated by AgNP treatment of embryos serve as a critical regulator of cell death type, leading to differential degrees of damage to embryo implantation, post-implantation development and fetal development through triggering apoptosis, necrosis or other cell death signaling cascades.

Novel Schiff's base-assisted synthesis of metal-ligand nanostructures for multi-functional applications: Detection of catecholamines/antibiotics, removal of tetracycline, and antifungal treatment against plant pathogens

The development of nanozymes (NZ) for the simultaneous detection of multiple target chemicals is gaining paramount attention in the field of food and health sciences, and waste management industries. Nanozymes (NZ) effectively compensate for the environmental vulnerability of natural enzymes. Considering the development gap of NZ with diverse applications, we synthesized versatile Schiff’s base ligands following a facile route and readily available starting reagents (glutaraldehyde, aminopyridines). DPDI, one of the synthesized ligands, readily reacted with transition metal ions (Cu+2, Ag+1, Zn+2 in specific) under ambient conditions, yielding the corresponding nanoparticles/MOF. The structures of ligands and their products were confirmed using various analytical techniques. The enzymatic efficacy of DPDI-Cu (km 0.25 mM=, Vmax = 10.75 µM/sec) surpassed Tremetese versicolor laccase efficacy (km 0. 5 mM=, Vmax = 2.15 µM/sec). Additionally, DPDI-Cu proved resilient to changing pH, temperature, ionic strength, organic solvent, and storage time compared to laccase and provided reusability. DPDI-Cu proved promising for colorimetric detection of dopamine, epinephrine, catechol, tetracycline, and quercetin. The mechanism of oxidative detection of TC was studied through LC/MS analysis. DPDI-Cu-bentonite composite efficiently adsorbed tetracycline with maximum Langmuir adsorption of 208 mg/g. Moreover, DPDI/Cu and DPDI-Ag nanoparticles possessed antifungal activity exhibiting a minimum inhibitory concentration of 400 µg/mL and 3.12 µg/mL against Aspergillus flavus. Florescent dye tracking and SEM/TEM analysis confirmed that DPDI-Ag caused disruption of the plasma membrane and triggered ROS generation and apoptosis-like death in fungal cells. The DPDI-Ag coating treatment of wheat seeds confirmed the non-phytotoxicity of Ag-NPs.

Tailored anthraquinone-based covalent organic frameworks boosted atrazine degradation through peroxymonosulfate activation driven by visible light

Atrazine (ATZ), a wildly used s-triazine herbicide to avoid grassy insects and weeds, causes biological and environmental issues due to its prolonged existence and various toxic properties. Peroxymonosulfate (PMS) photoactivation-based advanced oxidation processes (AOPs) meet the challenges of sustainable energy and environmental concerns, and thus are promising challenging for ATZ degradation. However, preparing photocatalysts to realize efficient ATZ degradation remains challenging. Here, we prepared the highly efficient visible-light photocatalyst with abundant anthraquinone groups, i.e. TpDQ-COF, which was employed to activate PMS for fast and efficient ATZ degradation. ATZ degradation in the TpDQ-COF/PMS system reached 0.127 min−1 under visible light (VL), which is ca. 17.9 times that of TpDA-COF without anthraquinone. It implies that anthraquinone units served as pivotal active sites for facilitating photoelectron separation and migration, which triggered ROS generation towards highly effective ATZ degradation. In addition, the radical-quenching and Electron Paramagnetic Resonance (EPR) experiments proved that •OH, •SO4- and 1O2 played pivotal roles in ATZ degradation under TpDQ-COF/PMS/VL system. The ATZ degradation pathways included dealkylation, dechlorination-hydroxylation, alkylic-hydroxylation, and alkylic-oxidation, which were confirmed by intermediates and density functional theory (DFT) analysis. Overall, TpDQ-COF showcased its excellent practical utility in the removal of organic pollutants in contaminated water.

Caffeic acid, a dietary polyphenol, pre-sensitizes pancreatic ductal adenocarcinoma to chemotherapeutic drug

Resistance to chemotherapeutics is an eminent cause that leads to search for options that help in diminution of pancreatic ductal adenocarcinoma (PDAC) by overcoming resistance issues. Caffeic acid (CFA), a polyphenol occurring in many dietary foods, is known to show antidiabetic and anticancer properties potential. To unveil the effect of CFA on PDAC, we carried out this research in PDAC cells, following which we checked the combination effect of CFA and chemotherapeutics and pre-sensitization effects of CFA. Multitudinous web-based approaches were applied for identifying CFA targets in PDAC and then getting their interconnections. Subsequently, we manifested CFA effects by in-vitro analysis showing IC50 concentrations of 37.37 and 15.06 µM on Panc-1 and Mia-PaCa-2, respectively. The combination index of CFA with different drugs was explored which showed the antagonistic effects of combination treatment leading to further investigation of the pre-sensitizing effects. CFA pre-sensitization reduced IC50 concentration of doxorubicin in both PDAC cell lines which also triggered ROS generation determined by 2′,7′-dichlorofluorescin diacetate assay. The differential gene expression analysis after CFA treatment showed discrete genes affected in both cells, i.e. N-Cad and Cas9 in Panc-1 and Pi3K/AkT/mTOR along with p53 in Mia-PaCa-2. Collectively, this study investigated the role of CFA as PDAC therapeutics and explored the mechanism in mitigating resistance of PDAC by sensitizing to chemotherapeutics. Communicated by Ramaswamy H. Sarma

Biodegradable nanocarrier of gemcitabine and tocopherol succinate synergistically ameliorates anti-proliferative response in MIA PaCa-2 cells

Gemcitabine (GEM) is an important chemotherapeutic agent used alone or in combination with other anticancer agents for the treatment of various solid tumors. In this study, the potential of a dietary supplement, α-tocopherol succinate (TOS) was investigated in combination with GEM by utilizing human serum albumin-based nanoparticles (HSA NPs). The developed nanoparticles were characterized using DLS, SEM and FTIR and evaluated in a panel of cell lines to inspect cytotoxic efficacy. The ratio metric selected combination of the NPs was further investigated in human pancreatic cancer cell line (MIA PaCa-2 cells) to assess the cellular death mechanism via a myriad of biochemical and bio-analytical assays including nuclear morphometric analysis by DAPI staining, ROS generation, MMP loss, intracellular calcium release, in vitro clonogenic assay, cell migration assay, cell cycle analysis, immunocytochemical staining followed by western blotting, Annexin V-FITC and cellular uptake studies. The desolvation-crosslinking method was used to prepare the NPs. The average size of TOS-HSA NPs and GEM-HSA NPs was found to be 189.47 ± 5 nm and 143.42 ± 7.4 nm, respectively. In combination, the developed nanoparticles exhibited synergism by enhancing cytotoxicity in a fixed molar ratio. The selected combination also significantly triggered ROS generation and mitochondrial destabilization, alleviated cell migration potential and clonogenic cell survival in MIA PaCa-2 cells. Further, cell cycle analysis, Annexin-V FITC assay and caspase-3 activation, up regulation of Bax and down regulation of Bcl-2 protein confirmed the occurrence of apoptotic event coupled with the G0/G1 phase arrest. Nanocarriers based this combination also offered approximately 14-folds dose reduction of GEM. Overall, the combined administration of TOS-HSA NPs and GEM-HSA NPs showed synergistic cytotoxicity accompanied with dose reduction of the gemcitabine. These encouraging findings could have implication in designing micronutrient based-combination therapy with gemcitabine and demands further investigation.

OsPDIL1-1 controls ROS generation by modulating NADPH oxidase in developing anthers to alter the susceptibility of floret fertility to heat for rice

High temperature (HT) at meiosis induces heat injury to pollen viability and floret fertility, which is closely associated with HT-induced endoplasmic reticulum (ER) stress and ROS damage in developing anthers. Disulfide isomerase like proteins (PDILs) play an essential role in the formation, reduction, and isomerization of disulfide bonds in nascent secretory proteins for the maintenance of cell viability and ER homeostasis. However, the underlying mechanism by which HT induces ROS burst in rice anthers and its relation to ER stress for the varying existence of PDILs is largely unknown. In this paper, we investigated the action of PDILs in the regulation of heat injury to floret fertility and its association with HT-induced ROS generation in developing anthers under well-controlled climatic conditions. Results showed that knock-down of OsPDIL1-1 by RNAi enhanced the activity of NADPH oxidase and caused the excessive ROS accumulation in developing anthers, consequently the up-grading sensitivity of pollen viability and floret fertility to heat stress. RBOHb is the primary site where HT exposure affected NADPH oxidase activity and triggered ROS generation in rice anthers because OsPDIL1-1 was found to interact with RBOHb in the ER-PM junction. Furthermore, HT exposure triggered the RBOHb-mediated ROS generation in a Ca 2+ -dependent manner, while the induction of HT exposure to ER stress was not necessarily associated with ROS generation derived from NADPH oxidase. • PDIL1-1 was essential for maintaining floret fertility at elevated temperatures. • PDIL1-1 directly interacts with RBOHb to modulate ROS generation in rice anthers. • HT triggered the RBOHb-mediated ROS generation in a Ca 2+ -dependent manner. • HT-induced ER stress was not associated with NADPH oxidase-derived ROS. • PDIL1-1 was found to interact with RBOHb in the ER-PM junction.

Anti-Cancer and Anti-Inflammatory Activities of a Short Molecule, PS14 Derived from the Virulent Cellulose Binding Domain of Aphanomyces invadans, on Human Laryngeal Epithelial Cells and an In Vivo Zebrafish Embryo Model.

In this study, the anti-cancer and anti-inflammatory activities of PS14, a short peptide derived from the cellulase binding domain of pathogenic fungus, Aphanomyces invadans, have been evaluated, in vitro and in vivo. Bioinformatics analysis of PS14 revealed the physicochemical properties and the web-based predictions, which indicate that PS14 is non-toxic, and it has the potential to elicit anti-cancer and anti-inflammatory activities. These in silico results were experimentally validated through in vitro (L6 or Hep-2 cells) and in vivo (zebrafish embryo or larvae) models. Experimental results showed that PS14 is non-toxic in L6 cells and the zebrafish embryo, and it elicits an antitumor effect Hep-2 cells and zebrafish embryos. Anticancer activity assays, in terms of MTT, trypan blue and LDH assays, showed a dose-dependent inhibitory effect on cell proliferation. Moreover, in the epithelial cancer cells and zebrafish embryos, the peptide challenge (i) caused significant changes in the cytomorphology and induced apoptosis; (ii) triggered ROS generation; and (iii) showed a significant up-regulation of anti-cancer genes including BAX, Caspase 3, Caspase 9 and down-regulation of Bcl-2, in vitro. The anti-inflammatory activity of PS14 was observed in the cell-free in vitro assays for the inhibition of proteinase and lipoxygenase, and heat-induced hemolysis and hypotonicity-induced hemolysis. Together, this study has identified that PS14 has anti-cancer and anti-inflammatory activities, while being non-toxic, in vitro and in vivo. Future experiments can focus on the clinical or pharmacodynamics aspects of PS14.

SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity.

A series of novel naphthoquinone-furan-2-cyanoacryloyl hybrids were designed; they were synthesized and preliminarily evaluated for their anti-proliferative activities in vitro against several cancer cell lines and normal cells. The most potent compound, 5c, inhibited the proliferation of HeLa cells (IC50 value of 3.10 ± 0.02 μM) and colony survival, and it induced apoptosis while having relatively weaker effects on normal cells. Compound 5c also triggered ROS generation and accumulation, thus partially contributing to the observed cell apoptosis. A Western blotting analysis demonstrated that compound 5c inhibited the phosphorylation of STAT3. Furthermore, a biolayer interferometry (BLI) analysis confirmed that compound 5c had a direct effect on STAT3, with a KD value of 13.0 μM. Molecular docking showed that 5c specifically occupied the subpockets in the SH2 domain, thereby blocking the whole transmission signaling process. Overall, this study provides an important structural reference for the development of effective antitumor agents.

Implication of methylselenocysteine in combination chemotherapy with gemcitabine for improved anticancer efficacy

The limitations associated with cancer monotherapy including dose dependent toxicity and drug resistance can be addressed by combination chemotherapy. The combination of antineoplastic agents improves the cytotoxic activity in comparison to the single-agent based therapy in a synergistic or an additive mode by reducing tumor growth as well as metastatic ability. In the present investigation, we explored the potential of methylselenocysteine (MSC) in combination chemotherapy with gemcitabine (GEM). The cytotoxic activity of GEM and MSC was determined in various cell lines and based on the activity, A549 cells were explored for the mechanistic studies including DAPI staining, measurement of oxidative stress, mitochondrial membrane potential loss, nitric oxide level, western blotting, cell migration and colony formation assays. A549 cells in combination treatment with MSC and GEM demonstrated enhanced cytotoxicity with more irregular cellular morphology as well as chromatin condensation and nuclear blebbing. The selected combination also significantly triggered ROS generation and mitochondrial destabilization, and alleviated cell migration potential and clonogenic propensity of A549 cells. Also, caspase-3 and PARP mediated apoptosis was observed in the combination treated cells. MSC based drug combination could offer the attributes of improved drug delivery and there was a 6-folds dose reduction of GEM in combination. Further, antitumor study in Ehrlich solid tumor model showed the efficacy of MSC combination with GEM for the enhanced antitumor activity. The proposed combination demonstrated the potential for further translational studies.

Rosmarinic Acid Inhibits Platelet Aggregation and Neointimal Hyperplasia In Vivo and Vascular Smooth Muscle Cell Dedifferentiation, Proliferation, and Migration In Vitro via Activation of the Keap1-Nrf2-ARE Antioxidant System.

The activation of platelets and proliferation of vascular smooth muscle cells (VSMCs) in the vascular intima play an essential role in the pathological mechanism of vascular restenosis (RS). Rosmarinic acid (RA) is a natural phenolic acid compound. However, its mechanism of action on platelets and VSMCs is still unclear. This study investigated the effects of RA on platelet function, VSMCs phenotypic conversion, proliferation, and migration in vascular remodeling with a specific focus on the Keap1-Nrf2-ARE signaling pathway. RA inhibited platelet aggregation and Ca2+ release and significantly reduced the release of platelet microvesicles. In addition, RA inhibited the phenotypic transition of VSMCs in vitro and in vivo. In vitro experiments showed that RA could effectively inhibit the proliferation and migration of VSMCs induced by the platelet-derived growth factor (PDGF)-BB. PDGF-BB triggered ROS generation and a decrease in mitochondrial membrane potential, which were inhibited by RA. Mechanistically, after artery injury or treatment with PDGF-BB, VSMCs presented with inhibition of the Nrf2/antioxidant response element (ARE) signaling pathway. RA treatment reversed this profile by activating the Nrf2/ARE signaling pathway; stabilizing Keap1 protein; upregulating HO-1, NQO1, GCLM, and GST protein levels; promoting typical Nrf2 nuclear translocation; and preventing VSMCs from oxidative stress damage. On the other hand, RA also inhibited the NF-κB pathway to reduce inflammation. In summary, these results indicate that RA inhibits platelet function and attenuates the proliferation, migration, and phenotypic transition of VSMCs induced by PDGF-BB in vitro and vascular remodeling in vivo. Therefore, RA treatment may be a potential therapy for preventing or treating RS.

Antibacterial, anti-biofilm, and anti-virulence potential of tea tree oil against leaf blight pathogen Xanthomonas oryzae pv. oryzae instigates disease suppression.

Bacterial leaf blight (BLB) disease, caused by Xanthomonas oryzae pv. oryzae (Xoo), causes major annual economic losses around the world. Inorganic copper compounds and antibiotics are conventionally used to control BLB disease. They often cause environmental pollution, contributing to adverse effects on human health. Therefore, research is now leading to the search for alternative control methods. Tea tree oil (TTO) is obtained from a traditional medicinal plant, Melaleuca alternifolia, with antibacterial properties. In this study, we found that TTO showed antibacterial activity against Xoo with a minimum inhibitory concentration (MIC) of 18mg/ml. These antagonistic activities were not limited only to planktonic cells, as further studies have shown that TTO effectively eradicated sessile cells of Xoo in both initial and mature biofilms. Furthermore, it was also observed that TTO reduced various key virulence properties of Xoo, such as swimming, swarming motility, and the production of extracellular polymeric substances, xanthomonadin, and exoenzymes. TTO triggered ROS generation with cell membrane damage as an antibacterial mode of action against Xoo. The in silico study revealed that 1,8-cineole of TTO was effectively bound to two essential proteins, phosphoglucomutase and peptide deformylase, responsible for the synthesis of EPS and bacterial survival, respectively. These antibacterial and anti-virulence activities of TTO against Xoo were further confirmed by an ex vivo virulence assay where TTO significantly reduced the lesion length caused by Xoo on rice leaves. All these data concluded that TTO could be a safe, environment-friendly alternative approach for the comprehensive management of BLB disease.

Hydrogen peroxide signalling mediates fertilization and post-fertilization development in the red alga Bostrychia moritziana.

Reactive oxygen species (ROS) signalling has a multitude of roles in cellular processes throughout biology. We hypothesized that red algal fertilization may offer an interesting model to study ROS-mediated signalling, as the stages of fertilization are complex and unique. We detected the localization of ROS production microscopically and monitored the expression of three homologues of NADPH oxidase in reproductive cells during fertilization. ROS were instantaneously produced by spermatia (sperm) when they attached to female trichogynes, diffused across the cell membrane in the form of H2O2, and triggered ROS generation in the carpogonium (egg) as well as carpogonial branch cells which are not in direct contact with spermatia. The expression of NADPH oxidase homologues, RESPIRATORY BURST OXIDASE HOMOLOGUES (BmRBOHs), began to be up-regulated in the female plant upon gamete binding, peaking during the fertilization process and descending back to their original level after fertilization. Pre-treatment with diphenylene iodonium or caffeine blocked gene expression as well as H2O2 production. Post-fertilization development was also inhibited when the redox state of the plants was perturbed with H2O2 at any time before or after the fertilization. Our results suggest that H2O2 acts as an auto-propagating signalling molecule, possibly through Ca2+ channel activation, and regulates gene expression in fertilization as well as post-fertilization development in red algae.

Antitumoral synergism between a copper(II) complex and cisplatin improves in vitro and in vivo anticancer activity against melanoma, lung and breast cancer cells

BackgroundIntrinsic resistance of cancer cells is a major concern for the success of chemotherapy, and this undesirable feature stimulates further research into the design of new compounds and/or alternative multiple drug chemotherapy protocols. MethodsIn this study, we investigated the antitumoral potential of the coordination compounds [Cu(HPClNOL)Cl]Cl (1), [Fe(HPClNOL)Cl2]NO3(2) and [Mn(HPClNOL)Cl2] (3). Using the human, MCF-7 and A549, and the murine melanoma, B16-F10, cell lines, we determined the cytotoxicity, DCFH oxidation, disruption of mitochondrial membrane potential (ΔΨm), Sub-G1 and TUNEL positive cells, and caspase 8 and 9 activities. Fractional inhibitory concentration (FIC) and xenograft models were also assessed to evaluate the efficacy of antitumoral potential. ResultsWe observed that only complex 1 was cytotoxic. The treatment of cancer cells with complex 1 triggered ROS generation and promoted the disruption of ΔΨm. Complex 1 increased the number of Sub-G1 and TUNEL positive cells, and the measurement of caspase 8 and 9 activity confirmed that apoptosis was triggered by the intrinsic pathway. FIC demonstrated that the combination of complex 1 with cisplatin was additive for the A549 cells whilst it was synergic for MCF-7 and B16-F10. Treatment with complex 1, either alone or combined with cisplatin, reduced tumor growth on xenograft models. ConclusionsThe present study brings new clues regarding the mechanism of action of [Cu(HPClNOL)Cl]Cl, either alone or in combination with cisplatin. General significanceThese results indicate that complex 1, administered either singly or in combination with current drugs, has real potential for use in cancer therapy.

Antioxidant responses are associated with differences in drought tolerance between maize and sorghum.

Drought is a major cause of decreased yield in crops worldwide. Sorghum (Sorghum bicolor) and maize (Zea mays) are two of the key crops in Africa serving as human food as well as livestock feed. For improved crop production, selection for drought resilient genotypes is imperative and the biological basis for drought tolerance ought to be fully understood to achieve such selection. Sorghum can tolerate drought better than maize and it is a key model for studying the physiological and biochemical mechanisms conferring drought tolerance. In this study, comparative analyses in terms of changes in growth, chlorophyll content, ROS content, lipid peroxidation level and the activity of antioxidant enzymes were investigated. Exposure to drought triggered ROS generation in both plant species. However, sorghum showed less cell damage under water deficit compared to maize. Furthermore, differences in antioxidant enzyme activity between maize and sorghum were identified. Our findings reveal differences in and association between the physiological and biochemical responses of maize and sorghum to drought, which may be relevant for breeding drought tolerant crops.

Vitamin C induces ferroptosis in anaplastic thyroid cancer cells by ferritinophagy activation

Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease. So far, there is no available established treatment which can prolong its survival. In this regard, effective therapies are urgently needed. Vitamin C widely serves as an anti-cancer agent. However, the potential effects of vitamin C against thyroid tumorigenesis remained unclear. The present study demonstrated that vitamin C could significantly inhibit ATC cells growth through ferroptosis activation, evidenced by the GPX4 inactivation, ROS accumulation and iron-dependent lipid peroxidation. Our results demonstrated that vitamin C treatment induced ferritinophagy and subsequent degradation of ferritin, leading to the release of free iron. Excessive iron further triggered ROS generation via Fenton reaction. The positive feedback mediated by ROS and iron sustained lipid peroxidation and further resulted in ferroptosis of ATC cells. The better understanding of the anti-cancer mechanisms of vitamin C provides a potential strategy for ATC therapy.

Cadmium exposure induces inflammation through the canonical NF-κΒ pathway in monocytes/macrophages of Channa punctatus Bloch

A vast range of research related to the toxicity of the heavy metal cadmium (Cd) has been carried out in a wide variety of fish species. However, Cd induced immunomodulation in monocytes/macrophages of Channa punctatus Bloch. has rarely been explored. The present study was designed to determine Cd induced immune response, role of NF-κB (nuclear factor kappa B) pathway and the subsequent downstream molecular responses in monocytes/macrophages of C. punctatus. Fish were sampled and acclimatized, with one group treated with cadmium chloride (CdCl2) (1.96 mg/L) and another kept as untreated control group, both under observation for 7 days. Exposure to CdCl2 was found to alter hematological profile of C. punctatus in addition to incurring histo-architectural damages in the HK (head kidney) and ultrastructural changes in the monocytes/macrophages. The innate immune potential was found to be significantly compromised as evident from decreased phagocytosis, intracellular killing, cell adhesion and reduced release of nitric oxide (NO) and myeloperoxidase (MPO) in Cd intoxicated group. Also Cd triggered ROS generation, reduced cellular NO levels by forming peroxynitrite along with the upregulated expression of the inflammatory marker iNOS (inducible nitric oxide synthase) in monocytes/macrophages, both at mRNA and protein levels, indicating inflammation. Inflammation is further verified from the upregulated expression of proinflammatory cytokines viz. TNF-α, IL-1β, IL-6, IL-12 along with a central inflammatory mediator NF-κΒ and downregulation of the anti-inflammatory cytokine IL-10, both at mRNA and protein levels. It can be concluded that, a sub-lethal exposure of Cd in C. punctatus for 7 days caused significant alterations in the hematological, histological and ultrastructural profile in monocytes/macrophages; impaired innate immune parameters, triggers ROS generation and inflammation as validated from the upregulated expression of NF-κΒ, iNOS, TNF-α, IL-1β, IL-6, IL-12 and IL-10 downregulation.

Molecular Mechanism of Platelet-Derived Growth Factor (PDGF)-BB-Mediated Protection Against MPP+ Toxicity in SH-SY5Y Cells

As an important endogenous growth factor, PDGF-BB can effectively promote neurogenesis, thus is considered as a potential agent for Parkinson's disease (PD) therapy. However, the protective function of PDGF-BB on neuronal cells, especially the molecular mechanism, remains less clear, which is needed to explore before its clinical practice. In this study, we investigated the function and mechanism of PDGF-BB against 1-methyl-4-phenylpyridinium (MPP+) toxicity in SH-SY5Y cells, a widely used cellular tool for PD-related molecular study. Our results indicated that PDGF-BB exerts a prominent protective effect against neurotoxin MPP+-triggered ROS generation and cellular loss. We further dissected the molecular mechanism involved in this process by using specific pharmacological inhibitors and validated that the distinct signaling pathways PI3K/Akt/GSK-3β and MEK/ERK are involved in the process against MPP+ toxicity upon PDGF-BB treatment. We also detected that activation of upstream PI3K/Akt/GSK-3β and MER/ERK signaling pathways contribute to phosphorylation and nuclear translocation of the downstream effector cyclic response element-binding protein (CREB), a known transcription factor to exhibit neuroprotective and growth-promoting effects. Using genetic approach, we further confirmed that the activation of CREB is involved in PDGF-BB-mediated protection in MPP+-exposed SH-SY5Y cells. Together, these data demonstrated the protective effect of PDGF-BB in MPP+-mediated toxicity in SH-SY5Y cells and verified the involved molecular mechanism in PDGF-BB-mediated neuroprotection.

Oxidative stress and inflammatory effects in human lung epithelial A549 cells induced by phenanthrene, fluorene, and their binary mixture.

Low molecular weight-Polycyclic aromatic hydrocarbons (LMW-PAHs) are ubiquitous environmental pollutants, which may contribute to respiratory diseases. However, studies of the relative mechanisms are limited. This study aimed to explore the effects of two LMW-PAHs [phenanthrene (Phe) and fluorene (Flu)], separately and as binary PAH mixture on oxidative stress and inflammation in A549 cells. Cell viability was firstly detected at various concentrations (200-800 μM) by Phe, Flu, and the mixture of Phe and Flu. ROS level, MDA content, SOD and CAT activities were then determined to evaluate oxidative damage. The protein and mRNA expressions of IL-6, TNF-α, TGF-β, and the protein content of SP-A were further determined to evaluate inflammation. Results showed that Phe, Flu, and their mixture triggered ROS generation and induced abnormal productions of MDA, SOD, and CAT. And the protein and mRNA expressions of TNF-α and IL-6 were increased by Phe, Flu, and their mixture, respectively. In addition, SP-A was also increased by Phe and Flu, while it was decreased by their mixture at 600 μM. The results demonstrated that Phe, Flu, and their mixture could induce oxidative stress and subsequent inflammation in A549 cells, while combined inflammatory response was stronger than single actions.

X-ray and NIR light dual-triggered mesoporous upconversion nanophosphor/Bi heterojunction radiosensitizer for highly efficient tumor ablation

Developing a multi-functional radiosensitizer with high efficiency and low toxicity remains challenging. Herein, we report a mesoporous heterostructure radiosensitizer (UCNP@NBOF-FePc-PFA) containing Lu-based upconversion nanophosphor (UCNP) and Bi-based nanomaterial loaded with iron phthalocyanine for X-ray and NIR light dual-triggered tri-modal tumor therapy. NaLuF4:Yb,Tm, a Lu-based UCNP, offers radiosensitization and upconversion luminescence for optical bio-imaging. However, Bi has a higher X-ray mass attenuation coefficient than Lu. Thus, after stepwise fabrication, Na0.2Bi0.8O0.35F1.91:Yb (NBOF) was assembled with the UCNP to form a mesoporous heterostructure composite. This enhanced the radiosensitization effect and drug load to realize multi-modal tumor therapy. After coating it with folate-conjugated amphiphilic PEG (PFA), UCNP@NBOF-FePc-PFA realized tumor photothermal/photodynamic/radio-therapy. The structure of UCNP@NBOF-FePc-PFA was well characterized. Different properties triggered by X-ray and NIR light were evaluated. Finally, a highly efficient tumor ablation effect was demonstrated in vitro and in vivo. Consequently, this kind of nanocomposite provides a unique strategy for designing a theranostic platform for oncotherapy. STATEMENT OF SIGNIFICANCE: The synergy of enhanced radiotherapy and photothermal/photodynamic therapy is found to improve tumor therapeutic efficacy. On that basis, a heterostructure nanohybrid containing Lu-based UCNP and Bi-based mesoporous material is synthesized. The heterostructure nanohybrid can be loaded with FePc and decorated with folate-modified amphiphilic PEG to form a multi-functional theranostic nano-platform. The platform exhibits upconversion luminescence capacity, X-ray attenuation property, photothermal effect, and X-ray and NIR dual-light triggered ROS generation capability. These features can not only enable upconversion luminescence/CT bioimaging of living beings but also be applied to the photothermal/photodynamic/radio- synergistic tumor ablation. To sum up, the nanomaterial offers a novel method for the construction of a new theranostic platform.