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Despite significant clinical breakthroughs in anti-tumor immunotherapy, its therapy efficiency remains hindered by insufficient "cold" tumor immune responses. The ample reactive oxygen species in photodynamic therapy (PDT) can trigger the immunogenic cell death (ICD) pathway for arousing the tumor system and realizing tumor immunotherapy. But the inherent hypoxic tumor microenvironment (TME) limits PDT efficacy. To simultaneously reverse the hypoxic TME and promote the ICD pathway, the multi-in-one nanostructure (FAIC) is designed, in which the catalase (CAT) and photosensitizer (I-Cy5) are encapsulated in a folate receptor-targeting liposome. Due to the endoplasmic reticulum (ER)-targeting ability of I-Cy5, H2O2 decomposition catalytic ability of CAT, and the tumor cell-targeting ability of folate receptor-targeting liposome, severe ER stress is triggered by the nano FAIC for arousing the ICD pathway. As a result, the infiltration of cytotoxic T lymphocytes is promoted, and the anti-tumor immune response is boosted. The design of nano FAIC and the corresponding mechanism provide a potential way to realize efficient tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Lung cancer is a major public health problem across the globe, since it is the second most frequent cancer and the leading cause of cancer fatalities. This necessitates careful assessment of current therapies for lung cancer and discovery of novel drug candidates. 1,2,3 triazole compounds have emerged as an important class of prospective chemotherapeutic drugs for the treatment of lung cancer, with promising anti-lung cancer activity shown via a variety of pathways. They may interact with a various enzymes and receptors in cancer cells, causing cell cycle arrest and the activation of apoptosis. The present study aims to investigate the cytotoxic potential of institutional molecule based on 1,2,3 triazole [IIIM(S)-RS98] on multiple cancer cell lines. The compound was found to be most active on A549 cells and displayed the selectivity index as 8.16 in normal cells (e.g. HEK293). The in vitro findings revealed that IIIM(S)-RS98 induced apoptosis, loss of mitochondrial membrane potential, enhanced ROS and nitric oxide levels, and arrest cells in the G1 phase of the cell cycle. It inhibits the cell migration and clonogenic potential of A549 cells. Additionally, the downregulation of PI3K and p-Akt pathway leads to the activation of pro-apoptotic proteins Bax, downregulation of bcl2, activation of caspase 9, cleaved caspase 3, and cleaved parp1 expression and finally contribute towards apoptosis. Furthermore, molecular docking analysis indicated the interactions of IIIM(S)-RS98 with the apoptotic target proteins. The results demonstrated the potential of IIIM(S)-RS98 in the therapy of lung cancer. [ABSTRACT FROM AUTHOR]

The role of mitochondria as the electric engine of cells is well established. Over the past two decades, accumulating evidence has pointed out that, despite the presence of a highly active glycolytic pathway (Warburg effect), a functional and even upregulated mitochondrial respiration occurs in cancer cells to meet the need of high energy and the biosynthetic demand to sustain their anabolic growth. Mitochondria are also the primary source of intracellular ROS. Cancer cells maintain moderate levels of ROS to promote tumorigenesis, metastasis, and drug resistance; indeed, once the cytotoxicity threshold is exceeded, ROS trigger oxidative damage, ultimately leading to cell death. Based on this, mitochondrial metabolic functions and ROS generation are considered attractive targets of synthetic and natural anticancer compounds. Tocotrienols (TTs), specifically the δ- and γ-TT isoforms, are vitamin E-derived biomolecules widely shown to possess striking anticancer properties since they regulate several intracellular molecular pathways. Herein, we provide for the first time an overview of the mitochondrial metabolic reprogramming and redox homeostasis perturbation occurring in cancer cells, highlighting their involvement in the anticancer properties of TTs. This evidence sheds light on the use of these natural compounds as a promising preventive or therapeutic approach for novel anticancer strategies. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) brings new hope for the treatment of breast cancer due to few side effects and highly effective cell killing; however, the low bioavailability of traditional photosensitizers (PSs) and their dependence on oxygen severely limits their application. Aggregation-induced emission (AIE) PSs can dramatically facilitate the photosensitization effect, which can have positive impacts on tumor PDT. To-date, most AIE PSs lack tumor targeting capability and possess poor cell delivery, resulting in their use in large quantities that are harmful to healthy tissues. In this study, a series of AIE PSs based on pyridinium-substituted triphenylamine salts (TTPAs 1 -6) with different alkyl chain lengths are synthesized. Results reveal that TTPAs 1 -6 promote the generation of type I and II ROS, including. OH and ¹O2. In particular, the membrane permeability and targeting of TTPAs 4 - 6 bearing C8-C10 side-chains are higher than TTPAs 1 - 3 bearing shorter alkyl chains. Additionally, they can assemble with albumin, thereby forming nanoparticles (TTPA 4 -6 NPs) in situ in blood, which significantly facilitates mitochondrial-targeting and strong ROS generation ability. Moreover, the TTPA 4 -6 NPs are pH-responsive, allowing for increased accumulation or endocytosis of the tumor and enhancing the imaging or therapeutic effect. Therefore, the in vivo distributions of TTPA 4 -6 NPs are visually enriched in tumor sites and exhibited excellent PDT efficacy. This work demonstrates a novel strategy for AIE PDT. [ABSTRACT FROM AUTHOR]

Abstract Calcium hydroxide nanoparticles (Ca(OH)2NPs) possess potent antimicrobial activities and unique physical and chemical properties, making them valuable across various fields. However, limited information exists regarding their effects on genomic DNA integrity and their potential to induce apoptosis in normal and cancerous human cell lines. This study thus aimed to evaluate the impact of Ca(OH)2NPs on cell viability, genomic DNA integrity, and oxidative stress induction in human normal skin fibroblasts (HSF) and cancerous hepatic (HepG2) cells. Cell viability and genomic DNA stability were assessed using the Sulforhodamine B (SRB) assay and alkaline comet assay, respectively. Reactive oxygen species (ROS) levels were measured using 2,7-dichlorofluorescein diacetate, while the expression level of apoptosis-related genes (p53, Bax, and Bcl-2) were quantified using real-time PCR (qRT-PCR). The SRB cytotoxicity assay revealed that a 48-hour exposure to Ca(OH)2NPs caused concentration-dependent cell death and proliferation inhibition in both HSF and HepG2 cells, with IC50 values of 271.93 µg/mL for HSF and 291.8 µg/mL for HepG2 cells. Treatment with the IC50 concentration of Ca(OH)2NPs selectively induced significant DNA damage, excessive ROS generation, and marked dysregulation of apoptotic (p53 and Bax) and anti-apoptotic (Bcl-2) gene expression in HepG2 cells, triggering apoptosis. In contrast, exposure of HSF cells to the IC50 concentration of Ca(OH)2NPs caused no significant changes in genomic DNA integrity, ROS generation, or apoptotic gene expression. These findings indicate that Ca(OH)2NPs exhibit concentration-dependent cytotoxicity in both normal HSF and cancerous HepG2 cells. However, exposure to the IC50 concentration was non-genotoxic to normal HSF cells while selectively inducing genotoxicity and apoptosis in HepG2 cancer cells through DNA breaks and ROS-mediated mechanisms. Further studies are required to explore the biological and toxicological properties and therapeutic potential of Ca(OH)2NPs in hepatic cancer treatment.

Abstract Breast cancer (BC) is one of the most life-threatening diseases of women’s health worldwide. This work was conducted to assess the anti-BC potency of a new Zn(II)-based complex. The Zn(II) complex coordinated to dimethoxy-substituted bipyridine was synthesized and its molecular structure was elucidated as [Zn(2Meobpy)3](clo4)2 ( 2Meo bpy-Zn) by single-crystal X-ray diffraction, 2Meobpy represents 4,4′-dimethoxy-2,2′-bipyridine. The cytotoxicity results indicated that 2Meo bpy-Zn, unlike cisplatin, acts potently and selectively on the human breast cancer cells (MCF-7) compared to normal murine embryo cells (NIH/3T3) by IC50 value of 4.6 ± 0.5 µm and selectivity index (SI) of 2.0 over 48 h. 2Meo bpy-Zn and cisplatin showed anti-metastatic activity as evidenced by inhibition of the colony formation and cell migration. The flow cytometric assessment of MCF-7 cells supported that 2Meo bpy-Zn and cisplatin exert their cytotoxic effect through the apoptotic pathway. Moreover, 2Meo bpy-Zn could induce overproduction of intracellular reactive oxygen species (ROS) in MCF-7 cells. The apoptotic mechanism in 2Meo bpy-Zn-treated MCF-7 cells is probably related to the regulation of apoptosis-relevant genes expression, including BAX and BCL2. Moreover, 2Meo bpy-Zn is able to cleave pUC19 plasmid DNA through the hydrolytic reaction pathway. Finally, 2Meo bpy-Zn’s affinity towards antiapoptosis-related proteins, as a potential apoptosis inducer, as well as breast cancer-relevant proteins, as a potential anti-BC agent, was evaluated by in silico molecular docking studies. Altogether, the results of this work strongly evidenced that 2Meo bpy-Zn can be the subject of experimental validation and clinical trials to introduce this complex as a promising BC therapeutic agent.

Nanomedicines loaded in macrophages (MAs) can actively target tumors without dominantly relying on the enhanced permeability and retention (EPR) effect, making them effective for treating EPR‐deficient malignancies. Herein, copper‐crosslinked carbon dot clusters (CDCs) are synthesized with both photodynamic and chemodynamic functions to manipulate MAs, aiming to direct the MA‐mediated tumor targeting. First, green fluorescent CDs (g‐CDs) are prepared by a one‐step hydrothermal method. Subsequently, the g‐CDs are complexed with divalent copper ions to form copper‐crosslinked CDCs (g‐CDCs/Cu), which are incubated with MAs for their manipulation. Experimental results revealed that the prepared g‐CDCs/Cu displayed good aqueous dispersibility and fluorescent emission properties. The nanoassemblies can be activated to deplete the overexpressed glutathione (GSH) and generate reactive oxygen species (ROS) in the presence of laser irradiation through the combined Cu‐mediated chemodynamic therapy and CD‐mediated photodynamic therapy. Furthermore, the ROS produced in MAs enabled polarization of MAs to antitumor M1 phenotype, suggesting the future potential use to reverse the immunosuppressive tumor microenvironment. These results obtained from the current study suggest a significant potential to develop g‐CDCs/Cu for GSH depletion, ROS generation, and MA M1 polarization as a theransotic agent to tackle cancer. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) lacks expression of the oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu), has an aggressive tumor phenotype, shows only a partial response to chemotherapy, and lacks clinically established targeted therapies. Therefore, there is a need to develop more effective drugs for the treatment of TNBC. The ferrocenyl benzoxazine and α‐aminocresols class of compounds gave a potential source of multimodal inhibitors of cancer based on previous studies. In this study, a set of ferrocenyl benzoxazines and α‐aminocresols were screened and characterized as potential inhibitors of TNBC in vitro. A panel of 11 compounds was screened for selective cytotoxicity to cancer cells over normal cell equivalents. Focusing on the previously proposed modes of action of their building blocks, α‐aminocresols 3a and 3b exhibited significant DNA binding capabilities and caused robust DNA damage in TNBC cells. In addition, both compounds exhibited significant ROS generation capability; however, introducing a ROS quencher in a cell viability assay only partially rescued the cells from the cytotoxicity effects of the α‐aminocresols. This, together with the observation that compounds 3a and 3b triggered significant protein aggregation in HCC1806 cells, supports a mixed mode of action for these compounds. [ABSTRACT FROM AUTHOR]

Chronic wounds with multidrug-resistant bacterial infections substantially delay the healing procedure and correlate with clinical implications, including pain increase and quality of life reduction. Therapeutic approaches that could kill bacteria and promote wound healing are highly desired for the treatment of chronic nonhealing wounds. Metal oxide-based nanoagents show increasing potential as a burgeoning type of antibiotic for multidrug-resistant bacterial infections. In this study, we developed two kinds of Fe- and Ca-incorporating mesoporous silica nanoparticles (FeCaSi) via a simple and practicable strategy. They can be applied for the administration of bacterial infection and wound healing. The antibacterial properties of FeCaSi nanoagents include bacterial cell wall capturing and subsequent reactive oxygen species (ROS)-producing activity; besides, the killing capacity can be tailored by adjusting the ratio between Fe and Ca to be 4:3 (FeCaSi4:3), which is optimal for the eradication of drug-resistant Escherichia coli and Staphylococcus aureus infection. Furthermore, treatment with FeCaSi4:3 could reduce the bacteria in the skin, promote collagen deposition, and accelerate the healing of bacterial-infected wounds in mice. Our study provided a simple but powerful way to engineer metal oxide mesoporous nanoparticles for antibacterial therapy. [ABSTRACT FROM AUTHOR]

Nanoparticles particularly titanium dioxide (TiO2) have demonstrated remarkable potential in both photocatalytic degradation of the toxic compounds and development of the effective photodynamic therapy (PDT) by harnessing light-induced reactive oxygen species (ROS) generation. In PDT, the choice of appropriate photosensitizers (PSs) and optimal light sources is crucial for the therapeutic efficacy. Pure titanium dioxide has the drawbacks of limited tissue penetration and high cytotoxicity due to the triggered traditional ultraviolet light sources, rapid recombination rate of the electron (e−)/hole (h+) pairs attributed to their broader band gap energy, and low solubility with high tendency to aggregation in water. Reproducible synthesis and efficiency optimization in ROS generation are also among the challenges. Addressing these challenges, this study focuses on the construction of a novel PDT nanoplatform: design and synthesis of the biocompatible N-doped-TiO2/FeTCPP (PFNT) by modifying TiO2 nanoparticles with urea as a safe nitrogen source (NT) to create an efficient type I PS, which expands the optical absorption capacity between 400 and 800 nm due to the facilitated localized nitrogen states within the titanium dioxide band gap, as well as by incorporating iron metalloporphyrin FeTCPP (tetra(4-carboxyphenyl) porphyrin) as an effective type II PS. Upon visible-light irradiation, FeTCPP not only sensitizes singlet oxygen, but also transfers electrons from excited FeTCPP* species to Ti4+-based N-TiO2 to afford FeTCPP•+ ligands and Ti3+ centers, thus propagating the production of hydrogen peroxide, superoxide, and hydroxyl radicals. By generating the substantial distinct ROS, significant tumor cell killing was obtained under LED irradiation, particularly in addressing melanoma. This research underscores substantial promise of the designed N‐TiO2/FeTCPP nanocomposites in advancing the field of PDT-based cancer therapy, paving the way for efficient and targeted treatments. [ABSTRACT FROM AUTHOR]

Dynamic tumor therapies (mainly including photodynamic therapy (PDT) and sonodynamic therapy (SDT)) offer new approaches to cancer treatment. They are often characterized by their noninvasive nature, high selectivity, and low toxicity. Sensitizers are crucial for dynamic therapy. Developing efficient sensitizers with good biocompatibility and controllability is an important aim in dynamic therapy. Porphyrins and metalloporphyrins attract great attention due to their excellent photophysical properties and low cytotoxicity under non-light. Compared to porphyrins, metalloporphyrins show greater potential for dynamic therapy due to their enhanced photochemical and photophysical properties after metal ions coordinate with porphyrin rings. This paper reviews some metalloporphyrin-based sensitizers used in photo/sonodynamic therapy and combined therapy. In addition, the probable challenges and bottlenecks in clinical translation are also discussed. [ABSTRACT FROM AUTHOR]

Abstract Calcium hydroxide (Ca(OH)2NPs), calcium titanate (CaTiO3NPs) and yttrium oxide (Y2O3NPs) nanoparticles are prevalent in many industries, including food and medicine, but their small size raises concerns about potential cellular damage and genotoxic effects. However, there are very limited studies available on their genotoxic effects. Hence, this was done to investigate the effects of multiple administration of Ca(OH)2NPs, CaTiO3NPs or/and Y2O3NPs on genomic DNA stability, mitochondrial membrane potential integrity and inflammation induction in mouse brain tissues. Mice were orally administered Ca(OH)2NPs, CaTiO3NPs or/and Y2O3NPs at a dose level of 50 mg/kg b.w three times a week for 2 weeks. Genomic DNA integrity was studied using Comet assay and the level of reactive oxygen species (ROS) within brain cells was analyzed using 2,7 dichlorofluorescein diacetate dye. The expression level of Presenilin-1, tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) genes and the integrity of the mitochondrial membrane potential were also detected. Oral administration of Ca(OH)2NPs caused the highest damage to genomic DNA and mitochondrial membrane potential, less genomic DNA and mitochondrial damage was induced by CaTiO3NPs administration while administration of Y2O3NPs did not cause any remarkable change in the integrity of genomic DNA and mitochondrial membrane potential. Highest ROS generation and upregulation of presenilin-1, TNF-α and IL-6 genes were also observed within the brain cells of mice administrated Ca(OH)2NPs but Y2O3NPs administration almost caused no changes in ROS generation and genes expression compared to the negative control. Administration of CaTiO3NPs alone slightly increased ROS generation and the expression level of TNF-α and IL-6 genes. Moreover, no remarkable changes in the integrity of genomic DNA and mitochondrial DNA potential, ROS level and the expression level of presenilin-1, TNF-α and IL-6 genes were noticed after simultaneous coadministration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs. Coadministration of Y2O3NPs with Ca(OH)2NPs and CaTiO3NPs mitigated Ca(OH)2NPs and CaTiO3NPs induced ROS generation, genomic DNA damage and inflammation along with restoring the integrity of mitochondrial membrane potential through Y2O3NPs scavenging free radicals ability. Therefore, further studies are recommended to study the possibility of using Y2O3NPs to alleviate Ca(OH)2NPs and CaTiO3NPs induced genotoxic effects.

Supramolecular nanoparticles containing peptides and drugs have recently gained recognition as an effective tumor treatment drug delivery system. A multitarget drug termed pemetrexed is effective against various cancers, including nonsmall cell lung cancer. The work aims to establish the capability of pemetrexed gold nanoparticles (PEM‐AuNPs) to induce apoptosis and explore molecular changes. X‐ray diffraction, Fourier‐transform infrared spectroscopy, ultraviolet–visible spectroscopy, scanning electron microscope, and transmission electron microscope were used to investigate the synthesized nanoparticles. The MTT assay was utilized to investigate the anticancer properties of PEM‐AuNPs at varying concentrations (50, 100, and 200 µM). PEM‐AuNPs demonstrated a decrease in cell viability with 55.87%, 43.04%, and 25.59% for A549 cells and 54.31%, 37.40%, and 25.84% for H1299 cells at the respective concentrations. To assess apoptosis and perform morphological analysis, diverse biochemical staining techniques, including acridine orange‐ethidium bromide and 4′,6‐diamidino‐2‐phenylindole nuclear staining assays, were employed. Additionally, 2′,7′‐dichlorofluorescein diacetate staining confirmed the induction of reactive oxygen species generation, while JC‐1 staining validated the impact on the mitochondrial membrane at the IC50 concentration of PEM‐AuNPs. Thus, the study demonstrated that the synthesized PEM‐AuNPs exhibited enhanced anticancer activity against both A549 and H1299 cells. [ABSTRACT FROM AUTHOR]

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine's broad-spectrum anticancer activity together with that of three other bisindoles—conophylline, leucophyllidine, and bipleiophylline—against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS), which are key cellular signalling molecules, are reactive chemicals containing oxygen. Cell survival or death is a critical issue in the inflammatory response. Accumulation of ROS involves ROS generation and scavenging, which determine ROS homeostasis. Understanding the roles of ROS in modulating the inflammatory response in fish is vital for helping protect fish from the damage of water pollutants in harsh environmental conditions. ROS‐related key genes and signalling pathways are relatively conserved in fish but vary among different species. Recent frequent incidences of fish diseases have posed a considerable challenge to large‐scale aquaculture. ROS is important in stress perception, integration of diverse stress‐responsive signalling networks, and activation of animal defence mechanisms, which frequently occur during inflammation in fish. This review summarises recent studies on ROS signalling pathways during inflammation in fish. Furthermore, it examines the relationship between ROS and inflammation in fish. This review may contribute to the understanding of the underlying mechanisms by which ROS regulate inflammation in fish and provide suggestions for sustainable development in aquaculture. [ABSTRACT FROM AUTHOR]

Alternative oxidase (AOX) is an enzyme that transfers electrons from reduced quinone directly to oxygen without proton translocation. When AOX from Ciona intestinalis is xenotopically expressed in mice, it can substitute the combined electron-transferring activity of mitochondrial complexes III/IV. Here, we used brain mitochondria from AOX-expressing mice with such a chimeric respiratory chain to study respiratory control bioenergetic mechanisms.AOX expression did not compromise the function of the mammalian respiratory chain at physiological conditions, however the complex IV inhibitor cyanide only partially blocked respiration by AOX-containing mitochondria. The relative fraction of cyanide-insensitive respiration increased at lower temperatures, indicative of a temperature-controlled attenuation of mammalian respiratory enzyme activity.As AOX does not translocate protons, the mitochondrial transmembrane potential in AOX-containing mitochondria was more sensitive to cyanide during succinate oxidation than during malate/pyruvate-supported respiration. High concentrations of cyanide fully collapsed membrane potential during oxidation of either succinate or glycerol 3-phosphate, but not during malate/pyruvate-supported respiration. This confirms AOX's electroneutral redox activity and indicates differences in the proton-translocating capacity of dehydrogenases upstream of the ubiquinone pool. Our respiration data refutes previous proposals for quinone partitioning within the supercomplexes of the respiratory chain, instead supporting the concept of a single homogeneous, freely diffusing quinone pool.Respiration with either succinate or glycerol 3-phosphate promotes reverse electron transfer (RET) towards complex I. AOX expression significantly decreased RET-induced ROS generation, with the effect more pronounced at low temperatures. Inhibitor-sensitivity analysis showed that the AOX-induced decrease in H2O2 release is due to the lower contribution of complex I to net ROS production during RET.Overall, our findings provide new insights into the role of temperature as a mechanism to control respiration and highlight the utility of AOX as a genetic tool to characterize both the distinct pathways of oxygen reduction and the role of redox control in RET.

Background: Hepatocellular carcinoma is the most prevalent type of primary liver cancer and remains the foremost cause of cancer-related deaths globally. Dill (Anethum graveolens) seeds, rich in phytoconstituents, is renowned for their pharmacological properties. Objectives: This study performed an in vitro evaluation to assess the cytotoxic effects of dill seed extract (DS-EE) on the Huh-7 hepatocellular carcinoma cell line. Moreover, the study investigated its effects on cell viability, cellular morphology, oxidative damage, levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and the expression of apoptosis-related genes in Huh-7 cells. Methods: Huh-7 cells were treated with DS-EE at concentrations ranging from 5 to 100 μg/mL for a duration of 24 h. Results: The cytotoxicity findings showed that DS-EE decreased cell viability and suppressed the growth of Huh-7 cells in a dose-dependent way, with an IC50 value of 60 μg/mL. Exposure to DS-EE extract for 24 h resulted in a significant elevation in lipid peroxidation (LPO) and a notable decrease in glutathione (GSH) content compared to the control. Furthermore, DS-EE significantly increased ROS production while notably decreasing the MMP level in Huh-7 cells. Moreover, DS-EE induces cell apoptosis by upregulating the expression of proapoptotic genes (p53, caspase-3, caspase-9, and Bax) and downregulating the expression of the antiapoptotic gene, Bcl-2. Conclusion: DS-EE exhibited a notable cytotoxic effect on Huh-7 cells by increasing oxidative damage and subsequently modulating the expression of apoptosis-related genes. The results of this study highlight the anticancer effectiveness of DS-EE, indicating its potential as a promising agent for hepatocellular carcinoma management.

Background and purpose: Carbon nanotubes (CNTs) are a significant discovery in nanotechnology, with widespread applications in modern technology. However, there are concerns about their potential toxicity, particularly in skin cells. This study aimed to investigate the mechanisms by which CNTs induced cytotoxicity and apoptosis in mouse skin fibroblasts. Experimental approach: The mice skin fibroblasts were isolated and exposed to two types of CNTs at various concentrations and then analyzed for changes in viability, reactive oxygen species (ROS) production, the levels of Bcl-2-associated X protein (Bax), and lactate production. Findings/Results: The results demonstrated that CNTs reduced cell viability and increased ROS production in a dose-dependent manner. Additionally, the current study found that CNTs increased the protein levels of Bax, a pro-apoptotic protein, in mouse skin fibroblasts. Furthermore, it was observed a significant decrease in lactate production in cells exposed to CNTs. Conclusion and implications: The findings concluded that CNTs have the potential to be toxic substances for skin fibroblasts, which serve as the body's first line of defense. This is evidenced by their ability to increase the production of ROS and the protein levels of Bax, as well as reduce lactic acid levels. As lactic acid has been reported to have beneficial effects on skin collagen production, further studies are needed to fully understand the impact of carbon nanotube exposure on human skin health.

The role of mitochondria as the electric engine of cells is well established. Over the past two decades, accumulating evidence has pointed out that, despite the presence of a highly active glycolytic pathway (Warburg effect), a functional and even upregulated mitochondrial respiration occurs in cancer cells to meet the need of high energy and the biosynthetic demand to sustain their anabolic growth. Mitochondria are also the primary source of intracellular ROS. Cancer cells maintain moderate levels of ROS to promote tumorigenesis, metastasis, and drug resistance; indeed, once the cytotoxicity threshold is exceeded, ROS trigger oxidative damage, ultimately leading to cell death. Based on this, mitochondrial metabolic functions and ROS generation are considered attractive targets of synthetic and natural anticancer compounds. Tocotrienols (TTs), specifically the δ- and γ-TT isoforms, are vitamin E-derived biomolecules widely shown to possess striking anticancer properties since they regulate several intracellular molecular pathways. Herein, we provide for the first time an overview of the mitochondrial metabolic reprogramming and redox homeostasis perturbation occurring in cancer cells, highlighting their involvement in the anticancer properties of TTs. This evidence sheds light on the use of these natural compounds as a promising preventive or therapeutic approach for novel anticancer strategies.

Background and purpose: Carbon nanotubes (CNTs) are a significant discovery in nanotechnology, with widespread applications in modern technology. However, there are concerns about their potential toxicity, particularly in skin cells. This study aimed to investigate the mechanisms by which CNTs induced cytotoxicity and apoptosis in mouse skin fibroblasts. Experimental approach: The mice skin fibroblasts were isolated and exposed to two types of CNTs at various concentrations and then analyzed for changes in viability, reactive oxygen species (ROS) production, the levels of Bcl-2-associated X protein (Bax), and lactate production. Findings/Results: The results demonstrated that CNTs reduced cell viability and increased ROS production in a dose-dependent manner. Additionally, the current study found that CNTs increased the protein levels of Bax, a pro-apoptotic protein, in mouse skin fibroblasts. Furthermore, it was observed a significant decrease in lactate production in cells exposed to CNTs. Conclusion and implications: The findings concluded that CNTs have the potential to be toxic substances for skin fibroblasts, which serve as the body's first line of defense. This is evidenced by their ability to increase the production of ROS and the protein levels of Bax, as well as reduce lactic acid levels. As lactic acid has been reported to have beneficial effects on skin collagen production, further studies are needed to fully understand the impact of carbon nanotube exposure on human skin health. [ABSTRACT FROM AUTHOR]

Radiation mutagenesis, which typically involves gamma rays, is important for generating new rice germplasm resources. Determining the appropriate radiation dose range is critical for the success of radiation mutagenesis. Clarifying the sensitivity and tolerance of genotypically diverse rice varieties to gamma irradiation as well as the radiation-induced changes to reactive oxygen species (ROS) generation and antioxidant enzyme activities is crucial for increasing the utility of radiation mutagenesis in rice breeding programs. The seeds of the following four rice varieties with different genotypes were used as test materials: indica Zhe 1613, glutinous indica Zhe 1708, japonica Zhejing 100, and glutinous japonica Zhenuo 65. Additionally,60Co was used as the source of gamma rays. The rice seeds were irradiated with 14 doses (0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, and 750 Gy). Non-irradiated seeds were used as the control. The seedling survival rate for each variety was recorded at 3, 7, 14, and 28 days after sowing. Moreover, the median lethal dose (LD50) and critical dose (LD40) were calculated according to the seedling survival rates at 28 days after sowing. The seedling superoxide anion (O2•−), hydrogen peroxide (H2O2), and malondialdehyde (MDA) contents and the superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) activities were analyzed at 7 days after sowing. As the radiation dose increased, the seedling survival rate decreased. The seedling survival rate also decreased significantly as the number of days after sowing increased. Among the rice genotypes, the rank-order of the radiation tolerance was as follows: indica Zhe 1613 > glutinous indica Zhe 1708 > japonica Zhejing 100 > glutinous japonica Zhenuo 65. The LD50 values were 426.7 Gy for Zhe 1613, 329.2 Gy for Zhe 1708, 318.3 Gy for Zhejing 100, and 316.6 Gy for Zhenuo 65. Increases in the radiation dose resulted in significant increases in the seedling O2•− and H2O2 contents, but only up to a certain point. Further increases in the radiation dose caused the seedling O2•− and H2O2 contents to decrease. The H2O2 content for each variety peaked when the radiation dose was very close to the LD50. We propose that the radiation dose associated with the highest H2O2 content (±50 Gy) should be used as the recommended dose for the gamma irradiation of rice. The radiation dose that resulted in peak seedling O2•− contents in the analyzed rice varieties was very close to the LD40. In all rice varieties, the MDA content increased as the radiation dose increased. The SOD, CAT, POD, and APX activities increased as the radiation dose increased within a certain range (less than 600 Gy for Zhe 1613 and 400 Gy for the other varieties), but there were slight differences among the rice varieties. Genotypically diverse rice varieties vary regarding their sensitivity to gamma irradiation. Our findings suggest that ROS generation and antioxidant enzyme activities are important factors associated with the radiation mutagenesis of rice. The close relationship between the activities of key antioxidant enzymes, such as SOD, POD, APX, and CAT, and the LD50 and LD40 may be exploited to enhance radiation mutagenesis through the use of plant growth regulators. [ABSTRACT FROM AUTHOR]

Abstract The work presents core–shell nanoparticles (NPs) built from the novel Cu(I) complexes with cyclic P2N2-ligands (1,5-diaza-3,7-diphosphacyclooctanes) that can visualize their entry into cancer and normal cells using a luminescent signal and treat cells by self-enhancing generation of reactive oxygen species (ROS). Variation of P- and N-substituents in the series of P2N2-ligands allows structure optimization of the Cu(I) complexes for the formation of the luminescent NPs with high chemical stability. The non-covalent modification of the NPs with triblock copolymer F-127 provides their high colloidal stability, followed by efficient cell internalization of the NPs visualized by their blue (⁓450 nm) luminescence. The cytotoxic effects of the NPs toward the normal and some of cancer cells are significantly lower than those of the corresponding molecular complexes, which correlates with the chemical stability of the NPs in the solutions. The ability of the NPs to self-enhanced and H2O2-induced ROS generation is demonstrated in solutions and intracellular space by means of the standard electron spin resonance (ESR) and fluorescence techniques correspondingly. The anticancer specificity of the NPs toward HuTu 80 cancer cells and the apoptotic cell death pathway correlate with the intracellular level of ROS, which agrees well with the self-enhancing ROS generation of the NPs. The enhanced level of ROS revealed in HuTu 80 cells incubated with the NPs can be associated with the significant level of their mitochondrial localization.

Respiratory burst oxidase homolog (Rboh) generates reactive oxygen species (ROS) as a defense response during biotic and abiotic stress. In Aquilaria plants, wounding and fungal infection result in biosynthesis and deposition of secondary metabolites as defense responses, which later form constituents of fragrant resinous agarwood. During injury and fungal invasion, Aquilaria tree generates ROS species via the Rboh enzymes. Despite the implication of Rboh genes in agarwood formation, no comprehensive genomic-level study of the Rboh gene family in Aquilaria is present. A systematic illustration of their role during stress and involvement in initiating signal cascades for agarwood metabolite biosynthesis is missing. In this study, 14 Rboh genes were retrieved from genomes of two Aquilaria species, A. agallocha and A. sinensis, and were classified into five groups. The promoter regions of the genes had abundant of stress-responsive elements. Protein-protein network and in silico expression analysis suggested their functional association with MAPK proteins and transcription factors such as WRKY and MYC2. The study further explored the expression profiles of Rboh genes and found them to be differentially regulated in stress-induced callus and stem tissue, suggesting their involvement in ROS generation during stress in Aquilaria. Overall, the study provides in-depth insight into two Rboh genes, AaRbohC and AaRbohA, highlighting their role in defense against fungal and abiotic stress, and likely during initiation of agarwood formation through modulation of genes involved in secondary metabolites biosynthesis. The findings presented here offer valuable information about Rboh family members, which can be leveraged for further investigations into ROS-mediated regulation of agarwood formation in Aquilaria species. [ABSTRACT FROM AUTHOR]

Potassium (K+) is the most abundant cation in the cytosol and is maintained at high concentrations within the mitochondrial matrix through potassium channels. However, many effects of K+ at such high concentrations on mitochondria and the underlying mechanisms remain unclear. This study aims to elucidate these effects and mechanisms by employing fluorescence imaging techniques to distinguish and precisely measure signals inside and outside the mitochondria. We stained the mitochondrial matrix with fluorescent dyes sensitive to K+, pH, reactive oxygen species (ROS), and membrane potential in plasma membrane-permeabilized C6 cells and isolated mitochondria from C6 cells. Fluorescence microscopy facilitated the accurate measurement of fluorescence intensity inside and outside the matrix. Increasing extramitochondrial K+ concentration from 2 mM to 127 mM led to a reduction in matrix pH and a decrease in the generation of highly reactive ROS. In addition, elevated K+ levels electrically polarized the inner membrane of the mitochondria and promoted efficient ATP synthesis via FoF1-ATPase. Introducing protons (H+) into the matrix through phosphate addition led to further mitochondrial polarization, and this effect was more pronounced in the presence of K+. K+ at high concentrations, reaching sub-hundred millimolar levels, increased H+ concentration within the matrix, suppressing ROS generation and boosting ATP synthesis. Although this study does not elucidate the role of specific types of potassium channels in mitochondria, it does suggest that mitochondrial K+ plays a beneficial role in maintaining cellular health. [ABSTRACT FROM AUTHOR]

Timolol (TIM) is a non-selective ß-adrenergic receptor antagonist used orally for the treatment of hypertension and heart attacks, and topically for treating glaucoma; lately, it has also been used in some specific dermatological problems. In the present study, its photodegradation and potential risk of phototoxicity were examined using chemical, in silico and in vitro methods. The UV/VIS irradiated solutions of TIM at pH 1–13 were subjected to LC-UV and UPLC-HRMS/MS analyses showing pseudo first-order kinetics of degradation and several degradation products. The structures of these photodegradants were elucidated by fragmentation path analysis based on high resolution (HR) fragmentation mass spectra, and then used for toxicity evaluation using OSIRIS Property Explorer and Toxtree. Potential risk of phototoxicity was also studied using chemical tests for detecting ROS under UV/VIS irradiation and in vitro tests on BALB/c 3T3 mouse fibroblasts (MTT, NRU and Live/Dead tests). TIM was shown to be potentially phototoxic because of its UV/VIS absorptive properties and generation ROS during irradiation. As was observed in the MTT and NRU tests, the co-treatment of fibroblasts with TIM and UV/VIS light inhibited cell viability, especially when concentrations of the drug were higher than 50 µg/mL. [ABSTRACT FROM AUTHOR]

This paper investigated the antibacterial mechanism of spermidine-capped carbon dots (S-PCDs) against Staphylococcus aureus. The results showed that there were a large number of amino groups on the surface of S-PCDs and they had a high positive charge (+47.06 mV), which could be adsorbed on the negatively charged bacterial surface through electrostatic interaction and changed the permeability of the bacterial cell membrane. The extracellular protein and nucleic acid contents of S. aureus treated with S-PCDs were 5.4 and 1.2 times higher than those of the control group, respectively. The surface folds and defects of the bacterial cell membrane, and the leakage of cell contents were observed using SEM and TEM. The expression of metabolic oxidation regulatory genes dmpI, narJ and narK was upregulated and the intracellular ROS generation was induced, causing bacterial oxidative stress and eventually bacterial death. S-PCDs can effectively inhibit biofilm formation and had low cytotoxicity. The S-PCD treatment successfully inhibited microbial reproduction when pasteurized milk was stored at 25 °C and 4 °C. These results provide important insights into the antimicrobial mechanism of S-PCDs and lay the foundation for their application in the food field as a potentially novel bacteriostatic nanomaterial. [ABSTRACT FROM AUTHOR]

The family Bignoniaceae includes Handroanthus impetiginosus trees, which are sparsely distributed in the northeast of Brazil. Natural products play a vital role in the discovery of drugs for various diseases. Many plants have been used as sources of medicines because of their chemical diversity and potent bioactivity. Handroanthus impetiginosus has been used traditionally to cure a wide range of illnesses, such as cancer, oxidative stress, and inflammation. This work highlights the cytotoxicity, cell death, and routes of apoptosis in lung cancer cells (A549) and the anti-inflammatory and antioxidant effects of roasted Handroanthus impetiginosus (lapacho/taheebo) in normal cells. The cell viability assay indicated that puffing roasted taheebo is nontoxic to a normal cell line up to 500 µg/mL but significantly toxic to A549 cells. The roasted lapacho/taheebo also increases reactive oxygen species (ROS) generation in A549 lung cancer cells, and cellular apoptosis via a mitochondrial intrinsic pathway was confirmed. The roasted lapacho/taheebo significantly inhibited both colony formation and cell migration ability, highlighting its potential as an anticancer agent. Additionally, this study demonstrates that roasted taheebo enhanced the expression of genes for BAX accumulation and decreased Bcl-2 gene expression through the p53 signaling pathway. Furthermore, research on the anti-inflammatory properties of roasted taheebo revealed a strong NO inhibition as well as the inhibition of inflammatory mediators (TNF-α, iNOS, COX-2, IL-6, and IL-8) through the NF-κB signaling pathway. However, in H2O2-induced HaCaT cells, roasted taheebo extract significantly reduced oxidative stress by upregulating the level of expression of antioxidative markers (SOD, CAT, GPx, and GST) at 50 μg/mL. As a result, roasted taheebo justifies investigation in animal and clinical trials as a possible source of antioxidants, anti-inflammatory substances, and anti-cancer compounds. [ABSTRACT FROM AUTHOR]

In this work, α-Ag2WO4 particles with different cross-sections were obtained using the co-precipitation method at different synthesis temperatures. The samples were characterized by X-ray diffraction (XRD), field-scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The antimicrobial activity was analyzed using the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) methods against the Escherichia coli and Salmonella spp. gram-negative bacteria. The antimicrobial tests against Escherichia coli and Salmonella spp. indicated that concentrations of 2.5–5 mg/mL and 5 mg/mL completely inhibit its growth, respectively. The antimicrobial activity was analyzed employing band-edge positions for ROS generations and the superficial distribution of Ag+ species that contribute to antimicrobial activity. Quantum-chemical calculations were used at the DFT level to investigate the surface-dependent reactivity of α-Ag2WO4, and we demonstrated how the antimicrobial properties could be tailored by the geometry and electronic structure of the exposed surfaces, providing guidelines for the morphology design.

Respiratory burst oxidase homolog (Rboh) generates reactive oxygen species (ROS) as a defense response during biotic and abiotic stress. In Aquilaria plants, wounding and fungal infection result in biosynthesis and deposition of secondary metabolites as defense responses, which later form constituents of fragrant resinous agarwood. During injury and fungal invasion, Aquilaria tree generates ROS species via the Rboh enzymes. Despite the implication of Rboh genes in agarwood formation, no comprehensive genomic-level study of the Rboh gene family in Aquilaria is present. A systematic illustration of their role during stress and involvement in initiating signal cascades for agarwood metabolite biosynthesis is missing. In this study, 14 Rboh genes were retrieved from genomes of two Aquilaria species, A. agallocha and A. sinensis, and were classified into five groups. The promoter regions of the genes had abundant of stress-responsive elements. Protein–protein network and in silico expression analysis suggested their functional association with MAPK proteins and transcription factors such as WRKY and MYC2. The study further explored the expression profiles of Rboh genes and found them to be differentially regulated in stress-induced callus and stem tissue, suggesting their involvement in ROS generation during stress in Aquilaria. Overall, the study provides in-depth insight into two Rboh genes, AaRbohC and AaRbohA, highlighting their role in defense against fungal and abiotic stress, and likely during initiation of agarwood formation through modulation of genes involved in secondary metabolites biosynthesis. The findings presented here offer valuable information about Rboh family members, which can be leveraged for further investigations into ROS-mediated regulation of agarwood formation in Aquilaria species.

Eight new functionalized spirooxindole-pyrrolizidine heterocyclic hybrids has been obtained from N-pyridinylmethyl-bisarylmethylidene-pyridinones, Isatin and L-Proline by a multi-component cycloaddition reaction. Such synthesized derivatives are being characterized systematically with the aid of instrumental facilities like FT-IR, NMR spectroscopy, and Mass spectrometry. Following this, all the compounds are tested for the anticancer potentials in vitro using HepG2 cells (cancer cells). The compound with no substitution on the aryl rings (phenyl rings), displayed the highest activity among the spirooxindole-pyrrolizidines. Further the most active heterocyclic hybrids are verified for toxicity effects against L929 cells (non-cancer cells; at 200 µg/mL for 24 h). Finally, the cell viability losses for these most active compounds (at its IC50 value) are addressed by assaying the activity of free radicals, apoptosis, and caspases.

Pentagamavunone-1 (PGV-1), an analog of curcumin, has been studied for its cytotoxic effects in 4T1, MCF7, MCF7/HER2, and T47D breast cancer cells. Its antiproliferative effect is partly mediated through G2/M arrest; however, its molecular mechanism during cell cycle progression remains unknown. In this study, we aimed to determine whether PGV-1 has any anticancer effects on highly aggressive breast cancer cells, with a focus on cell cycle regulatory activity, reactive oxygen species (ROS) generation, and their mediated effects on cancer cells. MDA-MB-231 (triple-negative) and HCC1954 (overexpressed HER2) immortalized human breast cancer cells were used in the study. PGV-1 exhibited cytotoxic activity with an irreversible antiproliferative impact on treated cells and had good selectivity when tested in fibroblast cells. Oral PGV-1 administration suppressed tumor growth in a cell-derived xenograft mouse model. PGV-1 induced the phosphorylation of Aurora A kinase and PLK1 in MDA-MB-231 cells, while PLK1 and cyclin B1 phosphorylation were enhanced in the PGV-1-treated HCC1954 cells during prometaphase arrest. Intracellular ROS production was substantially higher upon PGV-1 treatment following mitotic arrest, and this activity caused impairment of mitochondrial respiration, induced senescence, and subsequently triggered early-to-late apoptosis. Collectively, these results suggest that the molecular mechanism of PGV-1 involves the regulation of mitotic kinases to cause cell cycle arrest and the enhancement of ROS production to impair mitochondrial activity and induce cellular senescence. The therapeutic activities demonstrated by PGV-1 in this study show its potential as an appealing candidate for chemotherapy in breast cancer treatment.