Oxidative Stress-mediated Apoptosis Research Articles

Tinostamustine (EDO-S101) and Its Combination with Celecoxib or Temozolomide as a Therapeutic Option for Adult-Type Diffuse Gliomas

Adult-type diffuse gliomas are characterized by inevitable recurrence and very poor prognosis. Novel treatment options, including multimodal drugs or effective drug combinations, are therefore eagerly awaited. Tinostamustine is an alkylating and histone deacetylase inhibiting molecule with great potential in cancer treatment. Thus, the aim of this study was to investigate its effects on glioma cells. In this context, tinostamustine was evaluated in monotherapy and as a combination therapy, with either celecoxib or temozolomide; additionally, the results were compared to the golden glioma chemotherapy standard—temozolomide. Our experiments, conducted on both temozolomide-sensitive U-87 MG astrocytoma and temozolomide-resistant U-138 MG glioblastoma cells revealed that tinostamustine and its combination with either celecoxib or temozolomide exert dose-dependent cytotoxicity, cause cell cycle arrest, induce oxidative stress-mediated apoptosis of malignant glioma cells, and mitigate their migratory potential. Astrocytoma cells were more susceptible to the tested treatments than glioblastoma cells, and, generally, those dual therapies were superior in anti-glioma efficacy compared to temozolomide. Overall, our study provides evidence that tinostamustine and the combination therapies consisting of tinostamustine and celecoxib or tinostamustine and temozolomide may represent a new approach for the effective treatment of malignant gliomas.

Zingerone effects on arsenic-induced glucose intolerance and hepatotoxicity in mice via suppression of oxidative stress-mediated hepatic inflammation and apoptosis

BackgroundArsenic (As), a poisonous metalloid, is widely distributed in air, water, and soil and has been associated with the occurrence of diabetes and liver toxicity. Zingerone (ZNG), one of the active compounds in ginger, has several pharmacological benefits such as antioxidant and anti-inflammatory characteristics. The objective of this research was to assess the protective role of ZNG against arsenic (As)-induced glucose intolerance (GI) and hepatotoxicity in mice. MethodsMale NMRI mice were treated with ZNG (25, 50, and 100 mg/kg, oral gavage for 29 days) before As administration (10 mg/kg, oral gavage for 29 days). On the 29th day, fasting blood glucose (FBG) and glucose tolerance test were measured. The animals were euthanized (day 30), and samples from blood and tissue (liver and pancreas) were gathered for further evaluations. ResultsAdministration of ZNG inhibited As-induced elevation of FBG and GI. Moreover, hepatic tissue damage and decreased Langerhans islets' diameter caused by As administration were improved by ZNG treatment. Pretreatment with ZNG attenuated the elevation of serum liver enzymes induced by As (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase). Also, the reduction in total thiol content, as well as the decline in antioxidant enzyme activities (catalase, superoxide dismutase, and glutathione peroxidase) and the increase in lipid peroxidation marker (thiobarbituric acid reactive substances) in the liver tissue of As-exposed mice were reversed in ZNG-treated mice. Furthermore, ZNG prevented the increase of hepatic inflammatory markers (nitric oxide and tumor necrosis factor-alpha levels, and protein expression of nuclear factor-kappa B) and apoptosis-related marker (caspase-3 protein expression) in As-treated mice. ConclusionsThis study has provided evidence indicating that ZNG can act as a beneficial agent in preventing As-induced hepatotoxicity and diabetes.

Bufotalin Induces Oxidative Stress-Mediated Apoptosis by Blocking the ITGB4/FAK/ERK Pathway in Glioblastoma.

Bufotalin (BT), a major active constituent of Chansu, has been found to possess multiple pharmacological activities. Although previous studies have shown that BT could inhibit the growth of glioblastoma (GBM), the safety of BT in vivo and the potential mechanism are still unclear. We conducted a systematic assessment to investigate the impact of BT on GBM cell viability, migration, invasion, and colony formation. Furthermore, in vivo results were obtained to evaluate the effect of BT on tumor growth. The preliminary findings of our study demonstrate the effective inhibition of GBM cell growth and subcutaneous tumor development in mice by BT, with tolerable levels of tolerance observed. Mechanistically, BT treatment induced mitochondrial dysfunction, bursts of reactive oxygen species (ROS), and subsequent cell apoptosis. More importantly, proteomic-based differentially expressed proteins analysis revealed a significant downregulation of integrin β4 (ITGB4) following BT treatment. Furthermore, our evidence suggested that the ITGB4/focal adhesion kinase (FAK)/extracellular signal-related kinase (ERK) pathway involved BT-induced apoptosis. Overall, our study demonstrates the anti-GBM effects of BT and elucidates the underlying mechanism, highlighting BT as a potential therapeutic option for GBM.

Apocynin protects the dopaminergic cell line SH-SY5Y from fumonisin B1 induced cytotoxicity through attenuation of oxidative stress mediated apoptosis

BackgroundThe fusarium verticillioides produces the mycotoxin fumonisin b1 (Fb1), commonly infects corn and other agricultural commodities. The Fb1 showed hepatotoxicity, cytotoxicity, and carcinogenicity in animals. Aim of the studyThere are limited literature available on cytotoxicity exerted by Fb1. Hence, the present investigation aimed to evaluate the cytotoxic effects of Fb1 and its mechanism in the neuroblastoma (SH-SY5Y) cell line and its amelioration by apocynin. MethodsWe investigated the molecular mechanism of Fb1-induced cytotoxicity in SH-SY5Y cells and investigated the effect of Fb1 oxidative stress markers, and apoptosis. ResultsThe results explained that the Fb1 showed dose-dependent cytotoxicity in SH-SY5Y cells with the IC50 value 150 µM. Fb1 elevated reactive oxygen species and depolarized mitochondrial membrane potential, vacuolation and apoptotic changes were observed in SH-SY5Y cells. The protein expression of CAT and GPx were downregulated with Fb1 treatment, and apoptotic markers caspase-3 and caspase-8 were upregulated. When the apocynin was pretreated, followed by Fb1 exposure for 24 h, all the changes were normalized with the treatment. Hence, these results suggest that ROS is the primary upstream signal leading to increased Fb1-mediated cytotoxicity in SH-SY5Y cells. ConclusionApocynin reversed the Fb1-induced oxidative stress and apoptosis by its antioxidant potency in SH-SY5Y cell lines.

The Novel Application of EUK-134 in Retinal Degeneration: Preventing Mitochondrial Oxidative Stress-Triggered Retinal Pigment Epithelial Cell Apoptosis by Suppressing MAPK/p53 Signaling Pathway.

Age-related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK-134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light-induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK-134 in averting AMD using sodium iodate (NaIO3)-induced Balb/c mouse and ARPE-19 cells (adult RPE cell line). In vivo, EUK-134 effectively antagonized NaIO3-induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK-134-treated group significantly down-regulated the expression of cleaved caspase-3 compared with the group treated with NaIO3 alone. Our results found that EUK-134 notably improved cell viability by preventing mitochondrial ROS accumulation-induced membrane potential depolarization-mediated apoptosis in NaIO3-inducted ARPE-19 cells. Furthermore, we found that EUK-134 could inhibit p-ERK, p-p38, p-JNK, p-p53, Bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP by increasing Bcl-2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK-134 may effectively prevent mitochondrial oxidative stress-mediated retinal apoptosis in NaIO3-induced retinopathy.

Melatonin partially rescues defects induced by tranexamic acid exposure during oocyte maturation in mice.

Tranexamic acid (TXA) is widely used among young women because of its ability to whiten skin and treat menorrhagia. Nevertheless, its potential effects on oocyte maturation and quality have not yet been clearly clarified. Melatonin (MT) is an endogenous hormone released by the pineal gland and believed to protect cells from oxidative stress injury. In the present study, we used an in vitro maturation model to investigate the toxicity of TXA and the protective role of MT in mouse oocytes. Compared with the control group, the TXA-exposed group had significantly lower nuclear maturation (57.72% vs. 94.08%, P < 0.001) and early embryo cleavage rates (38.18% vs. 87.66%, P < 0.001). Further study showed that spindle organization (52.56% vs. 18.77%, P < 0.01) and chromosome alignment (33.23% vs. 16.66%, P < 0.01) were also disrupted after TXA treatment. Mechanistically, we have demonstrated that TXA induced early apoptosis of oocytes (P < 0.001) by raising the level of reactive oxygen species (P < 0.001), which was consistent with an increase in mitochondrial damage (P < 0.01). Fortunately, all these effects except the spindle defect were successfully rescued by an appropriate level of MT. Collectively, our findings indicate that MT could partially reverse TXA-induced oocyte quality deterioration in mice by effectively improving mitochondrial function and reducing oxidative stress-mediated apoptosis.NEW & NOTEWORTHY Tranexamic acid is increasingly used to whiten skin, reverse dermal damages, and treat heavy menstrual bleeding in young women. However, its potential toxicity in mammalian oocytes is still unclear. Our study revealed that tranexamic acid exposure impaired the mouse oocyte quality and subsequent embryo development. Meanwhile, melatonin has been found to exert beneficial effects in reducing tranexamic acid-induced mitochondrial dysfunction and oxidative stress.

Chlorogenic acid ameliorates memory dysfunction via attenuating frontal lobe oxidative stress and apoptosis in diabetic rat model.

Diabetes mellitus, characterized by hyperglycemia, causes various complications, one of which is memory dysfunction. The frontal lobe is known to be responsible for impaired memory function due to hyperglycemia and is associated with oxidative stress-mediated neuronal cell apoptosis. Chlorogenic acid (CGA) is reported to have neuroprotective effects. However, its effect on the frontal lobe in diabetes mellitus (DM) rats is not widely known. This research aimed to elucidate the effect of CGA on the mRNA expressions of SOD1, SOD2, p53, and Bcl-2 in the frontal lobe of DM rats. Thirty male Wistar rats (2-month-old, 150-200 gBW) were randomly divided into six groups: C (control), DM1.5 (1.5-month DM), DM2 (2-month DM), CGA12.5, CGA25 and CGA50 (DM+CGA 12.5, 25, and 50 mg/kgBW, respectively). A single dose of streptozotocin (60 mg/kgBW) was intraperitoneally injected. Intraperitoneal CGA injection was administered daily for DM1.5 rats for 14 days. Path length was measured in the Morris water maze (MWM) probe test. After termination, the frontal lobes were carefully harvested for RNA extraction. Reverse transcriptase PCR was performed to examine the mRNA expression of SOD1, SOD2, p53, and Bcl-2. The DM2 group demonstrated significant shorter path length on the MWM probe test and significantly lower mRNA expression of SOD1 and Bcl-2, compared to the C group. After CGA administration, the CGA25 group showed a significantly shorter path length than the C group. The CGA12.5 and CGA25 groups had significantly higher mRNA expression of SOD1 than the DM1.5 group. Compared to the DM1.5 and DM2 groups, SOD2 mRNA expression of the administration of all three CGA doses increased markedly. Furthermore, Bcl-2 mRNA expression was significantly increased in the CGA12.5 and CGA50 groups, compared with the DM2 group. Chlorogenic acid might improve memory function through upregulation of frontal lobes' SOD1, SOD2, and Bcl-2 mRNA expression in DM rats.

Benzalkonium chloride induces hematopoietic stem cell reduction and immunotoxicity in zebrafish larvae

Benzalkonium chloride (BAC) is a broad-spectrum antibacterial agent that possesses cleaning and bactericidal properties, but impact of BAC on wellbeing of aquatic organisms remains uncertain. Consequently, in this current study, we have examined the immunotoxic potential of BAC in zebrafish embryos, thus marking it as the pioneering effort in this field. According to the findings, zebrafish embryos exposed to BAC exhibited a decline in yolk area that varied with the concentration, along with a significant decrease in the count of neutrophils, macrophages, red blood cells, and thymus T-cells. We observed significantly up-regulated expression of immune-related signaling genes such as cxcl-c1c, il-8, tir4 and inf-γ, but expression of nf-κb was downregulated. In addition, we observed a marked reduction in the number of hematopoietic stem cells in zebrafish larvae after BAC exposure, which could be the result of oxidative stress-mediated apoptosis. We found that compared with the control group, the number of red blood cells in juvenile zebrafish in BAC-exposure group was significantly down-regulated, which could be attributed to hematopoietic stem cell defect. Astaxanthin restored immune cells and hematopoietic stem cells after BAC exposure, whereas Inhibitor of Wnt Response-1(IWR-1) restored neutrophils after BAC exposure. The research findings demonstrated that exposure to BAC displayed harmful effects on the development and immune system of zebrafish embryos. These effects might be associated with alterations in reactive oxygen species(ROS) levels and activation of the Wnt signaling pathway caused by BAC.

Transcriptional coactivation of NRF2 signaling in cardiac fibroblasts promotes resistance to oxidative stress

We recently discovered that steroid receptor coactivators (SRCs) SRCs-1, 2 and 3, are abundantly expressed in cardiac fibroblasts (CFs) and their activation with the SRC small molecule stimulator MCB-613 improves cardiac function and dramatically lowers pro-fibrotic signaling in CFs post-myocardial infarction. These findings suggest that CF-derived SRC activation could be beneficial in the mitigation of chronic heart failure after ischemic insult. However, the cardioprotective mechanisms by which CFs contribute to cardiac pathological remodeling are unclear. Here we present studies designed to identify the molecular and cellular circuitry that governs the anti-fibrotic effects of an MCB-613 derivative, MCB-613-10-1, in CFs. We performed cytokine profiling and whole transcriptome and proteome analyses of CF-derived signals in response to MCB-613-10-1. We identified the NRF2 pathway as a direct MCB-613-10-1 therapeutic target for promoting resistance to oxidative stress in CFs. We show that MCB-613-10-1 promotes cell survival of anti-fibrotic CFs exposed to oxidative stress by suppressing apoptosis. We demonstrate that an increase in HMOX1 expression contributes to CF resistance to oxidative stress-mediated apoptosis via a mechanism involving SRC co-activation of NRF2, hence reducing inflammation and fibrosis. We provide evidence that MCB-613-10-1 acts as a protectant against oxidative stress-induced mitochondrial damage. Our data reveal that SRC stimulation of the NRF2 transcriptional network promotes resistance to oxidative stress and highlights a mechanistic approach toward addressing pathologic cardiac remodeling.

Pelargonidin inhibits cell growth and promotes oxidative stress-mediated apoptosis in lung cancer A549 cells.

Lung cancer has the worst prognosis with an average 5-year survival rate of only 10%-20%. Lung cancer has the highest prevalence rate and a second most common cause of cancer-associated mortalities worldwide. The present study was planned to explore the anticancer effects of pelargonidin against the lung cancer A549 cells via analyzing oxidative stress-mediated apoptosis. The viability of both control and pelargonidin-treated A549 cells was analyzed using the MTT cytotoxicity assay at different time periods. The levels of endogenous ROS generation, mitochondrial membrane potential (Δψm), and apoptosis were assessed using corresponding fluorescent staining assays. The levels of oxidative stress biomarkers, including TBARS, SOD, CAT, and GSH, in the cell lysates of control and pelargonidin-treated A549 cells were examined using the assay kits. The pelargonidin treatment substantially suppressed the A549 cell growth. Further, pelargonidin promoted the ROS production and depleted the Δψm levels in the A549 cells. The fluorescent staining assays witnessed the occurrence of increased apoptosis in the pelargonidin-treated A549 cells. The pelargonidin also boosted the TBARS and reduced the antioxidant levels thereby promoted the oxidative stress-regulated apoptosis in the A549 cells. In summary, the findings' results of the current study demonstrated an anticancer activity of pelargonidin on A549 cells. The pelargonidin treatment substantially decreased the growth and encouraged the oxidative stress-regulated apoptosis in A549 cells. Therefore, it was evident that the pelargonidin could be employed as an effective anticancer candidate to treat the lung cancer.

Prolonged exposure to mercuric chloride induces oxidative stress-mediated nephrotoxicity in freshwater food fish Channa punctatus.

Mercury (Hg) is regarded as a serious hazard to aquatic life and is particularly prevalent in aquatic ecosystems. However, there is little evidence available regarding the toxicity of mercury chloride (HgCl2) in vital organs of fish. This study was conducted to assess the effects of HgCl2 (0.039mg/L and 0.078mg/L) on oxidative stress-mediated genotoxicity, poikilocytosis, apoptosis, and renal fibrosis after 15, 30, and 45days of the exposure period. According to the findings, HgCl2 intoxication in fish resulted in a significantly (P < 0.05) elevated lipid peroxidation (LPO), protein carbonyls (PC), lactate dehydrogenase (LDH) activity levels in kidney tissues and significantly (P < 0.05) increased reactive oxygen species (ROS), poikilocytosis, DNA tail length, and the frequency of apoptotic cells (AC%) in blood cells. Kidney's ultra-structure and histopathology revealed its fibrosis, which was evident by mRNA expression of targeted genes KIM1, NOX4, TGFβ, and NFϏβ. Different indicators of oxidative stress, apoptosis, and genotoxicity were altered in a dose and time-dependent manner, according to a two-way ANOVA analysis. There was a considerable positive link between oxidative stress and kidney fibrosis in the fish Channa punctatus, and it is evident from regression correlation and PCA data analysis. The kidney's ultra-structure evaluation and histopathology both revealed a noticeable fibrosis state. Additionally, a significant (P < 0.05) downregulation in PPARδ reveals that fish body was unable to combat diseases such as kidney fibrosis induced by HgCl2. This study shed fresh light on the mechanisms underlying nephrotoxicity caused by HgCl2 exposure.

Ethyl acetate layer of a methanol extract from Aquilaria crassna promotes oxidative stress-mediated apoptosis in non-small-cell lung cancer cells

Ethyl acetate layer of a methanol extract from Aquilaria crassna promotes oxidative stress-mediated apoptosis in non-small-cell lung cancer cells

Bortezomib suppresses acute myelogenous leukaemia stem-like KG-1a cells via NF-κB inhibition and the induction of oxidative stress.

Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti-AML activity of bortezomib (BTZ), emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem-like features of KG-1a cells, as observed by the reduction in CD34- and CD123-positive cells. A reduction in NF-κB p65 nuclear staining was observed in BTZ-treated KG-1a cells, in addition to upregulation of the NF-κB inhibitor gene NFΚBIB. BTZ-induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase-3 and cleaved PARP-(Asp 214) level in KG-1a cells. Furthermore, BTZ-induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z-VAD-(OMe)-FMK, indicating that BTZ induces caspase-mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.

Diazoxide attenuates DOX-induced cardiotoxicity in cultured rat myocytes.

Doxorubicin (DOX)-induced cardiotoxicity is a well known clinical problem, and many investigations have been made of its possible amelioration. We have investigated whether diazoxide (DIA), an agonist at mitochondrial ATP-sensitive potassium channels (mitoKATP), could reverse DOX-induced apoptotic myocardial cell loss, in cultured rat cardiomyocytes. The role of certain proteins in this pathway was also studied. The rat cardiomyocyte cell line (H9c2) was treated with DOX, and also co-treated with DOX and DIA, for 24 h. Distribution of actin filaments, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant and antioxidant status (TOS and TAS, respectively), and some protein expressions, were assessed. DOX significantly decreased SOD activity, increased ERK1/2 protein levels, and depolarised the mitochondrial membrane, while DIA co-treatment inhibited such changes. DIA co-treatment ameliorated DOX-induced cytoskeletal changes via F-actin distribution and mitoKATP structure. Co-treatment also decreased ERK1/2 and cytochrome c protein levels. Cardiomyocyte loss due to oxidative stress-mediated apoptosis is a key event in DOX-induced cytotoxicity. DIA had protective effects on DOX-induced cardiotoxicity, via mitoKATP integrity, especially with elevated SUR2A levels; but also by a cascade including SOD/AMPK/ERK1/2. Therefore, DIA may be considered a candidate agent for protecting cardiomyocytes against DOX chemotherapy.

Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage.

The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow-Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells.

Electrical stimulation promoting the angiogenesis in diabetic rat perforator flap through attenuating oxidative stress-mediated inflammation and apoptosis.

Skin flap transplantation is one of the effective methods to treat the diabetes-related foot ulceration, but the intrinsic damage to vessels in diabetes mellitus (DM) leads to the necrosis of skin flaps. Therefore, the discovery of a non-invasive and effective approach for promoting the survival of flaps is of the utmost importance. Electrical stimulation (ES) promotes angiogenesis and increases the proliferation, migration, and elongation of endothelial cells, thus being a potential effective method to improve flap survival. The purpose of this study was to elucidate the mechanism used by ES to effectively restore the impaired function of endothelial cells caused by diabetes. A total of 79 adult male Sprague-Dawley rats were used in this study. Gene and protein expression was assessed by PCR and western blotting, respectively. Immunohistochemistry and hematoxylin-eosin staining were performed to evaluate the morphology and density of the microvessels in the flap. The optimal duration for preconditioning the flap with ES was 7 days. The flap survival area percentage and microvessels density in the DMES group were markedly increased compared to the DM group. VEGF, MMP2, and MMP9 protein expression was significantly upregulated. ROS intensity was significantly decreased and GSH concentration was increased. The expression of IL-1β, MCP‑1, cleaved caspase-3, and Bax were downregulated in the DMES group, while TGF-β expression was upregulated. ES improves the angiogenesis in diabetic ischemic skin flaps by attenuating oxidative stress-mediated inflammation and apoptosis, eventually increasing their viability.

FNC (4'-azido-2'-deoxy-2'-fluoro(arbino)cytidine) as an Effective Therapeutic Agent for NHL: ROS Generation, Cell Cycle Arrest, and Mitochondrial-Mediated Apoptosis.

Cytotoxic nucleoside analogs (NAs) hold great promise in cancer therapeutics by mimicking endogenous nucleosides and interfering with crucial cellular processes. Here, we investigate the potential of the novel cytidine analog, 4'-azido-2'-deoxy-2'-fluoro(arbino)cytidine (FNC), as a therapeutic agent for Non-Hodgkin lymphoma (NHL) using Dalton's lymphoma (DL) as a T-cell lymphoma model. FNC demonstrated dose- and time-dependent inhibition of DL cell growth and proliferation. IC-50 values of FNC were measured at 1 µM, 0.5 µM, and 0.1 µM after 24, 48, and 72 h, respectively. Further elucidation of FNC's mechanism of action uncovers its role in inducing apoptosis in DL cells. Notable DNA fragmentation and nuclear condensation point to activated apoptotic pathways. FNC-induced apoptosis was concomitant with changes in cellular membranes, characterized by membrane rupture and altered morphology. The robust anticancer effects of FNC are linked to its capacity to induce reactive oxygen species (ROS) production, prompting oxidative stress-mediated apoptosis. Additionally, FNC disrupted mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction, further promoting apoptosis. Dysregulation of apoptotic genes, with upregulation of Bax and downregulation of Bcl-2 and Bcl-xl, implicates the mitochondrial-mediated apoptosis pathway. Furthermore, FNC-induced G2/M phase cell cycle arrest was mediated through modulation of the cell cycle inhibitor p21. Overall, this study highlights the potential of FNC as a promising therapeutic agent for NHL.

Review of neurotoxicity of T-2 toxin.

T-2 toxin is a representative trichothecene that is widely detected in corn, wheat and other grain feeds. T-2 toxin has stable physical and chemical properties, making it difficult to remove from food and feed. Hence, T-2 toxin has become an unavoidable pollutant in food for humans and animals. T-2 toxin can enter brain tissue by crossing the blood-brain barrier and leads to congestion, swelling and even apoptosis of neurons. T-2 toxin poisoning can directly lead to clinical symptoms (anti-feeding reaction and decline of learning and memory function in humans and animals). Maternal T-2 toxin exposure also exerted toxic effects on the central nervous system of offspring. Oxidative stress is the core neurotoxicity mechanism underlying T-2 toxin poison. Oxidative stress-mediated apoptosis, mitochondrial oxidative damage and inflammation are all involved in the neurotoxicity induced by T-2 toxin. Thus, alleviating oxidative stress has become a potential target for relieving the neurotoxicity induced by T-2 toxin. Future efforts should be devoted to revealing the neurotoxic molecular mechanism of T-2 toxin and exploring effective therapeutic drugs to alleviate T-2 toxin-induced neurotoxicity.

Nanomedicine for cancer targeted therapy with autophagy regulation.

Nanoparticles have unique physical and chemical properties and are currently widely used in disease diagnosis, drug delivery, and new drug development in biomedicine. In recent years, the role of nanomedical technology in cancer treatment has become increasingly obvious. Autophagy is a multi-step degradation process in cells and an important pathway for material and energy recovery. It is closely related to the occurrence and development of cancer. Because nanomaterials are highly targeted and biosafe, they can be used as carriers to deliver autophagy regulators; in addition to their favorable physicochemical properties, nanomaterials can be employed to carry autophagy inhibitors, reducing the breakdown of chemotherapy drugs by cancer cells and thereby enhancing the drug's efficacy. Furthermore, certain nanomaterials can induce autophagy, triggering oxidative stress-mediated autophagy enhancement and cell apoptosis, thus constraining the progression of cancer cells.There are various types of nanoparticles, including liposomes, micelles, polymers, metal-based materials, and carbon-based materials. The majority of clinically applicable drugs are liposomes, though other materials are currently undergoing continuous optimization. This review begins with the roles of autophagy in tumor treatment, and then focuses on the application of nanomaterials with autophagy-regulating functions in tumor treatment.

Ameliorative inhibition of sirtuin 6 by imidazole derivative triggers oxidative stress-mediated apoptosis associated with Nrf2/Keap1 signaling in non-small cell lung cancer cell lines.

Background: Redox homeostasis is the vital regulatory system with respect to antioxidative response and detoxification. The imbalance of redox homeostasis causes oxidative stress. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, also called Nfe2l2)/Kelchlike ECH-associated protein 1 (Keap1) signaling is the major regulator of redox homeostasis. Nrf2/Keap1 signaling is reported to be involved in cancer cell growth and survival. A high level of Nrf2 in cancers is associated with poor prognosis, resistance to therapeutics, and rapid proliferation, framing Nrf2 as an interesting target in cancer biology. Sirtuins (SIRT1-7) are class III histone deacetylases with NAD + dependent deacetylase activity that have a remarkable impact on antioxidant and redox signaling (ARS) linked with Nrf2 deacetylation thereby increasing its transcription by epigenetic modifications which has been identified as a crucial event in cancer progression under the influence of oxidative stress in various transformed cells. SIRT6 plays an important role in the cytoprotective effect of multiple diseases, including cancer. This study aimed to inhibit SIRT6 using an imidazole derivative, Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate, to assess its impact on Nrf2/Keap1 signaling in A549 and NCI-H460 cell lines. Method: Half maximal inhibitory concentration (IC50) of Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate was fixed by cell viability assay. The changes in the gene expression of important regulators involved in this study were examined using quantitative real-time PCR (qRT-PCR) and protein expression changes were confirmed by Western blotting. The changes in the antioxidant molecules are determined by biochemical assays. Further, morphological studies were performed to observe the generation of reactive oxygen species, mitochondrial damage, and apoptosis. Results: We inhibited SIRT6 using Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate and demonstrated that SIRT6 inhibition impacts the modulation of antioxidant and redox signaling. The level of antioxidant enzymes and percentage of reactive oxygen species scavenging activity were depleted. The morphological studies showed ROS generation, mitochondrial damage, nuclear damage, and apoptosis. The molecular examination of apoptotic factors confirmed apoptotic cell death. Further, molecular studies confirmed the changes in Nrf2 and Keap1 expression during SIRT6 inhibition. Conclusion: The overall study suggests that SIRT6 inhibition by imidazole derivative disrupts Nrf2/Keap1 signaling leading to oxidative stress and apoptosis induction.