Antioxidants in Mitigating Phthalate-Induced Male Reproductive Toxicity: A Comprehensive Review.

Phthalates, widely used as plasticizers, have been increasingly linked to male reproductive toxicity through mechanisms including oxidative stress, endocrine disruption, inflammation, and apoptosis. This comprehensive review evaluates the protective role of various antioxidants in mitigating the detrimental effects of phthalates such as di-(2-ethylhexyl) phthalate (DEHP), di-butyl phthalate (DBP), mono-(2-ethylhexyl) phthalate (MEHP), and monobutyl phthalate (MBP) on male reproductive health. Antioxidants such as lycopene, ellagic acid, genistein, and selenium compounds exhibit significant efficacy in counteracting phthalate-induced damage by neutralizing reactive oxygen species (ROS), enhancing endogenous antioxidant defenses, reducing inflammatory responses, and preventing apoptosis. Lycopene demonstrates broad-spectrum protective effects, particularly through its high ROS-scavenging capacity and ability to preserve mitochondrial function. Ellagic acid effectively ameliorates oxidative stress and inflammation, while genistein enhances the Nuclear factor erythroid-derived 2 (Nrf2) pathway and restores hormonal balance, offering robust protection against reproductive toxicity. Selenium compounds improve antioxidant enzyme activities, providing essential support against oxidative damage. These findings underscore the potential of antioxidants as therapeutic agents against phthalate-induced male reproductive dysfunction. Future research should focus on optimizing antioxidant combinations, understanding dose-response relationships, and assessing long-term efficacy and safety to develop effective interventions for safeguarding male reproductive health.

Total extracts from Abelmoschus manihot (L.) alleviate radiation-induced cardiomyocyte ferroptosis via regulating redox imbalances mediated by the NOX4/xCT/GPX4 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Radiation-induced heart disease (RIHD) is one of the most serious complications in patients receiving chest radiotherapy, partially offsetting its benefits. At present, there is a lack of effective treatments for RIHD. Ferroptosis is a newly discovered type of cell death that results from iron-dependent lipid peroxide accumulation. It was recently shown that irradiation generates severe ferroptosis, providing new insights for the treatment of RIHD. Abelmoschus manihot (L.) possesses excellent pharmacological properties and is widely used in treating various ischemic heart and brain diseases; however, its efficacy and mechanism in treating RIHD are unknown. AIM: This study aimed to investigate the efficacy and mechanism of total extracts from A. manihot (L.) (TEA) in treating RIHD. MATERIALS AND METHODS: C57BL/6 mice and H9C2 cells were exposed to irradiation to induce RIHD in vivo and in vitro, respectively. In vivo, we evaluated the protective effects of TEA (150 and 300 mg/kg) on RIHD. Body and heart weight changes of mice were calculated in each group, and malondialdehyde (MDA) level, glutathione/oxidized glutathione (GSH/GSSH) and nicotinamide adenine dinucleotide phosphate (NADPH/NADP+) ratios, western blot, heart histology, and immunohistochemistry were used to evaluate TEA effectiveness. We identified the potential mechanism of radiation-induced cardiomyocyte injury in H9C2 cells treated with small interfering RNA. We determined the effective dose of TEA (0.6 mg/mL) using a Cell Counting Kit-8 assay. Intracellular Fe2+ and lipid peroxidation levels were detected by Phen Green™ SK diacetate probe, BODIPY 581/591 C11 staining, and MDA, GSH, and NADPH kits, and the level of target protein was evaluated by immunofluorescence and western blot. RESULTS: Radiation inhibited system Xc-cystine (xCT)/glutathione peroxidase 4 (GPX4) expression and activity in cardiomyocytes in a time and dose-dependent manner. After silencing xCT/GPX4, MDA significantly increased and GSH/GSSH and NADPH/NADP+ ratios were reduced. xCT/GPX4 inhibition drove ferroptosis in radiation-induced H9C2 injury. Oxidative stress in H9C2 was significantly enhanced by irradiation, which also significantly increased NADPH oxidase 4 (NOX4) expression and inhibited nuclear factor E2-related factor 2 (Nrf2) expression in vivo and in vitro. Inhibition of xCT/GPX4 drove ferroptosis in radiation-induced H9C2 injury, which was aggravated by inactivation of Nrf2 and alleviated by inhibition of NOX4. Compared with the ionizing radiation-only group, TEA improved body weight loss, MDA levels, and histological changes induced by irradiation in mice hearts, and increased the ratio of GSH/GSSH and NADPH/NADP+in vivo; it also reduced lipid peroxidation and intracellular Fe2+ accumulation, restored MDA levels, and elevated the ratios of GSH/GSSH and NADPH/NADP+ in irradiation-injured H9C2 cells. TEA up-regulated Nrf2, xCT, and GPX4 expression and inhibited NOX4 expression in vivo and in vitro. CONCLUSIONS: Ferroptosis induced by redox imbalance mediated through the NOX4/xCT/GPX4 axis is a potential mechanism behind radiation-induced cardiomyocyte injury, and can be prevented by TEA.

Selenium-Doped Nanoheterojunctions for Highly Efficient Cancer Radiosensitization.

Exploring efficient and low-toxicity radiosensitizers to break through the bottleneck of radiation tolerance, immunosuppression and poor prognosis remains one of the critical developmental challenges in radiotherapy. Nanoheterojunctions, due to their unique physicochemical properties, have demonstrated excellent radiosensitization effects in radiation energy deposition and in lifting tumor radiotherapy inhibition. Herein, they doped selenium (Se) into prussian blue (PB) to construct a nano-heterojunction (Se@PB), which could promote the increase of Fe2+/Fe3+ ratio and conversion of Se to a high valence state with Se introduction. The Fe2+-Se-Fe3+ electron transfer chain accelerates the rate of electron transfer on the surface of the nanoparticles, which in turn endows it with efficient X-ray energy transfer and electron transport capability, and enhances radiotherapy physical sensitivity. Furthermore, Se@PB induces glutathione (GSH) depletion and Fe2+ accumulation through pro-Fenton reaction, thereby disturbs the redox balance in tumor cells and enhances biochemical sensitivity of radiotherapy. As an excellent radiosensitizer, Se@PB effectively enhances X-ray induced mitochondrial dysfunction and DNA damage, thereby promotes cell apoptosis and synergistic cervical cancer radiotherapy. This study elucidates the radiosensitization mechanism of Se-doped nanoheterojunction from the perspective of the electron transfer chain and biochemistry reaction, which provides an efficient and low-toxic strategy in radiotherapy.

Immune Responses to Mycobacterium tuberculosis Infection in the Liver of Diabetic Mice.

Individuals with uncontrolled diabetes are highly susceptible to tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) infection. Novel treatments for TB are needed to address the increased antibiotic resistance and hepatoxicity. Previous studies showed that the administration of liposomal glutathione (L-GSH) can mitigate oxidative stress, bolster a granulomatous response, and diminish the M. tb burden in the lungs of M. tb-infected mice. Nonetheless, the impact of combining L-GSH with conventional TB treatment (RIF) on the cytokine levels and granuloma formation in the livers of diabetic mice remains unexplored. In this study, we evaluated hepatic cytokine profiles, GSH, and tissue pathologies in untreated and L-GSH, RIF, and L-GSH+RIF treated diabetic (db/db) M. tb-infected mice. Our results indicate that treatment of M. tb-infected db/db mice with L-GSH+RIF caused modulation in the levels of pro-inflammatory cytokines and GSH in the liver and mitigation in the granuloma size in hepatic tissue. Supplementation with L-GSH+RIF led to a decrease in the M. tb burden by mitigating oxidative stress, promoting the production of pro-inflammatory cytokines, and restoring the cytokine balance. These findings highlight the potential of L-GSH+RIF combination therapy for addressing active EPTB, offering valuable insights into innovative treatments for M. tb infections.

A Consolidated Understanding of the Contribution of Redox Dysregulation in the Development of Hearing Impairment.

The etiology of hearing impairment is multifactorial, with contributions from both genetic and environmental factors. Although genetic studies have yielded valuable insights into the development and function of the auditory system, the contribution of gene products and their interaction with alternate environmental factors for the maintenance and development of auditory function requires further elaboration. In this review, we provide an overview of the current knowledge on the role of redox dysregulation as the converging factor between genetic and environmental factor-dependent development of hearing loss, with a focus on understanding the interaction of oxidative stress with the physical components of the peripheral auditory system in auditory disfunction. The potential involvement of molecular factors linked to auditory function in driving redox imbalance is an important promoter of the development of hearing loss over time.

Export of heme by the feline leukemia virus C receptor regulates mitochondrial biogenesis and redox balance in the hematophagous insect Rhodnius prolixus.

Heme is a prosthetic group of proteins involved in vital physiological processes. It participates, for example, in redox reactions crucial for cell metabolism due to the variable oxidation state of its central iron atom. However, excessive heme can be cytotoxic due to its prooxidant properties. Therefore, the control of intracellular heme levels ensures the survival of organisms, especially those that deal with high concentrations of heme during their lives, such as hematophagous insects. The export of heme initially attributed to the feline leukemia virus C receptor (FLVCR) has recently been called into question, following the discovery of choline uptake by the same receptor in mammals. Here, we found that RpFLVCR is a heme exporter in the midgut of the hematophagous insect Rhodnius prolixus, a vector for Chagas disease. Silencing RpFLVCR decreased hemolymphatic heme levels and increased the levels of intracellular dicysteinyl-biliverdin, indicating heme retention inside midgut cells. FLVCR silencing led to increased expression of heme oxygenase (HO), ferritin, and mitoferrin mRNAs while downregulating the iron importers Malvolio 1 and 2. In contrast, HO gene silencing increased FLVCR and Malvolio expression and downregulated ferritin, revealing crosstalk between heme degradation/export and iron transport/storage pathways. Furthermore, RpFLVCR silencing strongly increased oxidant production and lipid peroxidation, reduced cytochrome c oxidase activity, and activated mitochondrial biogenesis, effects not observed in RpHO-silenced insects. These data support FLVCR function as a heme exporter, playing a pivotal role in heme/iron metabolism and maintenance of redox balance, especially in an organism adapted to face extremely high concentrations of heme.

Zinc ameliorates acrylamide-induced oxidative stress and apoptosis in testicular cells via Nrf2/HO-1/NfkB and Bax/Bcl2 signaling pathway.

BACKGROUND: Acrylamide is a toxic substance formed in some foods that require high-temperature cooking processes and has been implicated as a gonadotoxic agent. Zinc, on the other hand, is a known antioxidant with fertility-enhancing properties. Hence, this study was designed to explore the possible ameliorative effect of zinc in acrylamide-induced gonadotoxicity. METHODS: Twenty-four male Wistar rats were randomized into control, acrylamide (10 mg/kg of acrylamide), acrylamide + 1 mg/kg of zinc, and acrylamide + 3 mg/kg of zinc. The administration was via the oral route and lasted for 56 days. RESULTS: Zinc treatment ameliorated acrylamide-impaired sperm quality, normal testicular histoarchitecture, and hormonal balance, which was accompanied by increased testicular malondialdehyde and interleukin-1ß and decreased testicular superoxide dismutase (SOD) and catalase (CAT). Furthermore, zinc prevented acrylamide-induced downregulation of testicular nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and B-cell lymphoma 2 (BCl2) expression and upregulation of testicular nuclear factor kappa B (NF-κB) and bcl-2-like protein 4 (bax) expression. CONCLUSION: In conclusion, zinc may protect against acrylamide-induced testicular toxicity, mediated by its antioxidant, anti-inflammatory, and antiapoptotic effects.

A 700 nm LED Light Activated Ru(II) Complex Destroys Tumor Cytoskeleton via Photosensitization and Photocatalysis.

Photoactivable chemotherapy (PACT) using metallic complexes provides spatiotemporal selectivity over drug activation for targeted anticancer therapy. However, the poor absorption in near-infrared (NIR) light region of most metallic complexes renders tissue penetration challenging. Herein, an NIR light triggered dinuclear photoactivable Ru(II) complex (Ru2) is presented and the antitumor mechanism is comprehensively investigated. The introduction of a donor-acceptor-donor (D-A-D) linker greatly enhances the intramolecular charge transition, resulting in a high molar extinction coefficient in the NIR region with an extended triplet excited state lifetime. Most importantly, when activated by 700 nm NIR light, Ru2 exhibits unique slow photodissociation kinetics that facilitates synergistic photosensitization and photocatalytic activity to destroy diverse intracellular biomolecules. In vitro and in vivo experiments show that when activated by 700 nm NIR light, Ru2 exhibits nanomolar photocytotoxicity toward 4T1 cancer cells via the induction of calcium overload and endoplasmic reticulum (ER) stress. These findings provide a robust foundation for the development of NIR-activated Ru(II) PACT complexes for phototherapeutic application.

Evaluation of nanoplastics-induced redox imbalance in cells, larval zebrafish, and daphnia magna with a superoxide anion radical fluorescent probe.

Nanoplastics (NPs) is a novel plastic contaminant that could be taken up by cells and lead to severe biotoxicity toxicity, NPs in cells can cause oxidant damage by inducing reactive oxygen species (ROS) production and lead to acute inflammation. As a major ROS which related to many kinds of physiological and pathological processes, superoxide anion radical (O2•-) could be utilized as a signal of oxidant damage effected by NPs exposure in vivo. To detect the toxic damage mechanism of NPs, a fluorescence probe Bcy-OTf has been developed to monitor O2•- fluctuations content in cells and aquatic organisms after exposure to NPs. The probe has a high sensitivity (LOD = 20 nM) and a rapid responsive time (within 6 min), and it has high selectivity and low cytotoxicity to analysis the levels of the endogenous O2•-. Endogenous O2•- induced by NPs in living cells, Daphnia magna and larval zebrafish were analyzed. Moreover, the results confirmed the key role of MAPK and NF-κB pathway in NPs stimulation mechanisms in cells. This study indicated that Bcy-OTf can precisely assess the fluctuations of endogenous O2•-, which has potential for applying in further analysis mechanisms of NPs biological risks.

Targeted Redox Balancing through Pulmonary Nanomedicine Delivery Reverses Oxidative Stress Induced Lung Inflammation.

Non-invasive delivery of drugs is important for the reversal of respiratory diseases essentially by-passing metabolic pathways and targeting large surface area of drug absorption. Here, we study the inhalation of a redox nano medicine namely citrate functionalized Mn3O4 (C-Mn3O4) duly encapsulated in droplet evaporated aerosols for the balancing of oxidative stress generated by the exposure of Chromium (VI) ion, a potential lung carcinogenic agent. Our optical spectroscopic in-vitro experiments demonstrates the efficacy of redox balancing of the encapsulated nanoparticles (NP) for the maintenance of a homeostatic condition. The formation of Cr-NP complex as an excretion of the heavy metal is also demonstrated through optical spectroscopic and high resolution transmission optical microscopy (HRTEM). Our studies confirm the oxidative stress mitigation activity of the Cr-NP complex. A detailed immunological assay followed by histopathological studies and assessment of mitochondrial parameters in pre-clinical mice model with chromium (Cr) induced lung inflammation establishes the mechanism of drug action to be redox-buffering. Thus, localised delivery of C-Mn3O4 NPs in the respiratory tract via aerosols can act as an effective nanotherapeutic agent against oxidative stress induced lung inflammation.

PM2.5 induce neurotoxicity via iron overload and redox imbalance mediated-ferroptosis in HT22 cells.

PM2.5 is an important risk factor for the development and progression of cognitive impairment-related diseases. Ferroptosis, a new form of cell death driven by iron overload and lipid peroxidation, is proposed to have significant implications. To verify the possible role of ferroptosis in PM2.5-induced neurotoxicity, we investigated the cytotoxicity, intracellular iron content, iron metabolism-related genes, oxidative stress indices and indicators involving in Nrf2 and ferroptosis signaling pathways. Neurotoxicity biomarkers as well as the ferroptotic cell morphological changes were determined by Western Blot and TEM analysis. Our results revealed that PM2.5 induced cytotoxicity, lipid peroxidation, as indicated by MDA content, and neurotoxicity via Aß deposition in a dose-related manner. Decreased cell viability and excessive iron accumulation in HT-22 cells can be partially blocked by ferroptosis inhibitors. Interestingly, GPX activity, Nrf2, and its regulated ferroptotic-related proteins (i.e. GPX4 and HO-1) were significantly up-regulated by PM2.5. Moreover, gene expression of DMT1, TfR1, IRP2 and FPN1 involved in iron homeostasis and NCOA4-dependent ferritinophagy were activated after PM2.5 exposure. The results demonstrated that PM2.5 triggered ferritinophagy-dependent ferroptotic cell death due to iron overload and redox imbalance. Activation of Nrf2 signaling pathways may confer a protective mechanism for PM2.5-induced oxidative stress and ferroptosis.

Nanomaterials-Induced Redox Imbalance: Challenged and Opportunities for Nanomaterials in Cancer Therapy.

Cancer cells typically display redox imbalance compared with normal cells due to increased metabolic rate, accumulated mitochondrial dysfunction, elevated cell signaling, and accelerated peroxisomal activities. This redox imbalance may regulate gene expression, alter protein stability, and modulate existing cellular programs, resulting in inefficient treatment modalities. Therapeutic strategies targeting intra- or extracellular redox states of cancer cells at varying state of progression may trigger programmed cell death if exceeded a certain threshold, enabling therapeutic selectivity and overcoming cancer resistance to radiotherapy and chemotherapy. Nanotechnology provides new opportunities for modulating redox state in cancer cells due to their excellent designability and high reactivity. Various nanomaterials are widely researched to enhance highly reactive substances (free radicals) production, disrupt the endogenous antioxidant defense systems, or both. Here, the physiological features of redox imbalance in cancer cells are described and the challenges in modulating redox state in cancer cells are illustrated. Then, nanomaterials that regulate redox imbalance are classified and elaborated upon based on their ability to target redox regulations. Finally, the future perspectives in this field are proposed. It is hoped this review provides guidance for the design of nanomaterials-based approaches involving modulating intra- or extracellular redox states for cancer therapy, especially for cancers resistant to radiotherapy or chemotherapy, etc.

Triglycerides Mediate the Influence of Body Mass Index on Non-Alcoholic Fatty Liver Disease in a Non-Obese Chinese Population with Normal Low-Density Lipoprotein Cholesterol Levels.

INTRODUCTION: Over 25% of the world's population has non-obese or lean non-alcoholic fatty liver disease (NAFLD), and the prevalence is higher than average in Asia. The present study focused on the relationship between body mass index (BMI) and non-obese NAFLD in non-overweight people in China, particularly the influence of triglycerides (TG) in the pathogenesis of non-obese NAFLD. The findings suggest new treatments for NAFLD patients with normal BMI, as well as provide an early warning system for the understanding and prevention of NAFLD in non-obese patients. METHODS: This cross-sectional study enrolled 159,959 Chinese subjects with BMI <24 kg/m2 and normal levels of low-density lipoprotein cholesterol (LDL-c). The average age was 40.21 ± 13.88 years, and males accounted for 45.7%. A total of 15,907 (9.94%) patients with NAFLD were diagnosed by ultrasonography. Biochemical indicators were measured using an automated analyzer (Abbott AxSYM). The BMI (kg/m2) was calculated from the weight (kg)/height in square meters (m2). The BMI quartile was used as the column-stratified variable to determine the baseline distribution, and logistic regression analysis was used to assess the relationship between NAFLD and its risk factors, with multiple logistic regression used to assess the relationships between BMI or TG and NAFLD and multivariate linear regression used to analyze the association between BMI and TG, while mediation analysis was used to assess the mediation effect of TG. RESULTS: After adjustment of all covariates, the odds ratios were 1.788 (95% CI: 1.749-1.829; p < 0.00001) and 1.491 (95% CI: 1.451-1.532; p < 0.00001) for the association between BMI and TG with NAFLD incidence. The multivariate linear regression coefficient of BMI and TG was ß = 0.027 (95% CI: 0.023-0.030; p < 0.00001). Mediation analysis showed that BMI contributed to 10.81% of lean NAFLD with a mediation effect of 2.98%. CONCLUSION: In a Chinese population with BMI <24 kg/m2 and normal LDL-c levels, BMI and TG were found to be independent predictors of NAFLD. The direct effect of BMI on non-obese NAFLD was 10.41%. The TG level was found to partially mediate the association.

De Novo Design of Near-Infrared Fluorescent Agents Activated by Peroxynitrite and Glutathione-Responsive Imaging for Diabetic Liver Disease.

Diabetes and its complications, such as diabetes liver disease, is a major problem puzzling people's health. The detection of redox states in its pathological process can effectively help us gain a deeper understanding of the disease. The pair of oxidation-reduction substances peroxynitrite (ONOO- ) and glutathione (GSH) is considered to be closely related to their occurrence and development. Thus, direct visualization of ONOO- and GSH in diabetes liver disease is critical to evaluate the disease at the molecular level. Herein, two activatable agents NTCF-ONOO- and NTCF-GSH are prepared for selectively detecting ONOO- and GSH through protection and deprotection strategies based on hydroxyl and amino groups of near-infrared fluorophore. Fluorescence imaging of exogenous and endogenous ONOO- and GSH changes in living cells and in vivo is observed. The ONOO- and GSH level in the diabetes liver disease cellular model are visualized and the possible redox imbalance mechanism related to the oxidized (NAD+ ) and reduced (NADH) nicotinamide adenine dinucleotides is explored in this process. Moreover, these probes can sensitively recognize ONOO- and GSH in the process of oxidative stress resulting from streptozotocin and streptozotocin/acetaminophen-induced complex diabetic liver disease in vivo. In addition, they can be applied for monitoring the clinical serum sample related with diabetic patients.

Involvement of brassinosteroids and abscisic acid in spikelet degeneration in rice under soil drying during meiosis.

Spikelet degeneration in rice (Oryza sativa L.) is a serious physiological defect, and can be regulated by soil moisture status and phytohormones. This study investigated the possibility that brassinosteroids (BRs) in collaboration with abscisic acid (ABA) are involved in mediating the effect of soil drying during meiosis on spikelet degeneration in rice. Three rice cultivars were field grown and three irrigation regimes including well watered (WW), moderate soil drying (MD), and severe soil drying (SD) were imposed during meiosis. MD significantly decreased spikelet degeneration in comparison with WW, due mainly to the alleviation in oxidative damage via enhancing ascorbate-glutathione (AsA-GSH) cycle activity in young panicles, and SD exhibited the opposite effects. Enhanced AsA-GSH cycle strength, decreased oxidative stress, and spikelet degeneration rate were closely associated with the synergistically elevated BR and ABA levels in young panicles in MD. In contrast, low BR and excessive ABA levels led to an increase in spikelet degeneration in SD. The three cultivars exhibited the same tendencies. The intrinsic link among AsA-GSH cycle, oxidative stress, spikelet degeneration rate, and BR and ABA levels was further verified by using transgenic rice lines and chemical regulators. BRs or ABA play a unique role in regulating spikelet degeneration. Synergistically increased BR and ABA levels in MD could work together to strengthen AsA-GSH cycle activity, leading to a reduction in oxidative damage and spikelet degeneration. On the other hand, a severe imbalance between low BR and excessive ABA levels may have contributed to the opposite effects in SD.

Supplementation of media with gamma-oryzanol as a novel antioxidant to overcome redox imbalance during bovine oocyte maturation in vitro.

This study evaluated the effect of supplementing IVM media with γ-oryzanol (ORY), a nutraceutical derived from rice bran oil, on the development of bovine oocytes and hindering the compromising effect of redox imbalance. An in vitro model of the bovine cumulus-oocyte complex was used for the evaluation of nuclear maturation and development. Antioxidant activity was investigated by assessing the level of ROS (Reactive Oxygen Species) and GSH (glutathione) in oocytes and quantitative changes in gene expression in matured oocytes and their respective cumulus cells. ORY supplementation increased the proportion of MII oocytes, cleaved embryos, and total blastocysts (p < .05) and was linked to higher and lower levels of intracellular GSH and ROS, respectively (p < .05). The treated oocytes and their respective cumulus-granulosa cells showed a modulation in the expression of genes related to apoptosis (downregulation of BAX and CHOP) and oxidative stress (upregulation of NRF2, CAT, and SOD). Also, relative upregulation of OCT-4 and IGF2R in treated oocytes was concomitant with higher subsequent development in terms of cleavage and total blastocyst rates (p < .05). Based on our findings, it appears that ORY supplementation can improve the nuclear maturation and development of bovine oocytes into blastocysts and augment their enzymatic and non-enzymatic antioxidant systems, maintaining the Redox balance and high enzymatic activity against ROS generation.

Aging-related NOX4-Nrf2 redox imbalance increases susceptibility to cisplatin-induced acute kidney injury by regulating mitophagy.

BACKGROUND: During aging, excessive ROS production in the kidneys leads to redox imbalance, which contributes to oxidative damage and impaired organ homeostasis. However, whether and how aging-related NOX4-Nrf2 redox imbalance increases susceptibility to cisplatin-induced acute kidney injury remain largely unknown. METHODS: In this study, we used cisplatin-challenged aging mouse models and senescent HK-2 cells to investigate the effects and mechanisms of aging on susceptibility to cisplatin-induced acute kidney injury. RESULTS: In vivo, we found that cisplatin stimulation caused more severe renal damage, oxidative stress, mitochondrial dysfunction and mitophagy impairment in aging mice than in young mice. Moreover, Nrf2 deficiency aggravated cisplatin-induced acute kidney injury by exacerbating NOX4-Nrf2 redox imbalance and defective mitophagy. In vitro experiments on D-gal-treated human renal tubular epithelial cells (HK-2) demonstrated that senescent renal epithelial cells exhibited increased susceptibility to cisplatin-induced apoptosis, NOX4-Nrf2 redox imbalance-mediated oxidative stress and defective mitophagy. Mechanistically, we found that knockdown of Nrf2 in HK2 cells resulted in increased ROS and aggravated mitophagy impairment, whereas these effects were reversed in NOX4-knockdown cells. CONCLUSION: The present study indicates that NOX4-Nrf2 redox imbalance is critical for mitophagy deficiency in aged renal tubular epithelial cells and is a therapeutic target for alleviating cisplatin-induced acute kidney injury in elderly patients.

Toxic effects of the heavy metal Cd on Apis cerana cerana (Hymenoptera: Apidae): Oxidative stress, immune disorders and disturbance of gut microbiota.

Cadmium (Cd) is a toxic non-essential metal element that can enter the honey bee body through air, water and soil. Currently, there is a lack of sufficient research on the effects of Cd on A. cerana cerana, especially the potential risks of long-term exposure to sublethal concentrations. In order to ascertain the toxicological effects of the heavy metal Cd on bees, we performed laboratory-based toxicity experiments on worker bees and conducted analyses from three distinctive facets: antioxidative, immunological, and gut microbiota. The results showed that exposure of bees to high concentrations of Cd resulted in acute mortality, and the increase in mortality was concentration dependent. In long-term exposure to sublethal concentrations, Cd reduced the number of transcripts of antioxidant genes (AccSOD1, AccTPx3 and AccTPx4) and superoxide dismutase activity, causing an increase in malondialdehyde content. Simultaneously, the transcription of immune-related genes (AccAbaecin and AccApidaecin) and acetylcholinesterase activities was inhibited. Furthermore, Cd changes the structural characteristics of bacterial and fungal communities in the gut, disrupting the balance of microbial communities. In conclusion, the health and survival of honey bees are affected by Cd. This study provides a scientific basis for investigating the toxicological mechanisms and control strategies of the heavy metal Cd on honey bees, while facilitating a better understanding and protection of these valuable honey bees.

In situ generation of hybrid alginate hydrogels for enhanced breast tumor ferrotherapy through multiplex magnifying redox imbalances.

Ferroptosis has drawn great attention to tumor treatments over the past decade. However, how to specifically boost tumoral redox imbalance by simultaneously superimposing iron-mediated reactive oxygen species and undermining antioxidative pathways at the tumor site is still a significant challenge in ferroptosis-based tumor ferrotherapy. In this study, we designed an in situ generable hydrogel that contains paclitaxel/chlorin e6-loaded iron-based metal-organic framework (Fe-MOF) nanoparticles for enhanced breast tumor ferrotherapy by multiplex magnifying redox imbalance. The polysaccharide sodium alginate can crosslink with tumoral calcium ions to generate a hydrogel patch, which promotes the retention of Fe-MOF and therapeutic molecules. The Fe-MOF holds peroxidase/glutathione oxidase mimicking properties, resulting in OH generation via the Fenton reaction and glutathione consumption. Local ultrasound treatment facilitates the release of therapeutics and stimulates the generation of signet oxygen by activating the sonosensitizer chlorin e6. In the meanwhile, the low-dose paclitaxel reduces tumoral pH value by downregulating the glutaminolysis-related gene (SLC7A11) which in turn enhances the catalytic activity of Fe-MOF and inhibits antioxidative pathways, respectively. Both in vivo and in vitro experiments show that our designed hybrid hydrogels can induce significant ferrotherapeutic effects by augmenting the tumoral oxidative stresses.