A Drug-Eluting Injectable NanoGel for Localized Delivery of Anticancer Drugs to Solid Tumors.

Systemically administered chemotherapy reduces the efficiency of the anticancer agent at the target tumor tissue and results in distributed drug to non-target organs, inducing negative side effects commonly associated with chemotherapy and necessitating repeated administration. Injectable hydrogels present themselves as a potential platform for non-invasive local delivery vehicles that can serve as a slow-releasing drug depot that fills tumor vasculature, tissue, or resection cavities. Herein, we have systematically formulated and tested an injectable shear-thinning hydrogel (STH) with a highly manipulable release profile for delivering doxorubicin, a common chemotherapeutic. By detailed characterization of the STH physical properties and degradation and release dynamics, we selected top candidates for testing in cancer models of increasing biomimicry. Two-dimensional cell culture, tumor-on-a-chip, and small animal models were used to demonstrate the high anticancer potential and reduced systemic toxicity of the STH that exhibits long-term (up to 80 days) doxorubicin release profiles for treatment of breast cancer and glioblastoma. The drug-loaded STH injected into tumor tissue was shown to increase overall survival in breast tumor- and glioblastoma-bearing animal models by 50% for 22 days and 25% for 52 days, respectively, showing high potential for localized, less frequent treatment of oncologic disease with reduced dosage requirements.

Combined Use of Photobiomodulation and Curcumin-Loaded Iron Oxide Nanoparticles Significantly Improved Wound Healing in Diabetic Rats Compared to Either Treatment Alone.

Introduction: Here, we assess the therapeutic effects of photobiomodulation (PBM) and curcumin (CUR)-loaded superparamagnetic iron oxide nanoparticles (SPIONs), alone or together, on the maturation step of a type 1 diabetes (DM1) rat wound model. Methods: Full-thickness wounds were inflicted in 36 rats with diabetes mellitus (DM) induced by the administration of streptozotocin (STZ). The rats were randomly allocated to four groups. Group one was untreated (control); group two received CUR; group 3 received PBM (890 nm, 80 Hz, 0.2 J/cm2); group 4 received a combination of PBM plus CUR. On days 0, 4, 7, and 15, we measured microbial flora, wound closure fraction, tensile strength, and stereological analysis. Results: All treatment groups showed a substantial escalation in the wound closure rate, a substantial reduction in the count of methicillin-resistant Staphylococcus aureus (MRSA), a substantial improvement in wound strength, a substantially improvement in stereological parameters compared to the control group, however, the PBM+CUR group was superior to the other treatment groups (all, P≤0.05). Conclusion: All treatment groups showed significantly improved wound healing in the DM1 rat model. However, the PBM+CUR group was superior to the other treatment groups and the control group in terms of wound strength and stereological parameters.

Fabrication of a microfluidic device for probiotic drug's dosage screening: Precision Medicine for Breast Cancer Treatment.

Breast cancer is the most common cancer in women; it has been affecting the lives of millions each year globally and microfluidic devices seem to be a promising method for the future advancements in this field. This research uses a dynamic cell culture condition in a microfluidic concentration gradient device, helping us to assess breast anticancer activities of probiotic strains against MCF-7 cells. It has been shown that MCF-7 cells could grow and proliferate for at least 24 h; however, a specific concentration of probiotic supernatant could induce more cell death signaling population after 48 h. One of our key findings was that our evaluated optimum dose (7.8 mg/L) was less than the conventional static cell culture treatment dose (12 mg/L). To determine the most effective dose over time and the percentage of apoptosis versus necrosis, flowcytometric assessment was performed. Exposing the MCF-7 cells to probiotic supernatant after 6, 24 and 48 h, confirmed that the apoptotic and necrotic cell death signaling were concentration and time dependent. We have shown a case that these types of microfluidics platforms performing dynamic cell culture could be beneficial in personalized medicine and cancer therapy.

Photobiomodulation therapy reverses spermatogenesis arrest in hyperthermia-induced azoospermia mouse model.

Testicular heat stress leads to impairment of spermatogenesis in mammals. Involved mechanism in this vulnerability to heat-induced injury remains unclear, and research is being conducted to find an approach to reverse spermatogenesis arrest caused by hyperthermia. Recently, different studies have utilized photobiomodulation therapy (PBMT) therapy for the improvement of sperm criteria and fertility. This study aimed at evaluating the effect of PBMT on the improvement of spermatogenesis in mouse models of hyperthermia-induced azoospermia. A total of 32 male NMRI mice were equally divided into four groups consisting of control, hyperthermia, hyperthermia + Laser 0.03 J/cm2, and hyperthermia + Laser 0.2 J/cm2. To induce scrotal hyperthermia, mice were anesthetized and placed in a hot water bath at 43 °C for 20 min for 5 weeks. Then, PBMT was operated for 21 days using 0.03 J/cm2 and 0.2 J/cm2 laser energy densities in the Laser 0.03 and Laser 0.2 groups, respectively. Results revealed that PBMT with lower intensity (0.03 J/cm2) increased succinate dehydrogenase (SDH) activity and glutathione (GSH)/oxidized glutathione (GSSG) ratio in hyperthermia-induced azoospermia mice. At the same time, low-level PBMT reduced reactive oxygen species (ROS), mitochondrial membrane potential, and lipid peroxidation levels in the azoospermia model. These alterations accompanied the restoration of spermatogenesis manifested by the elevated number of testicular cells, increased volume and length of seminiferous tubules, and production of mature spermatozoa. After conducting experiments and analyzing the results, it has been revealed that the use of PBMT at a dosage of 0.03 J/cm2 has shown remarkable healing effects in the heat-induced azoospermia mouse model.

Stem Cell Differentiation into Cardiomyocytes: Current Methods and Emerging Approaches.

Cardiovascular diseases (CVDs) are globally known to be important causes of mortality and disabilities. Common treatment strategies for CVDs, such as pharmacological therapeutics impose serious challenges due to the failure of treatments for myocardial necrosis. By contrast, stem cells (SCs) based therapies are seen to be promising approaches to CVDs treatment. In such approaches, cardiomyocytes are differentiated from SCs. To fulfill SCs complete potential, the method should be appointed to generate cardiomyocytes with more mature structure and well-functioning operations. For heart repairing applications, a greatly scalable and medical-grade cardiomyocyte generation must be used. Nonetheless, there are some challenges such as immune rejection, arrhythmogenesis, tumorigenesis, and graft cell death potential. Herein, we discuss the types of potential SCs, and commonly used methods including embryoid bodies related techniques, co-culture, mechanical stimulation, and electrical stimulation and their applications, advantages and limitations in this field. An estimated 17.9 million people died from CVDs in 2019, representing 32 % of all global deaths. Of these deaths, 85 % were due to heart attack and stroke.

Selective Toxicity Effect of Chrysaora quinquecirrha Crude Venom on Human Colorectal Tumor Cells by Directly Targeting Mitochondria.

OBJECTIVE: Compounds isolated from marine animals have different pharmacological effects. In this study, we investigated the effects of sea nettle (Chrysaora quinquecirrha) crude venom on human colon cancer mitochondria. METHODS: First, mitochondria were isolated from healthy colon tissue and cancerous colon tissue, and then mitochondrial function (SDH activity), reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release were measured. RESULTS: The results showed that crude venom of Chrysaora quinquecirrha (180, 360 and 720 µg/ml) can significantly impair mitochondrial function (**P<0.01 and ***P<0.001) and consequently increase the level of ROS (*P<0.05 and ****P<0.0001), collapse in MMP (*P<0.05 and ****P<0.0001), mitochondrial swelling (**** P<0.0001) and release of cytochrome c (* P<0.05 and *** P<0.001) only in mitochondria isolated from human colon cancer tissue. CONCLUSION: The results concluded that crude venom of Chrysaora quinquecirrha (180, 360 and 720 µg/ml) has no side effects on normal mitochondria and only selectively affects cancerous mitochondria. It seems that after further research, Chrysaora quinquecirrha can be considered as a drug candidate for the treatment of patients with colon cancer.

Toxicity of Hydrogen Sulfide on Rat Brain Neurons.

Hydrogen sulfide (H2S) is a toxic compound known as a member of the gasotransmitter family. H2S has the ability to inhibit the cytochrome c oxidase enzyme in the mitochondrial respiratory chain. Mitochondria play an important role in energy production and the brain needs energy for normal function. Mitochondrial dysfunction is associated with neurodegenerative diseases. This study investigated the mechanisms of cytotoxicity induced by H2S in brain neurons. thioacetamide has been used to produce H2S in water solutions. The results of the study showed that thioacetamide at concentrations of 116, 232 and 464 µg/ml was able to increase the level of reactive oxygen species (ROS), collapse in mitochondrial membrane potential (MMP), damage to the lysosomal membrane, increase in the level of oxidized glutathione (GSSG) and decrease in the level of reduced glutathione (GSH) in brain neurons. The results of the study suggested that H2S causes damage to mitochondria and lysosomes in brain neurons that could be associated with neurodegenerative diseases.

Selective cytotoxicity mechanisms and biodistribution of diamond nanoparticles on the skin cancer in C57 mouse.

The cytotoxicity of diamond nanoparticles (DNs) to various cell lines has been on focus by numerous scientists. The cellular toxicity system of DNs has not been fully understood or explained in skin cancer, at this point. This research was carried out to discover and reveal the potential impacts of DNs on the secluded brain, heart, liver, kidney, and skin in addition to evaluation of their cytotoxicity mechanism under test conditions. Their biological activities, for example cell viability, the level of reactive oxygen species (ROS), lipid peroxidation, cytochrome c release and Apoptosis/Necrosis were evaluated. Additionally, the bio-distribution of these nanomaterials in tissues was examined in the C57 mouse. Relying on the findings of the investigation, DNs were found to increase the ROS level, Malondialdehyde (MDA) content, release of cytochrome c, and cell death in skin significantly compared to other groups. In the C57 mouse, DNs were observed to have accumulated in skin tissue more intensively than they did in other organs. The present study presents for the proof that DNs can completely induce cell death signaling in skin cancer without bringing about a high cytotoxicity in other tissues. Results suggest that DNs can be valuable in recognition of skin cancer.

Evaluation of Cytotoxic Potentials of Novel Synthesized Chalconeferrocenyl Derivative against Melanoma and Normal Fibroblast and Its Anticancer Effect through Mitochondrial Pathway.

The treatment of melanoma is still challenging and therefore identification of novel agents is needed for its better management. Our previous study suggested that cyclooxygenase-2 (COX-2) would be a novel target for treatment of several cancers. In the present study, we searched selective cytotoxicity and mitochondria mediated apoptosis of novel synthesized chalconeferrocenyl derivative (1-Ferrocenyl-3-(dimethylamino)-3-(4-methylsulfonylphenyl) propan-1-one) (FDMPO) as a COX-2 inhibitor on normal and melanoma cells and their mitochondria. For this purpose, we evaluated the cellar parameters such as cytotoxicity, apoptosis% versus necrosis%, activation of caspase-3 and ATP content, and also mitochondrial parameters such as reactive oxygen species formation, mitochondrial swelling, mitochondrial membrane potential decline, mitochondrial membrane integrity, and cytochrome C release. Our results showed FDMPO could selectively induce cellular and mitochondrial toxicity (up to 50 µM) on melanoma cells and mitochondria without any toxic effects on normal fibroblast and their mitochondria. Taken together, the results of this study suggest that mitochondria are a potential target for the melanoma. Selective inhibition of mitochondrial COX-2 could be an attractive therapeutic option for the effective clinical management of therapy-resistant melanoma.

Photobiomodulation Therapy Improves Spermatogenesis in Busulfan-Induced Infertile Mouse.

About 50% of infertility is caused by men. This study aimed to investigate the efficiency of photobiomodulation on spermatogenesis in a busulfan-induced infertile mouse as a testicular degeneration treatment. Thirty-two adult NMRI male mice were divided into 4 groups: control, busulfan, PBMT 0.03 J/cm2, and laser 0.2 J/cm2. In the study, azoospermia was induced by busulfan as a testicular degeneration, and then, they were treated using photobiomodulation therapy at 0.03 J/cm2 and 0.2 J/cm2 energy densities. Sperm parameters, stereological analysis, serum testosterone levels, together with SDH activity, MDA production oxidized as a marker for lipid peroxidation, glutathione (GSSG) and glutathione (GSH), mitochondrial membrane permeability (MMP), reactive oxygen species (ROS) production, and ATP production as well as TUNEL assay were assessed. Photobiomodulation therapy with 0.03 J/cm2 energy densities group revealed a significant increase the testosterone hormone level and spermatogenic cells with the reduction of apoptotic cells and marked increase in GSH, ATP, and SDH levels and decrease the levels of MDA and ROS production in the busulfan-induced mice when compared with the control and sham groups. In conclusion, the photobiomodulation therapy (0.03 J/cm2 energy density) may provide benefits on the spermatogenesis following busulfan injection and might be an alternative treatment to the patients with oligospermia and azoospermia in a dose-dependent manner.

Curcumin-Loaded Iron Particle Improvement of Spermatogenesis in Azoospermic Mouse Induced by Long-Term Scrotal Hyperthermia.

Spermatogenesis process is sensitive to heat stress because the testicular temperature is 2 to 4 °C lower than the core body temperature. The current study aimed to investigate the effects of iron oxide nanoparticles containing curcumin on spermatogenesis in mice induced by long-term scrotal hyperthermia. In this experimental study, 18 mice were equally divided into the following three groups: control, scrotal hyperthermia, and scrotal hyperthermia + curcumin-loaded iron particles (NPs) (240 µL) (mice were treated for 20 days). Hyperthermia was induced by exposure to the temperature of 43 °C for 20 min every other day for 5 weeks. Afterward, the animals were euthanized; sperm samples were collected for sperm parameters analysis, and testis samples were taken for histopathology experiments, evaluation of serum testosterone level, and RNA extraction in order to examine the expression of c-kit, STRA8 and PCNA genes. Our study showed that curcumin-loaded iron particles could notably increase the volume of testis, length of seminiferous tubules, sperm parameters, and stereological parameters (i.e., spermatogonia, primary spermatocyte, round spermatid, and Leydig cells) thereby increasing serum testosterone level; in addition, TUNEL-positive cells showed a significant decrease in curcumin-loaded iron particle group. Thus, based on the obtained results, the expression of c-kit, STRA8, and PCNA genes was significantly increased in treatment groups by curcumin-loaded iron particles compared with scrotal hyperthermia-induced mice. In conclusion, curcumin-loaded iron particles can be considered an alternative treatment for improving the spermatogenesis process in scrotal hyperthermia-induced mice.

Toxicological assessment of 3-monochloropropane-1,2-diol (3-MCPD) as a main contaminant of foodstuff in three different in vitro models: Involvement of oxidative stress and cell death signaling pathway.

3-Monochloropropane-1,2-diol (3-MCPD) as a main source of food contamination has always been known as a carcinogenic agent. Kidney, liver, testis, and heart seem to be the main target organs for 3-MCPD. Because oxidative stress and mitochondrial dysfunction have been realized to be involved in 3-MCPD-induced cytotoxicity, the present study aimed to investigate the probable toxicity mechanisms of 3-MCPD in isolated mitochondria, HEK-293 cell line, and cell isolated from the rats' liver and kidney through measuring multiparametric oxidative stress assay. Based on the data indicating no significant difference between 3-MCPD-treated groups and control group, metabolites of 3-MCPD have a key role in organ toxicity caused by them. To further investigating the suggested hypothesis, the effect of 3-MCPD toxicity on HEK-293 cell line was examined. Although the proliferation declined after exposure to a low dose of 3-MCPD (10 to 200 µM), controversial responses in higher concentration (2 to 10 mM) have led to studies on the effect of oxidative stress and cell death signaling on isolated kidney and liver cells. Treatment of the isolated kidney and liver cells with 3-MCPD resulted in an increase in the level of reactive oxygen species (ROS), the collapse of mitochondrial membrane potential (MMP), and activation of cell death signaling without creating any significant difference in the amount of reduced glutathione. In fact, 3-MCPD can disrupt the mitochondrial electron transfer in isolated cells, which is correlated with the impairment of mitochondrial oxidative phosphorylation system, the rise of ROS level, and the failure of MMP, leading to the release of cytochrome c from mitochondria to cytosol and finally the activation of cell death signaling.

Role of Mitochondria and Lysosomes in the Selective Cytotoxicity of Cold Atmospheric Plasma on Retinoblastoma Cells.

Retinoblastoma (RB) is a common malignancy in childhood, with an incidence of 1 per 20,000 live births. Several approaches such as chemotherapy, laser, and radiotherapy have been used for the treatment of RB. However, the effectiveness of these methods is not sufficient and the mechanisms involved in the pathogenesis of the disease are not well understood. The disruption of the apoptotic process is considered as one of the mechanisms involved in the pathogenesis of RB. This study was designed to examine the in-vitro selective toxicity of cold atmospheric plasma (CAP) on RB cells' mitochondria and lysosomes. The results showed that CAP decreased cell viability and GSH content and also increased caspase-3 activity and lipid peroxidation (LPO) in cancerous ocular cells isolated from the rat model of RB compared to the normal rat ocular cells. Furthermore, results demonstrated that CAP significantly increased ROS generation, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release only in cancerous rat ocular mitochondria but not the normal rat ocular mitochondria. Furthermore, our results demonstrated that CAP significantly increased the lysosomal damage only in the cancer group. Altogether, the results of the study showed that CAP could selectively induce apoptosis on RB mitochondria. CAP may therefore be considered as a promising candidate for further in-vivo and clinical researches to reach a new anti- RB drug.

Investigation of the effect of magnetite iron oxide particles size on cytotoxicity in A549 cell line.

INTRODUCTION: Magnetite as iron oxide is widely used in various industries, in the pharmaceutical industry in particular where it is used for its magnetic properties. The environmental and occupational exposure to airborne nanoparticles and microparticles of iron oxide compounds have been reported. Since authors have reported contradictory results, the objective of this study was to investigate the effect of particles' size in their toxicities. METHODS: The human cell line A549 was exposed with magnetite iron oxide in two size categories of micro (≥5 µm) and nano (<100 nm), with four concentrations of 10, 50, 100, and 250 µg/ml at two time periods of 24 and 72 h. The cell viability, reactive oxygen species (ROS), changes in mitochondrial membrane potential, and incidence of apoptosis were studied. RESULTS: Nano and micro magnetite particles demonstrated diverse toxicity effects on the A549 cell line at the 24- and 72-h exposure periods; however, the effects produced were time- and concentration-dependent. Nano magnetite particles produced greater cellular toxicities in forms of decreased viabilities at concentration exposures greater than 50 µg/ml (p < 0.05), along with increased ROS (p < 0.05), decreased cellular membrane potential (p < 0.05), and reduced rate of apoptosis (p < 0.05). DISCUSSION: The results of this study demonstrated that magnetite iron in nano-range sizes had a greater absorbability for the A549 cell line compared to micro sizes, and at the same time, nanoparticles were more toxic than microparticles, demonstrating higher production of ROS and decreased viabilities. Considering the greater toxicity of nanoparticles of magnetite iron in this study, thorough precautionary control measures must be taken before they can be used in various industries.

Nickel oxide nanoparticles exert selective toxicity on skin mitochondria and lysosomes isolated from the mouse model of melanoma.

Nickel oxide nanoparticles (NiO-NPs) are progressively used for an immense number of new applications in modern industries sectors. Nevertheless, the toxic impact of NiO-NPs has not been clearly elucidated on human melanoma cell lines at the cellular and molecular level. Hence, this study was designed to examine the in vitro cytotoxicity potentials of NiO-NPs on malignant cutaneous melanoma (MCM) mitochondria. Results revealed that NiO-NPs significantly increased reactive oxygen species level, lipid peroxidation, and mitochondrial membrane potential and decreased succinate dehydrogenase activity, glutathione level, and ATP content on skin mitochondria isolated from the mouse model of melanoma compared with the non-cancerous mouse skin mitochondria. Our results revealed that NiO-NPs induced lysosomal membrane labialization on mentioned mitochondria. The current study showed that NiO-NPs could significantly induce selective cytotoxicity on MCM mitochondria. Therefore, this compound may be considered as a promising candidate for further in vivo and clinical studies to reach a new anti-MCM drug.

Mitochondrial Permeability Transition Pore Sealing Agents and Antioxidants Protect Oxidative Stress and Mitochondrial Dysfunction Induced by Naproxen, Diclofenac and Celecoxib.

Nonsteroidal anti-inflammatory drugs (NSAIDs) like naproxen, diclofenac and celecoxib used to reduce pain. Many of these drugs have been associated with an increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which NSAIDs induce CVD up to now is unknown. We investigated the effects of naproxen, diclofenac and celecoxib with different structures and mechanism action on isolated rat heart mitochondria. All tested NSAIDs increased reactive oxygen species (ROS) formation, mitochondrial membrane collapse (MMP), mitochondrial swelling, lipid peroxidation, and glutathione and ATP depletion, which all of them play important roles in developing cardiotoxicity. We reported that mitochondrial permeability transition (MPT) pore sealing agents and antioxidants have the capacity to significantly prevent mitochondrial toxicity. Therefore, the inhibition of mitochondrial oxidative stress and mitochondrial dysfunction by MPT pore sealing agents and antioxidants can double confirm NSAID-induced cardiomyocytes toxicity is resulted from induction of apoptosis signaling trough ROS-mediated mitochondrial permeability transition.

Effects of Sertoli Cell Transplantation on Spermatogenesis in Azoospermic Mice.

BACKGROUND/AIMS: The aim of this study was to evaluate the potential and significant applications of Sertoli cells (SCs) transplantation, and to explore the effect of transplantation on spermatogenesis process, in azospermic mice. METHODS: In this study, we utilized 18 adult mice (28‒30 g), divided into four experimental groups: (1) control, (2) vehicle (DMSO 2%) (10 µl) (3) busulfan and (4) busulfan+ SCs (1×104 cells/µL). SCs were isolated from the testis of 4-week-old mouse and after using anesthetics, 10 µl of SCs suspension (1×104 cells/µL) was injected over 3-5 min, into each testis and subsequently, sperm samples were collected from the tail of the epididymis. Afterward, the animals were euthanized and testis samples were taken for histopathology experiments, and RNA extraction, in order to examine the expression of c-kit, STRA8 and PCNA genes. RESULTS: Our data showed that SCs transplantation could notably increase the total sperm count and the number of testicular cells, such as spermatogonia, primary spermatocyte, round spermatid, SCs and Leydig cells, compared to the control, DMSO and busulfan groups. Furthermore, the result showed that the expression of c-kit and STRA8 were significantly decreased in busulfan and busulfan/SCs groups, at 8 weeks after the last injection (p<0.001), but no significant decrease was found for PCNA, compared to the control and DMSO groups (P<0.05). CONCLUSION: These findings suggest that SCs transplantation may be beneficial as a practical approach for therapeutic strategies in reproductive and regenerative medicine. We further highlighted the essential applications that might provide a mechanism for correcting fertility in males, suffering from cell deformity.

Gold nanorods reinforced silk fibroin nanocomposite for peripheral nerve tissue engineering applications.

Nowadays, regenerating peripheral nerves injuries (PNIs) remain a major clinical challenge, which has gained a great attention between scientists. Here, we represent a nanocomposite based on silk fibroin reinforced gold nanorods (SF/GNRs) to evaluate the proliferation and attachment of PC12 cells. The morphological characterization of nanocomposites with transmission electron microscopy (TEM) and Scanning electron microscopy (SEM) showed that the fabricated scaffolds have porous structure with interconnected pores that is suitable for cell adhesion and growth. GNRs significantly improved the poor electrical conductivity of bulk silk fibroin scaffold. Evaluating the morphology of PC12 cells on the scaffold also confirmed the normal morphology of cells with good rate of adhesion. SF/GNRs nanocomposites showed better cellular attachment, growth and proliferation without any toxicity compared with bulk SF scaffold. Moreover, immunostaining studies represented the overexpression of neural specific proteins like nestin and neuron specific enolase (NSE) in the cells cultured on SF/GNRs nanocomposites in comparison to neat SF scaffolds.

High doses of sodium tungstate can promote mitochondrial dysfunction and oxidative stress in isolated mitochondria.

Tungstate (W) is recognized as an agent of environmental pollution and a substitute to depleted uranium. According to some preliminary studies, tungstate toxicity is related to the formation of reactive oxygen species (ROS) under abnormal pathological conditions. The kidneys and liver are the main tungstate accumulation sites and important targets of tungstate toxicity. Since the mitochondrion is the main ROS production site, we evaluated the mechanistic toxicity of tungstate in isolated mitochondria for the first time, following a two-step ultracentrifugation method. Our findings demonstrated that tungstate-induced mitochondrial dysfunction is related to the increased formation of ROS, lipid peroxidation, and potential membrane collapse, correlated with the amelioration of adenosine triphosphate and glutathione contents. The present study indicated that mitochondrial dysfunction was associated with disruptive effects on the mitochondrial respiratory chain and opening of mitochondrial permeability transition (MPT) pores, which is correlated with cytochrome c release. Our findings suggest that high concentrations of tungstate (2 mM)-favored MPT pore opening in the inner membranes of liver and kidney mitochondria of rats. Besides, the results indicated higher tungstate susceptibility in the kidneys, compared with the liver.

Comparison of the effects of MnO2-NPs and MnO2-MPs on mitochondrial complexes in different organs.

Today, nanoparticles (NPs) have been widely used in various fields. Manganese oxide nanoparticles have attracted a lot of attention due to many applications. One of the major concerns regarding the widespread use of various NPs is the exposure and accumulation in human organs and finally toxicity. The generation of reactive oxygen species (ROS) by mitochondria is one of the most important mechanisms of toxicity suggested by published studies induced by other NPs. However, limited studies have been conducted on the mechanism of toxicity of MnO2-NPs and MnO2-microparticles (MnO2-MPs). In this study, we compared the accumulation of MnO2-NPs and MnO2-MPs in different tissues and evaluated their effects on mitochondrial complexes in isolated mitochondria. Our results showed that intravascular (iv) administration of the MnO2-NPs in the same dose compared to the MnO2-MPs resulted in more accumulation in the C57 mouse female tissues. The effect of MnO2-NPs and MnO2-MPs in mitochondria showed that complexes I and III play an important role in increasing ROS generation and this effect is related to type of tissue. Also, our results showed that exposure to MnO2-NPs and MnO2-MPs reduced the activity of mitochondrial complexes II and IV. Our results suggest that the toxicity of the MnO2-NPs is higher than that of the MnO2-MPs and can lead to the depletion of antioxidant status, likely induction of apoptosis, cancer, and neurodegenerative disease. Abbreviations: NPs: nanoparticles; ROS: reactive oxygen species; SDH: succinate dehydrogenase; DCFH-DA: dichloro-dihydro-fluorescein diacetate; ELISA: enzyme-linked immunosorbent assay; MnO2-NPs: manganese oxide nanoparticles.