Suspended particulate matter promotes epithelial-to-mesenchymal transition in alveolar epithelial cells via TGF-ß1-mediated ROS/IL-8/SMAD3 axis.

Epidemiological evidence presents that dust storms are related to respiratory diseases, such as pulmonary fibrosis (PF). However, the precise underlying mechanisms of SPM-elicited adverse effects still need to be investigated. Epithelial-mesenchymal transition (EMT) process is a characteristic of PF. We discussed whether suspended particulate matter (SPM) is involved in EMT induction via transforming growth factor-ß1 (TGF-ß1). In this study, a detailed elemental analysis (55 elements), particle size, and morphology were determined. To investigate the toxicity of SPM, an MTT test was performed to detect cell viability. Next, A549 cells were exposed to selected concentrations of SPM (20 and 40 µg/mL) for single and repeated exposures. The DCFH-DA assay showed that exposure to SPM could produce reactive oxygen species (ROS). The ELISA assay demonstrated increased levels of interleukin-8 (IL-8) and TGF-ß1 in the supernatant. Western blot was used to detect the expression of proteins associated with EMT and the SMAD3-dependent pathway. Results of western blot demonstrated that E-cadherin was reduced, whereas p-SMAD3, vimentin, and α-smooth muscle actin were elevated. Our findings indicated that SPM triggered EMT by induction of oxidative stress, inflammation, and the TGF-ß1/SMAD3 pathway activation.

The protective effect of herniarin on genotoxicity and apoptosis induced by cisplatin in bone marrow cells of rats.

Herniarin is a member of simple coumarins, which are a group of common secondary metabolites in plants. The aim of the present study was to investigate the effects of herniarin on genotoxicity and apoptosis induced by cisplatin in rat bone marrow cells. The experimental rats were treated with four different doses of herniarin (50, 100, 200, and 400 mg/kg.) for seven consecutive days. The cisplatin (5 mg/kg, i.p.) was injected into mice 1 h after the last oral herniarin administration on the seventh day. The protective effects of herniarin were investigated by hematological test, flow cytometry, micronucleus assay, and reactive oxygen species (ROS) level analysis. Herniarin caused a marked reduction in the frequencies of micronucleated polychromatic erythrocytes (MnPCEs) and micronucleated normochromatic erythrocytes (MnNCEs) 24 h after exposure to cisplatin at doses of 200 and 400 mg/kg. Furthermore, herniarin significantly increased the levels of both red and white blood cells in peripheral blood. Treatment of rats with herniarin before cisplatin, significantly decreased the percentage of apoptotic and necrotic cells and the ROS level in bone marrow cells. This study indicated that herniarin can be introduced as a new chemoprotective agent against cisplatin-induced genotoxicity in the future.

Ketotifen counteracts cisplatin-induced acute kidney injury in mice via targeting NF-κB/NLRP3/Caspase-1 and Bax/Bcl2/Caspase-3 signaling pathways.

Cisplatin (CIS) stands as one of the most effective chemotherapy drugs currently available. Despite its anticancer properties, the clinical application of CIS is restricted due to nephrotoxicity. Our research aimed to specify the impact of ketotifen fumarate (KET) against nephrotoxicity induced by CIS in mice. Male NMRI mice were treated with KET (0.4, 0.8, and 1.6 mg/kg, ip) for seven days. On the fourth day of the study, a single dose of CIS (13 mg/kg, ip) was administered, and the mice were sacrificed on the eighth day. The results indicated that administration of KET attenuated CIS-induced elevation of BUN and Cr in the serum, as well as renal KIM-1 levels. This improvement was accompanied by a significant reduction in kidney tissue damage, which was supported by histopathological examinations. Likewise, the decrease in the ratio of GSH to GSSG and antioxidant enzyme activities (CAT, SOD, and GPx), and the increase in lipid peroxidation marker (TBARS) were reversed in KET-treated mice. The ELISA results revealed that KET-treated mice ameliorated CIS-induced elevation in the renal levels of TNF-α, IL-1ß, and IL-18. Western blot analysis exhibited that KET suppressed the activation of the transcription factor NF-κB and the NLRP3 inflammasome in the kidney of CIS-treated mice. Moreover, KET treatment reversed the changes in the protein expression of markers related to apoptosis (Bax, Bcl2, Caspase-3, and p53). Interestingly, KET significantly enhanced the cytotoxicity of CIS in HeLa cells. In conclusion, this study provides valuable insights into the promising effects of KET in mitigating CIS-induced nephrotoxicity.

Protective Effects of Zingerone on Oxidative Stress in Doxorubicin-Induced Rat Hepatotoxicity.

Background: Doxorubicin, a commonly utilized anthracycline antibiotic and chemotherapeutic agent, has been associated with hepatotoxicity as an adverse effect. This study aimed to evaluate protective effects of zingerone, a bioactive compound derived from ginger renowned for its antioxidative attributes, on oxidative stress in doxorubicin-induced rat hepatotoxicity. Methods: In this experimental study, a total of 48 male Wistar rats were allocated into six distinct groups. The first group received a control treatment of normal saline. The second group was administered an intraperitoneal dose of 20 mg/kg of doxorubicin on day 5. The third group received an oral dose of 40 mg/kg of zingerone for 8 days. The fourth, fifth, and sixth groups were administered zingerone at doses of 10, 20, and 40 mg/kg, respectively, for the same 8-day period. On day 5, all groups, except the control group, received an intraperitoneal injection of doxorubicin. Following a 72-hour interval, the animals were anesthetized, and blood samples were collected to assess serum factors. Moreover, portions of the liver tissue were subjected to histopathological analysis and assessment of oxidative stress parameters. Results: The activity levels of serum enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), and liver malondialdehyde (MDA), increased in the doxorubicin group. Conversely, the levels of other parameters such as glutathione peroxidase (GPX), superoxide dismutase (SOD), and glutathione (GSH) decreased. However, the co-administration of zingerone effectively reversed these levels, restoring them back to normal. Conclusions: These findings suggest that zingerone, particularly at a high dose, exhibit a hepatoprotective effect in the doxorubicin-induced hepatotoxicity model.

Serum and urinary cadmium and zinc profiles in breast cancer patients and their association with estrogen and HER-2 receptors, and redox status.

BACKGROUND: Cadmium, a metal implicated in environmental toxicity, is linked to tumor growth and cancer. On the other hand, zinc plays an essential function in oxidative stress and can counteract cadmium toxicity and carcinogenicity. This research aims to evaluate the urine and serum values of cadmium and zinc in breast cancer (BC) patients and their association with estrogen (ER) and HER-2 receptors, and redox status. METHODS: Forty BC patients and thirty healthy subjects participated in this study. Cadmium and zinc levels were measured in serum and urine samples by atomic absorption spectrophotometer. Redox status markers were determined by colorimetric methods. RESULTS: The amount of cadmium in the BC patients was substantially greater than in the healthy subjects. Zinc levels were significantly lower in patients with BC compared to controls. Breast cancer patients with ER-positive tumors had significantly higher urinary cadmium concentrations (U-Cd) compared to patients with ER-negative tumors. There was no significant difference between the parameters of redox status and the value of cadmium and zinc between patients with BC in the HER-2 subgroup. Malondialdehyde levels in the serum were substantially greater in BC patients than in healthy subjects. Total thiol level and catalase and superoxide dismutase activity in serum were considerably lower in BC patients than in healthy subjects. CONCLUSIONS: The etiology of BC may be due to a disturbance in redox status and levels of elements. Increasing U-Cd and lowering zinc levels in the serum could be the risk factors for BC.

Cannabidiol attenuates arsenic-induced nephrotoxicity via the NOX4 and NF-κB pathways in mice.

Background and purpose: Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice. Experimental approach: 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7th to the 14th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7th to the 14th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed. Findings/Results: Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants. Conclusion and implications: CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-kB/Nox4 pathway.

The roles of some scorpions, Hemiscorpius lepturus and Androctonus crassicauda, in a scorpionism focus in Ramhormorz, southwestern Iran.

Scorpion stings are a common and important health problem in Iran, particularly in south and southwestern Iran, including the province of Khuzestan. In the area of Khuzestan near the city of Ramhormoz, Hemiscorpius lepturus (Scorpionida: Hemiscorpioiidae) and Androctonus crassicauda (Buthidae) are present. Ramhormoz is in southwestern Iran and is one of the most important foci of the scorpion sting problem. The current study was carried out to gain both epidemiological and medical information about scorpion stings in and around the city of Ramhormoz. In total, 179 people who were admitted to the Emergency Department of Ramhormoz Imam Khomeini Hospital during 2008 and 2009 after being stung by scorpions were monitored. Epidemiological and medical parameters including sex of the victim; the part of the body stung; the month when stung; the biochemical parameters comprising blood sugar (BS), blood urea nitrogen (BUN), and creatinine (CR); hematological parameters including white blood cells (WBC), count blood cells (CBC), red blood cells (RBC), hemoglobin (Hb), hematocrit (HCT), platelet (PLT); and urine analysis including hemoglobinuria were recorded. The current study showed that most of the victims were stung by H. lepturus, while very few were stung by A. crassicaud, but in over half of the cases the species was not known. Stings were most common from May to Aguust. 73% of the victims were female. The limbs were the part of the body most likely to be stung. Hemogobinuria was very common in H. lepturus victims.

Evaluation of the Total Oxidant Status to the Antioxidant Capacity Ratio as a Valuable Biomarker in Breast Cancer Patients.

Background: The oxidative balance is a state of equilibrium between oxidants and antioxidants disrupted in various disorders, including BC. This study aimed to assess this equilibrium in breast cancer (BC) patients by looking at the oxidant-to-antioxidant ratio. Methods: This case-control study comprised 40 women patients with breast cancer and 30 age-matched healthy individuals. The oxidation-reduction colorimetric technique was used to determine serum levels of total oxidant status (TOS) and total antioxidant capacity (TAC). The oxidant-to-antioxidant balance was estimated using the TOS- to- TAC ratio (TOS/TAC). Results: The mean TOS in healthy individuals was 8.40±2.06 µmol/L, while in BC patients it was 13.31±2.16 µmol/L (P< 0.001). The mean serum level of TAC was 1.43±0.21 mmol/L in healthy individuals and 1.19±0.15 mmol/L in BC patients (P< 0.001). The mean serum TOS/TAC was 6.01±0.32 in the healthy individuals and 11.42±0.41 in the BC patients (P< 0.0001). There were direct correlations between TAC and estrogen receptor (r=0.339, P=0.038). The TOS/TAC level has a sensitivity of 100% and specificity of 83.33%, distinguishing patients with BC from healthy controls (P< 0.001). A significant trend of increasing risk with rising TOS/TAC levels was also seen [OR=3.62, (95 % CI 1.79, 7.35)]. Conclusions: In breast cancer, the serum TOS to TAC ratio can better diagnose oxidative equilibrium than either component alone.

The Impact of Metformin on Dust-Induced Histopathological Changes and Oxidative Stress in the Liver: An Insight into Dust Concentration and Liver Biomarkers in Animal Models.

Background: Environmental pollution has a profound impact on both human and animal life. Khuzestan province, which has been plagued by intense dust storms and pollution for decades, is the focus of this study. The research aims to investigate the protective effects of metformin against the toxicity of particulate matter in the livers of rats. Methods: Male Wistar rats were selected for the study and divided into six groups: a control group, Metformin-treated groups, Iraqi dust-exposed group (Iraqi-D), Local dust-exposed group (Local-D), Iraqi dust-exposed with Metformin treatment group (Iraqi-D+Metformin), and Local dust-exposed with Metformin treatment group (Local-D+Metformin). The rats were exposed to local and Iraqi dust through a nebulizer and received oral metformin for a duration of 21 days. At the end of the intervention, liver biomarkers and oxidative stress factors were evaluated enzymatically. Results: The study revealed that rats exposed to Iraqi and local dust experienced a significant increase in liver biomarkers, including aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALK) levels, alongside a decrease in glutathione (GSH) concentrations and an increase in malondialdehyde (MDA) levels. However, treatment with metformin was effective in preventing the increase in these biomarkers, restoring GSH levels, and averting the rise in MDA levels, as compared to the control group. Conclusions: Exposure to particulate matter from Iraq and the local region can induce alterations in biomarkers and oxidative stress levels in the rat liver, and these effects can be mitigated through metformin treatment.

Multi-walled carbon nanotubes induce oxidative stress, apoptosis, and dysfunction in isolated rat heart mitochondria: protective effect of naringin.

Multi-walled carbon nanotubes (MWCNTs) are material with exclusive features that can be applied in different fields including industrial and medicine. It has been determined that the accumulation of MWCNTs in the organs is along with genotoxic and cytotoxic injuries. Previous studies have shown mitochondrial dysfunction in MWCNTs exposure with cell lines, but their exact mechanisms with isolated mitochondria have remained unclear. The present study evaluated toxicity induced by MWCNTs in isolated rat heart mitochondria and protective effect of naringin. Our results showed that MWCNTs toxicity caused the prevention of heart mitochondrial complex II activity. Treatment of isolated heart mitochondria with MWCNTs led to an increase in mitochondrial reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse, and mitochondrial malondialdehyde (MDA) and a decrease in mitochondrial glutathione (GSH) level and mitochondrial catalase (CAT) activity. Pretreatment of isolated heart mitochondria with naringin decreased mitochondrial oxidative damage through decreasing lipid peroxidation, returned mitochondrial complex II changes, decreasing MMP collapse and ROS production, and restoration of GSH level and CAT activity. Our findings indicated that MWCNTs had toxic effects on isolated heart mitochondria by inducing oxidative stress and possibly apoptosis pathway. The protection effects of naringin may be accompanied by mitochondrial conservation by its antioxidant property or due to its free radical scavenging. Our findings indicated that naringin had a possible role in preventing the mitochondria complaints in the heart.

Evaluation of the Protective Effects of Doxycycline on Acetaminophen-Induced Hepatotoxicity in Mice.

Acetaminophen (APAP) toxicity threatens human health due to increased mortality associated with its overdose. Doxycycline (DC) because of its properties such as antioxidant and anti-inflammatory can be a good therapeutic strategy to treat the acute toxicity induced by APAP. Male mice were divided into six groups in two periods of 3 h and 24 h as normal saline, APAP 400 mg/kg, DC 100 mg/kg and groups treated by 25, 50 and 100 mg/kg DC just before APAP, respectively. At the end of the 3 h and 24 h periods, the hepatic index, biochemical parameters including serum aspartate transaminase (AST) and alanine transaminase (ALT) activity and hepatic catalase activity, glutathione (GSH) and malondialdehyde (MDA) levels in liver and histopathological changes were evaluated. The results indicated that DC had no apparent effect on the hepatic index but significantly normalized the level of biochemical parameters and reduced APAP induced liver damage. Overall, it could be concluded that DC can inhibit or resolve harmful effects of APAP through antioxidant and anti-inflammatory properties. However, more studies are needed to understand exact mechanism of DC and its application for clinical use.

Determination of the mutagenicity potential of dillsun herbal medicine by single cell gel electrophoresis in rat hepatocytes.

BACKGROUND: Traditional medicines are among the oldest medicines and their extensive use in the recent years reflects the public's interest in alternatives to conventional medicine. OBJECTIVES: The aim of this study was to investigate the genotoxicity of Dillsun herbal medicine in DNA damage of rat hepatocytes compared to sodium dichromate using a comet assay technique. MATERIALS AND METHODS: Male Wistar rats were caught and their liver was washed with a perfusion buffer, followed by another wash with collagenase buffer. Hepatocytes were isolated and transferred on to a petri dish which contained a washing buffer. Hepatocytes were then separated and the cells were filtered and centrifuged at 1500 rpm for 3 minutes. The hepatocytes were counted using neubauer slides and kept in a bioreactor for 30 minutes. Cells were then exposed to different doses of Dillsun such 0.2, 1, 2.5, 5 and 10 mg/mL. Sodium dichromate was the positive control and incubated buffer was used as a negative control. Cell suspensions were placed on slides pre-coated with low melting point agarose and were covered with agarose gel. Agarose gels were then lysed and electrophoresis was done, followed by neutralization and staining. Slides were analyzed by fluorescence microscopy. The size and extent of DNA damage visualized by this technique was evaluated by examining cells. Migration behavior was classified according to the Kobayashi pattern. RESULTS: The results indicated that with an increase of Dillsun dose, the mutagenicity index slightly increased but compared to the positive control, there were significant differences, which suggests that the crude extract of Dillsun in vitro did not have mutagenic effects. CONCLUSIONS: In conclusion the results showed that Dillsun has no mutagenic effects when compared to the positive control. Although by increasing the Dillsun dose, DNA damage also increased but this increase was not significant.