Curcumin Mitigates Malathion-Induced Renal Injury: Suppression of Apoptosis and Modulation of NF-κß/TNF-α and Nrf2, and HO-1 Signaling.

Malathion is one of the most used organophosphorus pesticides that is used for many reasons such as agriculture and industry. Human exposure to malathion may occur through various means, such as eating food that has been treated with it. Malathion not only increases oxidative stress but also decreases the antioxidant capacity. Curcumin is a powerful antioxidant with many pharmacological actions. Curcumin can act as a free radical scavenger and inhibit the activation and nuclear translocation of NF-κB. Curcumin could combat the lipid peroxidation and antioxidant depletion that trigger the apoptotic pathways. This study aims to examine the antioxidant, anti-inflammatory, and antiapoptotic effects of curcumin. Twenty-four Sprague Dawley rats were divided into four groups (six rats each): control, curcumin, malathion, and malathion + curcumin groups. At the assigned time, blood samples were used for the assessment of serum creatinine, and the kidneys were excised and washed; parts of them were used for the assessment of total oxidant status (TOS), oxidative stress index (OSI), the oxidative stress marker malondialdehyde (MDA), total antioxidant capacity (TAC), and glutathione (GSH) activity, other parts were fixed in formalin for further staining. Histopathological evaluation was performed for the fixed specimens after staining with H&E, sirus red, and the immunohistochemical staining for NF-κß, TNF-α, Caspase-3, Nrf2, and HO-1. Curcumin significantly decreases the serum creatinine after malathion exposure and significantly restores the oxidant/antioxidant balance by increasing TAC and GSH and decreasing TOS, OSI, and MDA. Curcumin exerts its reno-protective effect and restores the histological architecture of the kidney by downregulating the immune expression of NF-κß, TNF-α, and Caspase-3 and upregulating the expression of Nrf2 and HO-1. This study concluded that curcumin protects against nephrotoxicity caused by malathion by exerting its antioxidant, anti-inflammatory, and anti-apoptotic capabilities.

Betulin prevents high fat diet-induced non-alcoholic fatty liver disease by mitigating oxidative stress and upregulating Nrf2 and SIRT1 in rats.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic disorder characterized by hepatic lipid accumulation. This study explored the effect of betulin (BE), a terpenoid with promising antioxidant, anti-inflammatory and insulin sensitizing effects, on NAFLD induced by high fat diet (HFD). Rats received HFD and BE (15 and 30 mg/kg) for 12 weeks and blood and liver samples were collected for analyses. HFD caused hyperlipidemia, cholesterol and triglycerides accumulation in the liver, hepatocellular ballooning, fibrosis, insulin resistance (IR), lipid peroxidation (LPO), and NF-kB p65 upregulation. BE ameliorated serum and liver lipids, blood glucose and insulin, liver LPO, prevented steatosis and fibrosis, suppressed NF-kB p65 and enhanced antioxidants in HFD-fed rats. BE downregulated acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS), and upregulated Nrf2, HO-1 and SIRT1 in the liver of HFD-fed rats. In silico investigations revealed the binding affinity of BE towards FAS, NF-kB, Keap1, HO-1 and SIRT1. In conclusion, BE attenuated HFD-induced NAFLD by ameliorating hyperlipidemia, IR, lipogenesis, liver lipid accumulation, and oxidative stress. The protective effect of BE was associated with enhanced Nrf2/HO-1 signaling and SIRT1.

Potential Association between Subclinical Hypothyroidism and Childhood Migraine.

Background and Objectives: Migraine is caused by genetic susceptibility that is triggered by environmental as well as biological factors, and it is also linked to many somatic comorbidities, including clinical and subclinical hypothyroidism. We aimed to estimate the potential association between subclinical hypothyroidism (ScH) and migraine in children at our tertiary hospital. Materials and Methods: Using a case−control strategy, 200 children and adolescents were assigned to two equal groups: a case group (patients with migraine) of 100 patients and a control group of 100 patients without migraine. Clinical and biochemical parameters (TSH, FT4) were compared between the groups using statistical analysis. Results: Thyroid function comparison between the groups showed higher TSH but normal FT4 among children with migraine headache compared to the control group, which means more frequent ScH cases among the migraine group relative to the control (17% vs. 2%, p < 0.001). Obesity and overweight were more frequent among patients with migraine than the control group (8 and 5% vs. 2 and 1%, respectively). The (overweight/obese) patients with migraine had about 77% ScH and 15.4% overt hypothyroidism compared to 8% ScH and no overt hypothyroidism among normal body weight migraine patients (p < 0.001). No significant difference in the prevalence of nodular goiter between patients with migraine and controls was found. Conclusions: Based on our results, subclinical hypothyroidism is significantly linked to childhood migraine. Obesity and being overweight are more frequent among patients with migraine. Therefore, it may be logical to test the thyroid function in migraineur children, especially those with high BMI. Further studies are recommended to discover the mechanism of this association in children.

Dual regulating of mitochondrial fusion and Timp-3 by leflunomide and diallyl disulfide combination suppresses diethylnitrosamine-induced hepatocellular tumorigenesis in rats.

AIMS: Hepatocellular carcinoma (HCC) is considered one of the main causes of cancer-related death globally. Combination therapy targeting different pathways can improve the efficacy of HCC management. Mitofusin 2 (Mfn2), a mitochondrial fusion protein, and a tissue inhibitor of matrix metalloproteinase 3 (Timp-3) were found to be downregulated in various cancers, including HCC. Our study aimed to evaluate the possible antineoplastic effect of a novel combination in the treatment of HCC through targeting mitochondrial fusion and metastatic proteins. MAIN METHODS: HCC induction was performed using a single intraperitoneal dose of diethylnitrosamine (200 mg/kg), followed by adding phenobarbital sodium (0.05%) to the drinking water for successive 18 weeks. Then, leflunomide (LF, 10 mg/kg) was administered orally for 28 days. Diallyl disulfide (DADS, 50 mg/kg) was also given orally for 28 days, either alone or in combination with LF. KEY FINDINGS: Treatment with LF or DADS could alleviate the HCC- induced histological and biochemical variations, including liver enzyme activities (ALT, AST), alpha-fetoprotein, Bax, cyclin D1, Ki67, malondialdehyde, and reduced glutathione. They could shift the mitochondrial dynamics toward mitochondrial fusion through upregulating the expression of Mfn2 and also exhibited antimetastatic activity through upregulating the expression of Timp-3 and decreasing hepatic MMP9 content. SIGNIFICANCE: the treatment with a combination of LF and DADS displayed a more potent effect than the treatment with each drug alone. Our results suggest that the combined use of LF and a naturally occurring DADS can be used as a promising novel combination in managing HCC.

Acute and Delayed Doxorubicin-Induced Myocardiotoxicity Associated with Elevation of Cardiac Biomarkers, Depletion of Cellular Antioxidant Enzymes, and Several Histopathological and Ultrastructural Changes.

Doxorubicin (DOX; Adricin) is an anthracycline antibiotic, which is an efficient anticancer chemotherapeutic agent that targets many types of adult and pediatric tumors, such as breast cancer, leukemia, and lymphomas. However, use of DOX is limited due to its cardiotoxic effects. This study sequentially investigated the mechanistic pathways of the cardiotoxic process of DOX in rats at different post-treatment periods using cumulative dose, which is used in therapeutic regimes. In this regard, 56 male albino rats were used for the experiment. The experimental animals were divided into seven groups (n = 8/group) based on dose and sacrifice schedule as follows: G1 (2 mg/kg body weight [BW] and sacrificed at day 4), G2 (4 mg/kg BW and sacrificed at day 8), G3 (6 mg/kg BW and sacrificed at day 15), G4 (8 mg/kg BW and sacrificed at day 30), G5 (10 mg/kg BW and sacrificed at day 60), G6 (10 mg/kg BW and sacrificed at day 90), and G7 (10 mg/kg BW and sacrificed at day 120). As expected, G1, G2, and G3-treated groups revealed features of acute toxic myocarditis associated with degenerative and necrotic changes in myocytes, mitochondrial damage, elevation of cardiac biomarkers, and depletion of cellular antioxidant enzymes. However, these changes increased in severity with subsequent treatment with the same dose until reaching a cumulative dose of 10 mg/kg BW for 30 d. Furthermore, after a cumulative dose of 10 mg/kg BW with a withdrawal period of 2-3 months, various predominant changes in chronicity were reported, such as disorganization and atrophy of myocytes, condensation and atrophy of mitochondria, degranulation of mast cells, and fibrosis with occasional focal necrosis, indicating incomplete elimination of DOX and/or its metabolites. Altogether, these data provide interesting observations associated with the cardiotoxic process of DOX in rats that would help understand the accompanying changes underlying the major toxic effects of the drug. Future research is suggested to explore more about the dose-dependent mechanisms of such induced toxicity of DOX that would help determine the proper doses and understand the resulting cardiomyopathy.

Morphological classification of crista fenestra of round window corridor during pediatric cochlear implantation.

OBJECTIVES: This study aimed to document the observation of the Crista Fenestra's morphological types (CF) of the round window and to detect its impact during cochlear implant operation. STUDY DESIGN: A prospective descriptive cohort study. SETTINGS: We conducted this study at tertiary referral institutions in Egypt. PATIENTS: This study included 140 children who underwent cochlear implantation. INTERVENTION: We observed the CF's morphological type during the operation according to (Baki-Elzayat) novel classification of CF anatomy, and the need for drilling in each CI operation. MAIN OUTCOME MEASURES: CF has two main types. Type A, in which CF was present at the same level of round window membrane and attached to it. Type B, in which CF was medial to the Round window membrane. RESULTS: Type (A) CF was detected in 125 cases (89.28%), while 25 cases (10.71%) showed type (B) CF. Drilling was needed in 10 cases (7.14%), including CF types A.3 and B2. Drilling was not needed in 130 cases (92.85%), including CF type A.1, A.2, and B.1. There was a statistically significant difference in the need for drilling (P-value <0.001). CONCLUSIONS: According to this prospective study, CF had complicated anatomy. Baki-Elzayat classified the CF into two main types. In type A, CF was at the same level of RWM and attached to it. In type B, CF was medial to RWM. We recommended drilling for partial removal of massive CF types (A.3 and B.2) for atraumatic safe insertion of the electrode without deflection. This classification can offer an easy language system for CI surgeons to describe and register CF during their operations and in the surgical files.

Potential of rosmarinic acid to ameliorate toxic effects of diethyl methoxy thio­phosphoryl thio­succinate on albino wistar rats' lung, mast cell infiltration inhibitory pathway.

Malathion (MA) is a widely used pesticide in agriculture. It can cause toxicity in different organs of the body. Rosmarinic acid (RO) is found in rosemary extract that can be absorbed through gastrointestinal tract mucosa with potent antioxidant, and anti-inflammatory potential. The current study is designed to investigate the potential of RO to protect the lung after MA administration. Forty albino rats were allocated equally to four groups. C-group received corn oil. RO-group received RO orally. MA-group received MA. MA-RO-group received RO in addition to MA. After three weeks the lungs were dissected for histopathological and biochemical investigations. MA-group showed manifestations of severe inflammation with inflammatory cells infiltration in the lung. MA-RO-group showed limited inflammatory cell infiltration. C-group and RO-group appeared with weak anti-survivin immunoreactivity. MA-group showed strong positive immunoreactivity. The reactivity was weakly positive in MA-RO-group. MA-group showed a significant decrease in SP-D gene expression in comparison to the C-group, in addition, MA-RO-group showed a significant increase in SP-D expression. In conclusion, the current study approves that oral administration of MA causes lung injury as it has inflammatory effects, caused by oxidative stress and reports the potential of RO to protect lung tissue against toxic effects of MA through its anti-inflammatory, antioxidant, and anti-apoptotic potential.

SGLT2 inhibitor empagliflozin monotherapy alleviates renal oxidative stress in albino Wistar diabetic rats after myocardial infarction induction.

Acute kidney injury (AKI) is a sudden insult of the kidney that happens within a short period of time, which is associated with poor prognosis in diabetic patients with myocardial infarction (MI). Subclinical AKI is a condition in which tubular damage biomarkers [Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1(KIM-1)] are positive even in the absence of elevated serum creatinine. Recent studies reported that SGLT-2 inhibitors could protect against subclinical AKI in diabetic patients by elevating the level of ß-Hydroxybutyric acid (ßOHB). This study aims to examine the reno-protective potential of empagliflozin (EMPA) against MI associated AKI in diabetic rats. Eighty Albino Wistar rats were divided into: (1) nondiabetic sham group (CS), (2) nondiabetic + myocardial infarction group (CM), (3) diabetic + myocardial infarction group (DM) and (4) diabetic + myocardial infarction + empagliflozin group (DME). At the end of the experiment, blood samples and kidneys were collected for biochemical analysis, histopathological, and immunohistochemical studies. After induction of myocardial infarction, there was a significant decrease in serum creatinine and NGAL levels in DME. After EMPA administration, mesangial matrix index and glomerular area were lowered in DME if compared to DM group. As a marker for tubular injury, we used anti-NGAL and anti-KIM-1 immunohistochemistry. Strong positive reaction was noticed in DM group if compared to DME group which showed weak positive reaction. Levels of renal mRNAs [NGAL; KIM-1; Nox-2,4; TLR-2,4; MyD88; TNF- α and IL-1 ß, 18] in DME group were reduced significantly compared to DM group. In conclusion, empagliflozin can protect against subclinical acute kidney injury in diabetic albino Wistar rats after myocardial infarction induction, which could improve the clinical outcome of SGLT-2 inhibitors in diabetic patients.

Protective effect of thymoquinone against lung intoxication induced by malathion inhalation.

Malathion is considered one of the vastest pesticides use all over the world. Malathion-inhalation toxicity commonly occurred in many occupational farmers. Therefore, this study aimed to ameliorate the possible malathion-induced pulmonary toxicity through thymoquinone administration. Forty animals were used to conduct our study, divided into five groups; G1 control group, G2 thymoquinone (50 mg/kg) group, G3 malathion group (animals inhaled 100 mg/ml/m3 for 15 min for 5 days/week for three weeks), G4 and G5 were subjected to the same malathion inhalation protocol beside oral thymoquinone administration at doses of 25 and 50 (mg/kg), respectively. Malathion-inhalation induced marked systemic toxicity as hepatotoxicity and nephrotoxicity associated with increased serum hepatic and renal enzymes, and hypersensitivity accompanied with increased total IgE serum level. The lung showed severe interstitial pneumonia associated with severe vascular damage and marked eosinophil infiltration. Moreover, the lung showed a marked decrease in the pulmonary surfactant protein, especially SP-D gene expression. While, thymoquinone treatment to malathion-inhaled animals decremented the following; hepatic enzymes and renal function tests, total IgE as well as pneumonia and hypersensitivity pathological features, and augmented the expression of SP-D. In conclusion, thymoquinone could be potentially used in pest control workers to ameliorate the systemic and pulmonary intoxication caused by one of the most field-used pesticides.