Combination of Niclosamide and Pirfenidone Alleviates Pulmonary Fibrosis by Inhibiting Oxidative Stress and MAPK/Nf-κB and STATs Regulated Genes.

The pathogenesis of pulmonary fibrosis (PF) is extremely complex and involves numerous intersecting pathways. The successful management of PF may require combining multiple agents. There is a growing body of evidence that suggests the potential benefits of niclosamide (NCL), an FDA-approved anthelminthic drug, in targeting different fibrogenesis molecules. This study aimed at investigating the anti-fibrotic potential of NCL alone and in combination with pirfenidone (PRF), an approved drug for PF, in a bleomycin (BLM) induced PF experimental model. PF was induced in rats by intratracheal BLM administration. The effect of NCL and PRF individually and in combination on different histological and biochemical parameters of fibrosis was investigated. Results revealed that NCL and PRF individually and in combination alleviated the histopathological changes, extracellular matrix deposition and myofibroblastic activation induced by BLM. NCL and PRF either individually or in combination inhibited the oxidative stress and subsequent pathways. They modulated the process of fibrogenesis by inhibiting MAPK/NF-κB and downstream cytokines. They inhibited STATs and downstream survival-related genes including BCL-2, VEGF, HIF-α and IL-6. Combining both drugs showed significant improvement in the tested markers in comparison to the monotherapy. NCL, therefore, has a potential synergistic effect with PRF in reducing the severity of PF.

Carnitine, apelin and resveratrol regulate mitochondrial quality control (QC) related proteins and ameliorate acute kidney injury: role of hydrogen peroxide.

Mitochondrial impairment is recognised as a prominent feature in kidney diseases. Therefore, we investigated whether the effects of resveratrol, L-carnitine, and apelin in the acute kidney injury model were associated with modulation of mitochondrial quality control (QC) related proteins, intra-renal renin-angiotensin (RAS) activity, adenosine triphosphate (ATP) and Na+-K+ ATPase gene expression. Rats were randomly assigned to 7 groups: Distilled water injected control group, DMSO injected control group, distilled water injected lipopolysaccharide (LPS) group, DMSO injected LPS group, resveratrol injected LPS group, L-carnitine injected LPS group and apelin 13 injected LPS group. We observed that resveratrol, L-carnitine, and apelin treatments altered mitochondrial (QC) related protein levels (Pink1, Parkin, BNIP-3, Drp1, and PGC1α), decreased intra-renal RAS parameters, increased ATP level and upregulated Na+-K+ ATPase gene expression in renal tissue. Our results provide new insight into the role of mitochondrial quality control and how different antioxidants exert beneficial effects on acute kidney injury.

Association of Apolipoprotein E gene polymorphism with the risk of T2DM and obesity among Egyptian subjects.

BACKGROUND: Numerous reports investigated the involvement of apolipoprotein E (APOE) polymorphisms with elevated risk of type 2 diabetes mellitus (T2DM) and obesity. The principal objective of this study is to assess the contribution of APOE polymorphisms (rs429358 and rs7412) with the risk of T2DM and obesity. SUBJECTS AND METHODS: This work was designed involving 400 participants [100 healthy controls, 100 T2DM patients, 100 obese patients, and 100 T2DM + obese patients]. Genomic deoxyribonucleic acid (DNA) of the APOE polymorphisms was characterized using the PCR-RFLP assay. RESULTS: The common predominant genotype of the study population is the APOE Ɛ3/Ɛ3 [T2DM patients (46%), obese patients (52%), T2DM + obese patients (37%), and healthy controls (58%)]. The frequencies of the APOE Ɛ4/Ɛ4 genotype and the APOE*Ɛ4 allele were significantly elevated among T2DM patients (p-value < 0.05). Additionally, the frequencies of the APOE Ɛ2/Ɛ2 genotype and the APOE*Ɛ2 allele were significantly increased among obese patients (p-value < 0.05). Moreover, the frequencies of the APOE Ɛ2/Ɛ2 genotype, APOE*Ɛ2 allele, APOE Ɛ4/Ɛ4 genotype, and APOE*Ɛ4 allele were statistically significant among T2DM + obese patients (p-value < 0.05). CONCLUSIONS: APOE*Ɛ2 and APOE*Ɛ4 alleles were considered as independent risk factor among T2DM + obese patients. Furthermore, the APOE*Ɛ2 allele was correlated with elevated risk of obesity, while the APOE*Ɛ4 allele was correlated with elevated risk of T2DM.

Effect of psychotropic drugs on cortical excitability of patients with major depressive disorders: A transcranial magnetic stimulation study.

Transcranial magnetic stimulation (TMS) can be used to evaluate the effects of pharmacological interventions. The aim of this study was to assess the impact of the selective serotonin reuptake inhibitor, sertraline, and the atypical antipsychotic drugs quetiapine and olanzapine, on cortical excitability in unmedicated patients with major depressive disorder (MDD). The study included 45 medication-free MDD patients diagnosed according to DSM V. They were divided randomly into three groups who received a single oral dose of one of the three drugs sertraline (50 mg), quetiapine (100 mg) and olanzapine (10 mg). Psychological evaluation was conducted using the Mini-Mental State Examination (MMSE) and Beck Depression Inventory Scale (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant before and at the time of maximum concentration of drug intake. There was significant increase in excitability of motor cortex after sertraline without changes in GABAB neurotransmission. Quetiapine and olanzapine potentiated inhibitory GABAB neurotransmission (prolongation of cSP); olanzapine additionally prolonged the iSP. Thus TMS can differentiate between the impact of different psychotropic drugs on excitatory and inhibitory transmission in motor cortex.

Global cortical hypoexcitability of the dominant hemisphere in major depressive disorder: A transcranial magnetic stimulation study.

BACKGROUND: Accumulating evidence suggests that major depressive disorders (MDD) are associated with an imbalance of excitation-inhibition within the prefrontal cortex (PFC), generated by a deficit of inhibitory synaptic transmission onto glutamatergic principal neurons. Transcranial magnetic stimulation (TMS) protocols can be used to measure neuronal excitability and GABAergic inhibition and thus provide additional evidence to evaluate this theory. OBJECTIVE: In the present study, TMS protocols were used to compare GABAergic function and cortical excitability of dominant hemisphere in unmedicated patients with MDD versus a control group of healthy individuals. METHODS: The study included 43 MDD patients according to DSM-V and 20 age- and sex- matched healthy volunteers. Psychological evaluation was conducted using the Beck Depression Inventory (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant. RESULTS: rMT and aMT were higher in MDD patients compared with the control group, while cSP and iSP were significantly shorter in duration. There were significant positive correlations between the BDI score and rMT, aMT (P=0.001 and 0.002 respectively), and a negative correlation with cSP duration (P=0.001). CONCLUSION: Global hypoexcitability of both pyramidal cortical neurons (elevated MTs) and GABAergic controls (shortened SPs) was evidenced within the left/dominant motor cortex in MDD. These results are consistent with previous reports of abnormal glutamate and GABA function in frontal cortex.

Cure rate of Helicobacter pylori infection in Egyptian children related to CYP2C19 gene polymorphism.

OBJECTIVES: This study was done in order to investigate the effect of CYP2C19 genetic polymorphism on the cure rate of children who received proton pump inhibitors (PPI)-based triple therapy for treating Helicobacter pylori (H. pylori) infection. METHODS: Participants included 100 children with H. pylori-positive gastritis diagnosed by endoscopy and biopsy in addition to H. pylori stool antigen test. Cure rate was assessed after 1 month of completion of a triple treatment course for 14 days. CYP2C19 polymorphism was analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Results showed that cases with a CYP2C19 genotypic status consistent with the heterozygote extensive metabolizers (HetEMs) had a higher cure rate of H. pylori when compared with the homozygote extensive metabolizers (HomEMs) although it was statistically nonsignificant (84.6 vs. 69.2). In addition, the poor metabolizers (PMs) had a higher cure rate compared with those of the HomEMs which was also statistically nonsignificant (77.8 vs. 69.2). The cure rate was also higher among both the groups of HetEMs and PMs combined together compared to the HomEMs (OR = 2.15, p > 0.05). Comparing cases regarding their age, gender, and severity of H. pylori gastritis revealed a better cure rate in the age group >10 years, in females and in mild and moderate cases than other cases although statistically nonsignificant. CONCLUSION: The higher cure rate of H. pylori infection using the triple therapy for 2 weeks among HetEMs and PMs cases compared to the HomEMs might warrant a need for a therapy augmentation or modification for the HomEMs.