Evaluation of CD44s, CD44v6, CXCR2, CXCL1, and IL-1β in Benign and Malignant Tumors of Salivary Glands

Background: Several studies have reported an association between high expression of CD44 in different types of cancer. However, no study has reported a link among CD44 expression, other biomarkers, and the aggressiveness of salivary gland tumors. Methods: A total of 38 specimens were obtained from non-tumorous salivary glands, benign and malignant tumors in salivary glands. Immunohistochemical analyses of CD44s, CD44v6, IL-1β, CXCL1, and CXCR2 were performed, and the area of positive cells was assessed. Results: We found that both CD44s and CXCR2 expression were increased in the benign and malignant groups. CD44v6 was also increased in both groups, but it had the highest level in the malignant group. IL-1β was the only biomarker that increased significantly in the malignant group in comparison to the other two groups. Conclusions: CD44s, CD44v6, CXCR2, and IL-1β expressions were found to be higher in salivary gland tumors. However, IL-1β alone may play a crucial role in the aggressiveness of salivary gland tumors as this cytokine was expressed only in the malignant group with high expression associated with high-grade malignancy

Erythropoietin administration exerted neuroprotective effects against cardiac ischemia/reperfusion injury

Acute myocardial infarction (AMI) leads to cardiac dysfunction and also causes brain dysfunction and pathology. The neuroprotective effects of erythropoietin (EPO), the hormone controlling the production of red blood cells, have been shown in case of cerebral ischemic/reperfusion (I/R) injury. However, the effects of EPO on the brain pathologies induced by cardiac I/R injury have not been investigated. We hypothesized that the administration of EPO attenuates brain damage caused by cardiac I/R injury through decreasing peripheral and brain oxidative stress, preserving microglial morphology, attenuating hippocampal necroptosis, and decreasing hippocampal apoptosis, and hippocampal dysplasticity. Male Wistar rats (n ​= ​38) were divided into two groups, sham (n ​= ​6) and cardiac I/R (n ​= ​32). All rats being subjected to the cardiac I/R operation were randomly divided into 4 subgroups (n ​= ​8/group): vehicle, EPO pretreatment, EPO given during ischemia, and EPO given at the onset of reperfusion. The EPO was given at a dosage of 5000 units/kg via intravenous injection. Left ventricle function, oxidative stress, brain mitochondrial function, microglial morphology, hippocampal necroptosis, hippocampal apoptosis, and hippocampal plasticity were measured. EPO administration exerted beneficial anti-oxidative, anti-inflammatory, and anti-apoptotic effects on the brain against cardiac I/R. Giving EPO before cardiac ischemia conferred the greatest neuroprotection against cardiac I/R injury through the attenuation of LV dysfunction, decrease in peripheral and brain oxidative stress, and the attenuation of microglial activation, brain mitochondrial dysfunction, apoptosis, and necroptosis, leading to the improvement of hippocampal dysplasticity under cardiac I/R conditions. EPO pretreatment provided the greatest benefits on brain pathology induced by cardiac I/R

Cyclosorus terminans Extract Ameliorates Insulin Resistance and Non-Alcoholic Fatty Liver Disease (NAFLD) in High-Fat Diet (HFD)-Induced Obese Rats

Interruptins A and B exhibited anti-diabetic, anti-inflammatory, and anti-oxidative effects. This study aimed to investigate the therapeutic ability of extract enriched by interruptins A and B (EEI) from an edible fern Cyclosorus terminans on insulin resistance and non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-induced obese rats and elucidate their possible mechanisms. HFD-induced obese rats were treated with EEI for 2 weeks. Real-time polymerase chain reaction (PCR) was used to examine the molecular basis. We found that EEI supplementation significantly attenuated body and liver weight gain, glucose intolerance, and insulin resistance. Concurrently, EEI increased liver and soleus muscle glycogen storage and serum high-density lipoprotein (HDL) levels. EEI also attenuated NAFLD, as indicated by improving liver function. These effects were associated with enhanced expression of insulin signaling genes (Slc2a2, Slc2a4, Irs1 and Irs2) along with diminished expression of inflammatory genes (Il6 and Tnf). Furthermore, EEI led to the suppression of lipogenesis genes, Srebf1 and Fasn, together with an increase in fatty acid oxidation genes, Ppara and Cpt2, in the liver. These findings suggest that EEI could ameliorate HFD-induced insulin resistance and NAFLD via improving insulin signaling pathways, inflammatory response, lipogenesis, and fatty acid oxidation

GSDMD-mediated pyroptosis dominantly promotes left ventricular remodeling and dysfunction in post-myocardial infarction: a comparison across modes of programmed cell death and mitochondrial involvement

Abstract Background Myocardial infarction (MI) has recently accounted for more than one-third of global mortality. Multiple molecular pathological pathways, such as oxidative stress, inflammation, and mitochondrial dysfunction, have been recognized as possible mechanisms in the development of MI. Furthermore, different phases of ischemic injury following the progression of MI were also associated with multiple types of programmed cell death (PCDs), including apoptosis, necroptosis, ferroptosis, and pyroptosis. However, it remains unknown whether which types of PCDs play the most dominant role in post-myocardial infarction (post-MI). Method In this study, we used a preclinical rat model of MI induced by permanent left anterior descending coronary artery (LAD) ligation (n = 6) or a sham operated rat model (n = 6). After a 5-week experiment, cardiac function and morphology, mitochondrial studies, and molecular signaling analysis of PCDs were determined. Results Herein, we demonstrated that post-MI rats had considerably impaired cardiac geometry, increased oxidative stress, myocardial injuries, and subsequently contractile dysfunction. They also exhibited worsened cardiac mitochondrial function and dynamic imbalance. More importantly, we found that post-MI mediated abundant myocardial cell death through multiple PCDs, including apoptosis, necroptosis, and pyroptosis, but not ferroptosis. Conclusion In this study, we provide the first insights into the mechanism of PCDs by pyroptosis, which is leveraged as the most dominant mode of cell death after MI

Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple programmed cell death pathways

Abstract Background Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC. Methods Male Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated. Results Trz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist. Conclusions Donepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC

Supplementary Material for: Testosterone Deprivation Aggravates Left-Ventricular Dysfunction in Male Obese Insulin-Resistant Rats via Impairing Cardiac Mitochondrial Function and Dynamics Proteins

<b><i>Background:</i></b> We have previously reported that testosterone deprivation at a very young age accelerated, but did not aggravate, left-ventricular (LV) dysfunction in obese insulin-resistant rats. However, the effects of testosterone deprivation during adulthood on LV function in obese insulin-resistant rats remains unclear. We hypothesized that testosterone deprivation aggravates LV dysfunction and cardiac autonomic imbalance via the impairment of cardiac mitochondrial function and dynamics proteins, a reduction in insulin receptor function, and an increase in apoptosis in obese insulin-resistant rats. <b><i>Methods:</i></b> Male rats were fed on either a normal diet (ND) or a high-fat diet (HFD) for 12 weeks. They were then subdivided into 2 groups: sham operation (NDS, HFS) and orchiectomy (NDO, HFO). Metabolic parameters, blood pressure, heart rate variability (HRV), and LV function were determined at baseline and before and after orchiectomy. Mitochondrial function and dynamics proteins, insulin signaling, and apoptosis were determined 12 weeks postoperatively. <b><i>Results:</i></b> HFS rats exhibited obese insulin resistance, depressed HRV, and LV dysfunction. In HFO rats, systolic blood pressure was increased with more excessive depression of HRV and increased LV dysfunction, compared with HFS rats. These adverse cardiac effects were consistent with markedly increased mitochondrial dysfunction, reduced mitochondrial complex I and III proteins, reduced mitochondrial fusion proteins, and increased apoptosis, compared with HFS rats. However, testosterone deprivation did not lead to any alteration in the insulin-resistant condition in HFO rats, compared with HFS rats. <b><i>Conclusion:</i></b> We concluded that testosterone deprivation during adulthood aggravated the impairment of mitochondrial function, mitochondrial respiratory complex, mitochondrial dynamics proteins, and apoptosis, leading to LV dysfunction in obese insulin-resistant rats