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Doxorubicin (DOX) is an effective chemotherapy drug used to treat many malignancies, including breast cancer. However, its clinical application is severely limited by cardiotoxicity. This study investigated if using thermo/pHsensitive magnetic nanoparticles decorated with folate (folate-poly-MNPs) as tumor-targeted drug delivery systems (DDSs) could reduce the cardiotoxicity and inflammatory properties of DOX in a rat model of breast cancer. In this study, forty rats were intravenously administered the control, DOX, DOX-poly-MNPs, and DOXfolate-poly-MNPs every 48 hours for 12 days. The cardiac health monitoring following breast cancer therapy confirmed that the novel smart DDS improved ECG pattern, left ventricular function, blood pressure parameters, and heart weight index. Moreover, it could decrease myocardial cell death by decreasing the protein levels of BAX, c-PARP1, and c-caspase-3, with concomitant downregulation of the BAX/Bcl-2 ratio, compared to the commercial DOX. In addition, the DOXfolate-poly-MNPs treatment significantly reduced NLRP3 inflammasome activation in cardiomyocytes, which was mediated by caspase-1 inhibition, and suppressed upregulation of IL-1β and IL18 protein expression to prevent myocardial damage. In this regard, the developed folatepolyMNPs could be represented as a new potential drug delivery system for breast cancer chemotherapy due to the combination of passive and active targeting aimed at preventing nonspecific body distribution, inhibiting NLRP3 inflammasome activation, and consequently reducing DOX cardiotoxicity as its main adverse effect.

Consumption of high fat diet (HFD) is a health concern in modern societies, which participate in wide range of diseases. One underlying mechanism in the HFD mediated pathologies is disruption of insulin signaling activity. It is believed that HFD activates several stress signaling molecules such as MAPKs signaling pathway and these molecules participate in harmful effects in different cell populations including hippocampal cells. However, the activity of MAPKs signaling molecules are time dependent, even causing some opposing effects. Given that, MAPKs activity fluctuate with time of stress, there is less cleared how different lengths of HFD consumption can affect hippocampal MAPK. To test how duration of HFD consumption affect hippocampal MAPKs and insulin signaling activity and animal's cognitive function, rats were fed with HFD for different lengths (up to 6 months) and after each point spatial memory performances of animals was tested, then the peripheral indices of insulin resistance and hippocampal MAPKs and insulin signaling activity was evaluated. Results showed that while different time courses of HFD, up to 6 months, did not bring about significant spatial memory impairment, meanwhile the peripheral insulin sensitivity as well as hippocampal insulin and MAPKs signaling showed significant fluctuations during the different time courses of high fat diet regime. These results showed that neuronal responses to HFD is not constant and differ in a time-dependent manner, it seems that in acute phase molecular responses aimed to compensate the HFD stress but in chronic states these responses failed and devastating effects of stress began.

Introduction It is well documented that insulin has neuroprotective and neuromodulator effects and can protect against different models of memory loss. Furthermore, cholinergic activity plays a significant role in memory, and scopolamine-induced memory loss is widely used as an experimental model of dementia. The current study aimed at investigating the possible effects of insulin against scopolamine-induced memory impairment in Wistar rat and its underlying molecular mechanisms. Methods Accordingly, animals were bilaterally cannulated in CA1, hippocampus. Intrahippocampal administration of insulin 6 MU and 12 MU in CA1 per day was performed during first 6 days after surgery. During next four days, the animal's spatial learning and memory were assessed in Morris water maze test (three days of learning and one day of retention test). The animals received scopolamine (1 mg/kg) Intraperitoneally (IP) 30 minutes before the onset of behavioral tests in each day. In the last day, the hippocampi were dissected and the levels of MAPK (mitogen-activated protein kinases) and caspase-3 activation were analyzed by Western blot technique. Results The behavioral results showed that scopolamine impaired spatial learning and memory without activating casapase-3, P38, and JNK, but chronic pretreatment by both doses of insulin was unable to restore this spatial memory impairment. In addition, scopolamine significantly reduced Extracellular signal-Regulated Kinases (ERKs) activity and insulin was unable to restore this reduction. Results revealed that scopolamine-mediated memory loss was not associated with hippocampal damage. Conclusion Insulin as a neuroprotective agent cannot restore memory when there is no hippocampal damage. In addition, the neuromodulator effect of insulin is not potent enough to overwhelm scopolamine-mediated disruptions of synaptic neurotransmission.

Thymulin is a peptide hormone which is mainly produced by thymic epithelial cells and it has immune-modulatory and anti-inflammatory effects. In this study, we investigated the effects of different doses and various timings of thymulin intraperitoneal administration on spinal microglial activity and intracellular pathways in an inflammatory rat model of Complete Freund's adjuvant (CFA). Thymulin treatment was implemented following CFA-induced inflammation for 21 days. After conducting behavioral tests (edema and hyperalgesia), the cellular and molecular aspects were examined to detect the thymulin effect on inflammatory factors and microglial activity. We demonstrated that thymulin treatment notably reduced thermal hyperalgesia and paw edema induced by CFA. Furthermore, molecular investigations showed that thymulin reduced CFA-induced activation of microglia cells, phosphorylation of p38 MAPK and the production of spinal pro-inflammatory cytokines (TNF-α, IL-6) during the study. Our results suggest that thymulin treatment attenuates CFA-induced inflammation. This effect may be mediated by inhibition of spinal microglia and production of central inflammatory mediators which seems to be associated with the ability of thymulin to reduce p38 MAPK phosphorylation. These data provide evidence of the anti-hyperalgesic effect of thymulin on inflammatory pain and characterize some of the underlying spinal mechanisms.

Despite the consensus that neuro-inflammation and insulin resistance (IR) are two hallmarks of Alzheimer disease (AD), the molecular mechanisms responsible for the development of IR remain uncharacterized. MAPKs are signaling molecules that are implicated in the pathology of AD and have a role in IR development. Given that inflammatory mediators are shown to interfere with insulin signaling pathway in different cell types, the present work aimed to investigate whether neuro-inflammation induced memory loss is associated with hippocampal IR and whether insulin treatment protects against this IR. Subsequently, possible roles of MAPKs in this situation were investigated. Male Wistar rats were cannulated, and LPS (15 µg, day 0), insulin (3 mU) or saline (vehicle) were administered intra-cerebroventricularly (ICV) (days 1-6). Spatial memory performance was assessed during days 7-10 by Morris Water Maze test. Consequently, analysis of the amount of hippocampal phosphorylated forms of P38, JNK, ERK, IRS1 (ser307) and Akt (ser473) were done by Western blot. The outcomes indicated that while LPS induced memory loss and hippocampal IR (shown by elevated IRS1 and decreased Akt phosphorylation), insulin treatment nullified these effects. Molecular results also showed that LPS mediated IR and memory loss are associated with P38 but not JNK and ERK activation; this P38 activation was reversed by insulin treatment. These observations implied that one of the ways by which neuro-inflammation participates in AD is via induction of IR. It seems that this IR is mainly mediated by P38. Therefore, P38 could be considered as a molecular target for preventing IR development., EXCLI Journal; 17:Doc825; ISSN 1611-2156

This study compared the effect of a multimodal training program and lecturing method on nurses' hand hygiene knowledge, belief, and practice. Two weeks and 3 months after the study, nurses' in both groups received significantly higher scores compared with the control group. Compared with the lecturing method, the multimodal training program is more effective in improving nurses' hand hygiene knowledge, belief, and practice 3 months after the study.