Translational research : the journal of laboratory and clinical medicine
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Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma (PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is critical to elucidate the mechanism of GEM chemoresistance. ⋯ In vitro and in vivo, ATO combined with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation, migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting a promising treatment for the disease.
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A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, individuals may return to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognized as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. ⋯ Importantly, this potentiation phenomenon remained even when limiting analyses to rats with longer inter-injury intervals, providing evidence that vulnerability to re-injury may not be exclusively dependent on inter-injury interval. Finally, NfL levels correlated with, and were predictive of, the severity of neurological signs following the second mTBI. These findings provide evidence that measurement of NfL during mTBI recovery may be reflective of the vulnerability to a second mTBI, and as such may have utility to assist return to sport, duty and work decisions.
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Cold storage is widely used to preserve an organ for transplantation; however, a long duration of cold storage negatively impacts graft function. Unfortunately, the mechanisms underlying cold exposure remain unclear. Based on the sphingosine-1-phosphate (S1P) signal involved in cold tolerance in hibernating mammals, we hypothesized that S1P signal blockage reduces damage from cold storage. ⋯ Pathological analysis revealed that it suppressed the interstitial edema, inflammatory cell infiltration, myocyte lesion, TUNEL-positive cell death, and fibrosis. In conclusion, S1PR3 antagonist reduced cold injury, extended the cold preservation time, and improved graft viability. Cold preservation strategies via S1P signaling may have clinical applications in organ preservation for transplantation and contribute to an increase in the donor pool.
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Dendritic cells (DCs) are key regulators of the adaptive immune response. Tolerogenic dendritic cells play a crucial role in inducing and maintaining immune tolerance in autoimmune diseases such as type 1 diabetes in humans as well as in the NOD mouse model. We previously reported that bone marrow-derived DCs (BM. ⋯ Furthermore, analysis of C/EBPβ-/- GM/DCs demonstrated that C/EBPβ is required for IL-23 production. Of physiological relevance, the level of protection from diabetes following transfusion of GM/DCs into young NOD mice was significantly reduced when NOD mice were transfused with GM/DCs pretreated with a PI3K inhibitor. Our data suggest that PI3K/C/EBPβ signaling is important in controlling tolerogenic function of GM/DCs by limiting their Th17-promoting cytokines.
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While natriuretic peptides (NPs) are primarily known for their renal and cardiovascular actions, NPs stimulate lipolysis in adipocytes and induce a thermogenic program in white adipose tissue (WAT) that resembles brown fat. The biologic effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which binds and degrades NPs. Knockout (KO) of NPRC protects against diet induced obesity and improves insulin sensitivity in obese mice. ⋯ These beneficial effects were accompanied by a decrease in infiltrating macrophages in adipose tissue, and reduced expression of inflammatory markers in both serum and WAT. These data suggest that inhibiting NP clearance may be an effective pharmacologic approach to promote weight loss and enhance insulin sensitivity in type 2 diabetes. Optimizing the therapeutic approach may lead to useful therapies for obesity and type 2 diabetes.