Augmented Mitochondrial Transfer Involved in Astrocytic PSPH Attenuates Cognitive Dysfunction in db/db Mice.

Diabetes-associated cognitive dysfunction (DACD) has ascended to become the second leading cause of mortality among diabetic patients. Phosphoserine phosphatase (PSPH), a pivotal rate-limiting enzyme in L-serine biosynthesis, has been documented to instigate the insulin signaling pathway through dephosphorylation. Concomitantly, CD38, acting as a mediator in mitochondrial transfer, is activated by the insulin pathway. Given that we have demonstrated the beneficial effects of exogenous mitochondrial supplementation on DACD, we further hypothesized whether astrocytic PSPH could contribute to improving DACD by promoting astrocytic mitochondrial transfer into neurons. In the Morris Water Maze (MWM) test, our results demonstrated that overexpression of PSPH in astrocytes alleviated DACD in db/db mice. Astrocyte specific-stimulated by PSPH lentivirus/ adenovirus promoted the spine density both in vivo and in vitro. Mechanistically, astrocytic PSPH amplified the expression of CD38 via initiation of the insulin signaling pathway, thereby promoting astrocytic mitochondria transfer into neurons. In summation, this comprehensive study delineated the pivotal role of astrocytic PSPH in alleviating DACD and expounded upon its intricate cellular mechanism involving mitochondrial transfer. These findings propose that the specific up-regulation of astrocytic PSPH holds promise as a discerning therapeutic modality for DACD.

MMP1 regulated by NEAT1/miR-361-5p axis facilitates the proliferation and migration of cutaneous squamous cell carcinoma via the activation of Wnt pathway.

Cutaneous squamous cell carcinoma (CSCC) is one of the most malignant tumors worldwide. It has been validated that matrix metallopeptidase 1 (MMP1) expression was obviously up-regulated in CSCC tissues. However, its specific role in CSCC is still unclear. RT-qPCR analysis and western blot assays were used to measure the mRNA and protein expressions, respectively. MTT and colony formation assays were conducted to assess proliferative ability. Transwell assays were adopted to evaluate migratory and invasive abilities. Flow cytometry and caspase-3/8/9 activity assays were carried out to evaluate cell apoptosis. Relevant mechanism experiments were finally performed to delineate molecular relationship among genes. We found that the expression of MMP1 was up-regulated in CSCC cells, and knockdown of MMP1 suppressed cell proliferation and invasion in CSCC. Subsequently, miR-361-5p was validated to target MMP1. Moreover, miR-361-5p was proved to be sponged by nuclear paraspeckle assembly transcript 1 (NEAT1) in CSCC. We further demonstrated that NEAT1 could activate Wnt pathway to affect cell proliferation and invasion. Finally, miR-361-5p inhibition rescued the suppressing effects of NEAT1 depletion on cell proliferation, invasion as well as Wnt pathway in CSCC. In summary, MMP1 regulated by NEAT1/miR-361-5p axis facilitated CSCC malignant behaviors via Wnt pathway activation.