TDP‐43 has been identified as the major component of protein aggregates found in affected neurons in FTLD‐TDP and amyotrophic lateral sclerosis (ALS) patients. TDP‐43 is hyperphosphorylated, ubiquitinated, and cleaved in the C‐terminus. CDC‐7 was reported to phosphorylate TDP‐43. There are no effective treatments for either FTLD‐TDP or ALS, being a pressing need for the search of new therapies. We hypothesized that modulating CDC‐7 activity with small molecules that are able to interfere with TDP‐43 phosphorylation could be a good therapeutic strategy for these diseases. Here, we have studied the effects of novel brain penetrant, thiopurine‐based, CDC‐7 inhibitors in TDP‐43 homeostasis in immortalized lymphocytes from FTLD‐TDP patients, carriers of a loss‐of‐function GRN mutation, as well as in cells derived from sporadic ALS patients. We found that selective CDC‐7 inhibitors, ERP1.14a and ERP1.28a, are able to decrease the enhanced TDP‐43 phosphorylation in cells derived from FTLD‐TDP and ALS patients and to prevent cytosolic accumulation of TDP‐43. Moreover, treatment of FTLD‐TDP lymphoblasts with CDC‐7 inhibitors leads to recovering the nuclear function of TDP‐43‐inducing CDK6 repression. We suggest that CDC‐7 inhibitors, mainly the heterocyclic compounds here shown, may be considered as promising drug candidates for the ALS/FTD spectrum.

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Clinopodium tomentosum (Kunth) Govaerts is an endemic species in Ecuador, where it is used as an anti-inflammatory plant to treat respiratory and digestive affections. In this work, effects of a Clinopodium tomentosum ethanolic extract (CTEE), prepared from aerial parts of the plant, were investigated on vascular endothelium functions. In particularly, angiogenesis activity was evaluated, using primary cultures of porcine aortic endothelial cells (pAECs). Cells were cultured for 24 h in the presence of CTEE different concentrations (10, 25, 50, and 100 μg/ml); no viability alterations were found in the 10-50 μg/ml range, while a slight, but significant, proliferative effect was observed at the highest dose. In addition, treatment with CTEE was able to rescue LPS-induced injury in terms of cell viability. The CTEE ability to affect angiogenesis was evaluated by scratch test analysis and by an in vitro capillary-like network assay. Treatment with 25-50 μg/ml of extract caused a significant increase in pAEC’s migration and tube formation capabilities compared to untreated cells, as results from the increased master junctions’ number. On the other hand, CTEE at 100 μg/ml did not induce the same effects. Quantitative PCR data demonstrated that FLK-1 mRNA expression significantly increased at a CTEE dose of 25 μg/ml. The CTEE phytochemical composition was assessed through HPLC-DAD; rosmarinic acid among phenolic acids and hesperidin among flavonoids were found as major phenolic components. Total phenolic content and total flavonoid content assays showed that flavonoids are the most abundant class of polyphenols. The CTEE antioxidant activity was also showed by means of the DPPH and ORAC assays. Results indicate that CTEE possesses an angiogenic capacity in a dose-dependent manner; this represents an initial step in elucidating the mechanism of the therapeutic use of the plant.

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