Tenacibactins K–M, cytotoxic siderophores from a coral-associated gliding bacterium of the genus Tenacibaculum

HPLC/DAD-based chemical investigation of a coral-associated gliding bacterium of the genus Tenacibaculum yielded three desferrioxamine-class siderophores, designated tenacibactins K (1), L (2), and M (3). Their chemical structures, comprising repeated cadaverine–succinic acid motifs terminated by a hydroxamic acid functionality, were elucidated by NMR and negative MS/MS experiments. Compounds 1–3 were inactive against bacteria and a yeast but displayed cytotoxicity against 3Y1 rat embryonic fibroblasts and P388 murine leukemia cells at GI50 in submicromolar to micromolar ranges. Their iron-chelating activity was comparable to deferoxamine mesylate.

Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40–60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40–60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50–58% of the 40–60 mg/Kg/day DFO-treated patients.

Identification of Type H Vessels in Mice Mandibular Condyle

Type H vessel is a specific vessel subtype that is strongly positive for CD31 and endomucin (CD31hiEmcnhi). It has already been identified that it can tightly regulate the coupling of angiogenesis and osteogenesis in the long bone of mice and human beings. The long bone is formed through endochondral ossification, which is the same type of process happening in mandibular condyle. Although the ossification of long bone and mandibular condyle has the same developmental process, the existence of type H vessels in the mouse condyle remains unclear. To address this, we identified that abundant type H vessels existed in the subchondral bone of the mouse condylar head and endosteum of the mouse condylar neck. Meanwhile, immunofluorescence imaging of the condyles in different ages of male C57BL/6J mice demonstrated that type H vessels decreased while aging. Furthermore, we validated a positive correlation between type H vessels and Osterix+ osteoprogenitors in the condyle induced by mandibular advancement. Mechanistically, we confirmed that deferoxamine mesylate, which promoted the proliferation of type H endothelial cells by activating hypoxia-inducible factor 1α (HIF-1α) signaling pathways, largely prevented the osteopenia in the condyle induced by botulinum toxin type A. Collectively, these results demonstrate that in the mouse condyle, type H vessels in areas of high function positively correlate with bone formation. In addition, we show a novel influence of HIF-1α signaling on osteogenesis via an increase in type H vessels. In conclusion, promoting angiogenesis of type H vessels is a promising strategy for the therapeutic improvement of osteogenesis in mandibular condyle.

Dihydroartemisinin promotes CHAC1 transcription to induce ferroptosis in primary liver cancer cells: activation of unfolded protein responses

Background: This study aimed to explore whether dihydroartemisinin (DHA), an artemisinin derivate drug, eliminates primary liver cancer (PLC) cells by inducing ferroptosis. Methods: Four PLC cell lines were treated with varied concentrations of DHA. RNA interference was performed to knock down the expression of unfolded protein response (UPR) sensors in vitro. Results: DHA-caused PLC cell death was irrelevant to p53 status. PLC cells exposed to DHA displayed classic ferroptosis features – increased lipid ROS, MDA and iron ions, and decreased activity or expression of GSH, GPX4, SLC7A11 and SLC3A2. The anti-tumor effects of DHA were significantly weakened by ferrostatin-1 and deferoxamine mesylate salt, but augmented by iron overload. DHA activated all three UPR branches, including PERK/eIF2/ATF4, IRE1α / XBP1 , and ATF6, in vitro . Further, to deactivate UPRs, exclusive siRNA was used to silence the expression of ATF4, XBP1 or ATF6 in PLC cells. Unexpectedly, ferroptosis induced by DHA was significantly attenuated when ATF4, XBP1 or ATF6 was knocked down. The transcription of CHAC1, a molecule that is capable of degrading GSH, was enhanced by DHA, but weakened when the above three UPR transcription factors were silenced.Conclusion: DHA effectively induces ferroptosis in PLC cells, which involves the activation of anti-survival UPRs.

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes.