Neurodegeneration in postmortem patients of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) has been correlated to distribution of dipeptide repeat proteins in the form of poly-GR. Scientists at the Erasmus University Medical Center Rotterdam have assessed the toxicity of poly-GR and found a possible suppression with the help of zebrafish, Trolox, and LifeTein’s own GR peptides and antibodies.

Trolox Suppresses Poly-GR Toxicity Identified by Antibodies

Using zebrafish as a model for C9FTD/ALS cases, scientists injected the embryos with RNA encoding ATG mediated codon-optimized 100xGR. These peptides provided by LifeTein were able to simulate the apoptosis in the brain and caused aberrant motor neuron morphology in the zebrafish embryos. Using LifeTein’s monoclonal antibody against poly-GR, the group was able to detect the poly-GR specifically in the brain.

The researchers’ study suggested inhibition of oxidative stress held the potential to suppress the poly-GR toxicity in these models. To apply this knowledge, the embryos were treated with Trolox, a known inhibitor of oxidative stress. Not only did this rescue the poly-GR toxicity, but it did so in vivo. This holds a promising future in treatment of C9FTD/ALS patients, indicating the possible role of oxidative stress implies the possible treatment by inhibiting the said stress.

References: Riemslagh FW, Verhagen RFM, van der Toorn EC, Smits DJ, Quint WH, van der Linde HC, van Ham TJ, Willemsen R. Reduction of oxidative stress suppresses poly-GR mediated toxicity in zebrafish embryos. Dis Model Mech. 2021 Oct 25:dmm.049092. doi: 10.1242/dmm.049092. Epub ahead of print. PMID: 34693978.

The use of mobile microrobots offers a promising solution for targeted medical theranostic applications at normally inaccessible regions of the human body. Namely, the circulatory system is an ideal region for said applications, but blood flow can complicate both navigation inside the body and preservation of the microrobots.

Researchers have designed microrollers able to be controlled via magnetic propulsion and steering, able to maneuver against physiologically relevant blood flow effectively. The rollers are composed of a magnetically responsive half-side and a silica half-side for cargo loading and biochemical functionalities. Once navigated to cancerous cell monolayers, the rollers utilize surface-functionalized cell-specific antibodies as well as photocleavable linkers to release doxorubicin (DOX), and anticancer drug molecule, onto the target area.

Both the azide-DOX and o-nitrobenzyl photocleavable linker used by the team were provided by LifeTein, allowing the mircorollers to release the drug on demand via UV light exposure. This method of on demand delivery of the drug molecules combined with maneuverability of the microrollers designed by the researchers opens the door for development of next-generation microrobots for controlled navigation and cargo delivery in the circulatory system.

Reference: Alapan et al., Sci. Robot. 5, eaba5726 (2020) 20 May 2020

LifeTein’s Innovative Synthetic Wasabi Receptor Toxin and Its Variants Propel Breakthrough in Chronic Pain Research

LifeTein’s groundbreaking work in synthetic peptides, including the Wasabi Receptor Toxin, its mutants, Biotinylated, and AlexaFluor-488 conjugated variants, has played a pivotal role in advancing our understanding of chronic pain mechanisms. This research supported the efforts of David Julius, who was awarded the Nobel Prize in Physiology or Medicine this year for his contributions.

Julius, along with his team at the University of California, San Francisco (UCSF), made a significant discovery involving a scorpion toxin that specifically targets the “wasabi receptor.” This receptor is an ion channel protein that triggers the intense sensations, such as the sinus-clearing effect of wasabi or the eye-watering pain from cutting onions.

The team’s research highlighted that the scorpion toxin, referred to as WaTx, activates the TRPA1 wasabi receptor, inducing a pain response to various irritants. Remarkably, WaTx is a novel type of cell-penetrating peptide that can enter cells directly across the plasma membrane without the need for channel proteins.

The implications of this discovery are vast, with potential applications in studying and treating chronic pain and inflammation. The unique properties of WaTx suggest it could be instrumental in developing new, non-opioid pain management therapies, as it induces pain and hypersensitivity without causing neurogenic inflammation.

David Julius’s research, particularly his exploration of receptors that detect temperature, has been recognized with the prestigious Nobel Prize in Physiology or Medicine 2021, underscoring the impact of his work on the medical and scientific community.

This research was documented in a study published by Lin King, J. V., Emrick, J. J., Kelly, M. J. S., Herzig, V., King, G. F., Medzihradszky, K. F., & Julius, D. (2019) in the journal Cell, where they discuss the mode-specific modulation of TRPA1 and its implications for pain management.

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. The malignant and treatment-resistant brain tumor is a target for anti-cancer studies.

Through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, H3K27M reshapes the epigenome and promotes oncogenesis of DIPG. Consequentially, the histone modification H3K36me2, antagonistic to H3K27me2/3, is elevated. The relationship and role of H3K36me2 in H3K27M-DIPG was investigated by approaches to its upstream catalyzing enzymes, NSD1 and NSD2, the “writers”, and its downstream binding factors, LEDGF and HDGF2, the “readers”.

Tumor-promoting transcriptional programs in H3K27M-DIPG were found to be disrupted by loss of NSD1 and NSD2, thus impeding cellular proliferation and tumorigenesis.
Downstream, a chemically modified peptide mimicking endogenous H3K36me2 was found to dislodge LEDGF and HDGF2 from chromatin. As LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2, dislodging them resulted in inhibition of H3K27M-DIPG proliferation.

In this study, the chemically modified peptides used were cell penetrating peptides purchased from LifeTein.

Reference: Sci. Adv. 2021 Jul 14; 7(29)