Medical Bulletin 16/ August/ 2024

In a recent research published in EMBO Molecular Medicine scientists have created a Trojan horse method that deceives malaria parasites into consuming a lethal dose of medication by capitalizing on their dependence on cholesterol for survival. By attaching cholesterol to the drugs, scientists can "sneak" the drugs into the parasites, where they then deliver their deadly impact.

Over a quarter of Australians aged 50 and older use cholesterol-lowering medications to prevent heart disease and strokes, but cholesterol is also essential for our survival. Scientists from The Australian National University (ANU) suggest that cholesterol's role as a fundamental component of life could be the key to treating deadly parasitic diseases, such as malaria.

The new Trojan horse technique has the potential to provide more effective and long-lasting treatments for malaria. Additionally, the scientists note that these findings could impact the agricultural sector, as parasites that infect and kill livestock can cause significant financial losses for farmers, amounting to billions of dollars.

Lead researcher Professor Alex Maier from ANU stated that the Trojan horse method of delivering drugs into parasites is 3 to 25 times more effective at eradicating them than drugs that are not attached to cholesterol.

The ANU scientists suggest that this new drug delivery system, which involves attaching drugs to cholesterol, could also be effective for treating other diseases such as giardia, an intestinal infection that causes diarrhoea. Additionally, it may be useful in treating leishmaniasis, a disease affecting the skin, mouth, nose, and throat that disproportionately impacts some of the world's poorest populations and can be fatal if left untreated.

Reference : Fraser M, Curtis B, Phillips P, Yates PA, Lam KS, Netzel O, van Dooren GG, Ingmundson A, Matuschewski K, McLeod MD, Maier AG. Harnessing cholesterol uptake of malaria parasites for therapeutic applications. EMBO Mol Med. 2024 Jul;16(7):1515-1532. doi: 10.1038/s44321-024-00087-1. Epub 2024 Jun 11. PMID: 38862600; PMCID: PMC11251039.

In a recent research published in Science advances, researchers from Duke-NUS Medical School and the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) have identified a new pathway to activate dormant neural stem cells. This breakthrough could pave the way for innovative treatments for neurodevelopmental disorders like autism, learning disabilities, and cerebral palsy.

The findings revealed that astrocytes, a type of glial cell previously believed to offer only structural and nutritional support, play a crucial role in activating dormant neural stem cells in the brains of fruit flies.

Using super-resolution microscopy with 10-times magnification, the team of scientists examined the tiny fiber structures characteristic of dormant neural stem cells in fruit flies. These structures, about 1.5 µm in diameter (or 20 times smaller than a human hair), are protrusions from the cell body rich in actin filaments. A specific Formin protein can activate and assemble these filaments.

The scientists found that astrocytes release a signaling protein called Folded gastrulation (Fog), which triggers a series of events, including the activation of the Formin protein pathway to regulate actin filament movement. This process reactivates dormant neural stem cells, causing them to divide and generate new neurons that aid in brain repair and development.

The receptor protein GPCR in neural stem cells responds to Fog from astrocytes, activating the signalling pathway that controls actin filament formation. GPCRs play crucial roles in many cellular processes, and the GPCR protein family is a major drug target, with 34% of FDA-approved drugs targeting these proteins. Thus, understanding this signalling pathway could lead to new strategies for repurposing existing drugs to treat neurodevelopmental disorders.

This study is part of ongoing efforts to enhance our understanding of the fundamental mechanisms in the human brain, aiming to develop new therapeutic strategies, particularly for individuals with neurological conditions.

Reference: Kun-Yang Lin et al., Astrocytes control quiescent NSC reactivation via GPCR signaling–mediated F-actin remodeling.Sci. Adv.10,eadl4694(2024).DOI:10.1126/sciadv.adl4694

The new study published in Nature Metabolism and led by researchers at Harvard T.H. Chan School of Public Health reveals that increased consumption of heme iron, which is primarily found in red meat and other animal products, rather than non-heme iron from plant-based sources, was linked to a greater risk of developing type 2 diabetes (T2D).

The researchers investigated the relationship between iron intake and type 2 diabetes (T2D) by analysing 36 years of dietary data from 206,615 adults who participated in the Nurses' Health Studies I and II and the Health Professionals Follow-up Study. They evaluated participants' consumption of different types of iron—total, heme, non-heme, dietary (from foods), and supplemental (from supplements)—and their T2D status, while accounting for other health and lifestyle variables.

The researchers also explored the biological mechanisms linking heme iron to type 2 diabetes (T2D) within smaller participant groups. They analysed plasma metabolic biomarkers related to insulin, blood sugar, blood lipids, inflammation, and iron metabolism in 37,544 participants. Additionally, they examined the metabolomic profiles of 9,024 participants, which included plasma levels of small-molecule metabolites involved in processes like digestion and chemical reactions.

The study revealed a significant correlation between higher heme iron intake and increased T2D risk. Those in the highest intake group had a 26% greater risk of developing T2D compared to those in the lowest intake group. Furthermore, heme iron was found to contribute to over half of the T2D risk linked to unprocessed red meat and a notable portion of the risk associated with several T2D-related dietary patterns. Consistent with earlier research, no significant link was found between non-heme iron intake from diet or supplements and T2D risk.

The researchers also identified a dozen blood metabolites-; including L-valine, L-lysine, uric acid, and several lipid metabolites-;that may play a role in the link between heme iron intake and TD2 risk. These metabolites have been previously associated with risk of T2D.

The researchers believe the study’s findings have significant implications for dietary guidelines and public health strategies aimed at reducing diabetes rates. Specifically, the addition of heme to plant-based meat alternatives—used to improve flavor and appearance—raises health concerns and requires further investigation.

Reference:Wang, F., et al. (2024). Integration of epidemiological and blood biomarker analysis links haem iron intake to increased type 2 diabetes risk. Nature Metabolism. doi.org/10.1038/s42255-024-01109-5.

‘Symptom triggered testing’, prompted by symptoms such as pain, abdominal bloating/swelling, and feeling full soon after starting to eat, can pick up early stage aggressive ovarian cancer in 1 in 4 of those affected, finds a data analysis, published online in the International Journal of Gynecological Cancer.

The study found that complete surgical removal of cancerous tissue was achievable in 60% of women diagnosed with ovarian cancer based on the study's approach. This challenged the assumption that symptoms always indicate advanced disease in ovarian cancer.

Ovarian cancer is the sixth leading cause of cancer-related deaths. While the five-year survival rate is over 93% for women diagnosed with early-stage (I or II) ovarian cancer, it drops significantly to just 13% for those with advanced-stage (III or IV) disease.

Research indicates that symptoms can precede diagnosis by 3 months to 3 years, but these symptoms are often vague, complicating early detection. Symptoms such as pain, abdominal swelling or bloating, and feeling full quickly after eating are linked to ovarian cancer and should prompt urgent investigation or 'symptom-triggered testing.'

The study analysed data from 1,741 women participating in the Refining Ovarian Cancer Test accuracy Scores (ROCkeTS) study. All participants had been fast-tracked for treatment under a symptom-triggered testing protocol.

Among these women, 119 (7%) were diagnosed with high-grade serous ovarian cancer. The average age of these women was 63, though ages ranged from 32 to 89, with 90% having gone through menopause.

Most of these women (112, or 94%) experienced minimal interference with their daily lives, being classified with a performance status of 0 or 1, meaning they were either fully active or able to perform all activities except strenuous ones.

This approach allows for the detection of high-grade serous ovarian cancer at an earlier stage, which can improve treatment outcomes and enhance the likelihood of successful surgical intervention. In the long run, further exploration of urine biomarkers may be desirable, considered the potential convenience of urinary assays in screening populations.

References: G.L. Andriole, D. Reding, R.B. Hayes, P.C. Prorok and J.K. Gohagan, The prostate, lung, colon, and ovarian (PLCO) cancer screening trial: Status and promise, Urol Oncol 22(4) (2004), 358–361.