bims-raghud 2025-08-17 papers

Issue of 2025–08–17
two papers selected by
Irene Sambri, TIGEM

Front Neurosci. 2025 ;19 1595880

mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons.

Elizabeth D Buttermore, Gayathri Rajaram Srinivasan, Hellen Jumo, Amanda C Swanson, Benjamin O'Kelly, Nina R Makhortova, Mustafa Sahin, Stelios T Tzannis.

The mechanistic target of rapamycin (mTOR) pathway plays an important role in regulating multiple cellular processes, including cell growth, autophagy, proliferation, protein synthesis, and lipid synthesis, among others. Given the central role of this pathway in multiple cellular processes, it is not surprising that mTOR pathway dysregulation is a key mechanism underlying several neurological disorders, including Tuberous Sclerosis Complex (TSC). TSC patients typically present with pathogenic variants in the TSC1 or TSC2 genes, which encode proteins forming a complex that plays an important role in modulating mTOR activity. We previously reported cellular and functional deficits in induced pluripotent stem cell (iPSC)-derived neurons from TSC patients. These deficits were reversed by inhibiting mTOR activity using rapamycin treatment, revealing the role of mTOR signaling in the regulation of cell morphology and hyperexcitability phenotypes in TSC patient-derived neurons. However, chronic rapamycin treatment inhibits both mTORC1 and mTORC2 activity and its clinical use is associated with significant side effects. With the development of novel mTORC1-selective compounds, we aimed to assess whether selective inhibition of mTORC1 likewise reversed the cellular and functional deficits found in TSC patient-derived neurons. Our results indicate that the novel, selective mTORC1 inhibitors nearly fully reversed the cellular and functional deficits of TSC2 -/ - iPSC-derived neurons in a fashion and magnitude similar to rapamycin, as they all reversed and near-normalized their neuronal hyperexcitability and abnormal morphology as compared to the DMSO-treated cells. These data suggest that mTORC1-specific compounds could provide clinical therapeutic benefit similar to rapamycin without the same side effects.

Keywords: TSC2; hyperexcitability; iPSC-derived neurons; mTOR; mTORC1; mTORC2; soma size

DOI: https://doi.org/10.3389/fnins.2025.1595880

Int J Mol Sci. 2025 Aug 01. pii: 7440. [Epub ahead of print]26(15):

Cardiorenal Syndrome: Molecular Pathways Linking Cardiovascular Dysfunction and Chronic Kidney Disease Progression.

Fabian Vasquez, Caterina Tiscornia, Enrique Lorca-Ponce, Valeria Aicardi, Sofia Vasquez.

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin-angiotensin-aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes.

Keywords: cardiorenal syndrome; cardiovascular disease; chronic kidney disease

DOI: https://doi.org/10.3390/ijms26157440