bims-raghud 2024-10-06 papers

Issue of 2024‒10‒06
four papers selected by
Irene Sambri, TIGEM

Int J Mol Sci. 2024 Sep 23. pii: 10225. [Epub ahead of print]25(18):

Current Understanding of Cardiovascular Calcification in Patients with Chronic Kidney Disease.

The burden of chronic kidney disease (CKD) is increasing, posing a serious threat to human health. Cardiovascular calcification (CVC) is one of the most common manifestations of CKD, which significantly influences the morbidity and mortality of patients. The manifestation of CVC is an unusual accumulation of mineral substances containing calcium and phosphate. The main component is hydroxyapatite. Many cells are involved in this process, such as smooth muscle cells (SMCs) and endothelial cells. CVC is an osteogenic process initiated by complex mechanisms such as metabolic disorders of calcium and phosphorus minerals, inflammation, extracellular vesicles, autophagy, and micro-RNAs with a variety of signaling pathways like Notch, STAT, and JAK. Although drug therapy and dialysis technology continue to advance, the survival time and quality of life of CVC patients still face challenges. Therefore, early diagnosis and prevention of CKD-related CVC, reducing its mortality rate, and improving patients' quality of life have become urgent issues in the field of public health. In this review, we try to summarize the state-of-the-art understanding of the progression of CVC and hope that it will help in the prevention and treatment of CVC in CKD.

Keywords: cardiovascular calcification; chronic kidney disease; mechanism; signaling pathway

DOI: https://doi.org/10.3390/ijms251810225

Cardiovasc Toxicol. 2024 Oct 04.

The Multifaceted Roles of Hippo-YAP in Cardiovascular Diseases.

Hao Wu, Yan-Nan Che, Qi Lan, Yi-Xiang He, Ping Liu, Ming-Tai Chen, Li Dong, Meng-Nan Liu.

The Hippo-yes-associated protein (YAP) signaling pathway plays a crucial role in cell proliferation, differentiation, and death. It is known to have impact on the progression and development of cardiovascular diseases (CVDs) as well as in the regeneration of cardiomyocytes (CMs). However, further research is needed to understand the molecular mechanisms by which the Hippo-YAP pathway affects the pathological processes of CVDs in order to evaluate its potential clinical applications. In this review, we have summarized the recent findings on the role of the Hippo-YAP pathway in CVDs such as myocardial infarction, heart failure, and cardiomyopathy, as well as its in CM development. This review calls attention to the potential roles of the Hippo-YAP pathway as a relevant target for the future treatment of CVDs.

Keywords: Cardiac repair; Cardiomyocytes; Cardiovascular diseases; Hippo; Yes-associated protein

DOI: https://doi.org/10.1007/s12012-024-09926-6

Cell Mol Biol Lett. 2024 Sep 27. 29(1): 125

mTOR/miR-142-3p/PRAS40 signaling cascade is critical for tuberous sclerosis complex-associated renal cystogenesis.

Shuyun Zhao, Shuai Hao, Jiasheng Zhou, Xinran Chen, Tianhua Zhang, Zhaolai Qi, Ting Zhang, Sajid Jalal, Chuanxin Zhai, Lu Yin, Yufei Bo, Hongming Teng, Yue Wang, Dongyan Gao, Hongbing Zhang, Lin Huang.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) develop renal cysts and/or angiomyolipomas (AMLs) due to inactive mutations of either TSC1 or TSC2 and consequential mTOR hyperactivation. The molecular events between activated mTOR and renal cysts/AMLs are still largely unknown.METHODS: The mouse model of TSC-associated renal cysts were constructed by knocking out Tsc2 specifically in renal tubules (Tsc2f/f; ksp-Cre). We further globally deleted PRAS40 in these mice to investigate the role of PRAS40. Tsc2-/- cells were used as mTOR activation model cells. Inhibition of DNA methylation was used to increase miR-142-3p expression to examine the effects of miR-142-3p on PRAS40 expression and TSC-associated renal cysts.
RESULTS: PRAS40, a component of mTOR complex 1, was overexpressed in Tsc2-deleted cell lines and mouse kidneys (Tsc2f/f; ksp-Cre), which was decreased by mTOR inhibition. mTOR stimulated PRAS40 expression through suppression of miR-142-3p expression. Unleashed PRAS40 was critical to the proliferation of Tsc2-/- cells and the renal cystogenesis of Tsc2f/f; ksp-Cre mice. In contrast, inhibition of DNA methylation increased miR-142-3p expression, decreased PRAS40 expression, and hindered cell proliferation and renal cystogenesis.
CONCLUSIONS: Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.

Keywords: PRAS40; Renal cystogenesis; Tuberous sclerosis complex; mTOR; miRNA

DOI: https://doi.org/10.1186/s11658-024-00638-x

Cell Death Dis. 2024 Sep 30. 15(9): 696

Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.

Boram Son, Wonhwa Lee, Hyeonjeong Kim, Heungsoo Shin, Hee Ho Park.

Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.

DOI: https://doi.org/10.1038/s41419-024-07077-8