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[reason]

In discussions of aging, references to klotho usually mean α-klotho, a transmembrane protein, and specifically the fragment of α-klotho that projects beyond the cell membrane and is shed to circulate in the body, also known as soluble α-klotho. Soluble α-klotho interacts with cell receptors to produce beneficial changes in cell function in a range of tissues. Klotho has long been of interest to researchers because increased expression of α-klotho slows aging, whereas reduced expression accelerates aging. Past research has focused on beneficial effects resulting from soluble α-klotho in the kidney and brain. Improved function in these organs might be enough to explain systemic benefits throughout the body, but as shown here soluble α-klotho likely has direct effects on cells in other tissues as well.

We investigate the effects of α-Klotho, an anti-aging hormone, on cell proliferation across three tissues with varying regenerative capacities in the context of aging. Using young and old wild-type mice, alongside old heterozygous Klotho-deficient mice, we administered soluble α-Klotho (sKL) daily for 10 weeks to elucidate the impact of α-Klotho deficiency and its supplementation. Our investigation spanned three organs: the small intestine, the kidney, and the heart.

We measured cell cycle markers (BrdU, Ki-67, and phospho-histone-3), Sirtuin-1, DNA-damage response pathways (gamma-H2Ax, ATM, CHK2), and the aging phenotypes. Supplementation of sKL significantly enhances proliferative markers and attenuates many aging changes. Mechanistic studies show that sKL acts through the Sirt1-CHK2 pathway to promote cell proliferation. In summary, Klotho deficiency exacerbated aging phenotypes, reduced regenerative capacity, and impaired cellular proliferation. Supplementation with sKL effectively counters these age-related declines across multiple tissues by enhancing cellular proliferation and attenuating aging phenotypes through the Sirt1-CHK2 signaling pathway.

Link: https://doi.org/10.1...514-025-00286-1

View the full article at FightAging

[zorba990]

Astragaloside IV Synergizes with Ferulic Acid to Alleviate Hepatic Fibrosis in Bile Duct-Ligated Cirrhotic Rats
https://pubmed.ncbi....h.gov/31900718/

Astragaloside IV Synergizes with Ferulic Acid to Alleviate Hepatic Fibrosis in Bile Duct-Ligated Cirrhotic Rats

Xue-Mei Zhao 1 , Jing Zhang 2 , Yi-Ni Liang 1 , Ying-Cai Niu 3
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PMID: 31900718 DOI: 10.1007/s10620-019-06017-3
Abstract

Background: Due to the multi-factorial etiology of hepatic fibrosis, multi-target therapeutics based on combinatory drugs is known to be a promising strategy for the disease.

Aims: The present study attempted to test the hypothesis that astragaloside IV combined with ferulic acid synergistically inhibits activation of hepatic stellate cells in vivo.

Methods: Bile duct-ligated rats were treated with astragaloside IV or/and ferulic acid for 28 days. Liver fibrosis was measured by histological examination. The oxidative stress-related biomarkers were measured with spectrophotometry. Expressions of mRNA and protein were measured by real-time PCR and Western blotting.

Results: Bile duct-ligated rat treatment with astragaloside IV and ferulic acid in combination resulted in synergistic alleviation of hepatic fibrosis. Simultaneously, activation of hepatic stellate cells was significantly inhibited by the combination therapy when compared with astragaloside IV or ferulic acid alone. Interestingly, astragaloside IV, but not ferulic acid, induced accumulation of Nrf2 in the nucleus, synthesized antioxidant enzymes through negative regulation of glycogen synthase kinase-3β, scavenged reactive oxygen species, and, in turn, suppressed hepatic stellate cells activation in bile duct-ligated rats. Conversely, ferulic acid, but not astragaloside IV, suppressed TGF-β1 and its receptors expression, which resulted in downregulation of Smad3 and Smad4.

Conclusions: These findings suggest that the combination of astragaloside IV and ferulic acid synergistically induces deactivation of hepatic stellate cells through inhibition of the TGF-β pathway and activation of the Nrf2 pathway, and suggest that combination of astragaloside IV and ferulic acid is a promising candidate for the treatment of hepatic fibrosis.

Keywords: Astragaloside IV; Ferulic acid; Hepatic fibrosis; Hepatic stellate cells; Synergism.