Akt-1 x Nrf2

Longevity is defined by the ability to maintain both physical and mental health throughout a long life and may results from adaptive mechanisms that mitigate aging's detrimental effects.

The 20-year follow-up study of 3,312 unrelated individuals aged 18-114 years from the Volga-Ural region of Eurasia investigated variants in cellular homeostasis genes IGF1, PIK3R1, AKT1, MTOR, NFE2L2, KEAP1, HIF1A, TP53, and SIRT1, to identify associations with clinical aging phenotypes and healthy longevity.

In men, KEAP1 (rs1048290) CC genotype was a longevity and survival marker (OR = 2.39, P = 3E-05, HR = 0.54, P = 2.4E-03). NFE2L2 (rs6721961) TT genotype was linked to higher mortality (HR = 1.77, P = 0.031), particularly combined with KEAP1 (rs1048290) G and AKT1 (rs3803304) C alleles (HR = 2.8, P = 0.023). In women, AKT1 (rs3803304) C allele interacted with NFE2L2 (rs6721961) TT genotype (SF = 0.13, P = 3.6E-03), and was linked to longevity (OR = 2.22, P = 6.3E-03) and protection against cerebrovascular diseases (OR = 0.62, P = 5.1E-03). AKT1 (rs3803304) GG genotype, along with HIF1A (rs11549465) T and SIRT1 (rs3758391) T alleles (SF = 2.52, P = 1.5E-03), promoted survival (HR = 0.71, P = 0.014). In men, HIF1A (rs11549465) TT genotype predicted cardiovascular mortality (HR = 7.5, P = 5.5E-03). SIRT1 (rs3758391) TT genotype was associated with improved survival in individuals with diabetes (HR = 0.4, P = 5.8E-03) and multimorbidity (HR = 0.48, P = 0.025).

Variants in NFE2L2, KEAP1, SIRT1, AKT1, and HIF1A, along with their interactions, were significantly associated with survival in age-related diseases and healthy longevity.

Cordyceps sinensis, a precious traditional Chinese herb, exhibits diverse polysaccharide structures and functions across strains. This study screened Hirsutella sinensis 02-3 and successfully extracted two mycopolysaccharides (fungal polysaccharides): ISP-AII (MW = 4.70 kDa) and ISP-BII (MW = 75.42 kDa). Chemical and monosaccharide composition analyses showed that ISP-AII comprised glucose, xylose, arabinose, galactose, and mannose (molar ratio 58.39:2.63:1.21:1.03:0.99), while ISP-BII contained additional fucose and exhibited a molar ratio of 57.82:1.07:1.06:0.39:0.37:0.32 for glucose, xylose, galactose, arabinose, fucose, and mannose, respectively. Techniques such as the Congo red test, Fourier transform infrared (FTIR), Scanning Electron Microscopy (SEM), and Nuclear Magnetic Resonance (NMR) were employed to characterize their structural features, suggesting both ISP-AII and ISP-BII were →4)-α-D-Glcp-(1 → main backbone. Functionally, ISP-BII had the highest 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) scavenging rate of 61.7 %, and ISP-AII scavenged 56.12 % of hydroxyl radicals. Both also showed high reducing power and reactive oxygen species (ROS) - scavenging ability. Moreover, they protected cardiomyocytes from apoptosis by regulating key factors in the Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) and mitochondrial BAX/Bcl-2/Caspase-3 apoptotic signaling pathways, and exerted antioxidant effects via the Keap1/Nrf2/ARE pathway. These results offer new insights into the cardioprotective functions of Cordyceps polysaccharides, and their potential applications in food, cosmetics, and pharmaceutical industries.

Paridis Rhizoma is a common traditional Chinese medicine (TCM), possessing therapeutic effects including heat-clearing, detoxification, and liver calming effects. It is frequently applied in TCM prescriptions for the treatment of liver disease. Studies have shown that total saponins derived from Paridis Rhizoma (PRS) have potent anti-liver fibrosis effect, but its mechanism in treating liver fibrosis has not been clarified. This study aimed to explore the therapeutic effect of PRS on liver fibrosis and elucidate their potential underlying pharmacological mechanisms.

The targets and pathways of Paridis Rhizoma Saponins on experimental liver fibrosis were analyzed using network pharmacology and molecular docking. PRS was administered to rats with CCL₄-induced liver fibrosis rats. Liver function, fibrosis, and inflammatory indicators were assessed using ELISA to measure serum AST and ALT, as well as liver tissue levels of HA, LN, Col IV, and PC-III fibrosis markers. Additionally, inflammatory markers IL-6, IL-β, and TNF-a were quantified. Liver morphological, H&E, and Masson's staining were used to observe the degree of liver fibrosis. The mRNA and protein expressions of Nrf2-HO-1/NQO-1 and TGF-β1/Smads signaling pathways in liver tissues were detected using immunohistochemistry (IHC) staining, Western blot (WB), and RT-qPCR.

Comprehensive network pharmacology and animal experiments show that PRS may act on STAT3, SRC, VEGFA, AKT1 and other targets through its polyphyllin I, polyphyllin II, polyphyllin VI, polyphyllin VII and other components.Analysis from ELISA showed that PRS could improve liver function, mitigate the progression of liver fibrosis, and regulate inflammatory responses in rats. Morphological, H&E, and Masson's staining demonstrated that PRS significantly improved liver tissue immune response and necrosis. Additionally, IHC staining, WB results, and RT-qPCR results showed that PRS positively regulates the Nrf2-HO-1/NQO-1 and TGF-β1/Smads signaling pathways to counteract the development of pathological liver fibrosis in rats.

These findings indicate that PRS can mitigate the impact of CCl₄-induced liver fibrosis in experimental animals by upregulating the Nrf2-HO-1/NQO-1 and downregulating the TGF-β1/Smads signaling pathways.