Akt x Nrf2 x PI3Ks

Osteolysis is a common complication in patients with multiple myeloma (MM). Our previous studies have demonstrated that MM cells can promote osteoclast differentiation of macrophages. In this study, we explored the effect of sulforaphane (SFN), a natural NRF2 activator found in broccoli, on MM cell-induced osteoclast differentiation.

Conditional medium (CM) derived from MM cells was used to induce osteoclast differentiation, and TRAP staining was performed to examine osteoclast. Gene expression was detected by western blotting or real-time PCR. Cell counting and EdU staining were performed to test macrophage proliferation.

We showed that the CM of MM cells downregulated the expression of ferroportin1 (Fpn1), the only known iron exporter in vertebrate cells, thereby increasing cellular iron levels in murine macrophage cells RAW264.7. Deferoxamine (DFO), an iron chelator, effectively blocked MM cell CM-induced osteoclast differentiation and macrophage proliferation, suggesting that iron overload played a key role in these cellular events. Subsequent mechanistic investigations revealed that MM cell CM induced osteoclast differentiation and macrophage proliferation by activating the JNK/AP-1/NFATC1 pathway and PI3K/AKT pathway. SFN was found to increase Fpn1 expression, leading to decreased cellular iron levels in RAW264.7 cells activated by MM cell CM. Importantly, the osteoclast differentiation and macrophage proliferation induced by MM cell CM were significantly inhibited by SFN.

Altogether, our findings indicated that SFN inhibits MM cell-induced osteoclast differentiation and macrophage proliferation by elevating FPN1 levels. SFN could be a promising therapeutic strategy for MM-associated osteolysis.

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.

The rising prevalence of heat stress (HS), because of global warming, presents a considerable challenge to both human and animal health and welfare. L-Theanine (LTA), a naturally occurring amino acid, may enhance poultry muscle yield and quality, suggesting its potential application in alleviating the negative impacts of HS. However, the molecular mechanisms through which LTA exerts its beneficial effects remain to be fully understood. This study explored the protective effects of LTA on cultured broiler skeletal muscle cells under oxidative stress induced by HS, focusing on the molecular mechanisms involved. Our findings indicate that treatment with LTA significantly improved cell survival, bolstered the activity of antioxidant enzymes, decreased reactive oxygen species (ROS) contents and diminished malondialdehyde (MDA) levels in HS-treated cultured cells. Furthermore, LTA enhanced the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways in HS-treated cultured cells, facilitating mitochondrial biogenesis and reducing cell apoptosis. The protective effects of LTA in HS-treated cultured cells were significantly reduced by the PI3K inhibitor LY294002 or the Nrf2 inhibitor ML385. In conclusion, our study showed that LTA protects cultured skeletal muscle cells from HS-induced oxidative damage by modulating the PI3K/AKT/Nrf2 signaling pathway, positioning LTA as a promising natural antioxidant for poultry feed additives aimed at improving muscle health.