PI3K signaling-regulated metabolic reprogramming: From mechanism to application.

Oncogenic signaling involved in tumor metabolic reprogramming. Tumorigenesis was not only determined by the mutations or deletion of oncogenes but also accompanied by the reprogramming of cellular metabolism. Metabolic alterations play a crucial regulatory role in the development and progression of tumors. Oncogenic PI3K/AKT signaling mediates the metabolic switch in cancer cells and immune cells in the tumor microenvironment. PI3K/AKT and its downstream effector branch off and connect to multiple steps of metabolism, such as glucose, lipids, and amino acids. Thus, PI3K inhibitor could effectively regulate metabolic pathway and impede the oncogenic process and some key metabolic proteins or critical enzymes also constitute biomarkers for tumor diagnosis and treatment. In the current review, we summarize the significant effect of PI3K/AKT signaling toward tumor metabolism, it enables us to obtain the better understanding for this interaction and develop more effective therapeutic strategies targeting cancer cell metabolism.

Trilobatin, an Active Dihydrochalcone from Lithocarpus polystachyus, Prevents Cisplatin-Induced Nephrotoxicity via Mitogen-Activated Protein Kinase Pathway-Mediated Apoptosis in Mice.

Although naturally occurring flavonoids have shown beneficial effects on the side effects caused by cisplatin, there are few reports on the protective effect of dihydrochalcone on the cisplatin-induced toxicity. Trilobatin (TLB), as the major sweetener and active ingredient in Lithocarpus polystachyus Rehd, is a dihydrochalcone-like compound that can be present in concentrations of up to 10% or more in tender leaves. Herein, a cisplatin-induced acute kidney injury (AKI) model was established to investigate the protective effect and mechanism of TLB against the cisplatin-induced nephrotoxicity in mice. The results showed that TLB significantly reversed the inhibition of CRE, BUN, and MDA levels compared with the cisplatin group. Furthermore, TLB treatment (50 and 100 mg/kg) for 10 days significantly alleviated cisplatin-induced renal pathological changes. TUNEL staining showed that TLB administration can effectively improve the occurrence of apoptosis of renal tissue cells caused by cisplatin exposure. Importantly, western blot analysis verified that TLB alleviated cisplatin-induced nephrotoxicity by regulating the AKT/MAPK signaling pathway and apoptosis. In summary, our findings showed clearly that TLB has a significant preventive effect on cisplatin-induced AKI.

20(S)-ginsenoside Rh1 alleviates T2DM induced liver injury via the Akt/FOXO1 pathway.

Diabetes-associated liver injury becomes a dominant hepatopathy, leading to hepatic failure worldwide. The current study was designed to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on liver injury induced by T2DM. A T2DM model was established using C57BL/6 mice through feeding with HFD followed by injection with streptozotocin at 100 mg·kg-1.. Then the mice were continuously administered with G-Rh1 (5 and 10 mg·kg-1), to explore the protective effects of G-Rh1 against liver injury. Results showed that G-Rh1 exerted significant effects on maintaining the levels of FBG and insulin, and ameliorated the increased levels of TG, TC and LDL-C induced by T2DM. Moreover, apoptosis in liver tissue was relieved by G-Rh1, according to histological analysis. Particularly, in diabetic mice, it was observed that not only the increased secretion of G6Pase and PEPCK in the gluconeogenesis pathway, but also inflammatory factors including NF-κB and NLRP3 were suppressed by G-Rh1 treatment. Furthermore, the underlying mechanisms by which G-Rh1 exhibited ameliorative effects was associated with its capacity to inhibit the activation of the Akt/FoxO1 signaling pathway induced by T2DM. Taken together, our preliminary study demonstrated the potential mechnism of G-Rh1 in protecting the liver against T2DM-induced damage.

Ginsenoside Rh1 Improves Type 2 Diabetic Nephropathy through AMPK/PI3K/Akt-Mediated Inflammation and Apoptosis Signaling Pathway.

Although ginseng (Panax ginseng C.A. Meyer) has received extensive attention in the treatment and prevention of type 2 diabetes mellitus (T2DM) in the past few decades, there are few studies on the complications of T2DM. At present, obesity-linked diabetic nephropathy (DN) has become the most prevailing element of the end-stage renal failure in the world. The aim of this work is to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on DN induced by high fat diet plus streptozotocin (HFD/STZ) through some potential and combined mechanisms of action. The results showed that G-Rh1 treatment at 5 and 10 mg/kg for 8 weeks exerted excellent effects in controlling fasting blood glucose (FBG), improving glucose tolerance, and increasing insulin level. In addition, G-Rh1 effectively prevents the excessive production of advanced glycation end products (AGEs), a diabetic nephropathy marker, in HFD/STZ induced DN mice. Meanwhile, oxidation indicators including SOD, GSH, and MDA were improved by G-Rh1 treatment to varying degrees. It is worth noting that G-Rh1 not only inhibits the secretion of Nox1 and Nox4 in kidney tissues, but also has an inhibitory effect on inflammatory factors and NF-[Formula: see text]B signaling pathway. Importantly, further in-depth research on molecular mechanisms provides vital evidence that the ameliorative effect of G-Rh1 on DN is related to the inhibition of apoptosis and the AMPK/PI3K/Akt signaling pathway. In summary, G-Rh1 may be of great value in improving the treatment of DN although more experimental data is needed.