Diabetic nephropathy (DN) is one of the most severe complications of diabetes. However, due to its complex pathological mechanisms, no effective therapeutic methods (other than ACEIs and ARBs) have been applied, which have been used for many years in clinical practice. Recent studies have shown that emerging therapeutics, including novel target-based pharmacotherapy, cell therapies, and dietary regulation, are leading to new hopes for DN management. This review aims to shed new light on the treatment of DN by describing the important pathological mechanisms of DN and by analysing recent advances in clinical treatment, including drug therapy, cell therapy, and dietary regulation. In pathological mechanisms, RAAS activation, AGE accumulation, and EMT are involved in inflammation, cellular stress, apoptosis, pyroptosis, and autophagy. In pharmacotherapy, several new therapeutics, including SGLT2 inhibitors, GLP-1 agonists, and MRAs, are receiving public attention. In addition, stem cell therapies and dietary regulation are also being emphasized. Herein, we highlight the importance of combining therapy and dietary regulation in the treatment of DN and anticipate more basic research or clinical trials to verify novel strategies.

With the advances in biomedical technologies, natural products have attracted substantial public attention in the area of drug discovery. Flavonoids are a class of active natural products with a wide range of pharmacological effects that are used for the treatment of several diseases, in particular chronic metabolic diseases. Diabetic nephropathy is a complication of diabetes with a particularly complicated pathological mechanism that affects at least 30% of diabetic patients and represents a great burden on public health. A large number of studies have shown that flavonoids can alleviate diabetic nephropathy. This review systematically summarizes the use of common flavonoids for the treatment of diabetic nephropathy. We found that flavonoids play a therapeutic role in diabetic nephropathy mainly by regulating oxidative stress and inflammation. Nrf-2/GSH, ROS production, HO-1, TGF-β1 and AGEs/RAGE are involved in the process of oxidative stress regulation. Quercetin, apigenin, baicalin, luteolin, hesperidin, genistein, proanthocyanidin and eriodictyol were found to be capable of alleviating oxidative stress related to the aforementioned factors. Regarding inflammatory responses, IL-1, IL-6β, TNF-α, SIRT1, NF-κB, and TGF-β1/smad are thought to be essential. Quercetin, kaempferol, myricetin, rutin, genistein, proanthocyanidin and eriodictyol were confirmed to influence the above targets. As a result, flavonoids promote podocyte autophagy and inhibit the overactivity of RAAS by suppressing the upstream oxidative stress and inflammatory pathways, ultimately alleviating DN. The above results indicate that flavonoids are promising drugs for the treatment of diabetic nephropathy. However, due to deficiencies in the effect of flavonoids on metabolic processes and their lack of structural stability in the body, further research is required to address these issues.

Paeoniflorin is derived from Paeonia suffruticosa Andr., Paeonia lactiflora Pall., or Paeonia veitchii Lynch and has been used in traditional medical applications for more than 2,000 years. Paeoniflorin is a monoterpenoid glycoside with various effects on liver diseases. Recent studies have revealed that paeoniflorin demonstrates a wide range of activities, including hepatic protection, cholestasis alleviation, liver fibrosis attenuation, nonalcoholic fatty liver disease prevention, and hepatocellular carcinoma inhibition involved in multiple pathways. Moreover, anti-inflammation, antioxidation, and immune regulation with the regulation of TLR4-NF-κB, ROCK/NF-κB, HO-1, mitochondria-dependent as well as HMGB1‐TLR4 signaling pathways are correlated with hepatic protection in liver injury and nonalcoholic fatty liver disease. Antioxidative mechanisms, anti-inflammation, and hepatic transporter regulation involved in NOX4, PI3K/Akt/Nrf2, NF‐κB, NTCP, BSEP, as well as MRP2 signals are mainly relevant to the anticholestatic effect of paeoniflorin. The inhibition of hepatic stellate cell activation and alleviation of extracellular matrix deposition via vast signals such as mTOR/HIF-1α, TGF-β1/Smads, and JAK2/STAT6 are primarily involved in the antifibrotic effect of paeoniflorin. The regulation of macrophages also contributes to the alleviation effect on liver fibrosis. In addition, the reduction of invasion, metastasis, and adhesion and the induction of apoptosis-related targets, including Bax, Bcl-2, and caspase-3, are related to its effect on hepatocellular carcinoma. The literature indicates that paeoniflorin might have potent efficacy in complex liver diseases and demonstrates the profound medicinal value of paeoniflorin.