Diabetic nephropathy (DN) is the leading cause of end‑stage renal disease. Although Ginkgo biloba extract has a protective effect on DN, the protective effect and mechanism of its active ingredient Ginkgolide B (GB) on DN remain unclear. The aim of the present study was to investigate whether GB improves DN via alleviating oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination in PA-G-induced mouse podocytes and DN mice. The study in vitro showed that GB effectively reduced serum total cholesterol, triglyceride concentrations and lipid accumulation in PA-G-induced MPC5 cells. In addition, GB promoted the expression of ferroptosis markers GPX4 and FTH1, while inhibited the expression of TfR1, fibrosis markers α-SMA and Collagen α1, as well as intracellular iron content and ROS levels. Interference of GPX4 expression with siRNA counteracted the effect of GB. And GB inhibited GPX4 ubiquitination in a dose-dependent manner. In vivo the experimental results showed that GB effectively reduced hyperglycemia, serum total cholesterol and triglyceride concentrations, reduced urinary albumin excretion and the number of renal lipid droplets, and improved changes in renal structure in DN mice. GB inhibited the expression of ferroptosis marker TfR1 and fibrosis markers α-SMA and Collagen α1, while promoted the expression of ferroptosis markers GPX4 and FTH1. In conclusion, the results suggested that GB may improve DN via protecting the kidney from ferroptosis and oxidative stress damage by inhibiting the ubiquitination of GPX4. These findings suggested that GB, a natural medicine, may be an effective therapeutic option for DN.

At present, the potential of natural products in new drug development has attracted more and more scientists’ attention, and natural products have become an important source for the treatment of various diseases or important lead compounds. Geniposide, as a novel iridoid glycoside compound, is an active natural product isolated from the herb Gardenia jasminoides Ellis (GJ) for the first time; it is also the main active component of GJ. Recent studies have found that geniposide has multiple pharmacological effects and biological activities, including hepatoprotective activity, an anti-osteoporosis effect, an antitumor effect, an anti-diabetic effect, ananti-myocardial dysfunction effect, a neuroprotective effect, and other protective effects. In this study, the latest research progress of the natural product geniposide is systematically described, and the pharmacological effects, pharmacokinetics, and toxicity of geniposide are also summarized and discussed comprehensively. We also emphasize the major pathways modulated by geniposide, offering new insights into the pharmacological effects of geniposide as a promising drug candidate for multiple disorders.

Diabetes mellitus (DM) damages male reproduction at multiple levels, such as endocrine secretion, spermatogenesis and penile erection. We herein investigated the protective effects and mechanism of loganin targeting the advanced glycation end products (AGEs)/receptor for AGEs (RAGE)/p38 mitogen‐activated protein kinase (p38MAPK)/NF‐κB signalling pathway. Loganin relieved the general DM symptoms and decreased the blood glucose level of KK‐Ay DM mice. Haematoxylin‐eosin staining demonstrated that loganin ameliorated testicular histology and function and enhanced the activities of testis‐specific markers lactate dehydrogenase (LDH), acid phosphatase (ACP) and gamma‐glutamyl transferase (γ‐GT). Loganin also showed evident anti‐oxidative stress, anti‐apoptotic and anti‐inflammatory effects on DM‐induced reproductive damage by restoring glutathione (GSH) level and superoxide dismutase (SOD) activity, as well as reducing reactive oxygen species (ROS) level and Bax/Bcl‐2 ratio in vivo and in vitro. Western blotting exhibited that loganin significantly inhibited the AGEs/RAGE/p38MAPK/NF‐κB signalling pathway. Acridine orange and ethidium bromide staining (AOEB) and Western blotting showed that loganin in combination with inhibitors of RAGE, p38MAPK and NF‐κB exerted stronger anti‐apoptotic effects on AGE‐induced GC‐2 cell damage compared with loganin alone. In conclusion, loganin can protect against DM‐induced reproductive damage, probably by suppressing the AGEs/RAGE/p38MAPK/NF‐κB pathway.