Dysmenorrhea refers to a kind of uterine cramping pain that occurs in women during the period of menstrual. Guizhi Fuling Capsules are mainly used for the treatment of various pain syndromes and especially effective in treating primary dysmenorrhea. However, the research on its modern pharmacology and mechanism of action have not been thoroughly carried out. It is not clear about the main active ingredients, potential targets and metabolic pathways involved in its efficacy. Therefore, this research project employed estradiol benzoate sensitization combined with oxytocin pain to construct the cold coagulation syndrome dysmenorrhea model, observed the anti-dysmenorrhea effect of Guizhi Fuling Capsules, and used the metabolomics to explore its mechanism. The results showed that Guizhi Fuling Capsules could considerably reduce the number of writhing times in dysmenorrhea rats, increasing the level of PGE2 and β-EP and reducing the contents of PGF2α in rat serum. Pathological sections of uterus and ovaries also showed that Guizhi Fuling Capsules could significantly relieve endometrial hyperplasia and improve ovarian function. The LC/MS-based metabolomics of rat uterine indicated that the model group has a great deviation from the control group. Compared with the model group, the Guizhi Fuling Capsules group had a tendency to shift to the control group, and the main metabolic changes was mainly concentrated on saturated and unsaturated fatty acids. Among them, arachidonic acid is in a pivotal position, and the expression of its rate-limiting enzyme (COX-2) involved in its cyclooxygenase metabolic pathway was significantly up-regulated in the model group, but significantly decreased after the intervention of Guizhi Fuling Capsules. In conclusion, Guizhi Fuling Capsules can effectively relieve primary dysmenorrhea, and this effect may be attributed to the regulation effects of Guizhi Fuling Capsules on endogenous metabolism, such as inhibiting arachidonic acid converted to prostaglandins through downregulate the expression of COX-2, which plays an anti-inflammatory effect.

Objective: Prostate cancer (PCa) is the most common malignant tumor diagnosed in men in developed countries. In developing countries, the PCa morbidity and mortality rates are also increasing rapidly. Since androgen receptor (AR) is a key driver and plays a critical role in the regulation of PCa development, AR-targeted agents provide a key component of current therapy regimens. However, even new-generation AR antagonists are prone to drug resistance, and there is currently no effective strategy for overcoming advanced PCa aggressiveness, including drug-resistance progression. The aim of this study was to evaluate the potential efficacy and novel therapy strategy of proxalutamide (a newly developed AR antagonist) in PCa. Methods: Four PCa cell lines with various biological heterogeneities were utilized in this study, namely, androgen-sensitive/-insensitive with/without AR expression. Proliferation, migration and apoptosis assays in PCa cells were used to evaluate the effective therapeutic activity of proxalutamide. The changes in lipid droplet accumulation and lipidomic profiles were analyzed to determine the influence of proxalutamide on lipogenesis in PCa cells. The molecular basis of the effects of proxalutamide on lipogenesis and the AR axis was then further investigated. Results: Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). Proxalutamide induced the caspase-dependent apoptosis of PCa cells. Proxalutamide significantly diminished the level of lipid droplets in PCa cells, changed the lipid profile of PCa cells and reduced the content of most lipids (especially triglycerides) in PCa cells. Proxalutamide attenuated de novo lipogenesis by inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, proxalutamide also decreased AR expression in PCa cells, and its inhibitory effect on lipogenesis did not depend on its ability to down-regulate AR expression. However, Enz had no effect on AR expression, lipid accumulation or lipid de novo synthesis in PCa cells. Conclusions: By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.

The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.