DEHP regulates ferritinophagy to promote testicular ferroptosis via suppressing SIRT1/PGC-1α pathway.

To increase elasticity and flexibility, di-2-ethylhexyl phthalate (DEHP) is used in a variety of industrial products, but excessive exposure to it can pose a threat to human health. In epidemiological studies of population exposure to DEHP, attention has been paid to damage to the male reproductive system. However, the toxicological mechanism of DEHP regarding testicular injury is not well understood. We used Western blot analysis, transmission electron microscopy, fluorescence staining, transient transfection and assay kit to detect relevant indicators, and the results were as follows: After DEHP exposure, the expression levels of ACSL4, COX2, TF, FTH1, LC3, AMPK, p-AMPK, ULK1, p-ULK1, serum iron, tissue iron and MDA in the exposure group were significantly increased. The expression levels of GPX4, NCOA4, p62, SIRT1, and PGC-1α, as well as the contents of GSH and ATP, decreased. Electron microscopy showed that more autophagosomes were observed. Our findings suggest that exposure to DEHP induced ferritinophagy and ferroptosis in the testis. In vitro, the promoting effect of ferritinophagy on ferroptosis was verified by applying the autophagy inhibitor (3-MA) and si-NCOA4. Moreover, Mono-(2-ethylhexyl) phthalate (MEHP) inhibited the mitochondrial regulatory protein SIRT1/PGC-1α, leading to mitochondrial dysfunction. Changes in mitochondrial reactive oxygen species (MtROS) and energy over-activated AMPK/ULK1 autophagy pathway, and then promoted ferritinophagy, which increased the sensitivity of TM4 cells to ferroptosis. This research offers a theoretical framework for the prevention and management of DEHP-induced harm.

Ferritinophagy: Molecular mechanisms and role in disease.

Ferritinophagy is a regulatory pathway of iron homeostasis. It is a process in which nuclear receptor coactivator 4 (NCOA4) carries ferritin to autophagolysosomes for degradation. After ferritin is degraded by autophagy, iron ions are released, which promotes the labile iron pool (LIP) to drive the Fenton reaction to cause lipid peroxidation. Furthermore, ferroptosis promoted by the accumulation of lipid reactive oxygen species (ROS) induced by ferritinophagy can cause a variety of systemic diseases. In clinical studies, targeting the genes regulating ferritinophagy can prevent and treat such diseases. This article describes the key regulatory factors of ferritinophagy and the mechanism of ferritinophagy involved in ferroptosis. It also reviews the damage of ferritinophagy to the body, providing a theoretical basis for further finding clinical treatment methods.

Curcumin inhibits PAT-induced renal ferroptosis via the p62/Keap1/Nrf2 signalling pathway.

Patulin (PAT), the most common mycotoxin, is widespread in foods and beverages which poses a serious food safety issue to human health. Our previous research confirmed that exposure to PAT can lead to acute kidney injury (AKI). Curcumin is the most abundant active ingredient in turmeric rhizome with various biological activities. The aim of this study is to investigate whether curcumin can prevent the renal injury caused by PAT, and to explore potential mechanisms. In vivo, supplementation with curcumin attenuated PAT-induced ferroptosis. Mechanically, curcumin inhibited autophagy, led to the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of nuclear factor E2 related factor 2 (Nrf2), and increased the expression of antioxidant stress factors in the process of ferroptosis. These results have also been confirmed in HKC cell experiments. Furthermore, knockdown of Nrf2 in HKC cells abrogated the protective effect of curcumin on ferroptosis. In conclusion, we confirmed that curcumin mitigated PAT-induced AKI by inhibiting ferroptosis via activation of the p62/Keap1/Nrf2 pathway. This study provides new potential targets and ideas for the prevention and treatment of PAT.

The dehydration-responsive protein PpFAS1.3 in moss Physcomitrium patens plays a regulatory role in lipid metabolism.

Moss plants appear in the early stages of land colonization and possess varying degrees of dehydration tolerance. In this study, a protein called PpFAS1.3 was identified, which contains a fasciclin 1-like domain and is essential for the moss Physcomitrium patens' response to short-term rapid dehydration. When the FAS1.3 protein was knocked out, leafyshoots showed a significant decrease in tolerance to rapid dehydration, resulting in accelerated water loss and increased membrane leakage. Phylogenetic analysis suggests that PpFAS1.3 and its homologous proteins may have originated from bacteria and are specifically found in non-vascular plants like mosses and liverworts. As a dehydration-related protein, FAS1.3 plays a significant role in regulating lipid metabolism, particularly in the synthesis of free fatty acids (FFA) and the metabolism of two phospholipids, PC and PA. This discovery highlights the close connection between PpFAS1.3 and lipid metabolism, providing new insights into the molecular mechanisms underlying plant adaptation to stresses.

The Protective Effects of Curcumin against Renal Toxicity.

Curcumin is a naturally polyphenolic compound used for hepatoprotective, thrombosuppressive, neuroprotective, cardioprotective, antineoplastic, antiproliferative, hypoglycemic, and antiarthritic effects. Kidney disease is a major public health problem associated with severe clinical complications worldwide. The protective effects of curcumin against nephrotoxicity have been evaluated in several experimental models. In this review, we discussed how curcumin exerts its protective effect against renal toxicity and also illustrated the mechanisms of action such as anti-inflammatory, antioxidant, regulating cell death, and anti-fibrotic. This provides new perspectives and directions for the clinical guidance and molecular mechanisms for the treatment of renal diseases by curcumin.

Mechanism of testicular injury induced by Di-ethylhexyl phthalate and its protective agents.

Di-ethylhexyl phthalate (DEHP) is used as an important plasticizer in a wide range of products such as paints, food packaging, medical devices and children's toys. In recent years, there has been increasing interest in the toxic effects of DEHP on the male reproductive organs, the testicles. Here, we reviewed the basic pathways of testicular damage caused by DEHP. The mechanism involves oxidative stress, ferroptosis, interfering with hypothalamic-pituitary-gonadal axis (HPGA) and testosterone level. We summarized the protective agents that have been shown to be effective in repairing this type of testicular damage in recent years. This provides a new perspective and direction for future research into the health effects and molecular mechanisms of DEHP.

The specific glycerolipid composition is responsible for maintaining the membrane stability of Physcomitrella patens under dehydration stress.

Land colonization is a major event in plant evolution. Little is known about the evolutionary characteristics of lipids during this process. Here, we proved that Physcomitrella patens, a bryophyte that appeared in the early evolution of terrestrial plants, has short-term desiccation resistance. The maintenance of membrane integrity is related to its specific glycerolipid composition and key genes for lipid metabolism. We analyzed 414 types of lipid molecules, and found that phospholipids accounted for 61.7%, mainly PC and PI; glycolipids accounted for only 26.5%, with a special MGDG molecular map. The most abundant MDGD, that is, MGDG34:6, contained rare 15- and 19-carbon acyl chains; the level of neutral lipids was higher. This was consistent with the results observed by TEM, with fewer lamellae and obvious lipid droplets. Slight dehydration accumulated a large number of TAG molecules, and severe dehydration degraded phospholipids and caused membrane leakage, but PA and MGDG fluctuated less. The key genes of lipid metabolism, DGAT and PAP, were actively transcribed, suggesting that PA was one of the main DAG sources for TAG synthesis. This work proves that Physcomitrella patens adopts high-constitutive PC and PI similar to plant seeds, abundant TAG, and its own specific MGDG to resist extreme dehydration. This result provides a new insight into the lipid evolution of early terrestrial plants against unfavorable terrestrial environments.