Polycystic ovarian syndrome (PCOS) is associated with hyperhomocysteinemia and polycystic ovaries (PCO) usually produce oocytes of poor quality. However, the intracellular mechanism linking hyperhomocysteinemia and oocyte quality remains elusive. In this study, the quality of the oocytes isolated from healthy and polycystic gilt ovaries was evaluated in vitro in association with one-carbon metabolism, mitochondrial DNA (mtDNA) methylation, and mitochondrial function. PCO oocytes demonstrated impaired polar body extrusion, and significantly decreased cleavage and blastocyst rates. The mitochondrial distribution was disrupted in PCO oocytes, together with decreased mitochondrial membrane potential and deformed mitochondrial structure. The mtDNA copy number and the expression of mtDNA-encoded genes were significantly lower in PCO oocytes. Homocysteine concentration in follicular fluid was significantly higher in PCO group, which was associated with significantly up-regulated one-carbon metabolic enzymes betaine homocysteine methyltransferase (BHMT), glycine N-methyltransferase (GNMT) and the DNA methyltransferase DNMT1. Moreover, mtDNA sequences coding for 12S, 16S rRNA and ND4, as well as the D-loop region were significantly hypermethylated in PCO oocytes. These results indicate that an abnormal activation of one-carbon metabolism and hypermethylation of mtDNA may contribute, largely, to the mitochondrial malfunction and decreased quality of PCO-derived oocytes in gilts.

Dysregulated activation of the cyclin-dependent kinases (CDKs) 4/6, leading to uncontrolled cell division, is hallmark of cancers. Further study of the cell cycle will advance the cancer treatment. As powerful and effective drugs, inhibitors of CDK 4/6 have been widely used in clinical practice for several malignancies, particularly against breast cancers driven by the estrogen receptor (ER). Three CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011) and abemaciclib (LY2835219), have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. However, CDK4/6 inhibitors act downstream of many mitogenic signaling pathways, and this has implications for resistance. It is worth to note that the mechanisms of resistance are not very clear. Up to now, a small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitors resistance in breast cancer. On this basis, rational and effective combination therapy is under development. Here we review the current knowledge about the mechanisms and efficacy of CDK4/6 inhibitors, and summarize data on resistance mechanisms to make future combination therapies more accurate and reasonable.

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Melatonin, a major hormone of the pineal gland, exerts many beneficial effects on mitochondria. Several studies have shown that melatonin can protect against toxin‐induced oocyte quality impairment during maturation. However, there is little information regarding the beneficial effects of melatonin on toxin‐exposed early embryos, and the mechanisms underlying such effects have not been determined. Rotenone, a chemical widely used in agriculture, induces mitochondrial toxicity, therefore, damaging the reproductive system, impairing oocyte maturation, ovulation, and fertilization. We investigated whether melatonin attenuated rotenone exposure‐induced impairment of embryo development by its mitochondrial protection effect. Activated oocytes were randomly assigned to four groups: the control, melatonin treatment, rotenone‐exposed, and “rotenone + melatonin” groups. Treatment with melatonin abrogated rotenone‐induced impairment of embryo development, mitochondrial dysfunction, and ATP deficiency, and significantly decreased oxidative stress and apoptosis. Melatonin also increased SIRT1 and PGC‐1α expression, which promoted mitochondrial biogenesis. SIRT1 knockdown or pharmacological inhibition abolished melatonin's ability to revert rotenone‐induced impairment. Thus, melatonin rescued rotenone‐induced impairment of embryo development by reducing ROS production and promoting mitochondrial biogenesis. This study shows that melatonin rescues toxin‐induced impairment of early porcine embryo development by promoting mitochondrial biogenesis.

Heavy-metal-associated (HMA) isoprenylated plant proteins (HIPPs) only exist in vascular plants. They play important roles in responses to biotic/abiotic stresses, heavy-metal homeostasis, and detoxification. However, research on the distribution, diversification, and function of HIPPs in Triticeae species is limited. In this study, a total of 278 HIPPs were identified from a database from five Triticeae species, and 13 were cloned from Haynaldia villosa. These genes were classified into five groups by phylogenetic analysis. Most HIPPs had one HMA domain, while 51 from Clade I had two, and all HIPPs had good collinear relationships between species or subgenomes. In silico expression profiling revealed that 44 of the 114 wheat HIPPs were dominantly expressed in roots, 43 were upregulated under biotic stresses, and 29 were upregulated upon drought or heat treatment. Subcellular localization analysis of the cloned HIPPs from H. villosa showed that they were expressed on the plasma membrane. HIPP1-V was upregulated in H. villosa after Cd treatment, and transgenic wheat plants overexpressing HIPP1-V showed enhanced Cd tolerance, as shown by the recovery of seed-germination and root-growth inhibition by supplementary Cd. This research provides a genome-wide overview of the Triticeae HIPP genes and proved that HIPP1-V positively regulates Cd tolerance in common wheat.