The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A–deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2–deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF₂α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2–deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2–deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2–dependent production of SP-A and PAF is crucial for this process.

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P₄) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called “contractile” genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E₂) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P₄ levels. However, in women, circulating levels of P₄ and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P₄ and estradiol-17β. The integrative roles of microRNAs also are considered.

Human uterus undergoes distinct molecular and functional changes during pregnancy and parturition. Hydrogen sulfide (H₂S) has recently been shown to play a key role in the control of smooth muscle tension. The role of endogenous H₂S produced locally in the control of uterine contractility during labour is unknown. Human myometrium biopsies were obtained from pregnant women undergoing cesarean section at term. Immunohistochemistry analysis showed that cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), the principle enzymes responsible for H₂S generation, were mainly localized to smooth muscle cells of human pregnant myometrium. The mRNA and protein expression of CBS as well as H₂S production rate were down-regulated in labouring tissues compared to nonlabouring tissues. Cumulative administration of L-cysteine (10⁻⁷–10⁻² mol/L), a precursor of H₂S, caused a dose-dependent decrease in the amplitude of spontaneous contractions in nonlabouring and labouring myometrium strips. L-cysteine at high concentration (10⁻³ mol/L) increased the frequency of spontaneous contractions and induced tonic contraction. These effects of L-cysteine were blocked by the inhibitors of CBS and CSE. Pre-treatment of myometrium strips with glibenclamide, an inhibitor of ATP-sensitive potassium (K_ATP) channels, abolished the inhibitory effect of L-cysteine on spontaneous contraction amplitude. The effects of L-cysteine on the amplitude of spontaneous contractions and baseline muscle tone were less potent in labouring tissues than that in nonlabouring strips. H₂S generated by CSE and CBS locally exerts dual effects on the contractility of pregnant myometrium. Expression of H₂S synthetic enzymes is down-regulated during labour, suggesting that H₂S is one of the factors involved in the transition of pregnant uterus from quiescence to contractile state after onset of parturition.

The steroid hormones progesterone (P₄) and estradiol-17β (E₂), produced by the placenta in humans and the ovaries in rodents, serve crucial roles in the maintenance of pregnancy, and the initiation of parturition. Because of their critical importance for species survival, the mechanisms whereby P₄ and its nuclear receptor (PR) maintain myometrial quiescence during pregnancy, and for the decline in P₄/PR and increase in E₂/estrogen receptor (ER) function leading to parturition, are multifaceted, cooperative, and redundant. These actions of P₄/PR include: (1) PR interaction with proinflammatory transcription factors, nuclear factor κB (NF-κB), and activating protein 1 (AP-1) bound to promoters of proinflammatory and contractile/contraction-associated protein (CAP) genes and recruitment of corepressors to inhibit NF-κB and AP-1 activation of gene expression; (2) upregulation of inhibitors of proinflammatory transcription factor activation (IκBα, MKP-1); (3) induction of transcriptional repressors of CAP genes (e.g., ZEB1). In rodents and most other mammals, circulating maternal P₄ levels remain elevated throughout most of pregnancy and decline precipitously near term. By contrast, in humans, circulating P₄ levels and myometrial PR levels remain elevated throughout pregnancy and into labor. However, even in rodents, wherein P₄ levels decline near term, P₄ levels remain higher than the K_d for PR binding. Thus, parturition is initiated in all species by a series of molecular events that antagonize the P₄/PR maintenance of uterine quiescence. These events include: direct interaction of inflammatory transcription factors (e.g., NF-κB, AP-1) with PR; increased expression of P₄ metabolizing enzymes; increased expression of truncated/inhibitory PR isoforms; altered expression of PR coactivators and corepressors. This article will review various mechanisms whereby P₄ acting through PR isoforms maintains myometrial quiescence during pregnancy as well as those that underlie the decline in PR function leading to labor. The roles of P₄- and E₂-regulated miRNAs in the regulation and integration of these mechanisms will also be considered.

Intervertebral disc degeneration (IVDD), a widely known contributor to low back pain (LBP), has been proved to be a global health challenging conundrum. Hesperidin (hesperetin-7-O-rutinoside, HRD) is a flavanone glycoside that belongs to the subgroup of citrus flavonoids with therapeutic effect on various diseases due to its anti-inflammatory, antioxidant properties. However, the effect of HRD on IVDD remains elusive. The human nucleus pulposus tissues were harvested for isolating human nucleus pulposus (HNP) cells to verify the expression of Nrf2. The biological effect of HRD on HNP cells were assessed in vitro, and the in vivo therapeutic effects of HRD were assessed in mice. Firstly, we found that the expression of Nrf2 was decreased with the progression of degeneration in degenerated human nucleus pulposus tissue. Subsequently, we confirmed that HRD could mitigate oxidative stress-induced ferroptosis in nucleus pulposus cells via enhancing the expression of Nrf2 axis and suppressing the NF-κB pathway to protect intervertebral disc from degeneration in vitro. Finally, the therapeutic effects of HRD were confirmed in vivo. The current study proved for the first time that HRD may protect HNP cells from degeneration by suppressing ferroptosis in an oxidative stress-dependent via enhancing the expression of Nrf2 and suppressing the NF-κB pathway. The evidence will provide a possible basis for future targeted treatment for IVDD