Myometrial Research Articles

Genome-wide causal mediation analysis identifies genetic loci associated with uterine fibroids mediated by age at menarche.

Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021. We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P < 10-10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P < 10-10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche. A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue. This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease. This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests. N/A.

Uterine Smooth Muscle Tumors: A Review

Uterine smooth muscle tumors heterogeneous tumors include at least six histologically defined tumor types. Smooth muscle tumors are divided into two categories: benign leiomyomas and malignant leiomyosarcomas. Uterine smooth muscle tumors have also morphological variants that are difficult to interpret and identify as benign or malignant called "smooth muscle tumors of uncertain malignant potential". Immunohistochemistry for progesterone receptor and p53 is useful as a supplement to morphological evaluation of uterine smooth muscle tumors that are causing problems. It might be hard to differentiate between endometrial stromal sarcomas and uterine smooth muscle tumors.

Clinicopathological and molecular characteristics of fumarate hydratase–deficient uterine smooth muscle tumors: a single-center study of 52 cases

The fumarate hydratase (FH) gene germline mutations cause hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), predisposing carriers to uterine and cutaneous leiomyomas and renal cell carcinoma. In this study, we aim to investigate morphology and the correlation between FH mutation in FH-deficient (FH-d) uterine smooth muscle tumors (uSMTs). We conducted immunohistochemical staining in 161 cases of uSMTs to detect FH deficiency. We identified 52 cases (52/161, 32%)of FH-d, including 34 leiomyomas with bizarre nuclei, 10 uSMTs of uncertain malignant potential (STUMPs), 4 cellular leiomyomas, 3 usual type leiomyomas, and 1 leiomyosarcoma. Patients with FH-d were aged 24-67 years (median, 40 years). The most common FH-d morphological features included staghorn-shaped blood vessels (87%), bizarre nuclei (81%), alveolar pattern edema (65%), macronucleoli surrounded by a halo (65%), cytoplasmic eosinophilic globules (56%), and chain-like distribution of smooth muscle cells (52%). A targeted next-generation sequence was performed in 11 of 52 FH-d tumors. Five cases (5/11, 45%) were found with FH germline mutations, including 4 leiomyomas with bizarre nuclei and 1 STUMP. The median age of patients with germline FH mutation was 30 years. The germline mutations included 3 pathogenic, 1 likely pathogenic, and 1 rare uncertain clinical significance variants. Our results revealed that FH-d uSMTs usually exhibit the distinct morphology features and high frequency of FH germline mutations. The combination of predictive morphology evaluation, FH immunotype, and molecular testing is helpful for the screening of HLRCC in uSMTs.

Deciphering the Role of Histone Modifications in Uterine Leiomyoma: Acetylation of H3K27 Regulates the Expression of Genes Involved in Proliferation, Cell Signaling, Cell Transport, Angiogenesis and Extracellular Matrix Formation.

Uterine leiomyoma (UL) is a benign tumor arising from myometrium (MM) with a high prevalence and unclear pathology. Histone modifications are altered in tumors, particularly via histone acetylation which is correlated with gene activation. To identify if the acetylation of H3K27 is involved in UL pathogenesis and if its reversion may be a therapeutic option, we performed a prospective study integrating RNA-seq (n = 48) and CHIP-seq for H3K27ac (n = 19) in UL vs MM tissue, together with qRT-PCR of SAHA-treated UL cells (n = 10). CHIP-seq showed lower levels of H3K27ac in UL versus MM (p-value < 2.2 × 10−16). From 922 DEGs found in UL vs. MM (FDR < 0.01), 482 presented H3K27ac. A differential acetylation (FDR < 0.05) was discovered in 82 of these genes (29 hyperacetylated/upregulated, 53 hypoacetylated/downregulated). Hyperacetylation/upregulation of oncogenes (NDP,HOXA13,COL24A1,IGFL3) and hypoacetylation/downregulation of tumor suppressor genes (CD40,GIMAP8,IL15,GPX3,DPT) altered the immune system, the metabolism, TGFβ3 and the Wnt/β-catenin pathway. Functional enrichment analysis revealed deregulation of proliferation, cell signaling, transport, angiogenesis and extracellular matrix. Inhibition of histone deacetylases by SAHA increased expression of hypoacetylated/downregulated genes in UL cells (p < 0.05). Conclusively, H3K27ac regulates genes involved in UL onset and maintenance. Histone deacetylation reversion upregulates the expression of tumor suppressor genes in UL cells, suggesting targeting histone modifications as a therapeutic approach for UL.

Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.

Investigation of the Role of Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Its Type 1 (PAC1) Receptor in Uterine Contractility during Endometritis in Pigs.

Uterine inflammation is a common pathology in animals, leading to disturbances in reproductive processes and reduced production profitability. Pituitary adenylate cyclase-activating peptide (PACAP) effects at the uterine level during inflammation are not known. In the current study, we analyzed the relative PACAP type 1 receptor (PAC1R) mRNA transcript and protein abundances in the myometrium (MYO), as well s PACAP and PAC1R involvement in the contractile function of inflamed pig uterus. To that end, E. coli suspension (E. coli group) or saline (SAL group) was injected into the uterine horns or laparotomy was performed (CON group). Eight days after the bacteria injections, severe acute endometritis and a reduced relative abundance of PAC1R protein in the MYO were observed. Compared to the period before PACAP in vitro administration, PACAP (10−7 M) in the CON and SAL groups decreased in amplitude in the MYO and endometrium (ENDO)/MYO, whereas in the E. coli group, increased amplitude in the MYO and reduced amplitude in the ENDO/MYO were observed. In the E. coli group, PACAP enhanced the amplitude in the MYO (10−7 M) and decreased the amplitude in the ENDO/MYO (10−8 M) compared with other groups. PACAP (10−7 M) increased the frequency of both kinds of strips in the CON and SAL groups compared with the pretreatment period. PACAP (both doses) did not significantly change the frequency in the E. coli group, whereas in response to PACAP (10−7 M), the frequency was reduced compared to other groups. In the MYO, PAC1R antagonist decreased the amplitude reduction (CON and SAL groups) and reversed a rise in PACAP (10−7 M)-evoked amplitude (E. coli group). PAC1R blocking reversed (MYO) and abolished (ENDO/MYO) the stimulatory effect of PACAP (10−7 M) on the frequency (CON and SAL groups). PAC1R antagonist and PACAP (10−7 M) evoked the appearance of frequency depression in both kinds of strips (E. coli group). In summary, in pigs, severe acute endometritis reduces the relative abundance of PAC1R protein in the MYO, and PAC1R mediates the influence of PACAP on inflamed uterus contractility.

Periodontal diseases in pregnant women as a risk factor: a concise systematic review

This study highlighted that periodontal diseases in pregnant women can be one of the determinants of low birth weight. Studies were carried out to verify the existence of an association between maternal periodontal disease and low birth weight. Gestational period, where the occurrence of periodontal diseases (PD) is more likely, due to its hormonal and physiological changes. Therefore, pregnant women must be alert and take proper care, have prenatal care with their dentist, in addition to their oral care, they must be alert to the risks of low birth weight and premature births. Infections in regions of the genitourinary tract, such as PD, may be associated with the occurrence of low birth weight newborns through the same mechanisms as other maternal and preterm birth infections. The contraction of the uterus and cervical dilation, acting as a trigger for premature birth, can be caused by inflammatory stimuli, which can induce hyperirritability of the uterine smooth muscles. The infection and the resulting inflammatory process can cause damage to the placenta, thereby restricting fetal development. Throughout life, a woman goes through several phases of hormonal fluctuations that, in addition to interfering with the reproductive system, exert influence on other organs and systems, such as the periodontium, particularly in the presence of preexisting gingival inflammation induced by plaque. During pregnancy, a woman is exposed to several significant hormonal changes, as the placenta produces high amounts of estrogen and progesterone, which in turn affect the oral tissues. It was concluded that black women aged over 40 years old are more likely to have PD, having a higher risk of low development to the fetus.

Recurrence of Uterine Smooth Muscle Tumor of Uncertain Malignant Potential: A Systematic Review of the Literature.

Background: This study aimed to systematically review the existing literature on uterine smooth muscle tumor of uncertain malignant potential (STUMP) to provide information about characteristics and outcomes of patients and the risk factors for recurrence over a period of 60 years (1960-2021). Methods: According to PRISMA guidelines, we searched for "uterine smooth muscle tumor of uncertain malignant potential" in PubMed (all fields) and Scopus (Title/Abstract/Keywords) databases (accessed on 1 January 2022). Relevant articles were obtained in full-text format and screened for additional references. The only filter used was the English language. Studies including full case description of patients with histopathological diagnosis of STUMP in accordance with Stanford criteria were included. Results: Thirty-four studies, including 189 cases, were included. The median age was 43 years, and in 21.5% of cases there was a recurrence of the disease. Bivariate analysis showed a significant association between use of morcellation without bag and risk of recurrence (p = 0.001). Unprotected morcellation during demolitive or conservative surgery was independently associated with a higher risk of disease recurrence with a relative risk of 2.94 (p &lt; 0.001). A significant progressive decrease in the recurrence rate was observed over time (r = -0.671, p = 0.008). The percentage of patients who underwent surgery followed by in-bag protected morcellation significantly increased after the publication of the U.S. Food and Drug Administration alert about the risk linked to this procedure (p = 0.01). Conclusions: Unprotected morcellation of the lesion is associated with the relapse of the disease. However, this clinical condition showed a drastic decrease over time. This could likely be due to the increased awareness by surgeons of the importance of customizing surgical treatment.

Oxytocin, Prostaglandin F2α, and Prostaglandin E2 Induced Contractions in Isolated Uterine Smooth Muscle Strips from Non‐pregnant, Late Pregnant, and Postpartum Rats

Objective/IntroductionNumerous studies have investigated uterotonic agents (e.g., oxytocin) in uterine smooth muscle (USM) from non‐pregnant (NP) and late‐pregnant (LP) women and/or animal models of pregnancy. Surprisingly, few studies have investigated USM from the post‐partum period to determine whether USM contractility returns to its pre‐pregnant state. We designed a study in rodents to investigate whether USM contractility to oxytocin (OXY), prostaglandin F2α (PGF2α), and prostaglandin E2 (PGE2) returned to pre‐pregnant values within 30 days postpartum.MethodsStudies were performed in NP (n=12), LP (21d gestation, n=4), 3 days post‐partum (PP3, n=2), and 30 days post‐partum (PP30, n=4) Sprague Dawley rats. Uterine horns were cleaned of connective tissue and cut along the longitudinal axis allowing isolation of USM (width: 2mm, length: 4±1mm) oriented in the longitudinal muscle (LM) or circular muscle (CM) direction. CM or LM strips were mounted in tissue baths containing Krebs and equilibrated @ 37°C for 60 min prior to starting one of the two following protocols.Protocol 1 identified the optimal resting tension (in grams: 0.25, 0.50, 1.0, and 1.5) to measure spontaneous contraction (SCA), K+‐induced contraction (60mM K+), and cumulative OXY‐induced contraction (10‐11 to 10‐7) in CM and LM of NP rats (N=4‐6).Protocol 2 was designed assess SCA, K+‐induced contraction, cumulative concentration‐response relationships to OXY (10‐11 to 10‐7), PGF2α (10‐8 to 10‐4), or PGE2 (10‐8 to 10‐4) in CM and LM, of NP, LP, PP3, and PP30 rats (N=2‐6).Statistical comparisons were made using either a t‐test or two‐way ANOVA, and considered statistically different at P&lt;0.05.ResultsProtocol 1‐ LM SCA was greater than CM SCA at all resting tensions. K+‐induced constrictions in LM and CM were similar at each resting tension. OXY‐induced contraction in LM was generally greater than CM (P&lt;0.05 at 0.25g, 0.5g, and 1.5g tension, comparable at 0.5, 1.0, and 1.5g tension).Protocol 2 ‐ SCA in NP, LM was greater than NP, CM (P&lt;0.05). There was no difference in SCA in CM vs LM in USM from LP, PP3, and PP30 animals. K+‐induced constrictions in CM and LM were similar in USM from NP, LP, PP3 and PP30 animals. OXY‐induced contractions were greater in LM than CM for all pregnancy states (P&lt;0.05). PGE2 contractions were greater in LM vs CM in USM from NP rats (P&lt;0.05), but were similar in USM from LP, PP3, and PP30 animals. In contrast, PGF2α‐contractions were similar in LM and CM for all pregnancy states.Summary/ConclusionOur preliminary data suggests that uterotonic agents be assessed at either 0.5g or 1.0g resting tension. In addition, uterotonic agents exhibit significantly greater contraction in longitudinal vs circular orientation. Finally, contractility to uterotonic agents returns to pre‐pregnant values by PP30.

Relaxing Effects of Paracetamol on Uterine Spontaneous Contraction in Rats in Vitro

Aim: Paracetamol is a commonly used drug in acute and chronic pain. It is known that paracetamol, which is a pain reliever and antipyretic drug, is safe to use during pregnancy. The aim of this study was to investigate the effects of paracetamol on the uterine smooth muscle contraction- relaxation mechanism in female rats in diestrus.Material and Methods: Wistar-albino intact female rats were used in the study. Longitudinal strips of myometrium obtained from animals at the diestroeus stage. Stripes were suspended in an isolated organ bath containing crebs solution under 1 g passive tension. After the regulation period, paracetamol were added non-cumulatively at 1000μM and 2000μM concentrations. Before and after the application, the area under the curve (AUC) and peak to peak (p-p) values were normalized as % change.Results: Paracetamol caused a statistically significant decrease in p-p and area under the curve parameters of spontaneous uterine contractions at 1000 and 2000 μM doses (p &amp;lt;0.001).Conclusion: Paracetamol causes uterine relaxation by inhibiting uterine contraction. This effect should be taken into account in clinical use.

Leiomyoma with nuclear atypia: Rare diseases that present a common diagnostic problem.

Leiomyoma with nuclear atypia describes a group of uterine smooth muscle tumors with a wide range of histologic and clinical presentations and remarkable nuclear atypia. These include fumarate hydratase-deficient leiomyoma (FH-LM), intravenous leiomyomatosis (IV-LM), and leiomyoma with bizarre nuclei (LM-BN). Other uterine mesenchymal tumors, such as perivascular epithelioid tumor (PEComa) and inflammatory myofibroblastic tumors (IMFT) are the mimickers of leiomyoma with nuclear atypia. LM-BN is the primary tumor model with a long history in gynecologic pathology, but the histogenesis of LM-BN remains largely unknown. Differentiating LM-BN from other benign variants, tumors with uncertain malignant potential (STUMP), or fully malignant leiomyosarcoma (LMS) can be diagnostically challenging. Recent progress has improved the diagnosis of many types of leiomyoma with nuclear atypia based on their specific histology and molecular alterations. LM-BN is now a diagnosis of exclusion. In this article, I review the history of leiomyoma with nuclear atypia and compare the clinical, histologic, and molecular features of LM-BN with those of its mimics. In particular, I highlight the current progress made in molecular genetics and pitfalls in the diagnosis of different myogenic tumors with nuclear atypia.

Medicinal plant affected respiratory, gastrointestinal, vascular and uterine smooth muscle contractility

In the current review, PubMed, Web Science, Science Direct, and Scopus were searched to investigate the medicinal plants which contracted or relaxed the respiratory, gastrointestinal, vascular and uterine smooth muscles with emphasis on their mode of action.

Medicinal plant affected respiratory, gastrointestinal, vascular and uterine smooth muscle contractility

Medicinal plant affected respiratory, gastrointestinal, vascular and uterine smooth muscle contractility

A mediator complex subunit 12 gain-of-function mutation induces partial leiomyoma cell properties in human uterine smooth muscle cells

To clarify whether a mediator complex subunit 12 (MED12) gain-of-function mutation induces leiomyoma cell properties in human uterine smooth muscle cells (USMCs). Experimental study. Academic research laboratory. Women undergoing hysterectomy for leiomyoma. CRISPR/Cas9-mediated genome editing to introduce an MED12 gain-of-function mutation (G44D) into human USMCs. Cell proliferation, collagen production, and invivo tumorigenicity of USMCs with vs. without the MED12 mutation. Uterine smooth muscle cells isolated from the uterine myometrium of a 44-year-old patient were subjected to lentiviral vector-mediated gene transduction of the fluorescent protein Venus, followed by long-term passage. Uterine smooth muscle cells with a normal female karyotype, high cell proliferative activity, and Venus expression, but without stem/progenitor cell populations, were obtained and designated as USMC44. Using CRISPR/Cas9-mediated genome editing, mtUSMC44 (MED12, 131G>A, p.G44D) and mock USMC44 without MED12 mutation (wtUSMC44) were established from USMC44. wtUSMC44 and mtUSMC44 showed similar cell proliferation activity, even in the presence of estradiol and progesterone (EP) together with transforming growth factor-beta 3 (TGFB3). In addition, wtUSMC44 and mtUSMC44 generated similar tiny smooth muscle-like tissue constructs when xenotransplanted beneath the kidney capsule in immunodeficient mice treated with EP alone or TGFB3. In contrast, mtUSMC44 produced more collagen type I than wtUSMC invitro, and this production was likely enhanced by EP and TGFB3. The results suggest that the MED12 gain-of-function mutation is involved in collagen production. Although approximately 70% of leiomyomas have MED12 mutations, additional factors and/or events other than MED12 and/or myometrialstem/progenitor cells may be required for fully inducing leiomyoma cell properties, including transformation, in USMCs.

Aberrant R-loop-induced replication stress in MED12-mutant uterine fibroids

Uterine fibroid (UF) driver mutations in Mediator complex subunit 12 (MED12) trigger genomic instability and tumor development through unknown mechanisms. Herein, we show that MED12 mutations trigger aberrant R-loop-induced replication stress, suggesting a possible route to genomic instability and a novel therapeutic vulnerability in this dominant UF subclass. Immunohistochemical analyses of patient-matched tissue samples revealed that MED12 mutation-positive UFs, compared to MED12 mutation-negative UFs and myometrium, exhibited significantly higher levels of R-loops and activated markers of Ataxia Telangiectasia and Rad3-related (ATR) kinase-dependent replication stress signaling in situ. Single molecule DNA fiber analysis revealed that primary cells from MED12 mutation-positive UFs, compared to those from patient-matched MED12 mutation-negative UFs and myometrium, exhibited defects in replication fork dynamics, including reduced fork speeds, increased and decreased numbers of stalled and restarted forks, respectively, and increased asymmetrical bidirectional forks. Notably, these phenotypes were recapitulated and functionally linked in cultured uterine smooth muscle cells following chemical inhibition of Mediator-associated CDK8/19 kinase activity that is known to be disrupted by UF driver mutations in MED12. Thus, Mediator kinase inhibition triggered enhanced R-loop formation and replication stress leading to an S-phase cell cycle delay, phenotypes that were rescued by overexpression of the R-loop resolving enzyme RNaseH. Altogether, these findings reveal MED12-mutant UFs to be uniquely characterized by aberrant R-loop induced replication stress, suggesting a possible basis for genomic instability and new avenues for therapeutic intervention that involve the replication stress phenotype in this dominant UF subtype.

Modulators of TRPM7-magnesium channels alter the contractile activity of rat uterine smooth muscle

Modulators of TRPM7-magnesium channels alter the contractile activity of rat uterine smooth muscle

Differential Regulation by Mechanical Stretch of the Expressions of Large-Conductance Ca2+-Activated K+ Channel and L-Type Voltage-Dependent Ca2+ Channel in Rat Uterine Smooth Muscle Cells.

Large-conductance Ca2+-activated K+ (BKCa) channel and L-type voltage-dependent Ca2+ channel (L-VDCC) play important roles in regulating uterine contractility. The uterus stretch, occurring during pregnancy, is a critical factor to trigger uterine contraction. However, how mechanical stimuli impact the two channels remains unknown. Here we investigated the effects of exposure to mechanical stretches with varying magnitudes and durations on expressions of the two channels in rat uterine smooth muscle cells. Our results show that stretch down-regulates the BKCa channel expression but upregulates the L-VDCC expression. These findings are helpful to better understand the roles of L-VDCC and BKCa channel in stretch-triggered uterine contraction.

Isoindolines and phthalides from the rhizomes of Ligusticum chuanxiong and their relaxant effects on the uterine smooth muscle

Three undescribed isoindoline alkaloids, (+)-(R)-3-butyl-3-ethoxyisoindolin-1-one, (+)-(3S,6S,7R)-3-butyl-6,7-dihydroxy-3-methoxy-4,5,6,7-tetrahydroisoindolin-1-one, and (−)-(3R,6S,7R)-3-butyl-6,7-dihydroxy-3-methoxy-4,5,6,7-tetrahydroisoindolin-1-one, along with nine known phthalides were isolated from a water decoction of the rhizomes of Ligusticum chuanxiong using chromatographic methods. Their structures and absolute configurations were determined by extensive spectroscopic analyses and ECD data calculations. The relaxant effects of the isolated compounds on uterine contractions induced by oxytocin were investigated using a rat uterine smooth muscle contraction model. Furthermore, the effects of riligustilide on extracellular Ca2+ influx and intracellular Ca2+ release were assessed using high-KCl solution-induced and oxytocin-induced uterine smooth muscle contraction in a Ca2+-free balanced salt solution. The results showed that all the tested phthalides had inhibitory effects on oxytocin-induced uterine smooth muscle contraction. Riligustilide, a phthalide dimer, was the most active. Further examinations indicated that riligustilide reduced uterine smooth muscle contraction by inhibiting extracellular Ca2+ influx and intracellular Ca2+ release.

A Case of Syncope Due to Intracardiac Leiomyomatosis

We present a case of a 46-year-old female presenting with syncope. Echocardiography initially showed a right atrial mass. Further evaluation revealed a mass arising from the fundus of the uterus, with a tumor thrombus in the left gonadal vein, extending into the left renal vein and through the inferior vena cava (IVC) into the right heart across the tricuspid valve. She was managed with surgical resection, and postoperative pathology was consistent with intravenous leiomyomatosis (IVL). IVL is a rare uterine smooth muscle cell neoplasm which extends into the venous system. Gynecological tumors are often overlooked in differential diagnosis for atrial masses. A benign tumor like fibroid, in rare circumstances, can extend into the right side of the heart causing dynamic obstruction to outflow tract, thus increasing mortality. The objective of this article is to present such a case and highlight the broad differentials of atrial masses, including IVL.

HMGA2: A Biomarker in Gynecologic Neoplasia.

High Mobility Group A2 gene (HMGA2), an oncofetal protein, is normally expressed in fetal development and completely shuts down in almost all organs and tissue types during adulthood. It is upregulated or overexpressed again in certain mesenchymal neoplasms due to chromosomal translocations and in malignant epithelial tumors through transcription regulation. HMGA2 overexpression can either drive tumor development or promote the aggressiveness of tumor growth. Many gynecologic neoplasms, including uterine smooth muscle tumors and ovarian cancer, are associated with HMGA2 overexpression. In this article, we review recent developments in the study of HMGA2 and its expression as a potential biomarker for gynecologic neoplasms and clinic application.