Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2.

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.

The Roles of MicroRNAs in Male Infertility.

MicroRNAs applications were vastly studied throughout the years, spanning from potential cancer biomarkers to targeted therapies for various diseases. Out of these utilizations, this paper focuses on their role in male infertility. Approximately 10-15% of worldwide couples are affected by infertility. Out of these, 50% are due to male determinants. The majority of cases still have an undetermined cause. Previous studies have found that the aberrant expression of microRNAs could be linked to certain reproductive dysfunctions in males. Further on, this study looked into the most recent literature published on this subject in order to assess the connection between the up-/down-regulation of various microRNAs and the roles they play in male infertility. MicroRNAs were found to be abundant and stable in the seminal liquid, which led to a facile identification using regular RNA detection methods. It was observed that the concentration of microRNAs in semen was modified in the case of patients suffering from asthenozoospermia and azoospermia. Moreover, idiopathic male infertility was associated with a single nucleotide polymorphism of the microRNA binding site. Future studies should focus their attention on discovering future treatments against male infertility targeting specific microRNAs and also on developing new and improved contraceptive methods.

Pregnancy-Related Extracellular Vesicles Revisited.

Extracellular vesicles (EVs) are small vesicles ranging from 20-200 nm to 10 µm in diameter that are discharged and taken in by many different types of cells. Depending on the nature and quantity of their content-which generally includes proteins, lipids as well as microRNAs (miRNAs), messenger-RNA (mRNA), and DNA-these particles can bring about functional modifications in the receiving cells. During pregnancy, placenta and/or fetal-derived EVs have recently been isolated, eliciting interest in discovering their clinical significance. To date, various studies have associated variations in the circulating levels of maternal and fetal EVs and their contents, with complications including gestational diabetes and preeclampsia, ultimately leading to adverse pregnancy outcomes. Furthermore, EVs have also been identified as messengers and important players in viral infections during pregnancy, as well as in various congenital malformations. Their presence can be detected in the maternal blood from the first trimester and their level increases towards term, thus acting as liquid biopsies that give invaluable insight into the status of the feto-placental unit. However, their exact roles in the metabolic and vascular adaptations associated with physiological and pathological pregnancy is still under investigation. Analyzing peer-reviewed journal articles available in online databases, the purpose of this review is to synthesize current knowledge regarding the utility of quantification of pregnancy related EVs in general and placental EVs in particular as non-invasive evidence of placental dysfunction and adverse pregnancy outcomes, and to develop the current understanding of these particles and their applicability in clinical practice.

Fatal Association of Mirror and Eisenmenger Syndrome during the COVID-19 Pandemic.

Mirror syndrome (MS) or Ballantyne's syndrome is a rare maternal condition that can be life-threatening for both mother and fetus. The condition is characterized by maternal signs and symptoms similar to those seen in preeclampsia in the setting of fetal hydrops. Despite recent advances in the field of maternal-fetal medicine, the etiopathogenesis of MS remains elusive. For patients and doctors, the COVID-19 pandemic has become an extra hurdle to overcome. The following case illustrates how patients' non-compliance associated with mirror syndrome and SARS-CoV-2 infection led to the tragic end of a 19-year-old patient. Therefore, knowledge of the signs and symptoms of mirror syndrome should always be part of the armamentarium of every obstetrician.

Simulation and Modeling of Telocytes Behavior in Signaling and Intercellular Communication Processes.

BACKGROUND: Telocytes (TCs) are unique interstitial or stromal cells of mesodermal origin, defined by long cellular extensions called telopodes (Tps) which form a network, connecting them to surrounding cells. TCs were previously found around stem and progenitor cells, and were thought to be most likely involved in local tissue metabolic equilibrium and regeneration. The roles of telocytes are still under scientific scrutiny, with existing studies suggesting they possess various functions depending on their location. METHODS: Human myometrium biopsies were collected from pregnant and non-pregnant women, telocytes were then investigated in myometrial interstitial cell cultures based on morphological criteria and later prepared for time-lapse microscopy. Semi-analytical and numerical solutions were developed to highlight the geometric characteristics and the behavior of telocytes. RESULTS: Results were gathered in a database which would further allow efficient telocyte tracking and indexing in a content-based image retrieval (CBIR) of digital medical images. Mathematical analysis revealed pivotal information regarding the homogeneity, hardness and resistance of telocytes' structure. Cellular activity models were monitored in vitro, therefore supporting the creation of databases of telocyte images. CONCLUSIONS: The obtained images were analyzed, using segmentation techniques and mathematical models in conjunction with computer simulation, in order to depict TCs behavior in relation to surrounding cells. This paper brings an important contribution to the development of bioinformatics systems by creating software-based telocyte models that could be used both for diagnostic and educational purposes.

Synchronous Cervical Adenocarcinoma and Ovarian Serous Adenocarcinoma-A Case Report and Literature Review.

Background/Aim: Synchronous gynecological malignancies are rarely encountered, and most often these cases are represented by synchronous ovarian and endometrial cancer. The aim of this paper is to present the case of a 53-year-old patient who was diagnosed with synchronous cervical and ovarian cancer. Case presentation: The patient had been initially investigated for vaginal bleeding and was submitted to a biopsy confirming the presence of a cervical adenocarcinoma. Once the diagnostic of malignancy was confirmed, the patient was submitted to a computed tomography which revealed the presence of large abdominal tumoral nodules of peritoneal carcinomatosis and was submitted to palliative chemotherapy with poor response. Eighteen months later she developed intestinal obstruction and was submitted to surgery. At that moment, synchronous ovarian and cervical tumors were diagnosed. Total radical hysterectomy with bilateral adnexectomy, pelvic and para-aortic lymph node dissection, omentectomy, and pelvic peritonectomy was performed; in the meantime, the histopathological studies confirmed the presence of two synchronous malignancies. Conclusion: Although synchronous lesions are rarely encountered, this eventuality should not be omitted. In such cases, surgery should be taken in consideration and the intent of radicality should regard both lesions.

Pleural Solitary Fibrous Tumors-A Retrospective Study on 45 Patients.

Introduction: The purpose of this paper is to study the type, the clinical presentation, and the best diagnostic methods for pleural solitary fibrous tumors (PSFTs), as well as to evaluate which is the most appropriate treatment, especially as PSFTs represent a rare occurrence in the thoracic pathology. Material and Method: A retrospective study was conducted on a group of 45 patients submitted to surgery between January 2015 and December 2019. In most cases, the diagnosis was established through imaging studies-thoracic computed tomography (CT) scan with or without contrast-but also using magnetic resonance imaging (MRI) or positron emission tomography (PET) scans when data from CT scans were scarce. All patients were submitted to surgery with curative intent. Results: Most patients included in this study were asymptomatic, with this pathology being more common in patients over 60 years of age, and more common in women. The occurrence of malignant PSFT in our study was 17.77% (8 cases). All cases were submitted to surgery with curative intent, with a single case developing further recurrence. In order to achieve complete resection en bloc resection of the tumor with the chest wall, resection was performed in two cases, while lower lobectomy, pneumectomy, and hemidiaphragm resection, respectively, were needed in each case. Postoperative mortality was null. Conclusion: Thoracic CT scan remains the most important imagistic investigation in diagnosing. MRI is superior to thoracic CT, especially in cases that involved the larger blood vessels within the thorax, spinal column, or diaphragm. Complete surgical resection is the gold standard in treatment of PSFT, and the prognosis in benign cases is very good.

Telocytes heterogeneity: From cellular morphology to functional evidence.

Telocytes (TCs), located ubiquitously in the internal organs of vertebrates, are a heterogeneous, recently described, cell population of the stromal space. Characterized by lengthy cytoplasmic extensions that can reach tens of microns and are called telopodes (Tps), TCs are difficult to see using conventional microscopes. It was the electron microscopy which led to their first identification and Popescu's team the first responsible for the reconstructions indicating TCs 'organization' in a three-dimensional (3D) network that is believed to be accountable for the complex roles of TCs. Gradually, it became increasingly evident that TCs are difficult to characterize in terms of immunophenotype and that their phenotype is different depending on the location and needs of the tissue at one time. This review discusses the growing body of evidence accumulated since TCs were discovered and highlights how the complex interplay between TCs and stem cells might be of importance for tissue engineering and regenerative medicine.

miR-21 suppression prevents cardiac alterations induced by d-galactose and doxorubicin.

d-galactose (d-gal)-induced cardiac alterations and Doxorubicin (Dox)-induced cardiomyocyte senescence are commonly used models to study cardiac aging. Accumulating evidence has suggested that microRNAs (miRNAs, miRs) are critically involved in the regulation of cellular and organismal aging and age-related diseases. However, little has been revealed about the roles of miRNAs in cardiac alterations induced by d-gal and Dox. In this study, we used miRNA arrays to investigate the dysregulated miRNAs in heart samples from 15month-old versus 2month-old male C57BL/6 mice and further validated them in d-gal-induced pseudo-aging mouse model and Dox-induced cardiomyocyte senescence in vitro model. We confirmed a significant increase of miR-21 in all these models by quantitative reverse transcription polymerase chain reactions. We further demonstrated that miR-21 was able to promote Dox-induced cardiomyocyte senescence whereas suppression of miR-21 could prevent that, as determined by percentage of ß-gal-positive cells and gene markers of aging. Phosphatase and tensin homolog (PTEN) was identified as a target gene of miR-21, mediating its effect in increasing cardiomyocyte senescence. Finally, we found that miR-21 knockout mice were resistant to d-gal-induced alterations in aging-markers and cardiac function. Collectively, this study provides direct evidence that inhibition of miR-21 is protective against d-gal-induced cardiac alterations and Dox-induced cardiomyocyte senescence via targeting PTEN. Inhibition of miR-21 might be a novel strategy to combat cardiac aging.

Telocytes in the reproductive organs: Current understanding and future challenges.

Over the past decades, we were witnessing spectacular molecular medicine advances. However, many of the reproductive medicine problems, such as fertility issues and premature birth still represent major challenges for obstetrics and gynecology worldwide. A new cell population - the telocytes (TCs) - were described in the interstitial space of many organs, and their possible implications in many important physiological and pathological processes should not be overlooked. In this article, we present a historical perspective outlining the landmarks in the discovery, evolution and achievements in the field of TCs over the last ten years. We focused on the potential roles of TCs in morphogenesis and maintenance of the normal three-dimensional architecture of tissues, in controlling of the stem cell microenvironment, as having anti-inflammatory and cancer-suppressing properties, participating in the immune surveillance, all mediated by direct homo- and heterocellular junctions or indirectly by extracellular vesicle release. Here, we overview the advances on TCs research in the reproductive organs (uterus and fallopian tube), accessory reproductive organs of female (mammary glands) and the temporary endocrine organ-placenta.

An in vitro investigation of telocytes-educated macrophages: morphology, heterocellular junctions, apoptosis and invasion analysis.

BACKGROUND: Telocytes (TCs), a recently discovered novel type of interstitial cells, were also found in a wide variety of human and mammalian reproductive organs/tissues, including uterus, oviduct and placenta. Previously, we demonstrated that TCs-conditioned media was capable of activating peritoneal macrophages (pMACs) through paracrine effects. This study investigates the hypothesis that direct interaction of TCs with pMACs will also play a significant role in immunoregulation of pMACs. METHODS: TCs and pMACs were derived from the uterus and intraperitoneal cavity of female BALB/c mice, respectively. TCs were identified by immunofluorescence and then co-cultured directly with pMACs for 24 h without added cytokines, to observe the in vitro biological behavior of pMACs. We used histochemical staining to study morphology and mitochondrial metabolism of pMACs, scanning electron microscopy to study heterocellular junctions, flow cytometry to investigate mitochondrial membrane potential (ΔΨm) and apoptosis, and transwell chambers to study invasion ability. Student-t test was used accordingly. RESULTS: Presently, TCs with typical structure and immunophenotype of double CD-34-positive/vimentin-positive were successfully isolated. pMACs co-cultured with TCs showed obviously morphological activation, with enhanced energy metabolism (P < 0.05). Meanwhile, direct physical cell-to-cell interaction promoted the development of heterocellular junctions between TCs and pMACs. Furthermore, TCs treatment markedly reduced the depletion of ΔΨm in co-cultured pMACs (all P < 0.05), and inhibited their apoptosis (P < 0.05). Functionally, pMACs co-cultured with TCs showed enhanced invasion ability (P < 0.05). CONCLUSIONS: Direct physical cell-to-cell interaction promoted the development of heterocellular junctions between TCs and pMACs, presumably responsible for the observed novel efficient way of pMACs activation via mitochondrial signaling pathway. TCs-educated pMACs might be a promising way to restore the defective immunosurveillance in endometriosis (EMs), led to the enhanced treatment efficacy of EMs in a simple and clinically feasible fashion.

Skeletal Muscle Damage in Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) represents a rate of fetal growth that is less than average for the population and the growth potential of a specific infant. IUGR produces infants who are small for gestational age (SGA) but also appropriate for gestational age (AGA). It refers to growth less than expected for gestational age and is most often under 10th percentiles for age. It develops during the late second and third trimesters of gestation. The etiology of IUGR is multifactorial. One of the most important factors which leads to IUGR is a decrease of nutrients and oxygen delivered to the fetus by the placenta. The growth of adipose tissue and skeletal muscle is limited by the declined fetal nutrient supply later in gestation. IUGR affects about 24% of babies born in developing countries. Worldwide, IUGR is the second cause of perinatal morbidity and mortality behind the premature birth and a major predisposing factor to metabolic disorders throughout postnatal life, even at adult age. Skeletal muscle represents about 35-40% of the body mass and plays an essential role in metabolic homeostasis, being responsible for 65% of fetal glucose consumption. A reduction in skeletal muscle growth characterizes IUGR fetuses compared to normal weight neonates. The decrease in muscle mass is not compensated after birth and persists until adulthood. This is a review of the literature, a neonatological, clinical point of view on the effects of IUGR on striated muscles. The available studies on this subject are currently the results of experimental research on animals, and information about the human fetus and newborn are scarce.

Myofibers.

Muscle tissue is a highly specialized type of tissue, made up of cells that have as their fundamental properties excitability and contractility. The cellular elements that make up this type of tissue are called muscle fibers, or myofibers, because of the elongated shape they have. Contractility is due to the presence of myofibrils in the muscle fiber cytoplasm, as large cellular assemblies. Also, myofibers are responsible for the force that the muscle generates which represents a countless aspect of human life. Movements due to muscles are based on the ability of muscle fibers to use the chemical energy procured in metabolic processes, to shorten and then to return to the original dimensions. We describe in detail the levels of organization for the myofiber, and we correlate the structural aspects with the functional ones, beginning with neuromuscular transmission down to the biochemical reactions achieved in the sarcoplasmic reticulum by the release of Ca2+ and the cycling of crossbridges. Furthermore, we are reviewing the types of muscle contractions and the fiber-type classification.

Beta-Estradiol Regulates Voltage-Gated Calcium Channels and Estrogen Receptors in Telocytes from Human Myometrium.

Voltage-gated calcium channels and estrogen receptors are essential players in uterine physiology, and their association with different calcium signaling pathways contributes to healthy and pathological conditions of the uterine myometrium. Among the properties of the various cell subtypes present in human uterine myometrium, there is increasing evidence that calcium oscillations in telocytes (TCs) contribute to contractile activity and pregnancy. Our study aimed to evaluate the effects of beta-estradiol on voltage-gated calcium channels and estrogen receptors in TCs from human uterine myometrium and to understand their role in pregnancy. For this purpose, we employed patch-clamp recordings, ratiometric Fura-2-based calcium imaging analysis, and qRT-PCR techniques for the analysis of cultured human myometrial TCs derived from pregnant and non-pregnant uterine samples. In human myometrial TCs from both non-pregnant and pregnant uterus, we evidenced by qRT-PCR the presence of genes encoding for voltage-gated calcium channels (Cav3.1, Ca3.2, Cav3.3, Cav2.1), estrogen receptors (ESR1, ESR2, GPR30), and nuclear receptor coactivator 3 (NCOA3). Pregnancy significantly upregulated Cav3.1 and downregulated Cav3.2, Cav3.3, ESR1, ESR2, and NCOA3, compared to the non-pregnant condition. Beta-estradiol treatment (24 h, 10, 100, 1000 nM) downregulated Cav3.2, Cav3.3, Cav1.2, ESR1, ESR2, GRP30, and NCOA3 in TCs from human pregnant uterine myometrium. We also confirmed the functional expression of voltage-gated calcium channels by patch-clamp recordings and calcium imaging analysis of TCs from pregnant human myometrium by perfusing with BAY K8644, which induced calcium influx through these channels. Additionally, we demonstrated that beta-estradiol (1000 nM) antagonized the effect of BAY K8644 (2.5 or 5 µM) in the same preparations. In conclusion, we evidenced the presence of voltage-gated calcium channels and estrogen receptors in TCs from non-pregnant and pregnant human uterine myometrium and their gene expression regulation by beta-estradiol in pregnant conditions. Further exploration of the calcium signaling in TCs and its modulation by estrogen hormones will contribute to the understanding of labor and pregnancy mechanisms and to the development of effective strategies to reduce the risk of premature birth.

Nonalcoholic fatty liver disease: one entity, multiple impacts on liver health.

Nonalcoholic fatty liver disease (NAFLD) is very prevalent and now considered the most common cause of chronic liver disease. Staging the severity of liver damage is very important because the prognosis of NAFLD is highly variable. The long-term prognosis of patients with NAFLD remains incompletely elucidated. Even though the annual fibrosis progression rate is significantly higher in patients with nonalcoholic hepatitis (NASH), both types of NAFLD (nonalcoholic fatty liver and nonalcoholic steatohepatitis) can lead to fibrosis. The risk for progressive liver damage and poor outcomes is assessed by staging the severity of liver injury and liver fibrosis. Algorithms (scores) that incorporate various standard clinical and laboratory parameters alongside imaging-based approaches that assess liver stiffness are helpful in predicting advanced fibrosis.

Mitochondrial DNA in Telocytes.

Telocyte (TC) is a new identified interstitial cell type with a small nuclear and one or several long and thin prolongations with enlargements on them. They were found in many mammals including humans, mouse, rats, dogs, and monkeys and play vital roles in many physiological and pathological conditions. The ultrastructure of mitochondria was observed in TCs, and the alterations were found in TCs from inflammatory ureter tissue. MtDNA is associated with mitochondria normal functions and involved in physiological and pathological processes. However, mitochondria and mtDNA in TCs were not investigated deeply. This review will introduce the origin, distribution, morphology, and functions of TCs and the distribution and functions of TC mitochondria in order to improve a better understanding of the potential functions of mtDNA in TCs.

MicroRNAs Mediate Beneficial Effects of Exercise in Heart.

MicroRNAs (miRNAs, miRs), a group of small non-coding RNAs, repress gene expressions at posttranscriptional level in most cases and are involved in cardiovascular physiology and disease pathogenesis. Increasing evidence has proved that miRNAs are potential regulators of exercise induced cardiac growth and mediate the benefits of exercise in a variety of cardiovascular diseases. In this chapter, we will review the regulatory effects of miRNAs in cardiac adaptations to exercise, and summarize their cardioprotective effects against myocardial infarction, ischemia/reperfusion injury, heart failure, diabetic cardiomyopathy, atherosclerosis, hypertension, and pulmonary hypertension. Also, we will introduce circulating miRNAs in response to acute and chronic exercise. Therefore, miRNAs may serve as novel therapeutic targets and potential biomarkers for cardiovascular diseases.

Exosomes-Based Biomarkers for the Prognosis of Cardiovascular Diseases.

Cardiovascular diseases (CVDs) have a high prevalence and annually increasing incidence with high mortality and morbidity. Identification of biomarkers with high sensitivity and specificity for assessing the prognosis of CVDs is necessary for optimizing personalized treatment and reducing mortality. Exosomes have been proved to be accessible in nearly all body fluids and they can reflect disease stage or progression. Here we summarized exosomes-based biomarkers for the prognosis of coronary artery diseases, heart failure, stroke, hypertension, cardiac arrhythmia, cardiomyopathy, valvular heart diseases and pulmonary arterial hypertension. If exosome-based biomarkers can achieve additionally benefits as compared to the present prognostic biomarkers remains to be determined and multicenter studies with large cohorts of patients are highly needed.

Circulating Exosomes in Cardiovascular Diseases.

Circulating exosomes could arrive in distant tissues via blood circulation, thus directly communicating with target cells and rapidly regulating intracellular signalings. Circulating exosomes and exosomal cargos are critically involved in cardiovascular pathophysiology, such as cardiomyocyte hypertrophy, apoptosis, and angiogenesis. Circulating exosomes enriched with various types of biological molecules can be changed not only in the number but also in the composite cargos upon cardiac injury, such as myocardial infarction, myocardial ischemia reperfusion injury, atherosclerosis, hypertension, and sepsis cardiomyopathy, which may further influence cardiomyocyte function and contribute to the pathogenesis of cardiovascular diseases. Thus, exosome-based therapeutic strategy may be used to attenuate myocardial injury and promote cardiac regeneration and repair. Also, more preclinical and clinical studies would be needed to investigate the potential of circulating exosomes as biomarkers for the diagnosis, risk stratification, and prognosis of cardiovascular diseases.

Formation of New Cardiomyocytes in Exercise.

Heart failure is a life-threatening disorder associated with the loss of cardiomyocytes. The heart has some endogenous although limited regenerative capacity, thus enhancing cardiac regeneration or stimulating endogenous repair mechanism after cardiac injury is of great interest. The benefits of exercise in heart diseases have been recognized for centuries. Besides the promotion of a favorable cardiac function, exercise is also associated with new cardiomyocytes formation. Exercise may lead to cardiomyocytes renewal from pre-existing cardiomyocytes proliferation or cardiac stem/progenitor cells differentiation. A deep understanding of exercise-induced formation of new cardiomyocytes will enable us to develop novel therapeutics for heart diseases.