The value of low-intensity pulsed ultrasound in reducing ovarian injury caused by chemotherapy in mice.

BACKGROUND: Ovarian damage and follicle loss are major side effects of chemotherapy in young female patients with cancer. However, effective strategies to prevent these injuries are still lacking. The purpose of this study was to verify low-intensity pulsed ultrasound (LIPUS) can reduce ovarian injury caused by chemotherapy and to explore its underlying mechanisms in mice model. METHODS: The mice were randomly divided into the Control group, Cisplatin group, and Cisplatin + LIPUS group. The Cisplatin group and Cisplatin + LIPUS group were intraperitoneally injected with cisplatin every other day for a total of 10 injections, and the Control group was injected with saline. On the second day of each injection, the Cisplatin + LIPUS group received irradiation, whereas the other two groups received sham irradiation. We used a variety of biotechnologies to detect the differences in follicle count, granulosa cell apoptosis, fibrosis, transcriptome level, oxidative damage, and inflammation in differently treated mice. RESULT: LIPUS was able to reduce primordial follicle pool depletion induced by cisplatin and inhibit the apoptosis of granulosa cells. Transcriptomic results confirmed that LIPUS can reduce ovarian tissue injury. We demonstrated that LIPUS can relieve ovarian fibrosis by inhibiting TGF-ß1/Smads pathway. Meanwhile, it can reduce the oxidative damage and reduced the mRNA levels of proinflammatory cytokines caused by chemotherapy. CONCLUSION: LIPUS can reduce the toxic effects of chemotherapy drugs on ovaries, inhibit ovarian fibrosis, reduce the inflammatory response, and redcue the oxidative damage, reduce follicle depletion and to maintain the number of follicle pools.

Inhibition of cisplatin-induced Acsl4-mediated ferroptosis alleviated ovarian injury.

Given that the severity of the chemotherapy-induced ovarian damage, effective fertility preservation is a necessary part of the treatment process. Ferroptosis is a regulated cell death triggered by excessive phospholipid peroxidation caused by iron and the role of ferroptosis in chemotherapy-induced ovarian damage remains unclear. In this study, we demonstrated that cisplatin treatment caused the accumulation of iron ions which induced ferroptosis in ovarian tissue. And our results show that ferrostatin-1 was able to suppress the ovarian injury and granulosa cell death caused by cisplatin (Cis) in vivo and in vitro. At the same time, we observed significant changes in the expression levels of Acyl-CoA synthetase long-chain family member 4 (Acsl4) and glutathione peroxidase 4 (GPX4). Similarly, Rosiglitazone, an inhibitor of Acsl4, administration alleviated the ovary damage of the mice undergoing chemotherapy. Further mechanistic investigation showed that cisplatin increased the expression level of specificity protein 1 (SP1), and SP1 could bind to the promoter of Acsl4 to increased Acsl4 transcription. Overall, ferroptosis plays an important role in Cis induced ovarian injury, and inhibition of ferroptosis protects ovarian tissues from damage caused by cisplatin, and for the first time, we have identified the potential of Fer-1 and Rosi to protect ovarian function in female mice undergoing chemotherapy.

Exercise improves cardiac function and attenuates myocardial inflammation and apoptosis by regulating APJ/STAT3 in mice with stroke.

Stroke can induce cardiac dysfunction without a primary cardiac disease. Exercise can promote the overall rehabilitation of stroke patients and be beneficial for all kinds of heart diseases. However, the mechanisms underlying the protective effects of exercise in stroke-induced cardiac dysfunction are poorly understood. Hence, we aimed to distinguish the different effects of acute and long-term exercise and further study the mechanism of protection against cardiomyopathy caused by stroke. Mice underwent a single acute session or long-term exercise for 30 days, followed by middle cerebral artery occlusion surgery. The expression of apoptosis-related proteins and proinflammatory factors in the heart was evaluated. Then, overexpression of apelin peptide jejunum (APJ) transfected adeno-associated virus type 9 (AAV9) and inhibition of signal transducer and activator of transcription 3 (STAT3) by Stattic were used in stroke mice or hypoxic cardiomyocytes. ML221 were used to inhibit APJ activity in exercise mouse. Thereafter, changes in apoptotic and proinflammatory factors were evaluated. The results demonstrated that chronic exercise prevented myocardial inflammation, apoptosis and cardiac dysfunction after stroke. However, acute exercise did not have similar effects. Exercise maintained the levels of APJ expression and decreased phosphorylated-STAT3 (p-STAT3) activation to protect cardiomyocytes. Moreover, APJ overexpression promoted cardiomyocyte survival and reduced p-STAT3 levels. STAT3 inhibition also reduced apoptosis and proinflammatory factors in mice hearts. Conversely, the protective effect of exercise was eliminated by APJ inhibition. This study showed that exercise can maintain APJ expression and inhibit p-STAT3, thus, conferring protection against myocardial inflammation and apoptosis induced by stroke.

The enrichment of Arg1+ILC2s and ILCregs facilitates the progression of endometriosis: A preliminary study.

Innate lymphoid cells (ILCs) are a kind of lymphocytes that reside in the tissue and have an essential function in the immune microenvironment. However, the relationship between endometriosis (EMS) and ILCs is complex and not fully understood. This study examines several groups of ILCs in the peripheral blood (PB), peritoneal fluid (PF) and endometrium of patients with EMS via flow cytometry. The study observed an increase in PB ILCs, particularly ILC2s and ILCregs subsets and Arg1+ILC2s in the EMS patients were highly activated. EMS patients had significantly higher levels of serum interleukin (IL)-10/33/25 compared to controls. We also found an elevation of Arg1+ILC2s in the PF and higher levels of ILC2s and ILCregs in ectopic endometrium compared with eutopic. Importantly, a positive correlation was observed between the enrichment of Arg1+ILC2s and ILCregs in the PB of EMS patients. The findings indicate that the involvement of Arg1+ILC2s and ILCregs fosters potentially endometriosis progression.

Activating α7nAChR helps post-myocardial infarction healing by regulating macrophage polarization via the STAT3 signaling pathway.

BACKGROUND: Monocytes/macrophages play critical roles in inflammation and cardiac remodeling following myocardial infarction (MI). The cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses by activating α7 nicotinic acetylcholine receptors (α7nAChR) in monocytes/macrophages. We investigated the effect of α7nAChR on MI-induced monocyte/macrophage recruitment and polarization and its contribution to cardiac remodeling and dysfunction. METHODS: Adult male Sprague Dawley rats underwent coronary ligation and were intraperitoneally injected with the α7nAChR-selective agonist PNU282987 or the antagonist methyllycaconitine (MLA). RAW264.7 cells were stimulated with lipopolysaccharide (LPS) + interferon-gamma (IFN-γ) and treated with PNU282987, MLA, and S3I-201 (a STAT3 inhibitor). Cardiac function was evaluated by echocardiography. Masson's trichrome and immunofluorescence were used to detect cardiac fibrosis, myocardial capillary density, and M1/M2 macrophages. Western blotting was used to detect protein expression, and the proportion of monocytes was measured using flow cytometry. RESULTS: Activating the CAP with PNU282987 significantly improved cardiac function and reduced cardiac fibrosis and 28-day mortality after MI. On days 3 and 7 post-MI, PNU282987 reduced the percentage of peripheral CD172a + CD43low monocytes and the infiltration of M1 macrophages in the infarcted hearts, whereas it increased the recruitment of peripheral CD172a + CD43high monocytes and M2 macrophages. Conversely, MLA exerted the opposite effects. In vitro, PNU282987 inhibited M1 macrophage polarization and promoted M2 macrophage polarization in LPS + IFN-γ-stimulated RAW264.7 cells. These PNU282987-induced changes in LPS + IFN-γ-stimulated RAW264.7 cells were reversed by administering S3I-201. CONCLUSION: Activating α7nAChR inhibits the early recruitment of pro-inflammatory monocytes/macrophages during MI and improves cardiac function and remodeling. Our findings suggest a promising therapeutic target for regulating monocyte/macrophage phenotypes and promoting healing after MI.

Comparative single-center study between modified laparoscopic radical hysterectomy and open radical hysterectomy for early-stage cervical cancer.

BACKGROUND: Since the release of the LACC trial results in 2018, the safety of laparoscopic radical hysterectomy (LRH) for cervical cancer has received huge attention and heated discussion. We developed modified laparoscopic radical hysterectomy (MLRH) incorporating a series of measures to prevent tumor spillage, which has been performed in our center since 2015. OBJECTIVE: Present study retrospectively analyzed relevant indicators of MLRH and evaluated disease-free survival (DFS) primarily in the treatment of early cervical cancer compared with open surgery. METHODS: Patients with 2014 International Federation of Gynecology and Obstetrics clinical stages 1B1 and 2A1 cervical cancer who underwent radical hysterectomy in the gynecological department of our hospital from October 2015 to June 2018 were enrolled retrospectively in this study. Patients were divided into two groups based on the surgical procedure: open radical hysterectomy (ORH) group (n = 336) and MLRH group (n = 302). Clinical characteristics, surgical indices, and survival prognosis were analyzed, including 2.5-year overall survival (OS) rate, 2.5-year DFS rate, recurrence rate, and recurrence pattern. RESULTS: Compared to the ORH group, the MLRH group exhibited a longer operative time, longer normal bladder function recovery time, less intraoperative blood loss volume, and more harvested pelvic lymph nodes (P < 0.05). No significant differences were observed in postoperative complications, the 2.5-year OS, 2.5-year DFS, and recurrence rate between the two groups (P > 0.05); however, the recurrence pattern was significantly different (P < 0.05). The MLRH group mainly exhibited local single metastasis (7/11), whereas the ORH group mainly exhibited distant multiple metastases (14/16). Stratified analysis revealed that overall survival rate was higher in the MLRH group than in the ORH group in patients with stage 1B1 and middle invasion (P < 0.05). CONCLUSION: MLRH does not show a survival disadvantage in the treatment of early-stage cervical cancer when compared with open surgery. In addition, MLRH shows a survival advantage in patients with stage 1B1 and middle 1/3 invasion. Considering this is a retrospective study, further prospective study is necessary for more sufficient data support. TRIAL REGISTRATION: Present research is a retrospective study. The study had retrospectively registered on Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ), and the registered number is ChiCTR1900026306.

Electroacupuncture Alleviates Neuropathic Pain through Regulating miR-206-3p Targeting BDNF after CCI.

Background: Electroacupuncture (EA) has benefits for neuropathic pain. However, the underlying mechanisms are still unknown. The current study explores the underlying mechanisms of EA in neuropathic pain of chronic constriction injury (CCI) rats. Material/Methods. Overall, 126 Sprague-Dawley (200-250 g) rats were divided into nine groups randomly: the sham-operated, CCI, CCI+EA, CCI+sham EA, CCI+NS, CCI+AAV-NC, CCI+AAV-miR-206-3p, CCI+EA+NS, and CCI+EA+AAV-miR-206-3p groups. The animals were sacrificed 14 days postsurgery. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests were used to determine differences in neurobehavioral manifestations. qPCR, western blotting, and immunofluorescence (IF) were carried out to detect the expression levels of miR-206-3p, BDNF, BAX/Bcl-2, TNF-α, and IL-6. Nissl staining was measured to observe morphological changes in neurons. Transmission electron microscopy (TEM) was employed to evaluate microscopic changes in dorsal horn synapses. Results: Hyperalgesia was reduced markedly by EA in the CCI model. The expression level of miR-206-3p was elevated, whereas the expression levels of BDNF, BAX/Bcl-2, TNF-α, and IL-6 were decreased in EA-treated CCI rats. However, a miR-206-3p inhibitor partially abrogated the analgesic effect of EA and resulted in poor behavioral performance and the BDNF, BAX/Bcl-2, TNF-α, and IL-6 expression was elevated as well. Conclusions: EA can relieve neuropathic pain by regulating the miR-206-3p/BDNF pathway, thus exerting anti-inflammatory and antiapoptotic effect.

Development of Aptamer-Based Molecular Tools for Rapid Intraoperative Diagnosis and In Vivo Imaging of Serous Ovarian Cancer.

Diagnosis and treatment of ovarian cancer are based on intraoperative pathology and debulking surgery. The development of a novel molecular tool is significant for rapid intraoperative pathologic diagnosis, which instructs the decision-making on excision surgery and effective chemotherapy. In this work, we represent a DNA aptamer named mApoc46, which is generated from cell-SELEX by targeting patient-derived primary serous ovarian cancer (pSOC) cells. An average dissociation constant (Kd) was determined to be 0.15 ± 0.05 µM by flow cytometry. The mApoc46 aptamer displays a robust specificity to pSOC cells. Labeled with FAM, mApoc46 can selectively stain living pSOC cells in 30 min without staining commercial OC cell lines and cell lines associated with other cancers. Interestingly, FAM-mApoc46 displayed superb selectivity toward high-grade serous ovarian cancer (HG-SOC) tissues in frozen sections against low-grade SOC, ovarian borderline tumor, other nonepithelial ovarian tumors, and healthy ovarian tissue. These results lead to a potential application in the identification of OCs' histological subtypes during operation. In the patient-derived tumor xenograft NCG mice model, Cy5-labeled mApoc46 was found to accumulate at the tumor area and served as an in vivo imaging probe. The mApoc46 probe shows a robust and stable performance to visualize SOC tumors in the body. Therefore, aptamer mApoc46 holds great potential in rapid intraoperative detection, pathological diagnosis, fluorescence image-guided cancer surgery, and targeted drug delivery and therapy.

Spontaneous unscarred uterine rupture in a twin pregnancy complicated by adenomyosis: A case report.

INTRODUCTION: Uterine rupture during pregnancy is a serious obstetric complication accompanied by a high incidence of maternal morbidity and mortality, and the presence of uterine scars is the main risk factor. In the present case, uterine rupture occurred in an unscarred uterus in a nonlaboring primigravida woman with adenomyosis and twin pregnancy in the third trimester. PATIENT CONCERNS: In this case, the patient suspected to have a history of endometriosis have got twin pregnancies following intracytoplasmic sperm injection, and complained of recurrent lower abdominal pain from 16 weeks to 29 weeks of gestation. DIAGNOSIS: After exploratory laparotomy, the patient was diagnosed with uterine rupture and adenomyosis. INTERVENTIONS: The patient was first administered expectant treatment such as antibiotics, tocolytics, and fluid replacement therapy. Symptoms then appeared repeatedly and worsened, followed by eventual peritoneal irritation, and exploratory laparotomy was performed. OUTCOMES: Two live female fetuses were extracted by cesarean section, and the uterine laceration was repaired. The mother recovered without any postoperative complications, and the babies were discharged after receiving one month of prematurity care without any postnatal complications. CONCLUSION: Adenomyosis and the conception of twins may lead to uterine rupture. For pregnant women with a history of adenomyosis with multiple gestations, close monitoring for signs of uterine rupture is necessary. Single-embryo transfer and multifetal pregnancy reduction should be recommended for infertile patients with adenomyosis.

CCDC68 Upregulation by IL-6 Promotes Endometrial Carcinoma Progression.

The elevation of circulating interleukin 6 (IL-6) is one of the major molecular characteristics of endometrial carcinoma. In this study, we investigated the role of coiled-coil domain-containing 68 (CCDC68) in IL-6-associated endometrial carcinoma progression. CCDC68 expression levels and the activation of IL-6 pathway were detected by qPCR and Western blot. Stable CCDC68 knockdown Ishikawa and RL-95 cells were created to investigate cancer cell proliferation, migration, and invasion with or without IL-6 administration. Kaplan-Meier's analysis was used to determine the correlation between CCDC68 expression and overall survival or recurrence-free survival in endometrial carcinoma patients. CCDC68 expression level is significantly uregulated by IL-6 stimulation. Increased CCDC68 expression predicts poor prognosis in endometrial carcinoma patients. CCDC68 knockdown dramatically inhibit IL-6-associated cancer cell proliferation, migration, invasion, and downregulate the expression of proto-oncogenes in endometrial carcinoma cells. CCDC68 acts as a cancer-promoting factor in IL-6-stimulated endometrial carcinoma cells, and blocking the expression of CCDC68 might be a novel therapeutic strategy for the endometrial carcinoma treatment.

Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a systematic review and meta-analysis of six randomized controlled trials / Efeitos da pressão positiva contínua nas vias aéreas na pressão arterial em pacientes com hipertensão resistente e apneia obstrutiva do sono: revisão sistemática e meta-análise de seis ensaios clínicos controlados aleatórios

ABSTRACT Objective: To evaluate systematically the effects of continuous positive airway pressure (CPAP) on blood pressure in patients with resistant hypertension and obstructive sleep apnea (OSA). Methods: The Cochrane Library, PubMed, ScienceDirect, and the Web of Science were searched for studies investigating the effects of CPAP on blood pressure in patients with resistant hypertension and OSA. The selected studies underwent quality assessment and meta-analysis, as well as being tested for heterogeneity. Results: Six randomized controlled trials were included in the meta-analysis. The pooled estimates of the changes in mean systolic blood pressure and mean diastolic blood pressure (as assessed by 24-h ambulatory blood pressure monitoring) were −5.40 mmHg (95% CI: −9.17 to −1.64; p = 0.001; I2 = 74%) and −3.86 mmHg (95% CI: −6.41 to −1.30; p = 0.00001; I2 = 79%), respectively. Conclusions: CPAP therapy can significantly reduce blood pressure in patients with resistant hypertension and OSA.

RESUMO Objetivo: Avaliar sistematicamente os efeitos da continuous positive airway pressure (CPAP, pressão positiva contínua nas vias aéreas) na pressão arterial em pacientes com hipertensão resistente e apneia obstrutiva do sono (AOS). Métodos: Estudos que investigassem os efeitos da CPAP na pressão arterial em pacientes com hipertensão resistente e AOS foram buscados nos seguintes bancos de dados eletrônicos: Cochrane Library; PubMed; ScienceDirect e Web of Science. Os estudos selecionados foram submetidos a avaliação de qualidade, meta-análise e teste de heterogeneidade. Resultados: Foram incluídos na meta-análise seis ensaios clínicos controlados aleatórios. As estimativas combinadas das alterações das médias de pressão arterial sistólica e pressão arterial diastólica (medidas por meio de monitoração ambulatorial da pressão arterial durante 24 h) foram de −5,40 mmHg (IC95%: −9,17 a −1,64; p = 0,001; I2 = 74%) e −3,86 mmHg (IC95%: −6,41 a −1,30; p = 0,00001; I2 = 79%), respectivamente. Conclusões: O tratamento com CPAP é capaz de reduzir significativamente a pressão arterial em pacientes com hipertensão resistente e AOS.

The abnormal expression of oxytocin receptors in the uterine junctional zone in women with endometriosis.

BACKGROUND: The junctional zone (JZ), also called as the endometrial-myometrial junction, is related to peristaltic-like movements in the non-pregnant uterus. Hyperperistalsis and dysperistalsis of uterus constructions might underlie many important disorders such as dysmenorrhea, infertility, endometriosis, implantation failure. The major proteins for uterine contraction of the non-pregnant uterus may be Oxytocin (OT) and oxytocin receptor (OTR). The objective of this study was to inspect the expression of OTR in isthmic and mid-fundal parts of the uterine junctional zone at different stages of the follicular cycle in patients with and without endometriosis. METHODS: Uterine biopsies containing endometrium and junctional zone were collected from the isthmic and mid-fundal parts of the anterior wall after hysterectomy. The OTR expression was evaluated by immunohistochemistry. RESULTS: In the control uterus, OTR expression in the isthmic region was significantly higher than in the fundal region in the proliferative phase (p < 0.05) but significantly lower in the secretory phase (p < 0.05). And the expression of OTR in the proliferative phase was significantly higher than that in the secretory phase in both isthmic and fundal regions (p = 0.000 and 0.049, respectively). However, in endometriosis uteri, OTR expression in the isthmic region showed no significant difference with that in the fundal region in both proliferative and secretory phases (p = 0.597 and 0.736, respectively). In both isthmic and fundal regions, OTR expression was not significantly different between the proliferative phase and secretory phase (p = 0.084 and 0.222, respectively). OTR expression in fundal regions of revised ASRM I and II endometriosis were lower than that of revised ASRM III and IV (p = 0.049). In the fundal region of JZ, the expression of OTR in ovarian endometriosis was significantly lower than that in deep infiltrating endometriosis (p = 0.046). The expression level of OTR in the funds region is positively associated with the severity of dysmenorrhea in endometriosis group (r = 0.870, p < 0.05). Comparing to normal uteri, the expression of OTR in the secretory phase was significantly higher in the endometriosis uteri (p < 0.05). In the fundus of endometriosis uteri, OTR expression was significantly higher in both the proliferative and secretory phases (p = 0.045 and 0.028, respectively). CONCLUSION: OTR expression in the JZ of women with endometriosis changes significantly, which may result in abnormal uterine contractile activity, reducing the endometriosis-related fertility and dysmenorrhea.

Polarity and hydrophobicity interactions in protein synthesis process.

About 30 years ago, experiments found that there are polarity and hydrophobicity (P and H) correlations and affinity between amino acids and their anticodons. Although it is shown that these experimental findings are important for explaining the origins of the genetic code, the great potential of P and H interactions in investigating other bio-functions have not been fully explored. Here, through raising, discussing and answering seven relevant questions hidden in tRNA aminoacylation, the formation of peptide bonds, and the ending of translations, etc., we show our theoretical findings that the P and H correlations and affinity take vital roles in the protein synthesis process. We found the relationship between the 3' end ACCN sequences of tRNA molecules and the activated amino acids and its biological significance, the rRNAs' consensus sequences 5'NCC...TGG3' or 5'TGG...NCC3' which may perform as functional segments of rRNAs to help triggering the reaction of peptide formation, and common nature of releasing factors that the first amino acid residue of releasing factors ERF, RF1 and RF2 are all Methionine, except a few Alanine, which may be necessary for releasing the translated polypeptide and stopping the translating process. In the terms of P and H correlations and affinity, we provide explanations of why only using the poly (G) as mRNA template cannot get the poly (Gly) in experiments deciphering the genetic code, why Gly often appears in beta turns and why translational bypassing might occur when translating 5'GGAUGA on mRNA. Since amino acids and nucleotides are the subunits, respectively, for composing proteins and nucleic acids, these findings will help in further understanding interactions among the bio-macromolecules. These findings are also helpful for investigating rRNAs, further understanding the protein synthesis process and analysing similar bio-problems, and should be proved useful for experimental biologists.