Role of Endometrial Extracellular Vesicles in Mediating Cell-to-Cell Communication in the Uterus: A Review.

There are several critical events that occur in the uterus during early pregnancy which are necessary for the establishment and maintenance of pregnancy. These events include blastocyst implantation, uterine decidualization, uterine neoangiogenesis, differentiation of trophoblast stem cells into different trophoblast cell lineages, and formation of a placenta. These processes involve several different cell types within the pregnant uterus. Communication between these cell types must be intricately coordinated for successful embryo implantation and the formation of a functional maternal-fetal interface in the placenta. Understanding how this intricate coordination transpires has been a focus of researchers in the field for many years. It has long been understood that maternal endometrial tissue plays a key role in intercellular signaling during early pregnancy, sending signals to nearby tissues in a paracrine manner. Recently, insights have been obtained into the mechanisms by which these signaling events occur. Notably, the endometrium has been shown to secrete extracellular vesicles (EVs) that contain crucial cargo (proteins, lipids, RNA, miRNA) that are taken up by recipient cells to initiate a response leading to the occurrence of critical events during implantation and placentation. In this review, we aim to summarize the role that endometrium-derived EVs play in mediating cell-to-cell communications within the pregnant uterus to orchestrate the events that must occur to establish and maintain pregnancy. We will also discuss how aberrant endometrial EV signaling may lead to pathophysiological conditions, such as endometriosis and infertility.

Desonide Nanoemulsion Gel for Transdermal Absorption Drug Delivery: Pharmacodynamic and Safety Evaluation.

BACKGROUND: When administered transdermally, desonide is ineffective due to its poor solubility. As a new transdermal delivery system, nanoemulsion gel has demonstrated significant advantages for drug delivery over conventional formulations. We have established desonide nanoemulsion gel (DES NE gel) for better transdermal absorption, but its efficacy and safety still need to be evaluated. This study aims to provide additional evidence demonstrating the improved pharmacodynamics and safety of transdermal delivery of Desonide via nanoemulsion gel. METHODS: Pharmacodynamics and safety of Desonide nanoemulsion gel were evaluated using Desonate ® as the reference formulation. To assess the difference in curative effect between DES NE gel and Desonate® and to ensure safety, atopic dermatitis (AD) models in KM mice were developed using 2,4-dinitrofluorobenzene (DNFB). The degree of ear swelling, ear mass difference, thymus, spleen index, and HE conventional pathology of mice were used as pharmacodynamic evaluation indexes, and the irritation was predicted by the New Zealand rabbit epidermal stimulation assay. RESULTS: Nanoemulsion gels may facilitate transdermal penetration of drugs by influencing the skin condition. Medium and high doses of DES NE gel significantly ameliorated the inflammation and swelling of the ear caused by dermatitis/eczema in mice. In addition, compared with DES gel, skin irritation extent did not increase. CONCLUSION: Nanoemulsion gel can be applied to improve the efficacy of drugs with low potency or poor solubility. DES NE gel provides a higher transdermal potential than other delivery systems. In this study, it was found that nanoemulsion gel is a promising percutaneous carrier of DES. DES NE-GEL has a significant curative effect on dermatitis/eczema in a mouse model and is expected to provide a new, efficient, and low toxic preparation for clinical treatment of dermatitis/eczema through the percutaneous system.

Analysis of aerobic exercise influence on intraocular pressure and ocular perfusion pressure in patients with primary open-angle glaucoma: A randomized clinical trial.

Purpose: To investigate the change pattern of ocular perfusion pressure (OPP) and intra-ocular pressure (IOP) after short-term and long-term aerobic exercise. Methods: In this prospective, single-masked, randomized clinical trial, 123 patients with a primary open angle glaucoma that locally used prostaglandin analog alone were randomly divided into the exercise and control groups. In the short-term study, all individuals underwent a cycling exercise at moderate intensity (20% Wmax for 10 minutes) and high intensity (60% Wmax for 5 minutes). During the long-term study, the exercise group is characterized by regular jogging exercise lasting for 30 minutes during 6: 00-10: 00 in the morning for 3 months, with the exercise frequency of at least 20 times per month, and with the intensity reflected by the target heart rate. The control group is designed as a group with irregular exercise. Results: After short-term aerobic exercise, IOP significantly decreased, whereas the ocular perfusion pressure (OPP) significantly increased. The decreasing amplitude of IOP is related to the baseline of IOP, the intensity of exercise, gender, and so on. After 3 months of long-term exercise, the changes in the IOP level of the exercise group indicated a decreasing trend. Conclusion: The significant decrement of IOP and the increment of OPP suggest that aerobic exercise is beneficial for patients with primary open-angle glaucoma and appropriate aerobic exercise is appropriate in treating glaucoma patients. Trial registration: ChiCTR, ChiCTR-TRC-10001055. Registered one October 2010-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj = 8483.

Extracellular Vesicles Secreted by Mouse Decidual Cells Carry Critical Information for the Establishment of Pregnancy.

The mouse decidua secretes many factors that act in a paracrine/autocrine manner to critically control uterine decidualization, neovascularization, and tissue remodeling that ensure proper establishment of pregnancy. The precise mechanisms that dictate intercellular communications among the uterine cells during early pregnancy remain unknown. We recently reported that conditional deletion of the gene encoding the hypoxia-inducible transcription factor 2 alpha (Hif2α) in mouse uterus led to infertility. Here, we report that HIF2α in mouse endometrial stromal cells (MESCs) acts via the cellular trafficking regulator RAB27b to control the secretion of extracellular vesicles (EVs) during decidualization. We also found that Hif2α-regulated pathways influence the biogenesis of EVs. Proteomic analysis of EVs secreted by decidualizing MESCs revealed that they harbor a wide variety of protein cargoes whose composition changed as the decidualization process progressed. The EVs enhanced the differentiation capacity of MESCs and the production of angiogenic factors by these cells. We also established that matrix metalloproteinase-2, a prominent EV cargo protein, modulates uterine remodeling during decidualization. Collectively, our results support the concept that EVs are central to the mechanisms by which the decidual cells communicate with each other and other cell types within the uterus to facilitate successful establishment of pregnancy.

Mingmu Xiaoyao granules regulate the PI3K/Akt/mTOR signaling pathway to reduce anxiety and depression and reverse retinal abnormalities in rats.

Objective: To investigate the effects of Mingmu Xiaoyao granules (MMXY) on the morphology and function of the retina and the mechanism of PI3K/Akt/mTOR pathway-related proteins in rats with anxiety and depression induced by chronic unpredictable mild stress (CUMS). Methods: Fifty-two male Sprague Dawley rats were randomly allocated to either a control (n = 14) or a simulated CUMS group (n = 38). The CUMS model was established successfully at 4 weeks. Six rats in each group were randomly selected to be sacrificed and their retinas isolated for histological examination. At 5 weeks, rats in the CUMS group were randomly allocated to the following groups: Model (CUMS + pure water), MMXY-H (CUMS + MMXY 7.2 g/kg/d), MMXY-L (CUMS + MMXY 3.6 g/kg/d), and CBZ (CUMS + Carbamazepine 20 mg/kg/d), with eight rats in each group. All rats were given the relevant intervention once a day. At 12 weeks, sucrose preference and open field tests were performed to evaluate the anxiety and depression status of rats. In live rats, optical coherence tomography angiography was used to measure retinal thickness and blood flow, while electroretinograms (ERGs) and visual evoked potentials (VEPs) were used to evaluate retinal function. The next day, the specimens were sacrificed for serological, histological, immunofluorescence, Western blot and transmission electron microscopy examinations to explore the mechanism of MMXY in CUMS rats. Results: MMXY improved the anxiety and depression-like behavior of rats. Results of optical coherence tomography angiography showed that MMXY improved retinal inner thickness and blood flow in CUMS rats. MMXY improved the amplitude of a- and b-waves in the scotopic and photopic ERG, as well as N2 and P2 peak time and amplitude in the flash-VEP in CUMS rats. Retinal histological staining and transmission electron microscopy showed that MMXY reversed retinal morphology and ultrastructure in CUMS rats. MMXY reduced the expression of Beclin1 and LC3I/II proteins, regulated the PI3K/Akt/mTOR pathway, inhibited autophagy, and had a protective effect on the retina in CUMS rats. Conclusion: MMXY may effectively improve retinal morphology and function as well as anxiety and depression-like behaviors in CUMS rats by regulating the PI3K/Akt/mTOR signaling pathway.

Extracellular vesicles secreted by human uterine stromal cells regulate decidualization, angiogenesis, and trophoblast differentiation.

In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua secretes various factors that act in an autocrine/paracrine manner to promote stromal differentiation, facilitate maternal angiogenesis, and influence trophoblast differentiation and development, which are critical for the formation of a functional placenta. Here, we investigated the mechanisms by which decidual cells communicate with each other and with other cell types within the uterine milieu. We discovered that primary human endometrial stromal cells (HESCs) secrete extracellular vesicles (EVs) during decidualization and that this process is controlled by a conserved HIF2α-RAB27B pathway. Mass spectrometry revealed that the decidual EVs harbor a variety of protein cargo, including cell signaling molecules, growth modulators, metabolic regulators, and factors controlling endothelial cell expansion and remodeling. We tested the hypothesis that EVs secreted by the decidual cells mediate functional communications between various cell types within the uterus. We demonstrated that the internalization of EVs, specifically those carrying the glucose transporter 1 (GLUT1), promotes glucose uptake in recipient HESCs, supporting and advancing the decidualization program. Additionally, delivery of HESC-derived EVs into human endothelial cells stimulated their proliferation and led to enhanced vascular network formation. Strikingly, stromal EVs also promoted the differentiation of trophoblast stem cells into the extravillous trophoblast lineage. Collectively, these findings provide a deeper understanding of the pleiotropic roles played by EVs secreted by the decidual cells to ensure coordination of endometrial differentiation and angiogenesis with trophoblast function during the progressive phases of decidualization and placentation.

Delivery room resuscitation and short-term outcomes of extremely preterm and extremely low birth weight infants: a multicenter survey in North China.

BACKGROUND: Delivery room resuscitation assists preterm infants, especially extremely preterm infants (EPI) and extremely low birth weight infants (ELBWI), in breathing support, while it potentially exerts a negative impact on the lungs and outcomes of preterm infants. This study aimed to assess delivery room resuscitation and discharge outcomes of EPI and ELBWI in China. METHODS: The clinical data of EPI (gestational age [GA] <28 weeks) and ELBWI (birth weight [BW] <1000 g), admitted within 72 h of birth in 33 neonatal intensive care units from five provinces and cities in North China between 2017 and 2018, were analyzed. The primary outcomes were delivery room resuscitation and risk factors for delivery room intubation (DRI). The secondary outcomes were survival rates, incidence of bronchopulmonary dysplasia (BPD), and risk factors for BPD. RESULTS: A cohort of 952 preterm infants were enrolled. The incidence of DRI, chest compressions, and administration of epinephrine was 55.9% (532/952), 12.5% (119/952), and 7.0% (67/952), respectively. Multivariate analysis revealed that the risk factors for DRI were GA <28 weeks (odds ratio [OR], 3.147; 95% confidence interval [CI], 2.082-4.755), BW <1000 g (OR, 2.240; 95% CI, 1.606-3.125), and antepartum infection (OR, 1.429; 95% CI, 1.044-1.956). The survival rate was 65.9% (627/952) and was dependent on GA. The rate of BPD was 29.3% (181/627). Multivariate analysis showed that the risk factors for BPD were male (OR, 1.603; 95% CI, 1.061-2.424), DRI (OR, 2.094; 95% CI, 1.328-3.303), respiratory distress syndrome exposed to ≥2 doses of pulmonary surfactants (PS; OR, 2.700; 95% CI, 1.679-4.343), and mechanical ventilation ≥7 days (OR, 4.358; 95% CI, 2.777-6.837). However, a larger BW (OR, 0.998; 95% CI, 0.996-0.999), antenatal steroid (OR, 0.577; 95% CI, 0.379-0.880), and PS use in the delivery room (OR, 0.273; 95% CI, 0.160-0.467) were preventive factors for BPD (all P < 0.05). CONCLUSION: Improving delivery room resuscitation and management of respiratory complications are imperative during early management of the health of EPI and ELBWI.

Nanoemulgel for Improved Topical Delivery of Desonide: Formulation Design and Characterization.

This research aimed to develop a novel drug delivery system to improve treatment of skin disorders. The system is comprised of a Carbopol 980-based nanoemulgel (NE-gel) containing a desonide (DES; 0.05%, w/w) nanoemulsion (NE), which has a small particle size, high encapsulation efficiency, good thermodynamic stability, good permeation ability, and high skin retention. DES-loaded NE (DES-NE) was prepared by high-pressure homogenization. The developed formulation was characterized by differential scanning calorimetry (DSC), X-ray diffraction, drug release, skin permeation, and drug retention. DES in vitro release and skin permeation studies with different formulations of artificial membrane and rat abdominal skin were performed with the Franz diffusion cell system. Confocal laser scanning microscopy (CLSM) was used to detect the localization and permeation pathways of drugs in the skin. Compared with commercially available gel (CA-gel) and NE, the NE-gel release process conformed to the Higuchi release model (R2 = 0.9813). NE-gel prolonged the drug release time and allowed for reduced administration dose and frequency. The unit cumulative permeation of NE and NE-gel through the skin for 12 h was 63.13 ± 2.78 and 42.53 ± 2.06 µg/cm2, respectively, values significantly higher (p < 0.01) than that of the CA-gel (30.65 ± 1.25 µg/cm2) and CA-cream (15.21 ± 0.97 µg/cm2). The DES-NE and DES NE-gel skin drug retention was significantly higher than commercially available formulations (p < 0.01). Hence, the prepared NE-gel is a potential vehicle for improved topical DES delivery for better treatment of skin disorders.

Arbutin inhibits inflammation and apoptosis by enhancing autophagy via SIRT1.

BACKGROUND: SIRT1 plays a protective role against diabetic retinopathy as it regulates inflammation, apoptosis and autophagy of cells. OBJECTIVES: This study was designed to investigate the effects of arbutin and to identify a potential mechanism of action. Adult human retinal pigment epithelial (ARPE-19) cells were exposed to high glucose (HG) or treated with different concentrations of arbutin. MATERIAL AND METHODS: The protein levels of pro-inflammatory cytokines, like tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß), IL-6, and p65 were assessed using enzyme-linked immunosorbent assay (ELISA). The expression of NF-κB p65 and cyclooxygenase-2 (COX-2) was detected with western blot assay. Cell apoptosis was analyzed with TUNEL assay, and expression levels of Bcl2, BAX, cleaved caspase-3, cleaved PARP, LC3II, LC3I, and beclin1 were detected with western blot assay. Autophagy levels were detected using LC3II immunofluorescence staining. RESULTS: Arbutin treatment markedly enhanced viability and autophagy mediators, decreased pro-inflammatory proteins and reduced apoptosis in ARPE cells under HG exposure, while increasing SIRT1 protein level. This could be blocked by Sirtinol treatment. Additionally, 3MA treatment significantly reduced the efficacy of arbutin against inflammatory markers and apoptosis in ARPE cells exposed to HG. CONCLUSIONS: Arbutin suppressed inflammation and apoptosis of ARPE cells induced by HG by promoting autophagy via SIRT1. A potential target, SIRT1, was identified for the treatment of DR, and new effects of and action mechanisms for arbutin were found and confirmed.

Preparation and characterization of bupivacaine multivesicular liposome: A QbD study about the effects of formulation and process on critical quality attributes.

This study extends QbD principles to liposomal products containing a hydrophilic active pharmaceutical ingredient (API). The feasibility and advantages of the QbD concept for multivesicular liposome-based systems were demonstrated. We selected the local anesthetic drug bupivacaine as a model compound. Desired properties for three critical attributes of multivesicular liposome drug products, namely, the particle size, morphology, and drug encapsulation efficiency, were defined and evaluated. The liposome preparation process significantly affected both the liposome particle size and drug encapsulation efficiency. In this study, the effects of material attributes and processing parameters during the preparation of liposomes were studied in detail using a microscope and particle size analyzer. We used risk assessment to monitor several factors that substantially affect the encapsulation rate and particle size.

Observation on the clinical effect of thunder-fire moxibustion combined with acupressure on ocular muscle spasm: A clinical randomized controlled trial.

INTRODUCTION: With the rapid development of social economy, peoples dependence on computers and mobile phones is increasing day by day. This causes people to often overuse. Therefore, the incidence of Ocular muscle spasm has been increasing year by year in recent years. The disease usually starts and hides, which seriously affects the patients social image, daily life, and work. METHODS/DESIGN: We will compare the clinical efficacy of thunder-fire moxibustion combined with acupressure with pure thunder-fire moxibustion on Ocular muscle spasm using random control method. DISCUSSION: We aim to find a simple, safe, simple and effective Chinese medicine nursing technology that relieves Ocular muscle spasm. TRIAL REGISTRATION: ClinicalTrials.gov,ChiCTR2000034187, Registered on 27 June 2020.

Clinical observation of Dan-Hong Hua-Yu oral solution in treating retinal vein occlusion.

INTRODUCTION: Retinal vein occlusion refers to diseases with decreased vision, dilated tortuous retinal veins visible on the fundus, and retinal hemorrhage, edema, and osmosis distributed along the vein. There is still no ideal intervention to treat central retinal vein occlusion. This study plan to observe the efficacy of Dan-Hong Hua-Yu oral solution in treating non-ischemic retinal vein occlusion, in order to provide new treatment ideas. METHODS/DESIGN: We plan to use random number table method, 64 cases of non-ischemic central retinal vein occlusion that meet the inclusion criteria will be randomly divided into a treatment group and a control group. The intervention group will be treated with Dan-Hong Hua-Yu oral solution according to the syndrome differentiation of Traditional Chinese medicine and the patient's fundus condition. Each group will take 4 weeks as a course of treatment and three consecutive courses of treatment without any interval during the course of treatment. Changes of visual acuity, fundus performance, and total clinical symptoms of patients before and after treatment will be observed. DISCUSSION: This study will observe the efficacy of Dan-Hong Hua-Yu oral solution in the treatment of non-ischemic central retinal vein occlusion, with a view to providing new treatment ideas. TRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR2000030625, Registered on March 08, 2020.

A hypoxia-induced Rab pathway regulates embryo implantation by controlled trafficking of secretory granules.

Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP-9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy.

Evidence-based practice guideline of Chinese herbal medicine for primary open-angle glaucoma (qingfeng -neizhang).

BACKGROUND: Primary open angle glaucoma (POAG) is a chronic, progressive optic neuropathy. The aim was to develop an evidence-based clinical practice guideline of Chinese herbal medicine (CHM) for POAG with focus on Chinese medicine pattern differentiation and treatment as well as approved herbal proprietary medicine. METHODS: The guideline development group involved in various pieces of expertise in contents and methods. Authors searched electronic databases include CNKI, VIP, Sino-Med, Wanfang data, PubMed, the Cochrane Library, EMBASE, as well as checked China State Food and Drug Administration (SFDA) from the inception of these databases to June 30, 2015. Systematic reviews and randomized controlled trials of Chinese herbal medicine treating adults with POAG were evaluated. Risk of bias tool in the Cochrane Handbook and evidence strength developed by the GRADE group were applied for the evaluation, and recommendations were based on the findings incorporating evidence strength. After several rounds of Expert consensus, the final guideline was endorsed by relevant professional committees. RESULTS: CHM treatment principle and formulae based on pattern differentiation together with approved patent herbal medicines are the main treatments for POAG, and the diagnosis and treatment focusing on blood related patterns is the major domain. CONCLUSION: CHM therapy alone or combined with other conventional treatment reported in clinical studies together with Expert consensus were recommended for clinical practice.