A novel frameshift mutation in RHAG leads to Rhnull phenotype in a Chinese individual.

BACKGROUND: We recently encountered a Rhnull phenotype proband within one family in the Chinese population. Rhnull is a rare autosomal recessive disorder characterized by the absence of the Rh antigens on the erythrocyte membrane, resulting in chronic hemolytic anemia. This study described the serological and molecular analysis of a Chinese Rhnull proband and his immediate family. METHODS: Red blood cells antigen phenotyping and antibody screening/identification were conducted. RHD, RHCE, and RHAG were analyzed using genomic DNA by polymerase chain reaction and sequence analysis. RESULTS: Serologic tests showed a D-C-E-c-e- phenotype in the proband associated with the suspicion of anti-Rh29 (titer 16). Molecular analyses showed a new mutation (c.406dupA) in exon 3 of RHAG. This duplication introduced a reading frameshift (p.Thr136AsnfsTer21). The RHAG mutation was found in the homozygous state for the proband and heterozygous state for his parents. CONCLUSION: We identified a novel RHAG mutation resulting in the Rhnull phenotype of the regulator type. Inheritance of the novel allele was shown by family study.

In vivo dynamics of senescence in rhabdomyolysis-induced acute kidney injury.

Cellular senescence is involved in the pathogenesis of various diseases, including acute kidney injury (AKI). AKI is defined as a sudden loss of kidney function. In severe AKI, irreversible loss of kidney cells can occur. Cellular senescence might contribute to this maladaptive tubular repair, though, its pathophysiological role in vivo is incompletely understood. In this study, we used p16-CreERT2-tdTomato mice in which cells with high p16 expression, a prototypical senescent marker, are labeled with tdTomato fluorescence. Then, we induced AKI by rhabdomyolysis and traced the cells with high p16 expression following AKI. We proved that the induction of senescence was observed predominantly in proximal tubular epithelial cells (PTECs) and occurred in a relatively acute phase within 1-3 days after AKI. These acute senescent PTECs were spontaneously eliminated by day 15. On the contrary, the generation of senescence in PTECs persisted during the chronic recovery phase. We also confirmed that the kidney function did not fully recover on day 15. These results suggest that the chronic generation of senescent PTECs might contribute to maladaptive recovery from AKI and lead to chronic kidney disease progression.

Characteristics and antioxidant properties of Harpadon nehereus protein hydrolysate-xylose conjugates obtained from the Maillard reaction by ultrasound-assisted wet heating in a natural deep eutectic solvents system.

BACKGROUND: Harpadon nehereus is a high-protein marine fish. A valuable way to add value to H. nehereus is to convert it into protein hydrolysate. The Maillard reaction is an effective way to improve the functional properties of peptides and proteins, which are affected by many factors such as reactant concentration, water activity, pH, temperature, and heating time. However, the traditional Maillard reaction method is inefficient. The purpose of this study was therefore to explore the effect of the ultrasound-assisted wet heating method on the Maillard reaction of H. nehereus protein hydrolysate (HNPH) in a new-type green solvent - a natural hypereutectic solvent (NADES). RESULTS: Harpadon nehereus protein hydrolysate-xylose (Xy) conjugates were prepared via a Maillard reaction in a NADES system using an ultrasound-assisted wet heating method. The effects of different treatment conditions on the Maillard reaction were studied. The optimized glycation degree (DG) of HNPH-Xy conjugates was obtained with a water content of 10%, a reaction temperature of 80 °C, a reaction time of 35 min, and an ultrasonic power level of 300 W. Compared with HNPH, the structure of HNPH-Xy conjugates were significantly changed. Moreover, the functional properties and antioxidant activity of HNPH-Xy were all superior to the HNPH. CONCLUSIONS: An ultrasound-assisted wet-heating Maillard reaction between HNPH and Xy in the NADES system could be a promising way to improve the functional properties of HNPH. © 2023 Society of Chemical Industry.

[Role of lymphatic system in coronary heart disease based on theory of combined phlegm and stasis].

According to the traditional Chinese medicine(TCM) theory, coronary heart disease(CHD) is mainly caused by heart vessel obstruction due to Qi stagnation, blood stasis, and phlegm turbidity. Chest impediment with combined phlegm and stasis is a common syndrome of CHD, with the manifestations of chest tightness, chest pain, and asthma. Lymphatic system is one of the important immune systems in the human body and has a close relationship with the Qi and blood movement in TCM. The dysfunction of the lymphatic system may lead to metabolism disorders, the generation of dampness pathogen which turns into sticky and difficult-to-dissolve phlegm turbidity. Moreover, it can affect blood circulation and coagulation, causing slow blood flow, increased blood viscosity, and microcirculation disorders. Alterations in lymphatic hydrodynamics may affect the interaction between blood circulation and the lymphatic system. A variety of small molecule drugs and TCM can treat cardiovascular diseases by targeting the lymphatic system. This review discusses the role of the lymphatic system in CHD based on the theory of combined phlegm and stasis, involving the influences of mechanical factors on lymphatic function and the effects and pharmacological mechanisms of TCM and chemicals that target lymphocyte function and lymphatic circulation. By expounding the development process of combined phlegm and stasis in CHD from the lymphatic system, this paper aims to provide new ideas for deciphering pharmacological mechanisms of TCM for resolving phlegm and stasis.

Identification of a hippocampal lncRNA-regulating network in a natural aging rat model.

BACKGROUND: Dysregulation of long noncoding RNA (lncRNA) expression is related to aging and age-associated neurodegenerative diseases, and the lncRNA expression profile in the aging hippocampus is not well characterized. In the present investigation, the changed mRNAs and lncRNAs were confirmed via deep RNA sequencing. GO and KEGG pathway analyses were conducted to investigate the principal roles of the clearly dysregulated mRNAs and lncRNAs. Subsequently, through the prediction of miRNAs via which mRNAs and lncRNAs bind together, a competitive endogenous RNA network was constructed. RESULTS: A total of 447 lncRNAs and 182 mRNAs were upregulated, and 385 lncRNAs and 144 mRNAs were downregulated. Real-time reverse transcription-polymerase chain reaction validated the reliability of mRNA and lncRNA sequencing. KEGG pathway and GO analyses revealed that differentially expressed (DE) mRNAs were associated with cell adhesion molecules (CAMs), the p53 signaling pathway (SP), phagosomes, PPAR SP and ECM-receptor interactions. KEGG pathway and GO analyses showed that the target genes of the DE lncRNAs were related to cellular senescence, the p53 signaling pathway, leukocyte transendothelial migration and tyrosine metabolism. Coexpression analyses showed that 561 DE lncRNAs were associated with DE mRNAs. A total of 58 lncRNA-miRNA-mRNA target pairs were confirmed in this lncRNA‒miRNA‒mRNA network, comprising 10 mRNAs, 13 miRNAs and 38 lncRNAs. CONCLUSIONS: We found specific lncRNAs and mRNAs in the hippocampus of natural aging model rats, as well as abnormal regulatory ceRNA networks. Our outcomes help explain the pathogenesis of brain aging and provide direction for further research.

Long non-coding RNA LINC01018 inhibits human glioma cell proliferation and metastasis by directly targeting miRNA-182-5p.

AIM: Accumulating evidence suggests that lncRNAs are potential biomarkers and key regulators of tumor development and progression. However, the precise function of most lncRNAs in glioma remains unknown. In this study, we explored the role of long intergenic non-protein coding RNA 1018 (LINC01018) in human glioma. METHODS: Expression levels of LINC01018 and miR-182-5p in clinical glioma tissues and cell lines were detected by quantitative real-time PCR (qRT-PCR). Cell proliferation, migration, and invasion were determined by Cell Counting Kit-8 (CCK-8) assay and Transwell assay. Epithelial-mesenchymal transition (EMT) related proteins were measured by Western blotting. Direct relationship between LINC01018 and miR-182-5p was tested by dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and rescue assays. Lastly, bioinformatics analyses were conducted to predict the downstream factors of LINC01018/miR-182-5p axis in glioma. RESULTS: LINC01018 was significantly down-regulated in glioma tissues and cell lines. Overexpression of LINC01018 dramatically inhibited cell proliferation, migration, and invasion and reverse EMT process in glioma. LINC01018 directly target to miR-182-5p. Forced up-regulation of miR-182-5p reversed the inhibitory effects on proliferative and metastatic abilities of glioma cells with LINC01018 overexpression. Lastly, the bioinformatics analyses revealed that LINC01018/miR-182-5p axis mediated a cluster of downstream genes (ADRA2C, RAB6B, RAB27B, RAPGEF5, STEAP2, TAGLN3, and UNC13C), which were potential key factors in the development of glioma. CONCLUSION: LINC01018 inhibits cell proliferation and metastasis in human glioma by targeting miR-182-5p, and should be considered as a potential therapeutic target in this cancer.

Survival outcome assessment for triple-negative breast cancer: a nomogram analysis based on integrated clinicopathological, sonographic, and mammographic characteristics.

OBJECTIVE: This study aimed to incorporate clinicopathological, sonographic, and mammographic characteristics to construct and validate a nomogram model for predicting disease-free survival (DFS) in patients with triple-negative breast cancer (TNBC). METHODS: Patients diagnosed with TNBC at our institution between 2011 and 2015 were retrospectively evaluated. A nomogram model was generated based on clinicopathological, sonographic, and mammographic variables that were associated with 1-, 3-, and 5-year DFS determined by multivariate logistic regression analysis in the training set. The nomogram model was validated according to the concordance index (C-index) and calibration curves in the validation set. RESULTS: A total of 636 TNBC patients were enrolled and divided into training cohort (n = 446) and validation cohort (n = 190). Clinical factors including tumor size > 2 cm, axillary dissection, presence of LVI, and sonographic features such as angular/spiculated margins, posterior acoustic shadows, and presence of suspicious lymph nodes on preoperative US showed a tendency towards worse DFS. The multivariate analysis showed that no adjuvant chemotherapy (HR = 6.7, 95% CI: 2.6, 17.5, p < 0.0005), higher axillary tumor burden (HR = 2.7, 95% CI: 1.0, 7.1, p = 0.045), and ≥ 3 malignant features on ultrasound (HR = 2.4, CI: 1.1, 5.0, p = 0.021) were identified as independent prognostic factors associated with poorer DFS outcomes. In the nomogram, the C-index was 0.693 for the training cohort and 0.694 for the validation cohort. The calibration plots also exhibited excellent consistency between the nomogram-predicted and actual survival probabilities in both the training and validation cohorts. CONCLUSIONS: Clinical variables and sonographic features were correlated with the prognosis of TNBCs. The nomogram model based on three variables including no adjuvant chemotherapy, higher axillary tumor load, and more malignant sonographic features showed good predictive performance for poor survival outcomes of TNBC. KEY POINTS: • The absence of adjuvant chemotherapy, heavy axillary tumor load, and malignant-like sonographic features can predict DFS in patients with TNBC. • Mammographic features of TNBC could not predict the survival outcomes of patients with TNBC. • The nomogram integrating clinicopathological and sonographic characteristics is a reliable predictive model for the prognostic outcome of TNBC.

Icariside II Attenuates Vascular Remodeling Via Wnt7b/CCND1 Axis.

ABSTRACT: Angioplasty often fails due to the abnormal proliferation of vascular smooth muscle cells (VSMCs). Success rates of angioplasty may increase following the administration of an agent that effectively ameliorates aberrant vascular remodeling. Icariside II (ICS-II) is a natural flavonol glycoside extract from the Chinese herbal medicine Epimedii that possesses several medicinal qualities that are beneficial in humans. Nevertheless, the role of ICS-II in addressing aberrant vascular remodeling have yet to be clarified. The current investigation studies the molecular effects of ICS-Ⅱ on balloon-inflicted neointimal hyperplasia in rats in vivo and on platelet-derived growth factor-induced vascular proliferation in primary rat aortic smooth muscle cells (VSMCs) in vitro. ICS-II was found to be as effective as rapamycin, the positive control used in this study. ICS-II inhibited neointimal formation in injured rat carotid arteries and notably reduced the expression of Wnt7b. ICS-Ⅱ significantly counteracted platelet-derived growth factor-induced VSMCs proliferation. Cell cycle analysis showed that ICS-II triggered cell cycle arrest during the G1/S transition. Western blot analysis further indicated that this cell cycle arrest was likely through Wnt7b suppression that led to CCND1 inhibition. In conclusion, our findings demonstrate that ICS-II possesses significant antiproliferative qualities that counteracts aberrant vascular neointimal hyperplasia. This phenomenon most likely occurs due to the suppression of the Wnt7b/CCND1 axis.

Epidemiology and lifestyle survey of non-alcoholic fatty liver disease in school-age children and adolescents in Shenyang, Liaoning.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is diagnosed increasingly in children and adolescents. We aimed to investigate the prevalence and related influencing factors of NAFLD in school-aged children and adolescents in Shenyang, Liaoning Province. Furthermore, we analyzed the relationship between lifestyle and fatty liver. METHODS: We conducted aprospective cohort study of 1309 school-aged children and adolescents between the ages of 7 and 18 years who underwent physical examination from November to December 2019. In addition, they were collected age, gender, learning stage, height, weight, BMI, waist circumference, hip circumference, and waist-hip ratio. Finally, a portion of the population was selected to complete a questionnaire survey to explore the impact of lifestyle habits on fatty liver disease. RESULTS: NAFLD was present in 23.83% of subjects. The prevalence of children and adolescents was 22.73% and 24.43%, respectively. Fatty liver prevalence differs significantly by gender and learning stages. The highest rate of fatty liver was seen in obese children (71.68%). Moreover, exercise, diet, and parental factors can affect children with fatty liver. CONCLUSIONS: NAFLD is very prevalent in children and adolescents in Shenyang city. Due to the close relationship between NAFLD and obesity, lifestyle plays a major role in the occurrence of NAFLD. TRIAL REGISTRATION: The First Affiliated Hospital of China Medical University, [2020] 2020-258-2. Registered 6 June 2020-Retrospectively registered.

Longitudinal association between poor parental supervision and risk-taking behavior: The role of self-control and school climate.

INTRODUCTION: Although poor parental supervision has been associated with an increased adolescents' propensity for risk-taking behavior, few researchers have investigated nuanced mechanisms of how and for whom from the perspective of "family × school." Inspired by ecological system theory and self-control theory, this study aimed to investigate the mediating role of self-control and the moderating role of school climate between the link between poor parental supervision and risk-taking behavior. METHODS: Four hundred and ninety-one Chinese adolescents (231 females, Mage = 15.39 ± 1.36) were recruited to participate in a three-wave longitudinal study (3 months apart) and complete questionnaires regarding poor parental supervision (W1), school climate (W1), self-control (W2), and risk-taking behavior (W1/W3). RESULTS: After controlling for W1 risk-taking behavior, our moderated mediation model indicated that W1 poor parental supervision was positively related to W3 risk-taking behavior by restraining the development of W2 self-control. Additionally, a high level of school climate as a protective factor buffered the negative impact of poor parental supervision on adolescents' self-control, further reducing risk-taking behavior. CONCLUSION: Our findings shed light on the processing mechanisms between poor parental supervision and risk-taking behavior among Chinese adolescents and underscore the importance of effective preventions and interventions to facilitate adolescents' healthy development.

Recent Progress in Metal-Organic Framework Based Fluorescent Sensors for Hazardous Materials Detection.

Population growth and industrial development have exacerbated environmental pollution of both land and aquatic environments with toxic and harmful materials. Luminescence-based chemical sensors crafted for specific hazardous substances operate on host-guest interactions, leading to the detection of target molecules down to the nanomolar range. Particularly, the luminescence-based sensors constructed on the basis of metal-organic frameworks (MOFs) are of increasing interest, as they can not only compensate for the shortcomings of traditional detection techniques, but also can provide more sensitive detection for analytes. Recent years have seen MOFs-based fluorescent sensors show outstanding advantages in the field of hazardous substance identification and detection. Here, we critically discuss the application of MOFs for the detection of a broad scope of hazardous substances, including hazardous gases, heavy metal ions, radioactive ions, antibiotics, pesticides, nitro-explosives, and some harmful solvents as well as luminous and sensing mechanisms of MOF-based fluorescent sensors. The outlook and several crucial issues of this area are also discussed, with the expectation that it may help arouse widespread attention on exploring fluorescent MOFs (LMOFs) in potential sensing applications.

[Mechanism of ferroptosis in regulating testicular spermatogenic dysfunction: Progress in research].

Ferroptosis is a new type of cell death found in recent years, which is characterized by iron overload, excessive accumulation of lipid peroxide and destruction of mitochondrial structure. Testicular spermatogenic dysfunction (TSD) is an important factor affecting the health and quality of life of middle-aged and elderly men. Studies show that ferroptosis plays an important role in the development and progression of TSD, mainly involved in the mechanisms of abnormal iron metabolism, lipid peroxidation, oxidative stress response and mitochondrial damage. It is believed that ferroptosis can induce a series of symptoms, such as sperm quality and quantity reduction and spermatogenesis disorder. Therefore, inhibiting the development of ferroptosis can provide a new basis for the study of the mechanisms of the disease. This review focuses on the concept and characteristics of ferroptosis and the advances in the studies of the its mechanism in regulating TSD, with the purpose of introducing the clinical application prospect of targeted inhibition of ferroptosis in the prevention and treatment of TSD and expanding the ideas for the treatment of TSD and other male reproductive diseases.

[A mini-review on anti-tumor effect of cannabidiol].

Cannabidiol is the main non-psychoactive component of Cannabis sativa, which has multiple medicinal activities, such as antiepileptic, immunomodulation, analgesic, antioxidant, anticonvulsant, anti-anxiety and other functions. In recent years, it has been found that cannabidiol can inhibit the proliferation of various tumor cells, induce apoptosis and autophagy of tumor cells, arrest cell cycle, interrupt invasion and metastasis of tumor cells, regulate tumor microenvironment, exert synergistic therapy with other chemotherapeutic drugs, and reduce the toxicity of chemotherapeutic drugs. However, its anti-tumor effect remains controversial and its application is limited. The study of microspheres, nano liposomes and other new drug delivery systems can improve the anti-tumor effect of cannabidiol. In this study, the anti-tumor mechanism and application of cannabidiol were summarized and discussed in order to provide inspirations for its further investigation and application.

Expression and functional analysis of cytoplasmic dynein during spermatogenesis in Portunus trituberculatus.

The mechanism of acrosome formation in the crab sperm is a hot topic in crustacean reproduction research. Dynein is a motor protein that performs microtubule-dependent retrograde transport and plays an essential role in spermatogenesis. However, whether cytoplasmic dynein participates in acrosome formation in the crab sperm remains poorly understood. In this study, we cloned the cytoplasmic dynein intermediate chain gene (Pt-DIC) from Portunus trituberculatus testis. Pt-DIC is composed of a p150glued-binding domain, a dynein light chain (DLC)-binding domain, and a dynein heavy chain (DHC)-binding domain. The Pt-DIC gene is widely expressed in different tissues, showing the highest expression in the testis, and it is expressed in different stages of spermatid development, indicating important functions in spermatogenesis. We further observed the colocalization of Pt-DIC and Pt-DHC, Pt-DHC and tubulin, and Pt-DHC and GM130, and the results indicated that cytoplasmic dynein may participate in nuclear shaping and acrosome formation via vesicle transport. In addition, we examined the colocalization of Pt-DHC and a mitochondrion (MT) tracker and that of Pt-DHC and prohibitin (PHB). The results indicated that cytoplasmic dynein participated in mitochondrial transport and mitochondrial degradation. Taken together, these results support the hypothesis that cytoplasmic dynein participates in acrosome formation, nuclear shaping, and mitochondrial transport during spermiogenesis in P. trituberculatus. This study will provide valuable guidance for the artificial fertilization and reproduction of P. trituberculatus.

A fluorescent probe bearing two reactive groups discriminates between fluoride-containing G series and sulfur-containing V series nerve agents.

Herein, we present an approach to design a fluorescent molecule for detection and discrimination of fluoride-containing G series and sulfur-containing V series nerve agents. FP1 bearing two reactive groups can react with fluorides and thiols from the two types of nerve agents and generate different products with obvious and diverse fluorescences, which will be helpful when dealing with terrorist crises.

Proteomic profile of TGF-ß1 treated lung fibroblasts identifies novel markers of activated fibroblasts in the silica exposed rat lung.

We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) on control and TGF-ß1-exposed rat lung fibroblasts to identify proteins differentially expressed between cell populations. A total of 196 proteins were found to be differentially expressed in response to TGF-ß1 treatment. Guided by these results, we next determined whether similar changes in protein expression were detectable in the rat lung after chronic exposure to silica dust. Of the five proteins selected for further analysis, we found that levels of all proteins were markedly increased in the silica-exposed rat lung, including the proteins for the very low density lipoprotein receptor (VLDLR) and the transmembrane (type I) heparin sulfate proteoglycan called syndecan 2 (SDC2). Because VLDLR and SDC2 have not, to our knowledge, been previously linked to the pathobiology of silicosis, we next examined whether knockdown of either gene altered responses to TGF-ß1 in MRC-5 lung fibroblasts. Interestingly, we found knockdown of either VLDLR or SDC2 dramatically reduced collagen production to TGF-ß1, suggesting that both proteins might play a novel role in myofibroblast biology and pathogenesis of silica-induced pulmonary fibrosis. In summary, our findings suggest that performing LC-MS/MS on TGF-ß1 stimulated lung fibroblasts can uncover novel molecular targets of activated myofibroblasts in silica-exposed lung.

The exploration of artificial incubation of Cherax quadricarinatus eggs.

The redclaw crayfish, Cherax quadricarinatus, is an economically valuable freshwater crayfish. However, some production obstacles, such as a low egg hatching rate and asynchronous hatching, are hindering its development in the aquaculture industry. Artificial incubation of eggs may solve these problems. This study explored the technology of artificial incubation of redclaw crayfish eggs. The following results were obtained: 1) 75% alcohol as a disinfectant for 60 s had a preferable antibacterial effect and promoted the hatching rate; 2) densities of 300 and 600 eggs/incubator resulted in significantly higher hatching and survival rates than a density of 900 eggs/incubator; 3) at a density of 600 eggs/incubator, the optimum number of net pieces for attachment of freshly hatched juveniles was 20 per incubator; 4) with a density of 600 eggs/incubator and 20 net pieces/incubator, the hatching rate was 82.05% ± 4.09%, the survival rate was 55.12% ± 7.51%, and a total of 129,200 SPF (specific pathogen-free) seedlings were cultivated. This artificial incubation system was maintained at close to an aseptic state, with an absence of white spot virus, iridovirus, Vibrio and ciliates; this was true for all water sources used and for incubation of both eggs and juvenile crayfish. In conclusion, if we implement reasonable methods of disinfection, SPF detection and pathogen isolation and utilize optimal egg densities and incubation systems, large-scale production of SPF seedlings of Cherax quadricarinatus is possible.

Pilot testing the caregiver self-management intervention for caregivers of relatives with dementia.

This study was designed to examine the feasibility of a caregiving self-management support program developed for caregivers of relatives with dementia in Shanghai. A total of 41 caregivers were recruited for a quasi-experimental study. The experimental group of 26 participants attended six bi-weekly social support group sessions. The control group of 15 participants received three monthly telephone instructions. All of participants received an illustrated caregiver educational booklet and three educational presentations during a six-month follow-up period. The results demonstrated a stronger sense of self-efficacy regarding the gathering of information about dementia care in both study groups compared to the baseline data. Caregivers participating in the group sessions reported better health-related quality of life, improved responses to behavioral disturbances, and efficacy in the management of stress than those who received telephone instructions. This study provided some preliminary information regarding ways to improve self-management for the target population in mainland China.

IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.

Multiple doses of stem cells maintain urethral function in a model of neuromuscular injury resulting in stress urinary incontinence.

Stress urinary incontinence (SUI) is more prevalent among women who deliver vaginally than women who have had a cesarean section, suggesting that tissue repair after vaginal delivery is insufficient. A single dose of mesenchymal stem cells (MSCs) has been shown to partially restore urethral function in a model of SUI. The aim of the present study was to determine if increasing the number of doses of MSCs improves urethral and pudendal nerve function and anatomy. We hypothesized that increasing the number of MSC doses would accelerate recovery from SUI compared with vehicle treatment. Rats underwent pudendal nerve crush and vaginal distension or a sham injury and were treated intravenously with vehicle or one, two, or three doses of 2 × 106 MSCs at 1 h, 7 days, and 14 days after injury. Urethral leak point pressure testing with simultaneous external urethral sphincter electromyography and pudendal nerve electroneurography were performed 21 days after injury, and the urethrovaginal complex and pudendal nerve were harvested for semiquantitative morphometry of the external urethral sphincter, urethral elastin, and pudendal nerve. Two and three doses of MSCs significantly improved peak pressure; however, a single dose of MSCs did not. Single, as well as repeated, MSC doses improved urethral integrity by restoring urethral connective tissue composition and neuromuscular structures. MSC treatment improved elastogenesis, prevented disruption of the external urethral sphincter, and enhanced pudendal nerve morphology. These results suggest that MSC therapy for postpartum incontinence and SUI can be enhanced with multiple doses.