Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here we report that bilirubin (BIL)-dependent cell death in auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.

Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

Development and its reliability and validity of the Knowledge, Attitude and Practice Scale for Informal Caregivers of Pressure Injury Patients. / åŽ‹åŠ›æ€§æŸä¼¤æ‚£è€ éžæ­£å¼ç §é¡¾è€ çŸ¥ä¿¡è¡Œé‡è¡¨çš„ç¼–åˆ¶åŠä¿¡æ•ˆåº¦æ£€éªŒ.

OBJECTIVES: There is a lack of scientifically validated tools to measure the knowledge attitude and practice (KAP) of informal caregivers for patients with pressure injury (PI). This study aims to develop a KAP Scale for Informal Caregivers of PI Patients and to evaluate its reliability and validity. METHODS: Based on the KAP theory framework and relevant literature, an initial pool of items was created through expert brainstorming sessions. The initial scale was formed after a Delphi expert consultation and a preliminary survey. From April to October 2023, a convenient sample of informal caregivers for PI patients was recruited from an inpatient department of the Third Xiangya Hospital of Central South University, as well as its associated community and nursing homes. The first round included 186 participants, and the second round included 213 participants, who were used for item analysis and reliability and validity testing. After a 3-week interval, 20 participants from the initial group were randomly selected for a retest to assess the test-retest reliability of the scale. RESULTS: The KAP Scale for informal caregivers of PI patients consists of 3 dimensions with 19 items. The overall internal consistency (Cronbach's α) of the scale was 0.916. The item-level content validity index (I-CVI) ranged from 0.826 to 1.000, and the scale level-content validity index/average (S-CVI/Ave) was 0.94. Exploratory factor analysis extracted 3 common factors, accounting for 64.643% of the total variance. Confirmatory factor analysis showed that the model fit the data well, with χ2/df=2.54, root mean square error of approximation (RMSEA)=0.085, comparative fit index (CFI)=0.920, and standardized root mean square residual (SRMR)=0.059. CONCLUSIONS: The KAP scale for informal caregivers of PI patients demonstrates good reliability and validity and can be used to assess the KAP levels of informal caregivers regarding PI.

Summary of best evidence for rehabilitation management of patients with motor dysfunction after stroke. / è„‘å’ä¸­è¿åŠ¨åŠŸèƒ½éšœç¢æ‚£è€ åº·å¤ç®¡ç†çš„æœ€ä½³è¯æ®æ€»ç»“.

OBJECTIVES: The rehabilitation work for patients with motor dysfunction after stroke is crucial. However, there is currently a lack of summarized evidence regarding the rehabilitation management of stroke patients in rehabilitation wards, communities, and at home. This study aims to compile relevant evidence on the rehabilitation management of patients with motor dysfunction after stroke, providing a reference for clinical and community health professionals to carry out rehabilitation interventions. METHODS: A systematic search was conducted in BMJ Best Practice, UpToDate, National Guidebook Clearinghouse, American Heart Association/American Stroke Association, Canadian Medical Association, National Institute for Health and Clinical Excellence, United States Department of Veterans Affairs/ Department of Defense, Registered Nurses Association of Ontario, JBI Evidence-Based Healthcare Center Database, The Cochrane Library, PubMed, Web of Science, Embase, CINAHL, CNKI, Wanfang Database, SinoMed, and other databases for all literature on the rehabilitation management of patients with motor dysfunction after stroke. This included clinical decision-making, guidelines, expert consensuses, recommended practices, systematic reviews, and evidence summaries, with the search period spanning from the establishment of each database to October 2023. Two researchers independently evaluated the quality of the literature. RESULTS: A total of twenty-one documents were included, consisting of 11 guidelines, 2 expert consensus, and 8 systematic reviews. Evidence was extracted and integrated from the included literature, summarizing forty-five pieces of evidence across nine areas: rehabilitation management model, rehabilitation institutions, rehabilitation teams, timing of rehabilitation interventions, rehabilitation assessment, rehabilitation programs, rehabilitation duration and frequency, rehabilitation intensity, and rehabilitation support These covered comprehensive rehabilitation management content for stroke patients in the early, subacute, and chronic phases. CONCLUSIONS: The best evidence summarized in this study for the rehabilitation management of patients with motor dysfunction after stroke is comprehensive and of high quality. It provides important guidance for clinical and community healthcare professionals in carrying out rehabilitation interventions. When applying the evidence, it is recommended to consider the current condition of the stroke patient, the extent of motor dysfunction, environmental factors, and the patient's preferences. Then, select the most appropriate rehabilitation plan, and adjust the type and intensity of training according to each patient's specific needs and preferences.

Phototrophic Biofilms Transform Soil-Dissolved Organic Matter Similarly Despite Compositional and Environmental Differences.

Dissolved organic matter (DOM) is the most reactive pool of organic carbon in soil and one of the most important components of the global carbon cycle. Phototrophic biofilms growing at the soil-water interface in periodically flooding-drying soils like paddy fields consume and produce DOM during their growth and decomposition. However, the effects of phototrophic biofilms on DOM remain poorly understood in these settings. Here, we found that phototrophic biofilms transformed DOM similarly despite differences in soil types and initial DOM compositions, with stronger effects on DOM molecular composition than soil organic carbon and nutrient contents. Specifically, growth of phototrophic biofilms, especially those genera belonging to Proteobacteria and Cyanobacteria, increased the abundance of labile DOM compounds and richness of molecular formulae, while biofilm decomposition decreased the relative abundance of labile components. After a growth and decomposition cycle, phototrophic biofilms universally drove the accumulation of persistent DOM compounds in soil. Our results revealed how phototrophic biofilms shape the richness and changes in soil DOM at the molecular level and provide a reference for using phototrophic biofilms to increase DOM bioactivity and soil fertility in agricultural settings.

Different doses of methimazole treatment of children and adolescents with graves' disease: a clinical study based on 161 cases of outpatients.

OBJECTIVE: This study aimed to evaluate the association between the initial dose of MMI and the clinical course, as well as adverse effects on young people with GD. METHODS: One hundred and sixty-one children and adolescents with newly diagnosed GD were enrolled for this study and categorized into four groups based on initial serum-free T3 and T4 levels and daily MMI doses: Group A (mild, 0.3-0.5 mg/kg/day, n = 78), Group B (moderate, 0.6-0.8 mg/kg/day, n = 37), Group C (severe, 0.6-0.8 mg/kg/day, n = 24), and Group D (severe, 0.8-1.0 mg/kg/day, n = 22). The thyroid function, blood cell analysis and liver function were examined before treatment and at 4, 8 and 12 weeks after treatment. Outcome of long-term follow-up were also observed. RESULTS: After 12 weeks of treatment, 91.0% of the patients in group A and 90.9% of the patients in group D recovered to normalization of FT3, which was slightly higher than the other two groups; 70.8% of the patients in group C recovered to normalization of FT4, which was slightly lower than that in the other three groups. The incidence of minor adverse effects was 12.8% in group A, 13.5% in group B, 16.7% in group C and 40.9% in group D (P < 0.01). Remission was achieved in 38 patients (23.6%). CONCLUSIONS: Lower doses of MMI (0.3-0.5 mg/kg/day) are suitable for mild GD, and higher doses of MMI (0.6-0.8 mg/kg/day) are advisable for moderate or severe GD. Much higher doses of MMI (0.8-1.0 mg/kg/day) are harmful for initial use in children and adolescents with GD patients.

Development and validation of a LASSO-based prediction model for immunosuppressive medication nonadherence in kidney transplant recipients.

INTRODUCTION: To establish a prediction model to predict immunosuppressive medication (IM) nonadherence in kidney transplant recipients (KTRs) based on a combined theory framework. METHODS: This polycentric, cross-sectional study included 1191 KTRs from October 2020 to February 2021 in China, with 1011 KTRs enrolled in the derivation set and 180 in the external validation set. Variables selected based on the combined theory of planned behavior (TPB)/health belief model (HBM) theory were analyzed by the least absolute shrinkage and selection operator (LASSO). Internal 10 cross-validation was conducted to determine the optimal lambda value. The receiver operating characteristic (ROC) curve, specificity, and sensitivity were used to evaluate the prediction model, and further assessment was run by external validation. RESULTS: IM nonadherence rate was 38.48% in the derivation set and 37.22% in the validation set. The LASSO model was developed with eight predictors for IM nonadherence: age, preoperative drinking history, education, marital status, perceived barriers, social support, perceived behavioral control, and perceived susceptibility. The model demonstrated acceptable discrimination with the area under the ROC curve of 0.797 (95% CI: 0.745-0.850) in the internal validation set and 0.757 (95% CI: 0.684-0.829) in the external validation set. The specificity and sensitivity in the internal validation and external validation set were 0.741, 0.748, 0.673, and 0.716, respectively. CONCLUSIONS: The LASSO model was developed to guide identifying high-risk nonadherent patients and timely and effective interventions to improve their prognosis and survival.

Effect of precision management scheme based on the best evidence summary on reducing catheter-associated urinary tract infection. / åŸºäºŽæœ€ä½³è¯æ®æ€»ç»“çš„ç²¾å‡†åŒ–ç®¡ç†æ–¹æ¡ˆå¯¹é™ä½ŽåŒ»é™¢å¯¼å°¿ç®¡ç›¸å ³å°¿è·¯æ„ŸæŸ“çš„æ•ˆæžœ.

OBJECTIVES: Catheter-associated urinary tract infection (CAUTI) is an important cause of prolonged hospital stay, which increases economic and medical burden for patients and hospitals, and it is a key focus of hospital infection prevention and control. However, there are currently few studies that convert evidence-based scientific evidence on CAUTI prevention and control into clinical applications and evaluation on its practical effects in combination with standardized infection ratio (SIR), the critical indicator of infection prevention and control. This study aims to establish a precision management plan for reducing the incidence of CAUTI, driven by the findings of a comprehensive evidence summary, to apply this plan across all the nursing units within the entire hospital, followed by a comparative analysis of CAUTI incidence, SIR, the average duration of indwelling urinary catheter for each patient, and the compliance rate on hand hygiene protocols for medical staff before and after the implementation of the precision management plan. METHODS: Based on a comprehensive review of the best evidence for preventing CAUTI, a precision management plan was meticulously developed through panel discussions and 2 rounds of expert consultations using Delphi technique. Subsequently, a historical control study was conducted to evaluate the plan's effectiveness. A total of 17 658 patients with indwelling urinary catheter in inpatient departments from January to December 2021 comprised the control group. These patients received standard nursing measures for CAUTI. Another 18 753 patients with indwelling urinary catheters in the inpatient departments from January to December 2022 comprised the intervention group, underwent the precision management scheme based on the best available evidence, to enhance CAUTI prevention. The incidence and SIR of CAUTI, the average duration of indwelling urinary catheter for each patient, and the compliance rate on hand hygiene protocols for medical staff were compared between the 2 groups. RESULTS: Compared with the control group, the incidence of CAUTI in the intervention group was significantly decreased (0.48‰ vs 1.12‰, χ2=20.814, P<0.001), SIR was decreased in the intervention group (0.55 vs 1.37); the average duration of indwelling urinary catheter for each patient was significantly decreased [(4.33±1.55) d vs (4.43±1.79) d, t=11.941, P<0.001]. The ratio of compliance rate of medical staff with strict hand hygiene protocols higher than 95% in the intervention group was significantly higher than that in the control group (93.3% vs 83.3%, χ2=5.822, P=0.016). CONCLUSIONS: The implementation of the precision management plan for reducing CAUTI based on a summary of the best available evidence on CAUTI prevention and control in patients with indwelling urinary catheters has found to be effective. This approach significantly reduces the incidence of CAUTI, reduces the average duration of indwelling urinary catheter, and enhances hand hygiene compliance among medical staff. It provides a scientific and efficient strategy for preventing and controlling CAUTI in the hospital, ultimately saving patients from unnecessary medical expense.

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation.

BACKGROUND: Prostate cancer (PCa) is a leading cause of death in men, and effective treatment of PCa requires further development. Our study aimed to investigate the potential role of vinculin (VCL) in PCa progression in vitro and in vivo. METHODS: We investigated the methylation level of the VCL promoter based on the TCGA database. The knockdown efficacy of VCL gene expression was confirmed by quantitative polymerase chain reaction, Western blot analysis, and immunofluorescence. Furthermore, morphological changes in PCa cells were detected using phalloidin staining. The mobility of PCa cells was measured using transwell assays and high-content analysis. Moreover, cell growth and viability were determined using the colony formation and cell counting kit-8 assays. The role of VCL in tumor growth in vivo was investigated using a subcutaneous xenograft model generated by injecting tumor cells into the right flank of BALB/c nude mice. RESULTS: The methylation level of the VCL promoter in PCa was significantly downregulated concomitant with age and the progression of nodal metastasis. VCL expression was markedly decreased by shRNA. Importantly, VCL knockdown significantly changed the cell morphology; inhibited the migration, invasion, and movement; and repressed colony formation and viability of PCa cells in vitro. Furthermore, downregulation of VCL suppressed tumor growth in vivo. CONCLUSIONS: Our study comprehensively evaluated the role of VCL in PCa progression in vivo and in vitro. The findings of the present study suggest that VCL can be a potential target for PCa prognosis and treatment.

Olfactory dysfunction is a risk factor for the comorbidity of mild cognitive impairment and Type 2 diabetes mellitus. / å— è§‰éšœç¢æ˜¯2åž‹ç³–å°¿ç— åˆå¹¶è½»åº¦è®¤çŸ¥åŠŸèƒ½éšœç¢çš„å±é™©å› ç´ .

OBJECTIVES: Diabetes can accelerate cognitive decline and hence affect the prognosis of patients with Type 2 diabetes mellitus (T2DM). Olfactory assessment can facilitate the early identification of cognitive impairment among T2DM patients. This study aims to evaluate the effects of olfactory function on mild cognitive impairment (MCI) in patients with T2DM. METHODS: A total of 472 T2DM patients who were hospitalized in a first-class hospital in Changsha City from June 2018 to June 2019 were enrolled for this study. Olfactory function and cognitive function were assessed by the alcohol sniff test and the Montreal Cognitive Assessment (MoCA) scale, respectively. Participants were categorized into a comorbidity of MCI and T2DM group and a T2DM group. General information was collected and some biochemical indices were tested. Difference in the alcohol sniff test score between the 2 groups was assessed by 2-sample t-test. Difference in the presence of olfactory dysfunction between the 2 groups was assessed by χ2 test, and multivariable logistic regression was used to determine the relevant factors contributing to the comorbidity of MCI and T2DM. RESULTS: Of the 472 participants, 162 were identified with MCI, making the comorbidity rate at 34.3%. Values of isopropyl alcohol sniff test were significantly different between the 2 groups [(9.15±3.22) cm vs (21.03±4.36) cm, P<0.05]. The number of patients with olfactory dysfunction also differed significantly between the 2 groups (120 vs 50). After adjustment for age, educational level, T2DM duration, fasting insulin, and glycosylated hemoglobin (HbA1c), multivariate logistic regression analysis showed older age (OR=1.14, 95% CI 1.09 to 1.20), longer course of diabetes (OR=1.21, 95% CI 1.12 to 1.31), and olfactory-impaired (OR=4.61, 95% CI 3.04 to 6.18) were independent risk factors for T2DM combined with MCI, and the high education level (OR=0.26, 95% CI 0.15 to 0.38) was an independent protective factor for T2DM combined with MCI. CONCLUSIONS: Olfactory dysfunction is an independent risk factor for the comorbidity of MCI and T2DM. Special attention should be paid to those with olfactory dysfunction when carrying out cognitive interventions in T2DM patients.

Use of Tregs as a cell-based therapy via CD39 for benign prostate hyperplasia with inflammation.

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg-associated cytokine production. Sorted CD39+/- Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL-10, IL-35 and TGF-ß. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down-regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39- Tregs in mice, however, CD39+ Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL-1ß and PSA secretion, and increasing IL-10 and TGF-ß secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.

M3 receptor modulates extracellular matrix synthesis via ERK1/2 signaling pathway in human bladder smooth muscle cells.

Extracellular matrix (ECM) accumulation plays a key role in the progression of bladder outlet obstruction (BOO). Muscarinic receptors have been widely reported to serve as pivotal regulators in lung tissue remodeling. However, the influence of them on human bladder smooth muscle cells (HBSMCs) and the underlying molecular mechanisms have not yet been evaluated. The purposes of the present study are to investigate the effect of muscarinic receptors on the synthesis of ECM in HBSMCs and the involvement of intracellular signal transducers. The results indicated that M1 -M5 muscarinic receptors were all encoded in HBSMCs. The expression rank order was M2 > M1 > M5 > M3 > M4 . The gene and protein expression of collagen I (COL1), TIMP-1, and TIMP-2 was carbachol (CCH) concentration-dependently enhanced. The synthesis of COL1 in the supernatant of cell culture medium was significantly elevated by exposure to CCH. The CCH-induced protein expression of COL1, TIMP-1, and TIMP-2, however, was obviously reduced by the pretreatment of muscarinic receptor antagonists, atropine, and M3 -preferring antagonist (1,1-dimethyl-4-diphenyl-acetoxypiperidinium iodide [4-DAMP]). Furthermore, ERK1/2 was activated by 100 µM CCH when compared with the control group and the pretreatment of ERK1/2 inhibitor significantly suppressed the synthesis of COL1 induced by 100 µM CCH. Besides, CCH-induced phosphorylation of ERK1/2 was remarkably restrained by the pretreatment of 4-DAMP. All in all, these findings demonstrated that M3 receptor can modulate extracellular matrix synthesis via the ERK1/2 signaling pathway, which may provide potential novel therapeutic targets for BOO.

[The application and prospects of three dimensional bioprinting in urinary system reconstruction].

Three dimensional (3D) bioprinting is a new biological tissue engineering technology in recent years. The development of 3D bioprinting is conducive to solving the current problems of clinical tissue and organ repairing. This article provides a review about the clinical and research status of 3D bioprinting and urinary system reconstruction. Furthermore, the feasibility and clinical value of 3D bioprinting in urinary system reconstruction will be also discussed.

Research progress in coping style assessment tools for elderly patients with urinary incontinence. / è€å¹´å°¿å¤±ç¦æ‚£è€ åº”å¯¹æ–¹å¼è¯„ä¼°å·¥å ·çš„ç ”ç©¶è¿›å±•.

Coping style is a cognitive or behavioral strategy taken by individuals in the face of stress. Positive coping style is of great significance for improving the physical and mental outcomes of elderly patients with urinary incontinence. Accurate assessment of coping styles for the elderly patients with urinary incontinence can provide reference for the subsequent development of intervention measures. The existing coping style assessment tools for elderly incontinence at home and abroad include specific scale of incontinence, relevant psychological assessment scale, and universal scale. In a word, the progress in the studies on relevant assessment tools is slow, and it mainly focuses on the assessment of female population. The assessment content is relatively single and lacks of pertinence and systematization. In the future, a comprehensive scale with strong adaptability should be developed based on the characteristics of elderly incontinence patients in China.

Suppression of microRNA-141 suppressed p53 to protect against neural apoptosis in epilepsy by SIRT1 expression.

We investigated that microRNA (miRNA)-141 protects against epilepsy-induced apoptosis and its reaction mechanism. The serum expression of miRNA-141 in epilepsy model mice and control volunteer was measured by quantitative reverse-transcription polymerase chain reaction. We found that miRNA-141 serum expression was upregulated in patients with epilepsy. Overexpression of miRNA-141 induced nerve cell apoptosis, suppressed proliferation, promoted caspase-3/9, Bax and p53 protein expression, and reduced silent information regulator 1 (SIRT1) protein expression in vitro model. In addition, the downexpression miRNA-141 using si-miRNA-141 reduced nerve cell apoptosis and increased proliferation, suppressed caspase-3/9, Bax and p53 protein expression, induced SIRT1 protein expression. SIRT1 inhibitor (nicotinamide) decreased SIRT1, reduced the effects of miRNA-141 on nerve cell apoptosis in vitro model of epilepsy through SIRT1/p53. SIRT1 agonist also reduced the effects of miRNA-141 overexpression on nerve cell apoptosis in vitro model of epilepsy through SIRT1/p53. Our preliminary findings indicate that anti-miRNA-141 protects against epilepsy-induced apoptosis via SIRT1/p53 expression.

VEGF attenuates lung injury by inducing homing of CD133+ progenitors via VEGFR1.

Although vascular endothelial growth factor (VEGF) promotes vascular permeability and results in edema, studies have suggested it may protect the lung from inflammatory injury via poorly understood mechanisms. Using a mouse model of extracorporeal circulation (ECC), we found that levels of intravenous VEGF increased in lung tissue and inhibited inflammation, thereby attenuating lung injury. These effects could be obtained by intravenous injection or inhalation of VEGF, and they were abolished by treatment with anti-VEGF antibody. Detailed analyses using immunofluorescence and flow cytometry showed that VEGF increased the homing of CD133+ VEGFR1+ progenitors to lung tissue, and this homing could be mimicked in a dose-dependent manner by treatment with VEGF receptor 1 (VEGFR1) agonist and blocked by treatment with anti-VEGFR1 antibody. Interestingly, we found that exposing pulmonary monocytes in vitro to VEGF did not inhibit ECC-induced inflammation. Our results suggest that VEGF enters lung tissues from the circulation and that it attenuates lung injury not by directly inhibiting release of pro-inflammatory factors but by binding to VEGFR1 to recruit CD133+ progenitors. These progenitors then inhibit local inflammation.

GJB2 c.235delC variant associated with autosomal recessive nonsyndromic hearing loss and auditory neuropathy spectrum disorder.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous neurosensory disorder, usually characterized by congenital or prelingual hearing loss. We report a Han Chinese male, born to consanguineous parents, presenting with nonsyndromic sensorineural hearing loss, whose clinical phenotype was also consistent with auditory neuropathy spectrum disorder (ANSD). After exome sequencing, a gap junction protein beta 2 gene (GJB2) c.235delC variant in the homozygous state was detected in the patient. Both parents were heterozygous for this variant, as documented by Sanger sequencing. The known pathogenic GJB2 c.235delC variant was not detected in 200 healthy controls. It is predicted to be a disease-causing alteration by generating a truncated protein p.(L79Cfs*3), disturbing the appropriate folding and/or oligomerization of connexins and leading to defective gap junction channels. This study shows that the association of homozygosity of the GJB2 c.235delC variant with ARNSHL and ANSD in a patient.

Physiological stretch induced proliferation of human urothelial cells via integrin α6-FAK signaling pathway.

AIMS: To test a kind of stretch pattern which is the optimum stress parameter to promote human urothelial cells (HUCs) proliferation, and to investigate the roles of integrin subunits and their pathway in the HUCs proliferation induced by physiological stretch. METHODS: HUCs were seeded on silicone membrane, and subjected to four kinds of stretch (0,5%,10%,15% elongation) for 24 h, as controlled by a BioDynamic® bioreactor. Cell proliferation, viability and cycle distribution were examined using Cell Counting Kit-8 and flow cytometry, respectively. The gene and protein expression of integrin subunits and focal adhesion kinase (FAK) in each group were assessed by Real-time PCR(RT-PCR) and western blot, respectively. Small interfering RNAs (siRNA) were applied to knockdown integrin α6 and FAK expression in HUCs, and FAK inhibitor was used to validate the role of α6 and FAK in cell proliferation under physiological stretch. RESULTS: The proliferation of HUCs were highest in the 5% elongation group compared to static control, 10% and 15% elongation group. RT-PCR and western blot showed that 5% cyclic stretch significantly promoted the expression of integrin α6 and FAK. The stretch-induced cell proliferation and FAK expression was inhibited by siRNA of integrin α6. Further study with FAK inhibitor revealed that elongation promoted proliferation though integrin α6 and FAK signaling pathway. CONCLUSIONS: Physiological stretch induced HUCs proliferation via integrin α6-FAK signaling pathway, and 5% elongation may be the optimal stress parameter to promote the cell proliferation.

[Research progress on preventions of ischemia-reperfusion injury during kidney transplant].

During kidney transplant, the non-specific inflammatory response induced by ischemia-reperfusion injury (IRI) will lead to decreased survival ability of transplanted kidney. However, the effect of IRI on long-term survival rate of allograft is not sure. Here we illuminated the relationship between early IRI and decreased long-term survival ability of allograft by retrospectively analyzing the clinical evidences and laboratory investigations. Previous studies showed that early IRI resulted in the graft loss through reduction of renal functional mass, vascular injury, chronic hypoxia and subsequent fibrosis. IRI was also one of the main factors to induce dysfunction of transplanted kidney and acute rejection reaction, and to decrease the allograft survival. Therefore, it's better to substitute traditional methods with novel measures during kidney transplant which may relieve the renal IRI much better.